@article {pmid39031772,
year = {2024},
author = {Meyer, T and Schumann, P and Weydt, P and Petri, S and Weishaupt, JH and Weyen, U and Koch, JC and Günther, R and Regensburger, M and Boentert, M and Wiesenfarth, M and Koc, Y and Kolzarek, F and Kettemann, D and Norden, J and Bernsen, S and Elmas, Z and Conrad, J and Valkadinov, I and Vidovic, M and Dorst, J and Ludolph, AC and Hesebeck-Brinckmann, J and Spittel, S and Münch, C and Maier, A and Körtvélyessy, P},
title = {Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28182},
pmid = {39031772},
issn = {1097-4598},
support = {(H4017703513237604)//Boris Canessa ALS Stiftung (Düsseldorf, Germany) and Martin Herrenknecht Fonds for ALS Research/ ; },
abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany.

METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS).

RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80).

DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.},
}

@article {pmid39022351,
year = {2024},
author = {Corvino, A and Caliendo, G and Fiorino, F and Frecentese, F and Valsecchi, V and Lombardi, G and Anzilotti, S and Andreozzi, G and Scognamiglio, A and Sparaco, R and Perissutti, E and Severino, B and Gargiulo, M and Santagada, V and Pignataro, G},
title = {Newly Synthesized Indolylacetic Derivatives Reduce Tumor Necrosis Factor-Mediated Neuroinflammation and Prolong Survival in Amyotrophic Lateral Sclerosis Mice.},
journal = {ACS pharmacology & translational science},
volume = {7},
number = {7},
pages = {1996-2005},
pmid = {39022351},
issn = {2575-9108},
abstract = {The debilitating neurodegenerative disease known as amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) in the brain, spinal cord, and motor cortex. The ALS neuroinflammatory component is being characterized and includes the overexpression of mediators, such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α). Currently, there are no effective treatments for ALS. Indeed, riluzole, an N-methyl-D-aspartate (NMDA) glutamate receptor blocker, and edaravone, a reactive oxygen species (ROS) scavenger, are currently the sole two medications approved for ALS treatment. However, their efficacy in extending life expectancy typically amounts to only a few months. In order to improve the medicaments for the treatment of neurodegenerative diseases, preferably ALS, novel substituted 2-methyl-3-indolylacetic derivatives (compounds II-IV) were developed by combining the essential parts of two small molecules, namely, the opioids containing a 4-piperidinyl ring with indomethacin, previously shown to be efficacious in different experimental models of neuroinflammation. The synthesized compounds were evaluated for their potential capability of slowing down neurodegeneration associated with ALS progression in preclinical models of the disease in vitro and in vivo. Notably, we produced data to demonstrate that the treatment with the newly synthesized compound III: (1) prevented the upregulation of TNF-α observed in BV-2 microglial cells exposed to the toxin lipopolysaccharides (LPS), (2) preserved SHSY-5Y cell survival exposed to β-N-methylamino-l-alanine (L-BMAA) neurotoxin, and (3) mitigated motor symptoms and improved survival rate of SOD1G93A ALS mice. In conclusion, the findings of the present work support the potential of the synthesized indolylacetic derivatives II-IV in ALS treatment. Indeed, in the attempt to realize an association between two active molecules, we assumed that the combination of the indispensable moieties of two small molecules (the opioids containing a 4-piperidinyl ring with the FANS indomethacin) might lead to new medicaments potentially useful for the treatment of amyotrophic lateral sclerosis.},
}

@article {pmid39019674,
year = {2024},
author = {Georges, M and Perez, T and Rabec, C and Jacquin, L and Finet-Monnier, A and Ramos, C and Patout, M and Attali, V and Amador, M and Gonzalez-Bermejo, J and Salachas, F and Morelot-Panzini, C},
title = {[Proposals from a French expert panel for respiratory care in ALS patients].},
journal = {Revue des maladies respiratoires},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.rmr.2024.06.006},
pmid = {39019674},
issn = {1776-2588},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres.

METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel.

RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients.

CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.},
}

@article {pmid39017978,
year = {2024},
author = {Vinceti, M and Urbano, T and Filippini, T and Bedin, R and Simonini, C and Sorarù, G and Trojsi, F and Michalke, B and Mandrioli, J},
title = {Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {39017978},
issn = {1559-0720},
support = {"PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.},
}

@article {pmid39007083,
year = {2024},
author = {Chidambaram, SB and Anand, N and Varma, SR and Ramamurthy, S and Vichitra, C and Sharma, A and Mahalakshmi, AM and Essa, MM},
title = {Superoxide dismutase and neurological disorders.},
journal = {IBRO neuroscience reports},
volume = {16},
number = {},
pages = {373-394},
pmid = {39007083},
issn = {2667-2421},
abstract = {Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.},
}

@article {pmid39006764,
year = {2024},
author = {Yang, C and Liu, G and Chen, X and Le, W},
title = {Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.},
journal = {MedComm},
volume = {5},
number = {7},
pages = {e638},
pmid = {39006764},
issn = {2688-2663},
abstract = {The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.},
}

@article {pmid39006715,
year = {2024},
author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J},
title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.},
journal = {Cureus},
volume = {16},
number = {6},
pages = {e62310},
pmid = {39006715},
issn = {2168-8184},
abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.},
}

@article {pmid39002811,
year = {2024},
author = {Huin, V and Blum, D and Delforge, V and Cailliau, E and Djeziri, S and Dujardin, K and Genet, A and Viard, R and Attarian, S and Bruneteau, G and Cassereau, J and Genestet, S and Kaminsky, AL and Soriani, MH and Lefilliatre, M and Couratier, P and Pittion-Vouyovitch, S and Esselin, F and De La Cruz, E and Guy, N and Kolev, I and Corcia, P and Cintas, P and Desnuelle, C and Buée, L and Danel-Brunaud, V and Devos, D and Rolland, AS},
title = {Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.},
journal = {Neurobiology of disease},
volume = {199},
number = {},
pages = {106603},
doi = {10.1016/j.nbd.2024.106603},
pmid = {39002811},
issn = {1095-953X},
abstract = {Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.},
}

@article {pmid38999592,
year = {2024},
author = {Li, Q and Wang, H and Yu, J and Zhang, W and Guo, W and Liu, Y},
title = {Metabolism-Based Herbicide Resistance to Mesosulfuron-methyl and Identification of Candidate Genes in Bromus japonicus.},
journal = {Plants (Basel, Switzerland)},
volume = {13},
number = {13},
pages = {},
pmid = {38999592},
issn = {2223-7747},
support = {23JCQNJC00450//Tianjin Natural Science Foundation/ ; 2021CXGC010811//Key R&D Program of Shandong Province, China/ ; },
abstract = {The evolved resistance of Bromus japonicus Houtt. to ALS-inhibiting herbicides is well established. Previous studies have primarily focused on target-site resistance; however, non-target-site resistance has not been well characterized. This investigation demonstrated that ALS gene sequencing did not detect any previously known resistance mutations in a mesosulfuron-methyl-resistant (MR) population, and notably, treatment with the P450 monooxygenase (P450) inhibitor malathion markedly heightened susceptibility to mesosulfuron-methyl. Utilizing UPLC-MS/MS analysis confirmed elevated mesosulfuron-methyl metabolism in MR plants. The integration of Isoform Sequencing (Iso-Seq) and RNA Sequencing (RNA-Seq) facilitated the identification of candidate genes associated with non-target sites in a subpopulation with two generations of herbicide selection. Through qRT-PCR analysis, 21 differentially expressed genes were characterized, and among these, 10 genes (comprising three P450s, two glutathione S-transferases, one glycosyltransferase, two ATP-binding cassette transporters, one oxidase, and one hydrolase) exhibited constitutive upregulation in resistant plants. Our findings substantiated that increased herbicide metabolism is a driving force behind mesosulfuron-methyl resistance in this B. japonicus population.},
}

@article {pmid38999371,
year = {2024},
author = {Dell'Anna, G and Fanti, L and Fanizza, J and Barà, R and Barchi, A and Fasulo, E and Elmore, U and Rosati, R and Annese, V and Laterza, L and Fuccio, L and Azzolini, F and Danese, S and Mandarino, FV},
title = {VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.},
journal = {Journal of clinical medicine},
volume = {13},
number = {13},
pages = {},
pmid = {38999371},
issn = {2077-0383},
abstract = {Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.},
}

@article {pmid38997748,
year = {2024},
author = {Kato, C and Ueda, K and Morimoto, S and Takahashi, S and Nakamura, S and Ozawa, F and Ito, D and Daté, Y and Okada, K and Kobayashi, N and Nakahara, J and Okano, H},
title = {Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery.},
journal = {Inflammation and regeneration},
volume = {44},
number = {1},
pages = {32},
pmid = {38997748},
issn = {1880-9693},
support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; },
abstract = {BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.

METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment.

RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search.

CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.},
}

@article {pmid38996764,
year = {2024},
author = {Montero, AS and Aliouat, I and Ribon, M and Canney, M and Goldwirt, L and Mourah, S and Berriat, F and Lobsiger, CS and Pradat, PF and Salachas, F and Bruneteau, G and Carpentier, A and Boillée, S},
title = {Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.},
journal = {EBioMedicine},
volume = {106},
number = {},
pages = {105235},
doi = {10.1016/j.ebiom.2024.105235},
pmid = {38996764},
issn = {2352-3964},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).

METHODS: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.

FINDINGS: Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.

INTERPRETATION: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.

FUNDING: Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).},
}

@article {pmid38990927,
year = {2024},
author = {Srinivasan, V and Homer, V and Barton, D and Clutterbuck-James, A and Jenkins, S and Potter, C and Brock, K and Logan, A and Smith, D and Bruce, L and Nagy, Z and Bach, SP},
title = {A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.},
journal = {PloS one},
volume = {19},
number = {7},
pages = {e0291285},
pmid = {38990927},
issn = {1932-6203},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; Treatment Outcome ; Adult ; Neuroprotective Agents/therapeutic use/administration & dosage/adverse effects ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics.

PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28.

FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection.

INTERPRETATION: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.

TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
Male
Female
Middle Aged
Aged
Prospective Studies
Treatment Outcome
Adult
Neuroprotective Agents/therapeutic use/administration & dosage/adverse effects

@article {pmid38975145,
year = {2024},
author = {Zhang, J and Xie, D and Jiao, D and Zhou, S and Liu, S and Ju, Z and Hu, L and Qi, L and Yao, C and Zhao, C},
title = {From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.},
journal = {Heliyon},
volume = {10},
number = {12},
pages = {e32688},
pmid = {38975145},
issn = {2405-8440},
abstract = {The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.},
}

@article {pmid38973130,
year = {2024},
author = {Corcia, P and Guy, N and Pradat, PF and Soriani, MH and Verschueren, A and Couratier, P},
title = {Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2024.2375330},
pmid = {38973130},
issn = {2167-9223},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.},
}

@article {pmid38972779,
year = {2024},
author = {Pelaez, MC and Fiore, F and Larochelle, N and Dabbaghizadeh, A and Comaduran, MF and Arbour, D and Minotti, S and Marcadet, L and Semaan, M and Robitaille, R and Nalbantoglu, JN and Sephton, CF and Durham, HD},
title = {Reversal of cognitive deficits in FUS[R521G] amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00388},
doi = {10.1016/j.neurot.2024.e00388},
pmid = {38972779},
issn = {1878-7479},
abstract = {Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS[R521G] or SOD1[G93A] to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS[R521G] mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1[G93A] mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.},
}

@article {pmid38972199,
year = {2024},
author = {Rosén, C and Mitre, B and Nellgård, B and Axelsson, M and Constantinescu, R and Andersen, PM and Dalla, K and Blennow, K and Nilsson, G and Zetterberg, H and Rosén, H},
title = {High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.},
journal = {Journal of the neurological sciences},
volume = {463},
number = {},
pages = {123112},
doi = {10.1016/j.jns.2024.123112},
pmid = {38972199},
issn = {1878-5883},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.},
}

@article {pmid38969143,
year = {2024},
author = {Jha, SK and Nelson, VK and Suryadevara, PR and Panda, SP and Pullaiah, CP and Nuli, MV and Kamal, M and Imran, M and Ausali, S and Abomughaid, MM and Srivastava, R and Deka, R and Pritam, P and Gupta, N and Shyam, H and Singh, IK and Pandey, BW and Dewanjee, S and Jha, NK and Jafari, SM},
title = {Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102386},
doi = {10.1016/j.arr.2024.102386},
pmid = {38969143},
issn = {1872-9649},
abstract = {Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce malfunction of psycho-motor functions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of its associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. Cannabidiol has gained attention as a promising therapeutic drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as its clinical applications in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.},
}

@article {pmid38967881,
year = {2024},
author = {Rojas-López, JC and Estrada-Gualdron, PI and Ramírez-Guerrero, S and Velásquez-Cárdenas, MJ and Redondo-Escobar, J and Vargas-Arenas, S and Palacios-Sánchez, L and Palacios-Espinosa, X},
title = {Efficacy of pain management strategies in adults with Amyotrophic Lateral Sclerosis (ALS): A Systematic Review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {38967881},
issn = {1590-3478},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Presence of pain in ALS patients is heterogeneously reported in studies, and mostly underrepresented in symptom scales. The aim of this study is to evaluate the efficacy of pharmacological and non-pharmacological therapeutic modalities for pain management in patients with ALS. A systematic review was conducted in four databases; PubMed, Scopus, Clinicaltrials.gov, and Cochrane-Ovid. Five randomized controlled clinical trials were included regarding pharmacological and non-pharmacological pain management interventions in adult patients with confirmed diagnosis of ALS in whom pain was objectively evaluated. Risk of bias assessment was evaluated using the RoB2.0 tool. Eligible studies were reported as a descriptive analysis. This systematic review was registered with PROSPERO ID: CRD42024495009. Five clinical trials regarding pain management strategies in ALS were eligible for analysis. Two out of five were non-pharmacological approaches whilst the remaining three provided pharmacological therapies. Of these, Mexiletine was efficient in terms of pain relief, particularly between 600 and 900 mg per day, whereas Mecasin showed no pain relief at both, high and low doses. Non-pharmacological therapies, such as exercise and osteopathic manual treatment also lacked efficacy in regard to pain management. Clinical trials focusing on pain management strategies for ALS patients are limited. Medical professionals, understandably focused on immediate life-threatening aspects, may inadvertently sideline the nuanced and intricate dimension of pain experienced by patients with ALS.},
}

