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04 Dec 2023 at 01:33
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Bibliography on: Amyotrophic Lateral Sclerosis


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RJR: Recommended Bibliography 04 Dec 2023 at 01:33 Created: 

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most common form of the motor neuron diseases. Early symptoms of ALS include stiff muscles, muscle twitches, and gradual increasing weakness and muscle wasting. Limb-onset ALS begins with weakness in the arms or legs, while bulbar-onset ALS begins with difficulty speaking or swallowing. Around half of people with ALS develop at least mild difficulties with thinking and behavior, and about 15% develop frontotemporal dementia. Motor neuron loss continues until the ability to eat, speak, move, and finally the ability to breathe is lost. Most cases of ALS (about 90% to 95%) have no known cause, and are known as sporadic ALS. However, both genetic and environmental factors are believed to be involved. The remaining 5% to 10% of cases have a genetic cause, often linked to a history of the disease in the family, and these are known as genetic ALS. About half of these genetic cases are due to disease-causing variants in one of two specific genes. The diagnosis is based on a person's signs and symptoms, with testing conducted to rule out other potential causes.

Created with PubMed® Query: ( ALS*[TIAB] OR "amyotrophic lateral sclerosis"[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2023-12-01

Deng X, EK Tan (2023)

Spinal Bulbar Muscular Atrophy -Kennedy's Disease.

QJM : monthly journal of the Association of Physicians pii:7457495 [Epub ahead of print].

A middle age man complained of progressive bilateral hand tremor and occasional muscle cramps. Examination showed tongue muscle atrophy and limb muscle fasciculation with resting and postural tremor in the upper extremities. Deep tendon reflexes were decreased. He had bilateral breast enlargement. Nerve conduction study and Electromyography revealed chronic sensory-motor neuropathy. DNA analysis identified an expanded number of CAG trinucleotide repeats in the androgen receptor gene consistent with a diagnosis of Kennedy's disease (KD). KD, also known as Spinal Bulbar Muscular Atrophy (SBMA), is a rare X-linked recessive lower motor neuron disorder characterized by proximal and bulbar muscle wasting due to degeneration of motor neurons in the brain stem and spinal cord. KD can present with non-specific symptoms initially and may be misdiagnosed as Amyotrophic Lateral Sclerosis or other neurological conditions. Molecular genetic testing enables the diagnosis by identifying the CAG trinucleotide repeat expansion.

RevDate: 2023-12-01

Sanghani N, Claytor B, Y Li (2023)

Electrodiagnostic findings in amyotrophic lateral sclerosis: Variation with region of onset and utility of thoracic paraspinal muscle examination.

Muscle & nerve [Epub ahead of print].

INTRODUCTION/AIMS: Limited data exist regarding variation of electrodiagnostic (EDX) findings in amyotrophic lateral sclerosis (ALS) patients with different onset regions and specificity of thoracic paraspinal muscle (TPSP) examination for confirming a diagnosis of ALS. We aimed to demonstrate the variation of EDX features and characterize the utility of TPSP muscle examination in the electrodiagnosis of ALS.

METHODS: This is a retrospective study of a large cohort of ALS patients who had a comprehensive EDX evaluation.

RESULTS: The study included 448 patients; all fulfilled the Gold Coast criteria for ALS. The average age at the time of EDX study was 64 years, and 41.1% were women. The onset region was identified as follows: bulbar (N = 149), cervical (N = 127), lumbosacral (N = 162), and other (N = 10). In contrast to limb onset, bulbar-onset patients more frequently demonstrated a pattern of normal or near normal needle electromyography (EMG) (p < .0001) and less frequently had abnormalities on EMG of TPSP (p = .002). Clinical or EDX diagnosis of sensory polyneuropathy was present in 12.6% patients, more frequently in the lumbosacral onset subgroup (p < .03). EMG showed active denervation in 9.6% and chronic denervation in 59% of craniobulbar muscles examined, without observed difference among different onset regions. TPSP showed higher frequencies of active and chronic denervation in ALS than a group of patients with non-ALS neuromuscular disorders.

DISCUSSION: EDX features may differ among ALS patients of different onset regions. TPSP EMG is highly useful in differentiating ALS from non-ALS neuromuscular disorders while the yield of craniobulbar muscles, especially for active denervation, is low.