@article {pmid38960473,
year = {2024},
author = {R, HC and Datta, A and S, UK and Zayed, H and D, TK and C, GPD},
title = {Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders.},
journal = {Advances in protein chemistry and structural biology},
volume = {141},
number = {},
pages = {177-201},
doi = {10.1016/bs.apcsb.2023.12.008},
pmid = {38960473},
issn = {1876-1631},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Motor Neuron Disease/genetics/metabolism ; },
abstract = {Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/metabolism
Gene Expression Profiling
Motor Neuron Disease/genetics/metabolism

@article {pmid38960099,
year = {2024},
author = {Bhandari, UR and Danish, SM and Ahmad, S and Ikram, M and Nadaf, A and Hasan, N and Kesharwani, P and Ahmad, FJ},
title = {New opportunities for antioxidants in amelioration of neurodegenerative diseases.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {111961},
doi = {10.1016/j.mad.2024.111961},
pmid = {38960099},
issn = {1872-6216},
abstract = {This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.},
}

@article {pmid38952156,
year = {2024},
author = {Marques-Santos, F and Faria, RX and Amendoeira, MRR},
title = {The Search for Drugs Derived from Natural Products for Toxoplasma gondii Infection Treatment in the Last 20 Years - A Systematic Review.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266299409240606062235},
pmid = {38952156},
issn = {1873-4294},
abstract = {INTRODUCTION: Toxoplasmosis is a worldwide distributed zoonosis caused by Toxo-plasma gondii (T. gondii), an obligate intracellular protozoan. The infection in immunocompetent hosts usually progresses with mild or no symptoms. However, in immunocompromised individu-als, this disease can cause severe or fatal symptoms.

METHOD: Sulfadiazine and pyrimethamine are two drugs used as standard therapies for human toxoplasmosis. Although they do not cause chronic infection, they may cause hematological tox-icity, hypersensitivity, intolerance, teratogenic effects, gastrointestinal disorders, and bone mar-row suppression.

RESULT: The limited effect, significant toxicity, and emerging resistance to current drugs available to treat T. gondii infections require investigating other effective, nontoxic, and well-tolerated al-ternatives. Medicinal plants are, traditionally, the most promising sources used to treat infectious diseases.

CONCLUSION: This review provides data on new therapeutic and prophylactic methods for T. gondii infection based on the use of extracts and/or compounds derived from natural products, which have been reported to be useful as alternative treatment options in the last 20 years.},
}

@article {pmid38951798,
year = {2024},
author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and , and , and Goldstein, DB and Harms, MB},
title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.},
journal = {BMC genomics},
volume = {25},
number = {1},
pages = {651},
pmid = {38951798},
issn = {1471-2164},
support = {P01 AG007232/AG/NIA NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; },
mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Ethnicity/genetics ; Genetic Predisposition to Disease ; Genetic Variation ; European People ; East Asian People ; African People ; Hispanic or Latino ; Middle Eastern People ; South Asian People ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10[-39]; OR = 4.73, p = 2 × 10[-10]; OR = 2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.},
}

Female
Humans
Male
*Amyotrophic Lateral Sclerosis/genetics
Ethnicity/genetics
Genetic Predisposition to Disease
Genetic Variation
European People
East Asian People
African People
Hispanic or Latino
Middle Eastern People
South Asian People

@article {pmid38946579,
year = {2024},
author = {Trucco, AP and Backhouse, T and Mioshi, E},
title = {Describing and assessing behavioural symptoms in amyotrophic lateral sclerosis with and without frontotemporal dementia: a scoping review.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
pmid = {38946579},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: Alongside motor and cognitive symptoms, amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (ALSFTD) present with behavioural symptoms, which can be challenging for all affected by the disease. A scoping review of studies published between 2011 and 2024 was conducted to present the breadth of behavioural symptoms in ALS and ALSFTD, explore how they are described and assessed, and identify patterns in the literature.

FINDINGS: This scoping review identified 3939 articles, with 111/3939 meeting eligibility criteria. Most studies were from Australia (23.22%), Italy (16.94%) and the UK (14.29%); 75.67% were cross-sectional. Sample size ranged from 1 to 1013, as case studies were included. Overall mean age (100/111 studies) was 61.32 (SD = 4.15). Proportion of male patients (reported 102/111 studies) was 61.49%; mean disease duration (reported in 86/111 records) was 32.63 months (SD = 24.72). Papers described a broad range of behavioural symptoms (465 examples), which were thematically collated into seven categories: disinhibition (27.74%), apathy (25.16%), perseverative/compulsive behaviours (17.42%), hyperorality (10.53%), loss of sympathy or empathy (8.6%), psychotic symptoms (7.74%), and loss of insight about disease and changes (2.8%). Most studies (78.37%) used validated behavioural assessments that elicited carer's perspectives.

SUMMARY: Despite extensive evidence of behavioural symptoms in ALS, implementation of assessments and management of behavioural symptoms in clinical care remain limited. Clinicians must assess behavioural symptoms, as these can negatively affect disease prognosis, patient treatment engagement and increase family distress. Measures capturing carers' perspectives through interviews are ideal as they can reveal anosognosia, lack of sympathy and lack of empathy.},
}

@article {pmid38944367,
year = {2024},
author = {Wankhede, NL and Rajendra Kopalli, S and Dhokne, MD and Badnag, DJ and Chandurkar, PA and Mangrulkar, SV and Shende, PV and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Koppula, S and Kale, MB},
title = {Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.},
journal = {Mitochondrion},
volume = {78},
number = {},
pages = {101926},
doi = {10.1016/j.mito.2024.101926},
pmid = {38944367},
issn = {1872-8278},
abstract = {Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.},
}

@article {pmid38942541,
year = {2024},
author = {Shukla, H and John, D and Banerjee, S and Tiwari, AK},
title = {Drug repurposing for neurodegenerative diseases.},
journal = {Progress in molecular biology and translational science},
volume = {207},
number = {},
pages = {249-319},
doi = {10.1016/bs.pmbts.2024.03.035},
pmid = {38942541},
issn = {1878-0814},
mesh = {Humans ; *Drug Repositioning ; *Neurodegenerative Diseases/drug therapy ; Animals ; },
abstract = {Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.},
}

Humans
*Drug Repositioning
*Neurodegenerative Diseases/drug therapy
Animals

@article {pmid38935506,
year = {2024},
author = {Halim, DO and Krishnan, G and Hass, EP and Lee, S and Verma, M and Almeida, S and Gu, Y and Kwon, DY and Fazzio, TG and Gao, FB},
title = {The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD.},
journal = {Cell reports},
volume = {43},
number = {7},
pages = {114375},
doi = {10.1016/j.celrep.2024.114375},
pmid = {38935506},
issn = {2211-1247},
abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.},
}

@article {pmid38929462,
year = {2024},
author = {De Marchi, I and Buffone, F and Mauro, A and Bruini, I and Vismara, L},
title = {Manual Therapy of Dysphagia in a Patient with Amyotrophic Lateral Sclerosis: A Case Report.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {60},
number = {6},
pages = {},
pmid = {38929462},
issn = {1648-9144},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Male ; *Deglutition Disorders/etiology/therapy ; Middle Aged ; Manipulation, Osteopathic/methods ; Treatment Outcome ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable rare neurodegenerative condition, with 45% of cases showing the symptom of dysphagia; its clinical signs are atrophy, weakness, and fasciculations of the facial muscles, tongue, and pharynx. Furthermore, dysphagia is the main cause of aspiration pneumonia. The traditional treatment for dysphagia varies based on the patient's difficulty of swallowing. The initial phase consists of dietary consistency adjustments, progressing to alternatives like nasogastric tubes or percutaneous endoscopic gastrostomy (PEG) in advanced stages. Osteopathic manipulative treatment (OMT) is a complementary 'hands-on' approach that has already shown positive results as an add-on therapy in various health conditions. This study is a case report of a man diagnosed with ALS with initial dysphagia, managed with a protocol that extraordinarily included OMT. The patient showed somatic dysfunctions in the mediastinal region, upper cervical region, and occipital area which are all anatomically related to the nervous system, especially the glossopharyngeal reflex. At the end of the rehabilitation protocol, there was a reduction in the swallowing problems measured with Strand Scale and swallowing tests, and the patient reported an improved psycho-physical well-being assessed with the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Instead, the neurological function measured with ALSFRS-S remained stable. Although the nature of this study design prevents any causal assumption, the positive results should lead to future randomized controlled trials to assess the effectiveness of OMT as an adjunctive therapeutic proposal to improve the health of ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/therapy
Male
*Deglutition Disorders/etiology/therapy
Middle Aged
Manipulation, Osteopathic/methods
Treatment Outcome

@article {pmid38928874,
year = {2024},
author = {Szulc, A and Wiśniewska, K and Żabińska, M and Gaffke, L and Szota, M and Olendzka, Z and Węgrzyn, G and Pierzynowska, K},
title = {Effectiveness of Flavonoid-Rich Diet in Alleviating Symptoms of Neurodegenerative Diseases.},
journal = {Foods (Basel, Switzerland)},
volume = {13},
number = {12},
pages = {},
pmid = {38928874},
issn = {2304-8158},
support = {533-0C20-GS0D-24//University of Gdansk/ ; },
abstract = {Over the past decades, there has been a significant increase in the burden of neurological diseases, including neurodegenerative disorders, on a global scale. This is linked to a widespread demographic trend in which developed societies are aging, leading to an increased proportion of elderly individuals and, concurrently, an increase in the number of those afflicted, posing one of the main public health challenges for the coming decades. The complex pathomechanisms of neurodegenerative diseases and resulting varied symptoms, which differ depending on the disease, environment, and lifestyle of the patients, make searching for therapies for this group of disorders a formidable challenge. Currently, most neurodegenerative diseases are considered incurable. An important aspect in the fight against and prevention of neurodegenerative diseases may be broadly understood lifestyle choices, and more specifically, what we will focus on in this review, a diet. One proposal that may help in the fight against the spread of neurodegenerative diseases is a diet rich in flavonoids. Flavonoids are compounds widely found in products considered healthy, such as fruits, vegetables, and herbs. Many studies indicated not only the neuroprotective effects of these compounds but also their ability to reverse changes occurring during the progression of diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis. Here, we present the main groups of flavonoids, discussing their characteristics and mechanisms of action. The most widely described mechanisms point to neuroprotective functions due to strong antioxidant and anti-inflammatory effects, accompanied with their ability to penetrate the blood-brain barrier, as well as the ability to inhibit the formation of protein aggregates. The latter feature, together with promoting removal of the aggregates is especially important in neurodegenerative diseases. We discuss a therapeutic potential of selected flavonoids in the fight against neurodegenerative diseases, based on in vitro studies, and their impact when included in the diet of animals (laboratory research) and humans (population studies). Thus, this review summarizes flavonoids' actions and impacts on neurodegenerative diseases. Therapeutic use of these compounds in the future is potentially possible but depends on overcoming key challenges such as low bioavailability, determining the therapeutic dose, and defining what a flavonoid-rich diet is and determining its potential negative effects. This review also suggests further research directions to address these challenges.},
}

@article {pmid38925911,
year = {2024},
author = {De La Cruz, E and Esselin, F and Polge, A and Mouzat, K and Guissart, C},
title = {Most SOD1 mutations are pathogenic, and their identification can lead to early access to treatment.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2024-333939},
pmid = {38925911},
issn = {1468-330X},
}

@article {pmid38924779,
year = {2024},
author = {Bratches, RWR and Cohen, J and Carpenter-Song, E and Mistler, L and Barr, PJ},
title = {The Feasibility and Acceptability of Sharing Video Recordings of Amyotrophic Lateral Sclerosis Clinical Encounters With Patients and Their Caregivers: Pilot Randomized Clinical Trial.},
journal = {JMIR formative research},
volume = {8},
number = {},
pages = {e57519},
doi = {10.2196/57519},
pmid = {38924779},
issn = {2561-326X},
abstract = {BACKGROUND: Multidisciplinary clinics (MDCs) provide benefits to patients with amyotrophic lateral sclerosis (ALS) and their caregivers, but MDC visits are information-heavy and can last 4 hours, with patients and caregivers meeting with multiple specialists within each MDC visit. There are questions about the effectiveness of current methods of sharing information from MDCs with patients. Video recordings are a promising new method of sharing information that may allow patients and caregivers to revisit the MDC and remind them of clinical recommendations and conversations.

OBJECTIVE: The objective of this trial is to determine the feasibility and acceptability of sharing information through video recordings of ALS MDC visits with patients and caregivers.

METHODS: This study was a randomized, controlled pilot trial with 3 months of follow-up from April 2021 to March 2022 in a rural multidisciplinary neurology clinic. We recruited patients with ALS, their caregivers, and their clinicians. Patients and their caregivers were randomized to either receive their normal after-visit summary (treatment as usual) or to receive their normal after-visit summary and a video recording of their MDC visit (video). Each specialist visit had its own recording and was accessible by patients and caregivers using a secure web-based platform called HealthPAL over a 3-month follow-up period. Primary study outcomes were feasibility and acceptability of the video intervention measured by recruitment rate (target: 70%), percentage of participants watching videos (target: 75%), and the Feasibility of Intervention Measure and Acceptability of Intervention Measure (targets: 3/5). We hypothesized that video recording would be feasible and acceptable to patients and their caregivers.

RESULTS: Of the 30 patients approached, 24 were recruited, while all caregivers (n=21) and clinicians (n=34) approached were recruited. A total of 144 specialist visits were recorded, approximately 12 specialist visits at a median of one MDC visit per patient. Of the recorded patients, 75% (9/12) viewed videos. High median intervention feasibility (4, SD 0.99) and acceptability (4, SD 1.22) of intervention measures were reported by patients and caregivers in the intervention arm. High median intervention feasibility (5, SD 0.21) and acceptability (4.88, SD 0.4) were reported by clinicians. Of the 24 patients, 50% (n=12) did not complete a 3-month follow-up, primarily due to death (n=10).

CONCLUSIONS: Video recording is highly feasible and acceptable for patients, caregivers, and clinicians at a rural ALS clinic. Our level of attrition is a useful benchmark for future studies in MDC populations. Despite high rates of patient death, 1-week assessments highlight the value of recordings for both patients and caregivers.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04719403; https://clinicaltrials.gov/study/NCT04719403.},
}

@article {pmid38924633,
year = {2024},
author = {Wolf, J and Buckley, GJ and Rozanski, EA and Fletcher, DJ and Boller, M and Burkitt-Creedon, JM and Weigand, KA and Crews, M and Fausak, ED and , },
title = {2024 RECOVER Guidelines: Advanced Life Support. Evidence and knowledge gap analysis with treatment recommendations for small animal CPR.},
journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)},
volume = {34 Suppl 1},
number = {},
pages = {44-75},
doi = {10.1111/vec.13389},
pmid = {38924633},
issn = {1476-4431},
support = {//Zoetis Animal Health/ ; //Boehringer Ingelheim Animal Health/ ; },
mesh = {Animals ; Dogs ; Cats ; *Dog Diseases/therapy/drug therapy ; Cardiopulmonary Resuscitation/veterinary/standards ; Cat Diseases/therapy/drug therapy ; Veterinary Medicine/standards ; Heart Arrest/veterinary/therapy ; },
abstract = {OBJECTIVE: To systematically review the evidence and devise clinical recommendations on advanced life support (ALS) in dogs and cats and to identify critical knowledge gaps.

DESIGN: Standardized, systematic evaluation of literature pertinent to ALS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by Evidence Evaluators, and findings were reconciled by ALS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk:benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4 weeks prior to finalization.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: Seventeen questions pertaining to vascular access, vasopressors in shockable and nonshockable rhythms, anticholinergics, defibrillation, antiarrhythmics, and adjunct drug therapy as well as open-chest CPR were reviewed. Of the 33 treatment recommendations formulated, 6 recommendations addressed the management of patients with nonshockable arrest rhythms, 10 addressed shockable rhythms, and 6 provided guidance on open-chest CPR. We recommend against high-dose epinephrine even after prolonged CPR and suggest that atropine, when indicated, is used only once. In animals with a shockable rhythm in which initial defibrillation was unsuccessful, we recommend doubling the defibrillator dose once and suggest vasopressin (or epinephrine if vasopressin is not available), esmolol, lidocaine in dogs, and/or amiodarone in cats.

CONCLUSIONS: These updated RECOVER ALS guidelines clarify the approach to refractory shockable rhythms and prolonged CPR. Very low quality of evidence due to absence of clinical data in dogs and cats continues to compromise the certainty with which recommendations can be made.},
}

Animals
Dogs
Cats
*Dog Diseases/therapy/drug therapy
Cardiopulmonary Resuscitation/veterinary/standards
Cat Diseases/therapy/drug therapy
Veterinary Medicine/standards
Heart Arrest/veterinary/therapy

@article {pmid38924627,
year = {2024},
author = {Burkitt-Creedon, JM and Boller, M and Fletcher, DJ and Brainard, BM and Buckley, GJ and Epstein, SE and Fausak, ED and Hopper, K and Lane, SL and Rozanski, EA and Wolf, J},
title = {2024 RECOVER Guidelines: Updated treatment recommendations for CPR in dogs and cats.},
journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)},
volume = {34 Suppl 1},
number = {},
pages = {104-123},
doi = {10.1111/vec.13391},
pmid = {38924627},
issn = {1476-4431},
support = {//Boehringer Ingelheim Animal Health/ ; //Zoetis Animal Health/ ; },
mesh = {Dogs ; Animals ; Cats ; *Cardiopulmonary Resuscitation/veterinary/standards/methods ; *Cat Diseases/therapy ; Dog Diseases/therapy ; Heart Arrest/veterinary/therapy ; },
abstract = {OBJECTIVE: After the 2012 Reassessment Campaign on Veterinary Resuscitation (RECOVER) CPR Guidelines, this is an update of evidence-based consensus guidelines for Basic Life Support (BLS), advanced life support (ALS), and periarrest monitoring.

DESIGN: These RECOVER CPR Guidelines were generated using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for evidence evaluation and translation of this evidence into clear and actionable clinical instructions. Prioritized clinical questions in the Population, Intervention, Comparator, and Outcome (PICO) format were used as the basis to conduct systematic literature searches by information specialists, to extract information from relevant publications, to assess this evidence for quality, and finally to translate the findings into treatment recommendations. These recommendations were reviewed by the RECOVER writing group and opened for comment by veterinary professionals for 4 weeks.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: A total of 40 worksheets were prepared to evaluate questions across the 3 domains of BLS, ALS and Monitoring, resulting in 90 individual treatment recommendations. High-dose epinephrine is no longer recommended, and atropine, if used, is only administered once. Bag-mask ventilation is prioritized over mouth-to-nose ventilation in nonintubated animals. In addition, an algorithm for initial assessment, an updated CPR algorithm, a rhythm diagnosis tool, and an updated drug dosing table are provided.

CONCLUSIONS: While the majority of the BLS and ALS recommendations remain unchanged, some noteworthy changes were made due to new evidence that emerged over the past 10 years. Indirectness of evidence remains the largest impediment to the certainty of guidelines formulation and underscores an urgent need for more studies in the target species of dogs and cats.},
}

Dogs
Animals
Cats
*Cardiopulmonary Resuscitation/veterinary/standards/methods
*Cat Diseases/therapy
Dog Diseases/therapy
Heart Arrest/veterinary/therapy

@article {pmid38924023,
year = {2024},
author = {Spoden, C and Wenzel, O and Erdmann, A and Neitzke, G and Hirschberg, I},
title = {Coping and end-of-life decision-making in ALS: A qualitative interview study.},
journal = {PloS one},
volume = {19},
number = {6},
pages = {e0306102},
doi = {10.1371/journal.pone.0306102},
pmid = {38924023},
issn = {1932-6203},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Middle Aged ; *Adaptation, Psychological ; *Decision Making ; *Terminal Care/psychology ; Aged ; *Qualitative Research ; Adult ; Germany ; Interviews as Topic ; },
abstract = {How do people with amyotrophic lateral sclerosis (PALS) deal with their diagnosis and engage in end-of-life decision-making? What informational or supportive needs do they have for counselling about life-sustaining treatment and end-of-life care? Which correlating conditions and influences relate to these needs and how do they connect to the wish to die or wish to live? We conducted a qualitative interview study with 13 people with ALS in Germany from March 2019 to April 2021. Data collection and analysis followed a grounded theory-based approach and revealed close relationships between coping, informational needs and the preparedness for decision-making. We identified the coping strategies 'avoid thinking about end-of-life' and its counterpart, 'planning ahead to be well-prepared,' and differentiated the latter into the patterns 'withdrawing from life and taking precautions against life-prolongation' and 'searching for a new meaning in life and preparing for life-sustaining treatment'. The approaches are based on individual perceptions, attitudes and motives and can be positively/negatively reinforced by healthcare professionals (HCP), family and other interpersonal networks, but also by disease progression and in reaction to health care services. Type and degree of needs concerning information and counselling differed according to coping strategies. These strategies may vary over time, resulting in different support needs. Our findings signify that deep insight is needed into PALS' coping processes to understand their decision-making about life-sustaining treatment. Healthcare professionals should be sensitive to illness experiences beyond medical aspects and foster coping as a biographical process to better support people with ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology
Male
Female
Middle Aged
*Adaptation, Psychological
*Decision Making
*Terminal Care/psychology
Aged
*Qualitative Research
Adult
Germany
Interviews as Topic

@article {pmid38923364,
year = {2024},
author = {Yang, XD and Gong, B and Chen, W and Chen, JJ and Qian, C and Lu, R and Min, Y and Jiang, T and Li, L and Yu, HQ},
title = {In Situ Quantitative Monitoring of Adsorption from Aqueous Phase by UV-vis Spectroscopy: Implication for Understanding of Heterogeneous Processes.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2402732},
doi = {10.1002/advs.202402732},
pmid = {38923364},
issn = {2198-3844},
support = {//Program for Changjiang Scholars and Innovative Research Team in University/ ; 51821006//National Natural Science Foundation of China/ ; 52027815//National Natural Science Foundation of China/ ; 52192684//National Natural Science Foundation of China/ ; 22276217//National Natural Science Foundation of China/ ; },
abstract = {The development of in situ techniques to quantitatively characterize the heterogeneous reactions is essential for understanding physicochemical processes in aqueous phase. In this work, a new approach coupling in situ UV-vis spectroscopy with a two-step algorithm strategy is developed to quantitatively monitor heterogeneous reactions in a compact closed-loop incorporation. The algorithm involves the inverse adding-doubling method for light scattering correction and the multivariate curve resolution-alternating least squares (MCR-ALS) method for spectral deconvolution. Innovatively, theoretical spectral simulations are employed to connect MCR-ALS solutions with chemical molecular structural evolution without prior information for reference spectra. As a model case study, the aqueous adsorption kinetics of bisphenol A onto polyamide microparticles are successfully quantified in a one-step UV-vis spectroscopic measurement. The practical applicability of this approach is confirmed by rapidly screening a superior adsorbent from commercial materials for antibiotic wastewater adsorption treatment. The demonstrated capabilities are expected to extend beyond monitoring adsorption systems to other heterogeneous reactions, significantly advancing UV-vis spectroscopic techniques toward practical integration into automated experimental platforms for probing aqueous chemical processes and beyond.},
}

@article {pmid38922880,
year = {2024},
author = {Goldschmidt-Clermont, PJ and Khan, A and Jimsheleishvili, G and Graham, P and Brooks, A and Silvera, R and Goldschmidt, AJP and Pearse, DD and Dietrich, WD and Levi, AD and Guest, JD},
title = {Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-23-01815},
pmid = {38922880},
issn = {1673-5374},
abstract = {Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 1012 (×2), and then consecutive infusions of 7.5 × 1012 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.},
}

@article {pmid38920997,
year = {2024},
author = {Nowak, I and Paździor, M and Sarna, R and Madej, M},
title = {Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases.},
journal = {Current issues in molecular biology},
volume = {46},
number = {6},
pages = {5436-5453},
doi = {10.3390/cimb46060325},
pmid = {38920997},
issn = {1467-3045},
abstract = {Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.},
}

@article {pmid38915796,
year = {2024},
author = {Thonhoff, JR and Beers, DR and Zhao, W and Faridar, A and Thome, A and Wen, S and Zhang, A and Wang, J and Appel, SH},
title = {A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1415106},
pmid = {38915796},
issn = {1664-2295},
abstract = {OBJECTIVE: To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS.

METHODS: In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 10[6] IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally.

RESULTS: CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants.

CONCLUSION: The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT06307301.},
}

@article {pmid38914784,
year = {2024},
author = {Sang, A and Zhuo, S and Bochanis, A and Manautou, JE and Bahal, R and Zhong, XB and Rasmussen, TP},
title = {Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.},
journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy},
volume = {},
number = {},
pages = {},
pmid = {38914784},
issn = {1179-190X},
support = {R35GM140862/GM/NIGMS NIH HHS/United States ; R01HL147028/HL/NHLBI NIH HHS/United States ; },
abstract = {Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].},
}

@article {pmid38914219,
year = {2024},
author = {Asahina, R and Takahashi, M and Takano, H and Yao, R and Abe, M and Goshima, Y and Ohshima, T},
title = {The role of CRMP4 in LPS-induced neuroinflammation.},
journal = {Brain research},
volume = {},
number = {},
pages = {149094},
doi = {10.1016/j.brainres.2024.149094},
pmid = {38914219},
issn = {1872-6240},
abstract = {Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown. In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4[-/-] mice compared to Crmp4[+/+]mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4[-/-] mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.},
}

@article {pmid38914173,
year = {2024},
author = {Tortarolo, M and Cecconi, ADR and Camporeale, L and Margotta, C and Nardo, G and Pasetto, L and Bonetto, V and Galbiati, M and Crippa, V and Poletti, A and Piccirillo, R and Bendotti, C},
title = {Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106576},
doi = {10.1016/j.nbd.2024.106576},
pmid = {38914173},
issn = {1095-953X},
abstract = {Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.},
}

@article {pmid38909349,
year = {2024},
author = {Ketabforoush, A and Faghihi, F and Azedi, F and Ariaei, A and Habibi, MA and Khalili, M and Ashtiani, BH and Joghataei, MT and Arnold, WD},
title = {Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {38909349},
issn = {1179-1918},
abstract = {The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.},
}

@article {pmid38909342,
year = {2024},
author = {Réginault, T and Wibart, P and Mathis, S and Le Masson, G and Pillet, O and Grassion, L},
title = {Factors associated with survival after early at-home NIV initiation in ALS patients.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {38909342},
issn = {1432-1459},
abstract = {BACKGROUND: The initiation of early non-invasive ventilation (NIV) often involves a careful balance between tolerance and effectiveness. In amyotrophic lateral sclerosis (ALS) patients, the establishment of a strategy, including the decision to focus on adhering to a cut-off, setting specific targets, or correcting all events, is crucial.