RevDate: 2023-12-01

Zhong G, Wang X, Li J, et al (2023)

Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.

Current neuropharmacology pii:CN-EPUB-135863 [Epub ahead of print].

Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.

RevDate: 2023-12-02

Karaśkiewicz J, R Wójcik (2023)

Modelling optimal water retention in hydrogenic habitats using LIDAR laser data.

The Science of the total environment, 912:168983 pii:S0048-9697(23)07612-X [Epub ahead of print].

Degradation of hydrogenic habitats in climate change increased rapidly. It is important that we take actions to stop this process. Solution is to increase efficiency of water usage by ecosystems - especially water based ones. Building devices for delaying surface water runoff - like locks and dams - should improve hydrogenic habitats conditions and allow surrounding ecosystems use rainwater more efficient. Modelling of small retention in forests is an important aspect in decision making schema. Aim of this paper is to point optimal solutions for height and placement of devices which delay surface water runoff to set necessary water table level for renaturalization and maintenance of degrading natural habitats. Data used for analyses were acquired in the Polanów Forest Inspectorate in West Pomeranian voivodeship because of the topography diversification and the drainage infrastructure presence. There were three research plots selected based on decreased stability of habitats and historic data stated that there were natural water reservoirs, which were drained in past. Based on 2012 LiDAR (Light Detection and Ranging) point cloud the digital terrain model (DTM) was built. Water outflow points - melioration canals - were identified and analysed for optimal device localization. In following part of research specific data for each hydrogenic habitat were used to model height of devices which delay surface water runoff. Optimal level of device and area covered by water were set for each site separately. The results were handed over to the investor for implementation, then the compliance of the assumptions of the simulation of raising the water table with the as-built field measurements was checked. Study shows that it is possible to use laser technology to optimize location and height of devices which delay surface water runoff what allows to restore degraded hydrogenic habitats. Presented method supports small local retention what increases limited water resources in this region, decreases rapid runoff of surface water which causes frequent floods. Proposed method of modelling the location and height of the dams or locks is universal. Even though results are unique for each object the method is possible to be applied to every other situation.

RevDate: 2023-11-30

Wang X, Zhu Z, Sun J, et al (2023)

Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system.

Progress in neuro-psychopharmacology & biological psychiatry pii:S0278-5846(23)00189-6 [Epub ahead of print].

The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.

RevDate: 2023-11-30

Khan S, Upadhyay S, Dave U, et al (2023)

Structural and mechanistic insights into ALS patient derived mutations in D-amino acid oxidase.

International journal of biological macromolecules pii:S0141-8130(23)05302-3 [Epub ahead of print].

The D-amino acid oxidase protein modulates neurotransmission by controlling the levels of d-serine, a co-agonist of N-methyl-d-aspartate receptors. Mutations in the DAO gene have been associated with ALS, with some studies reporting pathogenic mechanisms of the R199W mutation. We have characterized two novel mutations R38H and Q201R found in ALS patients and report certain novel findings related to the R199W mutation. We report the first instance of crystal structure analysis of a patient-derived mutant of DAO, R38H, solved at 2.10 Å. The structure revealed significant perturbations and altered binding with the cofactor (FAD) and the inhibitor benzoate, supported by biochemical assays. Q201R-DAO also exhibited significantly lower ligand binding efficiency. Furthermore, kinetic analysis across all variants revealed reduced oxidase activity and substrate binding. Notably, R38H-DAO exhibited near-WT activity only at high substrate concentrations, while R199W-DAO and Q201R-DAO displayed drastic activity reduction. Additionally, structural perturbations were inferred for R199W-DAO and Q201R-DAO, evident by the higher oligomeric state in the holoenzyme form. We also observed thermal instability in case of R199W-DAO mutant. We hypothesize that the mutant enzymes may be rendered non-functional in a cellular context, potentially leading to NMDAR-associated excitotoxicity. The study provides novel insights into structural and functional aspects of DAO mutations in ALS.

RevDate: 2023-12-02

Vukolova MN, Yen LY, Khmyz MI, et al (2023)

Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis-emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors.

Frontiers in cell and developmental biology, 11:1252953.

Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are implicated in various neurological disorders. In this review, we discuss the role of the two fastest iGluRs subtypes, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, in the pathogenesis and treatment of Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis. Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. Further studies of factors affecting the selective subunit expression and trafficking of AMPA and kainate receptors, and a reasonable approach to their regulation by the recently identified novel compounds remain promising directions for pharmacological research.

RevDate: 2023-12-02

Nakken O, Vaage AM, Stigum H, et al (2023)

Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk.

Brain, behavior, & immunity - health, 34:100704.

BACKGROUND: T cell infiltration around dying motor neurons is a hallmark of amyotrophic lateral sclerosis (ALS). It is not known if this immune response represents a cause or a consequence of the disease. We aimed to establish whether individual variation in regulation of a T cell driven immune response is associated with long-term ALS risk.

METHODS: Tuberculin skin test (TST) following BCG vaccination represents a standardized measure of a secondary T cell driven immune response. During a Norwegian tuberculosis screening program (1963-1975) Norwegian citizens born from 1910 to 1955 underwent TST. In those previously BCG vaccinated (median 7 years prior to TST), we related tuberculin skin tests to later ALS disease identified through validated Norwegian health registers. We fitted Cox proportional hazard models to investigate the association between tuberculin reactivity and ALS risk.

RESULTS: Among 324,629 participants (52 % women) with median age 22 (IQR 10) years at tuberculosis screening, 496 (50 % women) later developed ALS. Hazard ratio for ALS was 0.74 (95% CI 0.57-0.95) for those who remained TST negative compared to those who mounted a positive TST. The association was strongest when time between BCG immunization and TST was short. The associations observed persisted for more than four decades after TST measurement.

CONCLUSIONS: Negative TST responses after BCG vaccination is associated with decreased long-term risk for ALS development, supporting a primary role for adaptive immunity in ALS development.

RevDate: 2023-11-30

Ghasemi A, Sadedel M, MM Moghaddam (2023)

A wearable system to assist impaired-neck patients: Design and evaluation.

Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine [Epub ahead of print].

Patients with neurological disorders, such as amyotrophic lateral sclerosis, Parkinson's disease, and cerebral palsy, often face challenges due to head-neck immobility. The conventional treatment approach involves using a neck collar to maintain an upright head position, but this can be cumbersome and restricts head-neck movements over prolonged periods. This study introduces a wearable robot capable of providing three anatomical head motions for training and assistance. The primary contributions of this research include the design of an optimized structure and the incorporation of human-robot interaction. Based on human head motion data, our primary focus centered on developing a robot capable of accommodating a significant range of neutral head movements. To ensure safety, impedance control was employed to facilitate human-robot interaction. A human study was conducted involving 10 healthy subjects who participated in an experiment to assess the robot's assistance capabilities. Passive and active modes were used to evaluate the robot's effectiveness, taking into account head-neck movement error and muscle activity levels. Surface electromyography signals (sEMG) were collected from the splenius capitis muscles during the experiment. The results demonstrated that the robot covered nearly 85% of the overall range of head rotations. Importantly, using the robot during rehabilitation led to reduced muscle activation, highlighting its potential for assisting individuals with post-stroke movement impairments.

RevDate: 2023-12-01
CmpDate: 2023-12-01

Vanbilsen N, Kotz SA, Rosso M, et al (2023)

Auditory attention measured by EEG in neurological populations: systematic review of literature and meta-analysis.

Scientific reports, 13(1):21064.

Sensorimotor synchronization strategies have been frequently used for gait rehabilitation in different neurological populations. Despite these positive effects on gait, attentional processes required to dynamically attend to the auditory stimuli needs elaboration. Here, we investigate auditory attention in neurological populations compared to healthy controls quantified by EEG recordings. Literature was systematically searched in databases PubMed and Web of Science. Inclusion criteria were investigation of auditory attention quantified by EEG recordings in neurological populations in cross-sectional studies. In total, 35 studies were included, including participants with Parkinson's disease (PD), stroke, Traumatic Brain Injury (TBI), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). A meta-analysis was performed on P3 amplitude and latency separately to look at the differences between neurological populations and healthy controls in terms of P3 amplitude and latency. Overall, neurological populations showed impairments in auditory processing in terms of magnitude and delay compared to healthy controls. Consideration of individual auditory processes and thereafter selecting and/or designing the auditory structure during sensorimotor synchronization paradigms in neurological physical rehabilitation is recommended.

RevDate: 2023-11-29

Jacobs MT, San Gil R, AK Walker (2023)

UndERACting ion channels in neurodegeneration.