OBJECTIVE: To identify factors at 1 month after early at-home NIV initiation that are associated with improved survival in ALS patients. We explored the impacts of adherence (ADH), quality of treatment, and NIV parameters at 1 month after early at-home NIV initiation on patient survival.

METHODS: We conducted a retrospective study of 184 ALS patients at the Bordeaux ALS Centre for whom NIV was initiated between September 2017 and June 2021, and we collected data for a minimum period of 2 years after the last patient included. The primary outcome was the risk of death according to baseline characteristics of our population and the NIV parameters and monitoring during the early NIV initiation period. The secondary outcomes were association with NIV ADH during the early NIV initiation period on prognosis, and NIV ADH cut-off for good versus poor prognosis.

RESULTS: Among the 178 ALS patients analysed, we found that quality of NIV treatment and device settings did not significantly influence prognosis. However, low ADH was significantly associated with a higher risk of death. The use of NIV for > 5 h/day during the early NIV initiation period was linked to a decreased risk of death [hazard ratio = 0.4; 95% confidence interval: 0.27-0.9].

CONCLUSION: The use of NIV for > 5 h/day during the early NIV initiation period was associated with increased survival.},
}

@article {pmid38906677,
year = {2024},
author = {Au, WH and Miller-Fleming, L and Sanchez-Martinez, A and Lee, JA and Twyning, MJ and Prag, HA and Raik, L and Allen, SP and Shaw, PJ and Ferraiuolo, L and Mortiboys, H and Whitworth, AJ},
title = {Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.},
journal = {Life science alliance},
volume = {7},
number = {9},
pages = {},
pmid = {38906677},
issn = {2575-1077},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Oxidative Stress ; *NF-E2-Related Factor 2/metabolism/genetics ; *C9orf72 Protein/genetics/metabolism ; *Mitochondria/metabolism ; Animals ; *Disease Models, Animal ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Humans ; *Signal Transduction ; *Frontotemporal Dementia/genetics/metabolism ; *Phenotype ; Drosophila Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Mitophagy/genetics ; Dimethyl Fumarate/pharmacology ; Male ; },
abstract = {Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.},
}

*Amyotrophic Lateral Sclerosis/metabolism/genetics
*Oxidative Stress
*NF-E2-Related Factor 2/metabolism/genetics
*C9orf72 Protein/genetics/metabolism
*Mitochondria/metabolism
Animals
*Disease Models, Animal
*Kelch-Like ECH-Associated Protein 1/metabolism/genetics
Humans
*Signal Transduction
*Frontotemporal Dementia/genetics/metabolism
*Phenotype
Drosophila Proteins/metabolism/genetics
Reactive Oxygen Species/metabolism
Mitophagy/genetics
Dimethyl Fumarate/pharmacology
Male

@article {pmid38904729,
year = {2024},
author = {Portes E Silva, KR and Nogueira, EM and Jesus Mendes, AL and Pena, ALB and Simões E Silva, AC},
title = {The potential role of renin angiotensin system in acute leukemia: a narrative review.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {775},
pmid = {38904729},
issn = {1573-4978},
support = {304496/2023-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {Humans ; *Renin-Angiotensin System/physiology ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; *Angiotensin II/metabolism ; Leukemia, Myeloid, Acute/metabolism/pathology ; Signal Transduction ; Angiotensin I/metabolism ; Neovascularization, Pathologic/metabolism ; Animals ; Peptide Fragments/metabolism ; },
abstract = {Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.},
}

Humans
*Renin-Angiotensin System/physiology
*Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology
*Angiotensin II/metabolism
Leukemia, Myeloid, Acute/metabolism/pathology
Signal Transduction
Angiotensin I/metabolism
Neovascularization, Pathologic/metabolism
Animals
Peptide Fragments/metabolism

@article {pmid38898231,
year = {2024},
author = {Gao, J and Gunasekar, S and Xia, ZJ and Shalin, K and Jiang, C and Chen, H and Lee, D and Lee, S and Pisal, ND and Luo, JN and Griciuc, A and Karp, JM and Tanzi, R and Joshi, N},
title = {Gene therapy for CNS disorders: modalities, delivery and translational challenges.},
journal = {Nature reviews. Neuroscience},
volume = {},
number = {},
pages = {},
pmid = {38898231},
issn = {1471-0048},
abstract = {Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.},
}

@article {pmid38896262,
year = {2024},
author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L},
title = {Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {38896262},
issn = {1432-1459},
support = {XDB39040100//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; 2022-PUMCH-B-017//High-level Hospital Construction Project of Guangdong Provincial People's Hospital/ ; 2022YFC2703904//Key Technologies Research and Development Program/ ; 2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 81971293//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis.

METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed.

RESULTS: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset.

CONCLUSION: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.},
}

@article {pmid38895672,
year = {2024},
author = {Deng, J and Sun, WT and Gong, K and Wang, LP and Li, FZ},
title = {Internal limiting membrane peeling combined with silicone oil or air tamponade for highly myopic foveoschisis.},
journal = {International journal of ophthalmology},
volume = {17},
number = {6},
pages = {1079-1085},
pmid = {38895672},
issn = {2222-3959},
abstract = {AIM: To compare the efficacy of pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) and silicone oil or sterile air tamponade for the treatment of myopic foveoschisis (MF) in highly myopic eyes.

METHODS: This retrospective study included 48 myopic eyes of 40 patients with MF and axial lengths (ALs) ranging from 26-32 mm treated between January 2020 and January 2022. All patients were underwent PPV combined with ILM peeling followed by sterile air or silicone oil tamponade and followed up at least 12mo. Based on the features on spectral-domain optical coherence tomography (SD-OCT), the eyes were divided into the MF-only group (Group A, n=15 eyes), MF with central foveal detachment group (Group B, n=20 eyes), and MF with lamellar macular hole group (Group C, n=13 eyes). According to AL, eyes were further divided into three groups: Group D (26.01-28.00 mm, n=12 eyes), Group E (28.01-30.00 mm, n=26 eyes), and Group F (30.01-32.00 mm, n=10 eyes). The best-corrected visual acuity (BCVA), central foveal thickness (CFT), and complications were recorded.

RESULTS: The patients included 16 males and 24 females with the mean age of 56±9.82y. The BCVA and CFT improved in all groups after surgery (P<0.01), while there was no significant difference of the CFT in Group A, B, and C postoperatively (P>0.05). The intergroup differences of BCVA and CFT postoperatively were statistically significant in Group D, E, and F. Twenty eyes were injected with sterile air, and 28 eyes were injected with silicone oil for tamponade based on the AL. However, there was no statistically significant difference among Groups D, E, and F in terms of the results of sterile air or silicone oil tamponade. The mean recovery time was 5.9mo for MF patients subjected to silicone oil tamponade and 7.7mo for patients subjected to sterile air tamponade, and the difference was not statistically significant.

CONCLUSION: PPV and ILM peeling combined with silicone oil or sterile air tamponade can achieve good results for MF in highly myopic eyes with ALs≤32 mm.},
}

@article {pmid38895485,
year = {2024},
author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M},
title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.06.06.597745},
pmid = {38895485},
abstract = {UNLABELLED: Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.

AUTHOR SUMMARY: This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.},
}

@article {pmid38895204,
year = {2024},
author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC},
title = {FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 [S59L].},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.06.04.597429},
pmid = {38895204},
abstract = {Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10(CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing C2C10H [S81L] , and human cell models expressing CHCHD10 [S59L] , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 [S59L] . Evidences using in vitro/ in vivo genetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 [S59L] -induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 [S59L] -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 [S59L] -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H [S81L] . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 [S59L] . These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 [S59L] -induced ALS-FTD and possibly other related diseases.},
}

@article {pmid38891895,
year = {2024},
author = {Dabrowska, S and Turano, E and Scambi, I and Virla, F and Nodari, A and Pezzini, F and Galiè, M and Bonetti, B and Mariotti, R},
title = {A Cellular Model of Amyotrophic Lateral Sclerosis to Study the Therapeutic Effects of Extracellular Vesicles from Adipose Mesenchymal Stem Cells on Microglial Activation.},
journal = {International journal of molecular sciences},
volume = {25},
number = {11},
pages = {},
pmid = {38891895},
issn = {1422-0067},
mesh = {*Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology ; *Extracellular Vesicles/metabolism ; *Microglia/metabolism ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Cell Line ; Adipose Tissue/cytology/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS's pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS's pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu[+]/Zn[+] superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.},
}

*Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology
*Extracellular Vesicles/metabolism
*Microglia/metabolism
*Mesenchymal Stem Cells/metabolism
Humans
*Superoxide Dismutase-1/metabolism/genetics
Reactive Oxygen Species/metabolism
Cell Line
Adipose Tissue/cytology/metabolism

@article {pmid38891791,
year = {2024},
author = {Tokuda, E and Sakashita, Y and Tokoro, N and Date, A and Kosuge, Y and Miyasaka, T},
title = {MS785-MS27 Reactive Misfolded/Non-Native Zn-Deficient SOD1 Species Exhibit Cytotoxicity and Adopt Heterozygous Conformations in Motor Neurons.},
journal = {International journal of molecular sciences},
volume = {25},
number = {11},
pages = {},
pmid = {38891791},
issn = {1422-0067},
support = {2022-2025//The Takeda Science Foundation/ ; },
mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Motor Neurons/metabolism/pathology ; Mice ; *Zinc/metabolism/deficiency ; *Protein Folding ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Mutation ; Mice, Transgenic ; Heterozygote ; Protein Conformation ; },
abstract = {Misfolding of superoxide dismutase-1 (SOD1) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) with SOD1 mutations. The development of antibodies specific for misfolded SOD1 deepens our understanding of how the protein participates in ALS pathogenesis. Since the term "misfolding" refers to various disordered conformers other than the natively folded one, which misfolded species are recognized by specific antibodies should be determined. Here, we molecularly characterized the recognition by MS785-MS27, an antibody cocktail experimentally confirmed to recognize over 100 ALS-linked SOD1 mutants. Indirect ELISA revealed that the antibody cocktail recognized Zn-deficient wild-type and mutated SOD1 species. It also recognized conformation-disordered wild-type and mutated SOD1 species, such as unfolded and oligomeric forms, but had less affinity for the aggregated form. Antibody-reactive SOD1 exhibited cytotoxicity to a motor neuron cell model, which was blocked by Zn treatment with Zn-deficient SOD1. Immunohistochemistry revealed antibody-reactive SOD1 mainly in spinal motor neurons of SOD1[G93A] mice throughout the disease course, and the distribution after symptomatic stages differed from that of other misfolded SOD1 species. This suggests that misfolded/non-native SOD1 species exist as heterogeneous populations. In conclusion, MS785-MS27 recognizes various conformation-disordered SOD1 species lacking the Zn ion.},
}

Animals
*Superoxide Dismutase-1/genetics/metabolism/chemistry
*Motor Neurons/metabolism/pathology
Mice
*Zinc/metabolism/deficiency
*Protein Folding
*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
Humans
Mutation
Mice, Transgenic
Heterozygote
Protein Conformation

@article {pmid38891289,
year = {2024},
author = {Idziak, R and Waligóra, H and Majchrzak, L and Szulc, P},
title = {Multifunctional Adjuvants Affect Sulfonylureas with Synthetic Auxin Mixture in Weed and Maize Grain Yield.},
journal = {Plants (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
pmid = {38891289},
issn = {2223-7747},
abstract = {A field study in the years 2017-2019 was carried out to evaluate the impact of novel adjuvant formulations on the efficacy of sulfonylurea and synthetic auxin herbicides. Treatments included nicosulfuron + rimsulfuron + dicamba (N+R+D) at full and reduced rates with three multicomponent (TEST-1, TEST-2, TEST-3) as well as standard (MSO, S) adjuvants. In this greenhouse study, Echinochloa crus-galli seeds were planted and treated with N+R+D at 2-3 leaf stages. The water with the desired pH (4, 7, and 9) for the preparation of the spray liquid was prepared by incorporating citric acid or K3PO4 to either lower or raise the pH of the water. Adjuvant TEST-1 added to the spray liquid at pH 4 increased the effectiveness to 68%, TEST-2 to 81%, and TEST-3 to 80%, compared to 73% and 66% with the MSO and S. The efficacy of N+R+D at pH 7 with TEST-1 increased to 83%, TEST-2 to 82%, and TEST-3 to 77%, but with MSO, it increased to 81%, and 71% with S. Adjuvants TEST-1, TEST-2, and TEST-3 in the liquid at pH 9 increased efficacy to 76 and 80%, compared to 79 and 63% with MSO or S adjuvants. N+R+D applied with TEST-1, TEST-2, and TEST-3 provided greater weed control than herbicides with surfactant (S) and similar or even better than with standard methylated seed oil (MSO) adjuvants. Maize grain yield after herbicide-with-tested-adjuvant application was higher than from an untreated check, and comparable to yield from herbicide-with-MSO treatment, but higher than from S treatment.},
}

@article {pmid38891059,
year = {2024},
author = {Dashtmian, AR and Darvishi, FB and Arnold, WD},
title = {Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies.},
journal = {Cells},
volume = {13},
number = {11},
pages = {},
pmid = {38891059},
issn = {2073-4409},
support = {1R01AG067758, R01AG078129, and R01AG067758-02S2//national institute of health/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; *Aging/pathology ; Senotherapeutics/pharmacology/therapeutic use ; Animals ; Cellular Senescence ; Mitochondria/metabolism/pathology ; DNA Damage ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.},
}

*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy
Humans
*Aging/pathology
Senotherapeutics/pharmacology/therapeutic use
Animals
Cellular Senescence
Mitochondria/metabolism/pathology
DNA Damage

@article {pmid38891021,
year = {2024},
author = {Nguyen, L},
title = {Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.},
journal = {Cells},
volume = {13},
number = {11},
pages = {},
pmid = {38891021},
issn = {2073-4409},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/drug therapy ; Animals ; C9orf72 Protein/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/drug therapy
Animals
C9orf72 Protein/genetics

@article {pmid38891002,
year = {2024},
author = {Genchi, G and Lauria, G and Catalano, A and Carocci, A and Sinicropi, MS},
title = {Neuroprotective Effects of Curcumin in Neurodegenerative Diseases.},
journal = {Foods (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
pmid = {38891002},
issn = {2304-8158},
abstract = {Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.},
}

@article {pmid38889403,
year = {2024},
author = {Zhu, Y and Wang, F and Xia, Y and Wang, L and Lin, H and Zhong, T and Wang, X},
title = {Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {38889403},
issn = {2191-0200},
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.},
}

@article {pmid38887384,
year = {2024},
author = {Tang, X and Li, Q and Huang, G and Chen, Z and Huang, Y and Pei, X and Zhao, S and Liu, Z and Guo, T and Liang, F},
title = {Immediate Efficacy of Contralateral Acupuncture on SI3 Combined with Active Exercise for Acute Lumbar Sprains: Protocol for a Randomized Controlled Trial.},
journal = {Journal of pain research},
volume = {17},
number = {},
pages = {2099-2110},
pmid = {38887384},
issn = {1178-7090},
abstract = {PURPOSE: Acute lumbar sprain (ALS) is a common clinical disease characterized by persistent intolerable low back pain and limitation of movement, and quick pain relief and restoration of mobility in a short time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of contralateral acupuncture (CAT) on SI3 combined with active exercise in treating ALS.

METHODS AND ANALYSIS: This study is a randomized controlled trial which will recruit 118 eligible participants aged 18 to 55 years with ALS at the Second Affiliated Hospital of Yunnan University of Chinese Medicine between March 2024 and December 2026. Participants will be randomly assigned to the acupuncture group or the sham-acupuncture group in a 1:1 ratio. The acupuncture group will receive a 10-minute acupuncture treatment combined with active exercise, while the sham-acupuncture group will receive a 10-minute sham acupuncture treatment combined with active exercise. Randomization will use a computer-generated sequence with allocation concealed in opaque envelopes. The primary outcome will be the pain visual analogue scale (VAS) scores after 10 minutes of treatment. Secondary outcomes will include the pain VAS scores at other time points (2, 4, 6, and 8 minutes post-treatment), the lumbar range of motion (ROM) scores at various time points, blinded assessment, the treatment effect expectancy scale, and the rescue analgesia rate. The analysis will follow the intention-to-treat principle. The primary outcome will be analyzed using ANCOVA, and secondary outcomes with repeated measures ANOVA. The rescue analgesia rate will be assessed using either the χ[2] test or Fisher's exact test.

DISCUSSION: This study is the first randomized controlled trial to assess the immediate efficacy of CAT in combination with active exercise for ALS. This study will provide a simple, rapid, and effective treatment for the clinical management of ALS.},
}

@article {pmid38886938,
year = {2025},
author = {Helmold, BR and Ahrens, A and Fitzgerald, Z and Ozdinler, PH},
title = {Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets.},
journal = {Neural regeneration research},
volume = {20},
number = {3},
pages = {725-739},
doi = {10.4103/NRR.NRR-D-23-02068},
pmid = {38886938},
issn = {1673-5374},
abstract = {Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as "causative" for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration-approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.},
}

@article {pmid38878774,
year = {2024},
author = {Kumbier, K and Roth, M and Li, Z and Lazzari-Dean, J and Waters, C and Hammerlindl, S and Rinaldi, C and Huang, P and Korobeynikov, VA and , and Phatnani, H and Shneider, N and Jacobson, MP and Wu, LF and Altschuler, SJ},
title = {Identifying FUS amyotrophic lateral sclerosis disease signatures in patient dermal fibroblasts.},
journal = {Developmental cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.devcel.2024.05.011},
pmid = {38878774},
issn = {1878-1551},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, highly heterogeneous neurodegenerative disease, underscoring the importance of obtaining information to personalize clinical decisions quickly after diagnosis. Here, we investigated whether ALS-relevant signatures can be detected directly from biopsied patient fibroblasts. We profiled familial ALS (fALS) fibroblasts, representing a range of mutations in the fused in sarcoma (FUS) gene and ages of onset. To differentiate FUS fALS and healthy control fibroblasts, machine-learning classifiers were trained separately on high-content imaging and transcriptional profiles. "Molecular ALS phenotype" scores, derived from these classifiers, captured a spectrum from disease to health. Interestingly, these scores negatively correlated with age of onset, identified several pre-symptomatic individuals and sporadic ALS (sALS) patients with FUS-like fibroblasts, and quantified "movement" of FUS fALS and "FUS-like" sALS toward health upon FUS ASO treatment. Taken together, these findings provide evidence that non-neuronal patient fibroblasts can be used for rapid, personalized assessment in ALS.},
}

@article {pmid38878554,
year = {2024},
author = {Mincic, AM and Antal, M and Filip, L and Miere, D},
title = {Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {43},
number = {7},
pages = {1832-1849},
doi = {10.1016/j.clnu.2024.05.036},
pmid = {38878554},
issn = {1532-1983},
abstract = {BACKGROUND AND AIMS: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles.

RESULTS: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND.

CONCLUSIONS: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND.},
}

@article {pmid38878150,
year = {2024},
author = {Wang, F and Wen, H and Liu, L and Aisa, HA and Xin, X},
title = {A Pair of Epimers of Lignan Alleviate Neuroinflammatory Effects by Modulating iNOS/COX-2 and MAPK/NF-κB Signaling Pathways.},
journal = {Inflammation},
volume = {},
number = {},
pages = {},
pmid = {38878150},
issn = {1573-2576},
support = {2020YFE0205600//the National Key Research and Development Program of China/ ; U1703235//the National Natural Science Foundation of China/ ; },
abstract = {Neuroinflammation is a causative factor in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Previous studies have shown that Artemisia mongolica has anti-inflammatory properties. Aschantin (AM3) has been shown to have anti-inflammatory effects. However, the mechanism of AM3 and its epimer epi-aschantin (AM2) remains controversial. Therefore, the present study explored the mechanism of neuroinflammation by AM2 and AM3 and attempted to reveal the relationship between the structure of AM2 and AM3 and anti-neuroinflammatory activity. We isolated for the first time 12 lignans from A. mongolica that inhibited NO content at 10 μM in LPS-stimulated BV2 cells. Among them, epi-aschantin (AM2) and Aschantin (AM3) showed significant inhibition in NO screening. With further studies, we found that both AM2 and AM3 effectively inhibited the overproduction of NO, PGE2, IL-6, TNF-α and MCP-1, as well as the overexpression of COX-2 and iNOS. Mechanistic studies have shown AM2 and AM3 significantly inhibited the phosphorylation of ERK, JNK and P-38 in the MAPK signaling pathway and p-IκBα,p-p65 and blocked p65 entry into the nucleus. The results suggested that the pair of epimers (AM2 and AM3) can be used as potential therapeutic agents in the treatment of various brain disorders and that structural differences do not differ in anti-neuroinflammatory effects.},
}

@article {pmid38875517,
year = {2024},
author = {Michielsen, A and van Veenhuijzen, K and Janse van Mantgem, MR and van Es, MA and Veldink, JH and van Eijk, RPA and van den Berg, LH and Westeneng, HJ},
title = {Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.},
journal = {Neurology},
volume = {103},
number = {2},
pages = {e209603},
doi = {10.1212/WNL.0000000000209603},
pmid = {38875517},
issn = {1526-632X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/metabolism/pathology ; *Magnetic Resonance Imaging ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; Disease Progression ; Cognition/physiology ; Adult ; Energy Metabolism/physiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival.

METHODS: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate.

RESULTS: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029).

DISCUSSION: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology
Male
Female
Middle Aged
*Hypothalamus/diagnostic imaging/metabolism/pathology
*Magnetic Resonance Imaging
Aged
Cross-Sectional Studies
Longitudinal Studies
Disease Progression
Cognition/physiology
Adult
Energy Metabolism/physiology

@article {pmid38873369,
year = {2024},
author = {Hong, J and Kim, GC and Cha, JG and Park, J and Park, B and Park, SY and Kim, SU},
title = {Transcholecystic Duodenal Drainage as an Alternative Decompression Method for Afferent Loop Syndrome: Two Case Reports.},
journal = {Journal of the Korean Society of Radiology},
volume = {85},
number = {3},
pages = {661-667},
pmid = {38873369},
issn = {2951-0805},
abstract = {Afferent loop syndrome (ALS) is a rare complication of gastrectomies and gastrointestinal reconstruction. This can predispose patients to fatal conditions, such as cholangitis, pancreatitis, and duodenal perforation with peritonitis. Therefore, emergency decompression is necessary to prevent these complications. Herein, we report two cases in which transcholecystic duodenal drainage, an alternative decompression treatment, was performed in ALS patients without bile duct dilatation. Two patients who underwent distal gastrectomy with Billroth II anastomosis sought consultation in an emergency department for epigastric pain and vomiting. On CT, ALS with acute pancreatitis was diagnosed. However, biliary access could not be achieved because of the absence of bile duct dilatation. To overcome this problem, a duodenal drainage catheter was placed to decompress the afferent loop after traversing the cystic duct via a transcholecystic approach. The patients were discharged without additional surgical treatment 2 weeks and 1 month after drainage.},
}

@article {pmid38872258,
year = {2024},
author = {Xiong, B and Yang, C and Yang, X and Luo, S and Li, S and Chen, C and He, K and Nie, L and Li, P and Li, S and Huang, H and Liu, J and Zhang, Z and Xie, Y and Zou, L and Yang, X},
title = {Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1[G93A] transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1β/NF-κB pathways.},
journal = {CNS neuroscience & therapeutics},
volume = {30},
number = {6},
pages = {e14692},
pmid = {38872258},
issn = {1755-5949},
support = {SZSM201611090//Sanming Project of Medicine in Shenzhen/ ; 82171583//National Natural Science Foundation of China/ ; JCYJ20200109144418639//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; JCYJ20200109150717745//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; SZXK069//Shenzhen Key Medical Discipline Construction Fund/ ; },
mesh = {Animals ; *Mice, Transgenic ; *Sirtuin 1/metabolism ; Mice ; *NF-kappa B/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *Furans/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Interleukin-1beta/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Lignans/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Male ; Motor Neurons/drug effects/pathology/metabolism ; Spinal Cord/drug effects/pathology/metabolism ; },
abstract = {AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated.

METHODS: A-1 at 33.3 mg/kg was administrated in SOD1[G93A] transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit.

RESULTS: A-1 administration in SOD1[G93A] mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1β, pIκBα/IκBα, and pNF-κB/NF-κB.

CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1β/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.},
}

Animals
*Mice, Transgenic
*Sirtuin 1/metabolism
Mice
*NF-kappa B/metabolism
*AMP-Activated Protein Kinases/metabolism
*Furans/pharmacology
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism
*Interleukin-1beta/metabolism
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Lignans/pharmacology/therapeutic use
Signal Transduction/drug effects
Superoxide Dismutase-1/genetics/metabolism
Male
Motor Neurons/drug effects/pathology/metabolism
Spinal Cord/drug effects/pathology/metabolism

@article {pmid38869826,
year = {2024},
author = {Wang, H and Zeng, R},
title = {Aberrant protein aggregation in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {38869826},
issn = {1432-1459},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.},
}

@article {pmid38867220,
year = {2024},
author = {Jia, Q and Song, Y and Zhang, C and Li, M and Feng, L and Sugimoto, K and Zhang, X and Liu, J and Gao, Y},
title = {Reasons and experience for patients with amyotrophic lateral sclerosis using traditional Chinese medicine: a CARE-TCM based mixed method study.},
journal = {BMC complementary medicine and therapies},
volume = {24},
number = {1},
pages = {231},
pmid = {38867220},
issn = {2662-7671},
support = {QN2021110001L//National Foreign Expert Project/ ; 2018, 12//Chinese Medicine Inheritance and Innovation Talent Project Leading Talent Support Program of National Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Medicine, Chinese Traditional/methods ; Female ; Male ; Middle Aged ; Surveys and Questionnaires ; Aged ; China ; Adult ; Quality of Life ; Qualitative Research ; },
abstract = {BACKGROUND AND AIM: Traditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue.

MATERIALS AND METHODS: This study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires' outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes.

RESULTS: Fifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n = 52), with the majority (n = 44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable.