Trends in neurosciences pii:S0166-2236(23)00262-X [Epub ahead of print].

In a recent study, Guo and colleagues characterised the function of an elusive endoplasmic reticulum (ER) anion channel protein, Chloride Channel CLiC Like 1 (CLCC1), and identified rare CLCC1 variants in people with amyotrophic lateral sclerosis (ALS). CLCC1 mutants disrupted ER function in vitro and promoted ALS-like pathology and neurodegeneration in mice. This work reveals a previously uncharacterised pathway involved in ER calcium release and highlights new pathogenic mechanisms underlying neurodegeneration.

RevDate: 2023-11-29

Song J (2023)

Molecular mechanisms of phase separation and amyloidosis of ALS/FTD-linked FUS and TDP-43.

Aging and disease pii:AD.2023.1118 [Epub ahead of print].

FUS and TDP-43, two RNA-binding proteins from the heterogeneous nuclear ribonucleoprotein family, have gained significant attention in the field of neurodegenerative diseases due to their association with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). They possess folded domains for binding ATP and various nucleic acids including DNA and RNA, as well as substantial intrinsically disordered regions (IDRs) including prion-like domains (PLDs) and RG-/RGG-rich regions. They play vital roles in various cellular processes, including transcription, splicing, microRNA maturation, RNA stability and transport and DNA repair. In particular, they are key components for forming ribonucleoprotein granules and stress granules (SGs) through homotypic or heterotypic liquid-liquid phase separation (LLPS). Strikingly, liquid-like droplets formed by FUS and TDP-43 may undergo aging to transform into less dynamic assemblies such as hydrogels, inclusions, and amyloid fibrils, which are the pathological hallmarks of ALS and FTD. This review aims to synthesize and consolidate the biophysical knowledge of the sequences, structures, stability, dynamics, and inter-domain interactions of FUS and TDP-43 domains, so as to shed light on the molecular mechanisms underlying their liquid-liquid phase separation (LLPS) and amyloidosis. The review further delves into the mechanisms through which ALS-causing mutants of the well-folded hPFN1 disrupt the dynamics of LLPS of FUS prion-like domain, providing key insights into a potential mechanism for misfolding/aggregation-prone proteins to cause neurodegenerative diseases and aging by gain of functions. With better understanding of different biophysical aspects of FUS and TDP-43, the ultimate goal is to develop drugs targeting LLPS and amyloidosis, which could mediate protein homeostasis within cells and lead to new treatments for currently intractable diseases, particularly neurodegenerative diseases such as ALS, FTD and aging. However, the study of membrane-less organelles and condensates is still in its infancy and therefore the review also highlights key questions that require future investigation.

RevDate: 2023-11-29

Kumar R, Madhavan T, Ponnusamy K, et al (2023)

Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators.

Frontiers in genetics, 14:1282234.

Introduction: Kinesin family member 5A (KIF5A) is a motor neuron protein expressed in neurons and involved in anterograde transportation of organelles, proteins, and RNA. Variations in the KIF5A gene that interfere with axonal transport have emerged as a distinguishing feature in several neurodegenerative disorders, including hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), and Amyotrophic Lateral Sclerosis (ALS). Methods: In this study, we implemented a computational structural and systems biology approach to uncover the role of KIF5A in ALS. Using the computational structural biology method, we explored the role of non-synonymous Single Nucleotide Polymorphism (nsSNPs) in KIF5A. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS. Results: We found KIF5A[S291F] variant showed the most structure destabilizing behavior and the phytocompound "epigallocatechin gallate" showed the highest binding affinity (-9.0 Kcal/mol) as compared to wild KIF5A (-8.4 Kcal/mol). Further, with the systems biology approach, we constructed the KIF5A protein-protein interaction (PPI) network to identify the associated Kinesin Families (KIFs) proteins, modules, and their function. We also constructed a transcriptional and post-transcriptional regulatory network of KIF5A. With the network topological parameters of PPIN (Degree, Bottleneck, Closeness, and MNC) using CytoHubba and computational knock-out experiment using Network Analyzer, we found KIF1A, 5B, and 5C were the significant proteins. The functional modules were highly enriched with microtubule motor activity, chemical synaptic transmission in neurons, GTP binding, and GABA receptor activity. In regulatory network analysis, we found KIF5A post-transcriptionally down-regulated by miR-107 which is further transcriptionally up-regulated by four TFs (HIF1A, PPARA, SREBF1, and TP53) and down-regulated by three TFs (ZEB1, ZEB2, and LIN28A). Discussion: We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and KIF5A associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases.