CONCLUSION: Nonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021).},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
*Medicine, Chinese Traditional/methods
Female
Male
Middle Aged
Surveys and Questionnaires
Aged
China
Adult
Quality of Life
Qualitative Research

@article {pmid38864944,
year = {2024},
author = {Wang, LY and Zhang, L and Bai, XY and Qiang, RR and Zhang, N and Hu, QQ and Cheng, JZ and Yang, YL and Xiang, Y},
title = {The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.},
journal = {Neurochemical research},
volume = {},
number = {},
pages = {},
pmid = {38864944},
issn = {1573-6903},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.},
}

@article {pmid38860943,
year = {2024},
author = {Zhang, Y and Xia, Y and Sun, J},
title = {Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.},
journal = {Gut microbes},
volume = {16},
number = {1},
pages = {2363880},
pmid = {38860943},
issn = {1949-0984},
mesh = {Animals ; *Probiotics/administration & dosage/pharmacology ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; *Gastrointestinal Microbiome ; Disease Progression ; Humans ; Neuroglia/metabolism ; Disease Models, Animal ; Mutation ; Cytokines/metabolism ; Male ; Blood-Brain Barrier/metabolism ; Mice, Transgenic ; Spinal Cord/metabolism ; Mice, Inbred C57BL ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.},
}

Animals
*Probiotics/administration & dosage/pharmacology
Mice
*DNA-Binding Proteins/metabolism/genetics
*Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy
*Gastrointestinal Microbiome
Disease Progression
Humans
Neuroglia/metabolism
Disease Models, Animal
Mutation
Cytokines/metabolism
Male
Blood-Brain Barrier/metabolism
Mice, Transgenic
Spinal Cord/metabolism
Mice, Inbred C57BL

@article {pmid38859699,
year = {2024},
author = {Finsterer, J and Strobl, W},
title = {Gastrointestinal involvement in neuromuscular disorders.},
journal = {Journal of gastroenterology and hepatology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgh.16650},
pmid = {38859699},
issn = {1440-1746},
abstract = {Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.},
}

@article {pmid38856890,
year = {2024},
author = {Tripathi, S and Bhawana, },
title = {Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic.},
journal = {Neurochemical research},
volume = {},
number = {},
pages = {},
pmid = {38856890},
issn = {1573-6903},
abstract = {Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.},
}

@article {pmid38560980,
year = {2024},
author = {Xiang, SR and Ma, Q and Dong, J and Ren, YF and Lin, JZ and Zheng, C and Xiao, P and You, FM},
title = {Contrasting Effects of Music Therapy and Aromatherapy on Perioperative Anxiety: A Systematic Review and Meta-Analysis.},
journal = {Complementary medicine research},
volume = {31},
number = {3},
pages = {278-291},
doi = {10.1159/000538425},
pmid = {38560980},
issn = {2504-2106},
mesh = {*Aromatherapy ; *Music Therapy ; Humans ; *Anxiety/therapy ; Heart Rate ; },
abstract = {INTRODUCTION: Music therapy and aromatherapy have been demonstrated effective for perioperative anxiety. However, the available studies have indicated discordant results about which adjunct treatment is better for perioperative anxiety. Therefore, we conducted this meta-analysis to explore the contrasting effects between them.

METHODS: Six electronic databases were searched for clinical trials evaluating the efficacy of music therapy compared with aromatherapy in alleviating perioperative anxiety. The primary outcome was the postintervention anxiety level. Secondary outcomes included differences in blood pressure and heart rate before and after the intervention as well as pain scores at intraoperative and postoperative time points. The study protocol was registered on PROSPERO (CRD42021249737).

RESULTS: Twelve studies (894 patients) were included. The anxiety level showed no statistically significant difference (SMD, 0.28; 95% CI: -0.12, 0.68; p = 0.17). The analysis of blood pressure and heart rate also did not identify statistically significant differences. Notably, the pain scores at the intraoperative time point suggested that aromatherapy was superior to music therapy (WMD, 0.29 cm; 95% CI: 0.05, 0.52; p = 0.02), while those at 4 h after surgery indicated the opposite results (WMD, -0.48 cm; 95% CI: -0.60, -0.36; p < 0.001).

CONCLUSION: Low-to-moderate quality evidence suggests that music therapy and aromatherapy have similar potential to relieve perioperative anxiety. The potential data indicate that the two therapies have different benefits in intervention duration and age distribution. More direct high-quality comparisons are encouraged in the future to verify this point.

UNLABELLED: Musik- und Aromatherapie haben sich bei perioperativen Angstzuständen als wirksam erwiesen. Die verfügbaren Studien zeigten jedoch widersprüchliche Ergebnisse zur Frage, welche adjuvante Therapie bei perioperativen Angstzuständen besser ist. Daher führten wir die vorliegende Metaanalyse durch, um die unterschiedlichen Effekte der beiden Therapien zu untersuchen.Sechs (6) elektronische Datenbanken wurden nach klinischen Studien zur Wirksamkeit von Musiktherapie im Vergleich zur Aromatherapie bei der Linderung perioperativer Angstzustände durchsucht. Primäres Zielkriterium war das Angstniveau nach der Intervention. Die sekundären Zielkriterien umfassten die Unterschiede bei Blutdruck und Herzfrequenz vor und nach der Intervention sowie die Schmerz-Scores zu intra- und postoperativen Zeitpunkten. Das Studienprotokoll wurde auf PROSPERO (CRD42021249737) registriert.Zwölf (12) Studien (894 Patienten) wurden eingeschlossen. Das Angstniveau zeigte keinen statistisch signifikanten Unterschied (SMD, 0,28; 95%-KI: −0,12, 0,68, p = 0,17) und auch die Analyse von Blutdruck und Herzfrequenz ergab keine statistisch signifikanten Unterschiede. Insbesondere die Schmerz-Scores zum intraoperativen Zeitpunkt sprachen dafür, dass die Aromatherapie gegenüber der Musiktherapie überlegen war (WMD, 0,29 cm; 95%-KI: 0,05, 0,52; p = 0,02), während die Werte 4 Stunden nach der Operation gegenteilige Ergebnisse zeigten (WMD, −0,48 cm; 95%-KI: −0,60, −0,36, p < 0,001).Evidenzen von geringer bis mässiger Qualität deuten darauf hin, dass Musik- und Aromatherapie ein vergleichbares Potenzial bei der Linderung perioperativer Ängste besitzen. Die potenziellen Daten zeigen, dass die beiden Therapien unterschiedliche Vorteile hinsichtlich Interventionsdauer und Altersverteilung haben. Künftig sollten mehr direkte und qualitativ hochwertige Vergleiche durchgeführt werden, um diesen Aspekt zu überprüfen.},
}

*Aromatherapy
*Music Therapy
Humans
*Anxiety/therapy
Heart Rate

@article {pmid38531340,
year = {2024},
author = {Lee, KH and Kim, MH and Kim, J and Nam, HJ},
title = {Acupuncture for Tinnitus: A Scoping Review of Clinical Studies.},
journal = {Complementary medicine research},
volume = {31},
number = {3},
pages = {292-301},
doi = {10.1159/000538236},
pmid = {38531340},
issn = {2504-2106},
mesh = {Humans ; *Acupuncture Therapy/methods ; *Tinnitus/therapy ; Randomized Controlled Trials as Topic ; Acupuncture Points ; },
abstract = {BACKGROUND: Acupuncture treatment for tinnitus has received attention owing to its potential as an alternative to conventional treatment modalities. We conducted a scoping review to identify detailed information on acupuncture treatment methods used in clinical studies and to provide useful information for practitioners, patients, and researchers.

METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA), and the China National Knowledge Infrastructure (CNKI) were searched from their inception to December 2023. This review included single-arm trials, open-label randomized controlled trials (RCTs), and double-blind RCTs using needle-type acupuncture to treat tinnitus in English, Chinese, and Korean. We investigated basic and detailed information on the acupuncture treatment methods, assessment methods, and study outcomes. Network analysis was also conducted to evaluate the centrality between acupoints in the double-blind RCTs.

RESULTS: We included 106 articles. There were 11 single-arm trials, 90 open-label RCTs, and 5 double-blind RCTs. Most (89.6%) of these studies were conducted in China. Manual acupuncture was the most common type of acupuncture in treatment group. A total of 119 acupuncture points were used 1,138 times. The most frequently used acupoints were local points around the ear (TE17, GB2, SI19, and TE21). Both local and distant acupoints were used simultaneously in these studies. The treatment duration of 20-39 days, 10 to 19 sessions of treatment, the mean acupuncture duration of 30 min, needle diameter of 0.30 mm × 40 mm, and needling depth over 30 mm and less than 50 mm were confirmed as the most common.

CONCLUSION: These study outcomes will enable future acupuncture studies on tinnitus to perform more effective and standardized acupuncture treatments in selecting acupoints and procedures. Furthermore, the study has implications for informing clinicians and students about more impactful acupuncture strategies for addressing tinnitus.

UNLABELLED: Die Anwendung von Akupunktur bei Tinnitus erhält seit einiger Zeit Aufmerksamkeit als potenzielle Alternative zu konventionellen Behandlungsmodalitäten. Wir führten einen Scoping-Review durch, um detaillierte Informationen zu den in klinischen Studien angewandten Akupunktur-Behandlungsmethoden zu sammeln und nützliche Informationen für Praktiker, Patienten und Forscher bereitzustellen.MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA) und die China National Knowledge Infrastructure (CNKI) wurden von ihrem jeweiligen Beginn bis Dezember 2023 durchsucht. In diese Übersichtsarbeit wurden einarmige Studien, offene, randomisierte, kontrollierte Studien (RCTs) sowie doppelt verblindete RCTs zu Nadel-Akupunktur zur Behandlung von Tinnitus in englischer, chinesischer und koreanischer Sprache einbezogen. Wir untersuchten grundlegende und detaillierte Informationen zu den Akupunktur-Behandlungsmethoden, Untersuchungsmethoden und Studienergebnissen. Außerdem wurden Netzwerkanalysen zur Beurteilung der Zentralität zwischen Akupunkten in den doppelt verblindeten RCTs durchgeführt.106 Artikel wurden eingeschlossen. Sie behandelten 11 einarmige Studien, 90 offene RCTs und 5 doppelt verblindete RCTs. Die meisten (89,6%) dieser Studien waren in China durchgeführt worden. Manuelle Akupunktur war die häufigste Form der Akupunktur in den Behandlungsgruppen. 119 Akupunkturpunkte wurden insgesamt 1’138 Mal verwendet. Die am häufigsten verwendeten Akupunkte waren lokale Punkte im Bereich des Ohrs (TE17, GB2, SI19 und TE21). Jedoch wurden in den Studien lokale und entfernte Akupunkte gleichzeitig angewendet. Außerdem wurde festgestellt, dass die Behandlungsdauer am häufigsten 20 bis 39 Tage betrug, die Zahl der Sitzungen 10 bis 19, die mittlere Akupunkturdauer 30 Minuten, die Nadelgröße 0.30 mm × 40 mm und die Einstichtiefe zwischen 30 mm und weniger als 50 mm.Diese Studienergebnisse bieten eine Grundlage für künftige Studien zu Akupunktur bei Tinnitus, um durch die Auswahl der Akupunkte und Verfahren wirksamere und standardisierte Akupunkturbehandlungen durchzuführen. Darüber hinaus hat die Studie Implikationen für die Aufklärung von Praktikern und Schülern über wirkungsvollere Akupunkturstrategien zur Behandlung von Tinnitus.},
}

Humans
*Acupuncture Therapy/methods
*Tinnitus/therapy
Randomized Controlled Trials as Topic
Acupuncture Points

@article {pmid38471489,
year = {2024},
author = {D'Souza, A and Zink, K and Langhorst, J and Wildner, M and Stupp, C and Keil, T},
title = {How Effective Is Drinking Natural Mineral Water against Heartburn from Functional Dyspepsia, Gastroesophageal Reflux Disease, or Other Causes? A Systematic Review of Clinical Intervention Studies.},
journal = {Complementary medicine research},
volume = {31},
number = {3},
pages = {253-265},
doi = {10.1159/000536528},
pmid = {38471489},
issn = {2504-2106},
mesh = {Humans ; *Mineral Waters/therapeutic use ; *Gastroesophageal Reflux/therapy/drug therapy ; *Heartburn/drug therapy ; *Dyspepsia/drug therapy ; Randomized Controlled Trials as Topic ; },
abstract = {BACKGROUND: For centuries, spring and other natural waters have been recommended as external or internal remedies for numerous diseases. For studies that examined the effects of drinking mineral waters against heartburn, gastroesophageal reflux disease (GERD), or functional dyspepsia, a systematic review is lacking.

OBJECTIVES: The main aim of this systematic review was to examine the effects of drinking natural mineral waters on heartburn from various causes by identifying all published intervention studies and critically appraising their methods as well as summarizing their results.

METHODS: We systematically searched the largest medical literature database MEDLINE, further relevant web sources, and gray literature for randomized and nonrandomized trials, with or without control groups, up to September 2021 and no language restrictions. Further inclusion criteria were adult patients with heartburn, drinking cure with natural mineral water as the intervention, compared to no or other interventions (care-as-usual, waiting list). We defined the reduction of heartburn symptoms and duration of disease episodes as primary and quality of life as secondary outcomes. Two reviewers independently carried out the study quality assessments (risk of bias) using the National Institutes of Health-Study Quality Assessment Tools.

RESULTS: Nine trials comprising 393 patients from Italy, Russia, Ukraine, and Germany fulfilled all inclusion criteria. We identified three randomized controlled trials (all with poor methodological quality), plus six before-after (pre/post) intervention studies without a control group. The intervention groups of the three comparative trials seemed to show a stronger reduction of self-reported heartburn symptoms, and duration of heartburn episodes than the respective control groups; however, they all had poor methodological quality.