RevDate: 2023-11-29

Pisciottani A, Croci L, Lauria F, et al (2023)

Neuronal models of TDP-43 proteinopathy display reduced axonal translation, increased oxidative stress, and defective exocytosis.

Frontiers in cellular neuroscience, 17:1253543.

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease mostly affecting people around 50-60 years of age. TDP-43, an RNA-binding protein involved in pre-mRNA splicing and controlling mRNA stability and translation, forms neuronal cytoplasmic inclusions in an overwhelming majority of ALS patients, a phenomenon referred to as TDP-43 proteinopathy. These cytoplasmic aggregates disrupt mRNA transport and localization. The axon, like dendrites, is a site of mRNA translation, permitting the local synthesis of selected proteins. This is especially relevant in upper and lower motor neurons, whose axon spans long distances, likely accentuating their susceptibility to ALS-related noxae. In this work we have generated and characterized two cellular models, consisting of virtually pure populations of primary mouse cortical neurons expressing a human TDP-43 fusion protein, wt or carrying an ALS mutation. Both forms facilitate cytoplasmic aggregate formation, unlike the corresponding native proteins, giving rise to bona fide primary culture models of TDP-43 proteinopathy. Neurons expressing TDP-43 fusion proteins exhibit a global impairment in axonal protein synthesis, an increase in oxidative stress, and defects in presynaptic function and electrical activity. These changes correlate with deregulation of axonal levels of polysome-engaged mRNAs playing relevant roles in the same processes. Our data support the emerging notion that deregulation of mRNA metabolism and of axonal mRNA transport may trigger the dying-back neuropathy that initiates motor neuron degeneration in ALS.

RevDate: 2023-11-29

Donison N, Hintermayer M, Subramaniam M, et al (2023)

Upregulation of LRRK2 following traumatic brain injury does not directly phosphorylate Thr[175] tau.

Frontiers in cellular neuroscience, 17:1272899.

Phosphorylated microtubule-associated protein tau (tau) aggregates are a pathological hallmark of various neurodegenerative diseases, including chronic traumatic encephalopathy and amyotrophic lateral sclerosis with cognitive impairment. While there are many residues phosphorylated on tau, phosphorylation of threonine 175 (pThr[175] tau) has been shown to initiate fibril formation in vitro and is present in pathological tau aggregates in vivo. Given this, preventing Thr[175] tau phosphorylation presents a potential approach to reduce fibril formation; however, the kinase(s) acting on Thr[175] are not yet fully defined. Using a single controlled cortical impact rodent model of traumatic brain injury (TBI), which rapidly induces Thr[175] tau phosphorylation, we observed an upregulation and alteration in subcellular localization of leucine-rich repeat kinase 2 (LRRK2), a kinase that has been implicated in tau phosphorylation. LRRK2 upregulation was evident by one-day post-injury and persisted to day 10. The most notable changes were observed in microglia at the site of injury in the cortex. To determine if the appearance of pThr[175] tau was causally related to the upregulation of LRRK2 expression, we examined the ability of LRRK2 to phosphorylate Thr[175]in vitro by co-transfecting 2N4R human WT-tau with either LRRK2-WT, constitutively-active LRRK2-G2019S or inactive LRRK2-3XKD. We found no significant difference in the level of pThr[175] tau between the overexpression of LRRK2-WT, -G2019S or -3XKD, suggesting LRRK2 does not phosphorylate tau at Thr[175]. Further, downstream events known to follow Thr[175] phosphorylation and known to be associated with pathological tau fibril formation (pSer[9]-GSK3β and pThr[231] tau induction) also remained unchanged. We conclude that while LRRK2 expression is altered in TBI, it does not contribute directly to pThr[175] tau generation.

RevDate: 2023-11-29

Narayan MS, Sameer M, V Viburajah (2023)

Hip Fracture in a Patient with Overlap Syndrome - Conundrums Involved in the Management - A Case Report.

Journal of orthopaedic case reports, 13(11):106-111.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition producing symptoms of varying severity depending on the extent and progression of the disease pathology most importantly respiratory insufficiency and pulmonary complications. Myasthenia gravis (MG) on the other hand is an autoimmune condition due to the pathology involving failure of neuromuscular transmission causing muscle weakness exacerbated by activity and involvement of the respiratory muscles leading to respiratory failure. Overlap syndrome is a condition wherein both motor neuron disease (MND) and MG are present in the same patient. The safety of using muscle-relaxing agents in patients with MG undergoing major surgical procedures has so far been assessed as insufficient. There have been many concerns regarding anesthetic management in relation to complications with respiratory function in patients with ALS, with regional anesthesia being considered slightly safer.

CASE REPORT: An 81-year-old female presented with a closed injury to her left hip, and she was diagnosed to have a left neck of femur fracture. She was also a known case of bulbar MND with an overlap syndrome of MG. She was hypertensive and controlled with regular medication. She was planned for a left hip bipolar arthroplasty. Anesthetic requirements and management of these patients require a high degree of expertise and anesthesia in patients undergoing surgery is prone to more complications and mortality. In addition, as the patient had an overlap of both MG and MND, more meticulous assessment and management strategies were necessary.

CONCLUSION: The importance and purpose of this study are to highlight a case of overlap syndrome of MND and MG patients who sustained a left neck femur fracture and underwent bipolar arthroplasty highlighting the anesthetic considerations in the patient for the procedure. We concluded that the choice of mode of anesthesia needs to be individualized based on each patient's requirements after careful analysis of the risk-benefit ratio of general versus regional. Regional anesthesia was successfully administered for this patient.

RevDate: 2023-11-29

Audrain M, Egesipe AL, Tentillier N, et al (2023)

Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF.

Brain communications, 5(6):fcad306.

In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of the pharmacokinetic/pharmacodynamic effect for the monoclonal antibody, ACI-5891.9, in vivo and in vitro confirmed that a CSF concentration of ≍1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.

RevDate: 2023-11-29

Maselli F, D'Antona S, Utichi M, et al (2023)

Computational analysis of five neurodegenerative diseases reveals shared and specific genetic loci.

Computational and structural biotechnology journal, 21:5395-5407 pii:S2001-0370(23)00383-5.

Neurodegenerative diseases (ND) are heterogeneous disorders of the central nervous system that share a chronic and selective process of neuronal cell death. A computational approach to investigate shared genetic and specific loci was applied to 5 different ND: Amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Lewy body dementia (LBD). The datasets were analyzed separately, and then we compared the obtained results. For this purpose, we applied a genetic correlation analysis to genome-wide association datasets and revealed different genetic correlations with several human traits and diseases. In addition, a clumping analysis was carried out to identify SNPs genetically associated with each disease. We found 27 SNPs in AD, 6 SNPs in ALS, 10 SNPs in PD, 17 SNPs in MS, and 3 SNPs in LBD. Most of them are located in non-coding regions, with the exception of 5 SNPs on which a protein structure and stability prediction was performed to verify their impact on disease. Furthermore, an analysis of the differentially expressed miRNAs of the 5 examined pathologies was performed to reveal regulatory mechanisms that could involve genes associated with selected SNPs. In conclusion, the results obtained constitute an important step toward the discovery of diagnostic biomarkers and a better understanding of the diseases.

RevDate: 2023-11-29

Li X, Liu Q, Niu T, et al (2023)

Sleep Disturbances as a Potential Risk Factor for Deterioration of Respiratory Function in Patients with Amyotrophic Lateral Sclerosis.

Annals of Indian Academy of Neurology, 26(5):754-760.

OBJECTIVES: Sleep disturbances are common in amyotrophic lateral sclerosis (ALS). However, previous studies have explored sleep quality at the cross-sectional level and the longitudinal variability characteristics are currently unknown. Our study aimed to longitudinally explore the effect of sleep quality on disease progression in patients with ALS.

METHODS: All enrolled patients with ALS were first diagnosed and completed the 6- and 12-month follow-ups. Subjective sleep disturbance was assessed using the Pittsburgh Sleep Quality Index (PSQI). Based on the PSQI score at baseline, patients with ALS were classified as poor sleepers (PSQI >5) and good sleepers (PSQI ≤5). Disease progression was assessed using the rate of disease progression, the absolute change from baseline forced vital capacity (ΔFVC) and the percentage change from baseline FVC (ΔFVC%) over the follow-up period.