CONCLUSION: Based on the best available evidence of clinical studies, we cannot recommend or advise against drinking natural mineral waters as a treatment for heartburn. The potential benefits of natural mineral waters that were reported in some studies with a lower evidence level (e.g., lacking a control group) should be verified by good quality randomized clinical trials with adequate comparison groups and longer follow-up periods.

UNLABELLED: Seit Jahrhunderten werden Quell- und andere natürliche Wässer als äußerliche oder innerliche Heilmittel für zahlreiche Krankheiten empfohlen. Für Studien, die die Wirkung des Trinkens von Mineralwasser gegen Sodbrennen, gastroösophageale Refluxkrankheit (GERD) oder funktionelle Dyspepsie untersuchten, fehlt eine systematische Übersicht.Das Hauptziel dieser systematischen Übersichtsarbeit war es, die Auswirkungen von Trinkkuren mit natürlichen Mineralwässern auf Sodbrennen verschiedener Ursachen zu untersuchen, indem alle veröffentlichten Interventionsstudien identifiziert und ihre Methoden kritisch bewertet sowie ihre Ergebnisse zusammengefasst wurden.Wir durchsuchten systematisch die größte medizinische Literaturdatenbank MEDLINE, weitere relevante Internetquellen und graue Literatur nach randomisierten und nicht-randomisierten Studien, mit oder ohne Kontrollgruppen, bis September 2021 und ohne sprachliche Einschränkungen. Weitere Einschlusskriterien waren erwachsene Patienten mit Sodbrennen, Trinkkur mit natürlichem Mineralwasser als Intervention, im Vergleich zu keiner oder anderen Interventionen (care-as-usual, Warteliste). Wir definierten die Abnahme der Symptome des Sodbrennens und die Dauer der Krankheitsepisoden als primäre und die Lebensqualität als sekundäre Endpunkte. Zwei Gutachter bewerteten unabhängig voneinander die Qualität der Studien (Verzerrungsrisiko) anhand der National Institutes of Health-Study Quality Assessment Tools.Neun Studien mit 393 Patienten aus Italien, Russland, der Ukraine und Deutschland erfüllten alle Einschlusskriterien. Wir identifizierten drei randomisierte kontrollierte Studien (alle mit schlechter methodischer Qualität) sowie sechs Vorher-Nachher-Studien (Prä-/Post-Studien) ohne Kontrollgruppe. Die Interventionsgruppen der drei randomisierten Vergleichsstudien schienen eine stärkere Verringerung der selbstberichteten Symptome und der Dauer der Episoden des Sodbrennens zu zeigen als die jeweiligen Kontrollgruppen, allerdings waren sie alle von schlechter methodischer Qualität.Auf der Grundlage der besten verfügbaren Belege aus klinischen Studien können wir das Trinken natürlicher Mineralwässer zur Behandlung von Sodbrennen weder empfehlen noch davon abraten. Die potenziellen Vorteile natürlicher Mineralwässer, die in einigen Studien mit geringerer Evidenz (z. B. ohne Kontrollgruppe) berichtet wurden, sollten durch qualitativ hochwertige randomisierte klinische Studien mit angemessenen Vergleichsgruppen und längeren Nachbeobachtungszeiträumen überprüft werden.},
}

Humans
*Mineral Waters/therapeutic use
*Gastroesophageal Reflux/therapy/drug therapy
*Heartburn/drug therapy
*Dyspepsia/drug therapy
Randomized Controlled Trials as Topic

@article {pmid38856793,
year = {2024},
author = {Kumari, S and Kamiya, A and Karnik, SS and Rohilla, S and Dubey, SK and Taliyan, R},
title = {Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {38856793},
issn = {1559-1182},
abstract = {Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.},
}

@article {pmid38855716,
year = {2024},
author = {Morganroth, J and Bardakjian, TM and Dratch, L and Quinn, CC and Elman, LB},
title = {Enhancing Clinical Infrastructure for the Delivery of Intrathecal and Genetic Therapies: A Qalsody (Tofersen) Model for Patients With SOD1-ALS.},
journal = {Neurology. Clinical practice},
volume = {14},
number = {4},
pages = {e200303},
pmid = {38855716},
issn = {2163-0402},
abstract = {BACKGROUND: Qalsody (tofersen), an intrathecal therapy (IT) antisense oligonucleotide (ASO), was granted accelerated approval by the Food and Drug Administration for the treatment of SOD1-mediated amyotrophic lateral sclerosis (ALS) on April 25, 2023. Academic centers need to be prepared for expedited drug delivery. The purpose of this model was to predict the number of SOD1-ALS patients whom we expect to see at our center at the time of Qalsody approval and to use it to extrapolate to a model for a hypothetical sporadic IT ALS therapy.

RECENT FINDINGS: We predicted that 6 symptomatic and 14 presymptomatic SOD1 patients would come to our center, whereas a sporadic therapy would generate 108 patients, creating excess office visits, lumbar punctures, and genetic counseling visits.

IMPLICATIONS FOR PRACTICE: As new therapies for neurologic diseases come to market, preparing for increased office volume and complex drug delivery are essential for optimal care.},
}

@article {pmid38853922,
year = {2024},
author = {Dilliott, AA and Costanzo, MC and Burtt, NP and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, MA and Flannick, J and Farhan, SMK},
title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.05.27.24307990},
pmid = {38853922},
abstract = {Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.},
}

@article {pmid38852112,
year = {2024},
author = {Leighton, DJ and Ansari, M and Newton, J and Cleary, E and Stephenson, L and Beswick, E and Carod Artal, J and Davenport, R and Duncan, C and Gorrie, GH and Morrison, I and Swingler, R and Deary, IJ and Porteous, M and Chandran, S and Pal, S and , },
title = {Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {38852112},
issn = {1432-1459},
support = {CAF/MND/15/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; CAF/MND/15/01/MNDA_/Motor Neurone Disease Association/United Kingdom ; CAF/MND/15/01//MND Scotland/ ; },
abstract = {BACKGROUND: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations.

METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.

RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.

CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.},
}

@article {pmid38850875,
year = {2024},
author = {Coen, M and Benyamine, A and Delmont, E and Kaplanski, G and Bouabdallah, R and Xerri, L and Attarian, S and Serratrice, J},
title = {Tell-tale immune-related neurological syndromes: Should we look for and underlying low-grade B-cell lymphoma? A retrospective study on 12 cases.},
journal = {Pathology, research and practice},
volume = {260},
number = {},
pages = {155377},
doi = {10.1016/j.prp.2024.155377},
pmid = {38850875},
issn = {1618-0631},
abstract = {INTRODUCTION: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas.

METHODS: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected.

RESULTS: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease.

CONCLUSION: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case.},
}

@article {pmid38848664,
year = {2024},
author = {Morioka, D and Sagisaka, R and Nakagawa, K and Takahashi, H and Tanaka, H},
title = {Effect of timing of advanced life support on out-of-hospital cardiac arrests at home in Japan.},
journal = {The American journal of emergency medicine},
volume = {82},
number = {},
pages = {94-100},
doi = {10.1016/j.ajem.2024.05.021},
pmid = {38848664},
issn = {1532-8171},
abstract = {AIM: In cases of out-of-hospital cardiac arrests (OHCA) occurring at home, Japanese emergency medical services personnel decide whether to provide treatment on the scene or during transport based on their judgment. This study aimed to evaluate the association between the timing of advanced life support (ALS) (i.e., endotracheal intubation [ETI] or adrenaline administration) for OHCA at home and prognosis.

METHOD: This retrospective cohort study used data from the Japan Utstein Registry and emergency transport data collected from patients who underwent pre-hospital ETI (n = 6806) and received adrenaline (n = 22,636) between 2016 and 2019. The timing of ETI or adrenaline administration was determined as "on the scene" or "in the ambulance." Multiple logistic regression analysis was used to estimate the association among the timing of ALS implementation, pre-hospital return of spontaneous circulation (ROSC), and survival at 1 month.

RESULT: ETI on the scene was significantly positively associated with pre-hospital ROSC (adjusted odds ratio [AOR], 1.81; 95% confidence interval [CI], 1.57-2.09) and survival at 1 month (AOR, 1.81; 95% CI, 1.47-2.23). Adrenaline administration on the scene was significantly positively associated with pre-hospital ROSC (AOR, 2.51; 95% CI, 2.33-2.70) and survival at 1 month (AOR, 2.13; 95% CI, 1.89-2.40).

CONCLUSION: Our analysis suggests performing ALS on the scene was associated with pre-hospital ROSC and survival at 1 month. Further efforts are needed to increase the rate of ALS implementation on the scene by emergency life-saving technicians.},
}

@article {pmid38840222,
year = {2024},
author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML},
title = {TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.},
journal = {Molecular brain},
volume = {17},
number = {1},
pages = {32},
pmid = {38840222},
issn = {1756-6606},
support = {RF1 NS112719/NS/NINDS NIH HHS/United States ; RF1NS112719/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *MutL Protein Homolog 1/metabolism ; *DNA Damage ; *Protein Binding/drug effects ; Cell Line, Tumor ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Neurons/metabolism ; Middle Aged ; Male ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.},
}

Humans
*DNA-Binding Proteins/metabolism
*MutL Protein Homolog 1/metabolism
*DNA Damage
*Protein Binding/drug effects
Cell Line, Tumor
Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
Neurons/metabolism
Middle Aged
Male

@article {pmid38835175,
year = {2024},
author = {Barclay, G and Barbato, M and Yerbury, R and Harnish, L and Miranda, N},
title = {Bispectral Index monitoring of palliative sedation for home withdrawal of tracheostomy ventilation: A case report.},
journal = {Palliative medicine},
volume = {},
number = {},
pages = {2692163241257580},
doi = {10.1177/02692163241257580},
pmid = {38835175},
issn = {1477-030X},
abstract = {BACKGROUND: Tracheostomy ventilation in motor neurone disease is an uncommon life-sustaining treatment. Best practice is having a plan for ventilation withdrawal, but the literature to guide practice is limited. Case reports have documented standard doses of opioids and benzodiazepines used for sedation in such cases.

CASE: A 49-year-old man was diagnosed with motor neurone disease in 2016. He commenced tracheostomy ventilation in 2018. In 2022 and 2023, planning was undertaken, at the patient's request, for withdrawal of tracheostomy ventilation at home, when he was no longer able to communicate with technology.

CASE PLANNING: Planning included Bispectral Index monitoring prior to cessation of ventilation, ensuring this only occurred when deep sedation was achieved. After ventilation withdrawal in 2023, a retrospective review of medications given and his level of sedation on monitoring was undertaken, with family consent.

OUTCOME: Ventilation withdrawal was initiated after deep sedation was achieved, 6 h after commencing subcutaneous infusions of morphine, midazolam, clonazepam and phenobarbital.

LESSONS: Doses required to achieve acceptable sedation exceeded literature reports. Achieving deep sedation was a longer than expected process.

CONCLUSION: More research using an objective measure of sedation is required, as clinical assessment of sedation in this context is compromised.},
}

@article {pmid38833116,
year = {2024},
author = {Mubeen, H and Masood, A and Zafar, A and Khan, ZQ and Khan, MQ and Nisa, AU},
title = {Insights into AlphaFold's breakthrough in neurodegenerative diseases.},
journal = {Irish journal of medical science},
volume = {},
number = {},
pages = {},
pmid = {38833116},
issn = {1863-4362},
abstract = {Neurodegenerative diseases (ND) are disorders of the central nervous system (CNS) characterized by impairment in neurons' functions, and complete loss, leading to memory loss, and difficulty in learning, language, and movement processes. The most common among these NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), although several other disorders also exist. These are frontotemporal dementia (FTD), amyotrophic lateral syndrome (ALS), Huntington's disease (HD), and others; the major pathological hallmark of NDs is the proteinopathies, either of amyloid-β (Aβ), tauopathies, or synucleinopathies. Aggregation of proteins that do not undergo normal configuration, either due to mutations or through some disturbance in cellular pathway contributes to the diseases. Artificial Intelligence (AI) and deep learning (DL) have proven to be successful in the diagnosis and treatment of various congenital diseases. DL approaches like AlphaFold (AF) are a major leap towards success in CNS disorders. This 3D protein geometry modeling algorithm developed by DeepMind has the potential to revolutionize biology. AF has the potential to predict 3D-protein confirmation at an accuracy level comparable to experimentally predicted one, with the additional advantage of precisely estimating protein interactions. This breakthrough will be beneficial to identify diseases' advancement and the disturbance of signaling pathways stimulating impaired functions of proteins. Though AlphaFold has solved a major problem in structural biology, it cannot predict membrane proteins-a beneficial approach for drug designing.},
}

@article {pmid38830181,
year = {2024},
author = {Weemering, DN and Beelen, A and Kliest, T and van Leeuwen, LAG and van den Berg, LH and van Eijk, RPA},
title = {Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.},
journal = {Neurology},
volume = {103},
number = {1},
pages = {e209503},
doi = {10.1212/WNL.0000000000209503},
pmid = {38830181},
issn = {1526-632X},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Clinical Trials as Topic ; *Patient Participation ; Patient Selection ; },
abstract = {BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation.

METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models.

RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001).

DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.},
}

Humans
*Neurodegenerative Diseases/drug therapy
*Clinical Trials as Topic
*Patient Participation
Patient Selection

@article {pmid38829866,
year = {2024},
author = {Laurido-Soto, OJ and Faust, IM and Nielsen, SS and Racette, BA},
title = {Adherence to practice parameters in Medicare beneficiaries with amyotrophic lateral sclerosis.},
journal = {PloS one},
volume = {19},
number = {6},
pages = {e0304083},
pmid = {38829866},
issn = {1932-6203},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Medicare ; Male ; Female ; United States ; Aged ; Retrospective Studies ; Aged, 80 and over ; Guideline Adherence/statistics & numerical data ; Middle Aged ; Practice Patterns, Physicians'/statistics & numerical data ; },
abstract = {OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence.

METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age ≥20 with ≥1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider specialty (neurologist vs. non-neurologist). Outcomes were use of practice parameters, which included feeding tubes, non-invasive ventilation (NIV), riluzole, and receiving care from a neurologist.

RESULTS: Overall, 42.9% of patients with ALS received neurologist care. Black beneficiaries (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.67), older beneficiaries (OR 0.964, 95% CI 0.961-0.968 per year), and those living in disadvantaged areas (OR 0.70, 95% CI 0.61-0.80) received less care from neurologists. Overall, only 26.7% of beneficiaries received a feeding tube, 19.2% NIV, and 15.3% riluzole. Neurologist-treated patients were more likely to receive interventions than other ALS patients: feeding tube (OR 2.80, 95% CI 2.52-3.11); NIV (OR 10.8, 95% CI 9.28-12.6); and riluzole (OR 7.67, 95% CI 6.13-9.58), after adjusting for sociodemographics. These associations remained marked and significant when we excluded ALS patients who subsequently received a code for other diseases that mimic ALS.

CONCLUSIONS: ALS patients treated by neurologists received care consistent with practice parameters more often than those not treated by a neurologist. Black, older, and disadvantaged beneficiaries received less care consistent with the practice parameters.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy
*Medicare
Male
Female
United States
Aged
Retrospective Studies
Aged, 80 and over
Guideline Adherence/statistics & numerical data
Middle Aged
Practice Patterns, Physicians'/statistics & numerical data

@article {pmid38829511,
year = {2024},
author = {Jiang, S and Xu, R},
title = {The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {38829511},
issn = {1559-1182},
support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.},
}

@article {pmid38829431,
year = {2024},
author = {Sabatelli, M and Cerri, F and Zuccarino, R and Patanella, AK and Bernardo, D and Bisogni, G and Tanel, R and Sansone, V and Filosto, M and Lattante, S and Martello, F and Doronzio, PN and Stano, S and Zanfini, BA and Coccia, M and Costantini, EM and Lizio, A and Lucioli, G and Padovani, A and Merlini, GP and Conte, A},
title = {Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {38829431},
issn = {1432-1459},
abstract = {BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant.

METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients.

RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy.

CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.},
}

@article {pmid38826483,
year = {2024},
author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML},
title = {TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-4439430/v1},
pmid = {38826483},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons.},
}

@article {pmid38826246,
year = {2024},
author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B},
title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.05.24.595817},
pmid = {38826246},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1 [G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H 2 O 2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.},
}

@article {pmid38825034,
year = {2024},
author = {Fang, T and Pacut, P and Bose, A and Sun, Y and Gao, J and Sivakumar, S and Bloom, B and Nascimento Andrade, EI and Trombetta, B and Ghasemi, M},
title = {Clinical and genetic factors affecting diagnostic timeline of amyotrophic lateral sclerosis: a 15-year retrospective study.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/01616412.2024.2362578},
pmid = {38825034},
issn = {1743-1328},
abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) diagnosis can take 10-16 months from symptom onset, leading to delays in treatment and patient counselling. We studied the impact of clinical and genetic risk factors on the diagnostic timeline of ALS.

METHODS: Baseline characteristics, family history, gene testing, onset location, time from symptom onset to diagnosis, and time from first doctor visit to suspected ALS was collected. We used multiple regression to assess the interaction of these factors on ALS diagnostic timeline. We analysed a subgroup of patients with genetic testing and compared positive or negative tests, sporadic or familial and ALS-related genes to time for diagnosis.

RESULTS: Four hundred and forty-eight patients diagnosed with ALS at the University of Massachusetts Chan Medical Center between January 2007 and December 2021 were analysed. The median time to ALS diagnosis was 12 months and remained unchanged from 2007 to 2021 (p = 0.20). Diagnosis was delayed in patients with sporadic compared with familial ALS (mean months [standard deviation], 16.5[13.5] and 11.2[8.5], p < 0.001); cognitive onset (41[21.26]) had longer time to diagnosis than bulbar (11.9[8.2]), limb (15.9[13.2]), respiratory (19.7[13.9]) and ALS with multiple onset locations (20.77[15.71], p < 0.001). One hundred and thirty-four patients had gene testing and 32 tested positive (23.8%). Gene testing (p = 0.23), a positive genetic test (p = 0.16), different ALS genes (p = 0.25) and sporadic (p = 0.92) or familial (p = 0.85) ALS testing positive for ALS genes did not influence time to diagnosis.

DISCUSSION: Time for ALS diagnosis remained unchanged from 2007 to 2021, bulbar-onset and familial ALS made for faster diagnosis.},
}

@article {pmid38823229,
year = {2024},
author = {Roman-Pognuz, E and Rigutti, S and Colussi, G and Lena, E and Bonsano, M and Lucangelo, U},
title = {Acute esophageal necrosis following cardiac arrest: A rare and lethal syndrome with diagnostic challenges.},
journal = {International journal of surgery case reports},
volume = {120},
number = {},
pages = {109751},
doi = {10.1016/j.ijscr.2024.109751},
pmid = {38823229},
issn = {2210-2612},
abstract = {Acute esophageal necrosis (AEN) is a condition characterized by the necrosis of the distal portion of the esophageal mucosa. Risk factors predisposing to this condition are associated to compromised vascular perfusion (e.g. diabetes mellitus, chronic kidney disease, advanced age, and hypertension, shock states). Complications of AEN can be severe including UGI stricture, perforation and overall increased mortality. The true incidence of AEN remains uncertain due to potential subclincal presentations and early resolution.

CASE PRESENTATION: The case outlined involves a 66-years-old obese male with history of alcoholism and lymph-edema of the left leg who presented to the emergency department with hematemesis, haemodynamic instability and impaired consciousness. Shortly after initial assessment, the patient went into cardiac arrest with pulse-less electrical activity (PEA). Return of spontaneous circulation (ROSC) was achieved following instigation of ALS protocol, fluid resuscitation and the administration of a total of 5 mg of adrenaline. Following stabilization, a CT scan was performed which reported a moderately enlarged esophagus with a thickened wall, liquid hypodense material within the esophagus and stomach, and liver cirrhosis. The emergent esophagogastroduodenoscopy (EGDS) revealed extensive mucosal findings indicative of diffuse necrosis with initial scarring, which was later diagnosed as AEN. The patient unfortunately deceased in ICU after developing progression of the AEN, post-cardiac arrest syndrome and liver failure.

CLINICAL DISCUSSION: The presented case highlights several crucial clinical issues and management problems related to AEN. To diagnose AEN, EGDS is still the gold-standard since it allows direct inspection of the esophageal mucosal layer. The management of AEN necessitates a multidisciplinary approach that includes aggressive resuscitation, treatment of underlying comorbidities, and supportive care (e.g. proton pump inhibitors). The mortality rate for AEN remains high despite improvements in diagnosis and treatment highlighting the need to recognize this condition early and intervene promptly in the patients affected. Moreover, long-term sequelae like stricture formation of the esophagus and impaired esophageal motility may contribute to morbidity requiring continuos monitoring. Therefore, to optimize outcomes while reducing complications among affected patients, prompt identification associated with appropriate medical measures are essential. More research needs to be done aiming to better understand the pathophysiology of AEN thereby identifying strategies for its prevention or cure.

CONCLUSIONS: AEN is a rare syndrome characterized by upper gastrointestinal bleeding and hypoxic damage of the esophageal mucosa, often associated with ischemia, gastric outlet obstruction, and compromised protective barriers. Treatment involves aggressive resuscitation, proton pump inhibitors, and monitoring for infection or perforation. However, despite intensive efforts, the mortality rate for AEN remains high at 32 %.},
}

@article {pmid38822985,
year = {2024},
author = {Faysal, M and Dehbia, Z and Zehravi, M and Sweilam, SH and Haque, MA and Kumar, KP and Chakole, RD and Shelke, SP and Sirikonda, S and Nafady, MH and Khan, SL and Nainu, F and Ahmad, I and Emran, TB},
title = {Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.},
journal = {Neurochemical research},
volume = {},
number = {},
pages = {},
pmid = {38822985},
issn = {1573-6903},
abstract = {Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca[2+] stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.},
}

@article {pmid38819717,
year = {2024},
author = {Tappenden, P and Hardiman, O and Kwon, SH and Mon-Yee, M and Galvin, M and McDermott, C and , },
title = {A Model-Based Economic Evaluation of Hypothetical Treatments for Amyotrophic Lateral Sclerosis in the UK: Implications for Pricing of New and Emerging Health Technologies.},
journal = {PharmacoEconomics},
volume = {},
number = {},
pages = {},
pmid = {38819717},
issn = {1179-2027},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon.

OBJECTIVES: The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective.

METHODS: We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness.

RESULTS: Starting from King's stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of £68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed £735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness.

CONCLUSIONS: Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care.},
}

@article {pmid38819491,
year = {2024},
author = {Juarez, D and Handal-Silva, A and Morán-Perales, JL and Torres-Cifuentes, DM and Flores, G and Treviño, S and Moreno-Rodriguez, A and Guevara, J and Diaz, A},
title = {New insights into sodium phenylbutyrate as a pharmacotherapeutic option for neurological disorders.},
journal = {Synapse (New York, N.Y.)},
volume = {78},
number = {4},
pages = {e22301},
doi = {10.1002/syn.22301},
pmid = {38819491},
issn = {1098-2396},
support = {IN214117//PAPITT-UNAM/ ; DIFA-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; TEMS-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; },
mesh = {Humans ; *Phenylbutyrates/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; },
abstract = {Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.},
}

Humans
*Phenylbutyrates/therapeutic use/pharmacology
Animals
*Nervous System Diseases/drug therapy/metabolism

@article {pmid38818523,
year = {2024},
author = {Shen, J and Wang, X and Wang, M and Zhang, H},
title = {Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases.},
journal = {Frontiers in physiology},
volume = {15},
number = {},
pages = {1337442},
pmid = {38818523},
issn = {1664-042X},
abstract = {Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.},
}

@article {pmid38807021,
year = {2024},
author = {Rahimian, S and Najafi, H and Webber, CA and Jalali, H},
title = {Advances in Exosome-Based Therapies for the Repair of Peripheral Nerve Injuries.},
journal = {Neurochemical research},
volume = {},
number = {},
pages = {},
pmid = {38807021},
issn = {1573-6903},
abstract = {Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.},
}

@article {pmid38805053,
year = {2024},
author = {Bjelica, B and Bartels, MB and Hesebeck-Brinckmann, J and Petri, S},
title = {Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {38805053},
issn = {1432-1459},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of both upper and lower motor neurons. A defining histopathological feature in approximately 97% of all ALS cases is the accumulation of phosphorylated trans-activation response (TAR) DNA-binding protein 43 protein (pTDP-43) aggregates in the cytoplasm of neurons and glial cells within the central nervous system. Traditionally, it was believed that the accumulation of TDP-43 aggregates and subsequent neurodegeneration primarily occurs in motor neurons. However, contemporary evidence suggests that as the disease progresses, other systems and brain regions are also affected. Despite this, there has been a limited number of clinical studies assessing the non-motor symptoms in ALS patients. These studies often employ various outcome measures, resulting in a wide range of reported frequencies of non-motor symptoms in ALS patients. The importance of assessing the non-motor symptoms reflects in a fact that they have a significant impact on patients' quality of life, yet they frequently go underdiagnosed and unreported during clinical evaluations. This review aims to provide an up-to-date overview of the current knowledge concerning non-motor symptoms in ALS. Furthermore, we address their diagnosis and treatment in everyday clinical practice.},
}

@article {pmid38802175,
year = {2024},
author = {Malaspina, A},
title = {Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.},
journal = {International review of neurobiology},
volume = {176},
number = {},
pages = {171-207},
doi = {10.1016/bs.irn.2024.04.010},
pmid = {38802175},
issn = {2162-5514},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/genetics/metabolism/drug therapy ; *Biomarkers ; *Clinical Trials as Topic/methods ; },
abstract = {Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/diagnosis/genetics/metabolism/drug therapy
*Biomarkers
*Clinical Trials as Topic/methods

@article {pmid38802174,
year = {2024},
author = {Hobson, E and McDermott, C},
title = {Advances in symptom management and in monitoring disease progression in motor neuron disease.},
journal = {International review of neurobiology},
volume = {176},
number = {},
pages = {119-169},
doi = {10.1016/bs.irn.2024.04.004},
pmid = {38802174},
issn = {2162-5514},
mesh = {Humans ; *Motor Neuron Disease/therapy/physiopathology ; *Disease Progression ; Disease Management ; Quality of Life ; },
abstract = {The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.},
}

Humans
*Motor Neuron Disease/therapy/physiopathology
*Disease Progression
Disease Management
Quality of Life

@article {pmid38791160,
year = {2024},
author = {Bocheva, G and Bakalov, D and Iliev, P and Tafradjiiska-Hadjiolova, R},
title = {The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.},
journal = {International journal of molecular sciences},
volume = {25},
number = {10},
pages = {},
pmid = {38791160},
issn = {1422-0067},
mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Brain/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Kynuramine/metabolism/analogs & derivatives ; },
abstract = {While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.},
}

*Melatonin/metabolism/pharmacology/therapeutic use
Humans
*Brain/metabolism/drug effects
*Aging/metabolism/drug effects
Animals
*Neurodegenerative Diseases/metabolism/drug therapy
*Neuroprotection/drug effects
*Neuroprotective Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects
Kynuramine/metabolism/analogs & derivatives