RESULTS: Sixty-three patients were included in the study, 24 (38.1%) were poor sleepers and 39 were good sleepers. The percentage of patients with poor sleep quality was 38.1% at baseline, increasing to 60.3% and 74.6% at 6- and 12-month, respectively. Compared to good sleepers, ΔFVC and ΔFVC% values were greater in poor sleepers (P < 0.001 and P = 0.001, respectively). Poor sleep quality at diagnosis is associated with rapid deterioration of respiratory function during disease progression.

CONCLUSIONS: Sleep disturbances maybe a potential risk factor for deterioration of respiratory function in patients with ALS. The role of sleep disturbances in disease progression deserves attention, and early assessment and intervention may slow disease progression and improve life quality of patients with ALS.

RevDate: 2023-11-29

Chawla T, V Goyal (2023)

Tofersen: Silver Lining or Hyperbole??.

Annals of Indian Academy of Neurology, 26(5):638-640.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not have a cure for this disorder. Edaravone, Riluzole, and combination of phenylbutyrate and taurursodiol are a handful of FDA-approved drugs that only delay the progression of the disease by a few months. Tofersen, an antisense oligonucleotide, in SOD1 related ALS, has joined the bandwagon of FDA-approved drugs for ALS recently. It is a gene therapy that has been found to lower SOD1 concentrations and neurofilament light chain concentrations in blood and CSF, a known biomarker of ALS, leading to the accelerated approval of the drug. Although it did not show any statistically significant clinical improvement. In this article, we discuss the development and approval process of the first gene-based therapy, Tofersen, for ALS.

RevDate: 2023-11-29

Hiew FL (2023)

Sleep and Survival in Amyotrophic Lateral Sclerosis (ALS): The Parallelism in Motor and Non-Motor Progression.

Annals of Indian Academy of Neurology, 26(5):628.

RevDate: 2023-11-29

Jain A, Madkan S, P Patil (2023)

The Role of Gut Microbiota in Neurodegenerative Diseases: Current Insights and Therapeutic Implications.

Cureus, 15(10):e47861.

Small microscopic entities known as microbes, having a population of hundreds of billions or perhaps even in trillions, reside in our gastrointestinal tract. A healthy immune system, digestion, and creation of vitamins and enzymes are all thanks to these microbes. However, new research has shown a hitherto unrecognized connection between the microbiota of the intestines and the genesis of neurodegenerative diseases. Neurons in the CNS gradually deteriorate in neurodegenerative illnesses like multiple sclerosis and Parkinson's disease (PD). This deterioration impairs cognitive and physical function. Amyotrophic lateral sclerosis (ALS), PD, and Alzheimer's disease (AD) are just a few examples of neurodegenerative illnesses that pose a serious threat to world health and have few effective treatments. Recent research suggests that the gut microbiota, a diverse microbial population found in the gastrointestinal system, may substantially impact the cause and development of various diseases. The discovery of altered gut microbiota composition in people with these illnesses is one of the most critical lines of evidence connecting gut microbiota dysbiosis to neurodegenerative diseases. AD patients have a distinct characteristic of having a particular microbiota profile. In addition, an excess population of a specific microbe data profile is seen as compared to a healthy individual. Similar changes in the gut microbiota composition have been noted in people with multiple sclerosis and PD. The latest study indicates the potential that dysbiosis, a condition characterized by alteration in the intestinal microbiota's makeup and functioning, may have an effect on the onset and progression of neurodegenerative diseases, including PD and multiple sclerosis. In order to emphasize any potential underlying mechanisms and examine potential treatment repercussions, the review article's goal is to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders. The review article aims to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders, highlighting potential underlying mechanisms and examining potential treatment repercussions.

RevDate: 2023-11-29

Munoz NR, Agwuegbo CC, Ghorbani A, et al (2023)

Takotsubo Cardiomyopathy Induced by Stress From Amyotrophic Lateral Sclerosis and a Mechanical Fall.

Cureus, 15(10):e47068.

Named after the Japanese octopus trap, Takotsubo cardiomyopathy is an acute myocardial condition characterized by a reversible ventricular dysfunction with ballooning of the left ventricle (LV) during systole. A catecholamine surge is likely the primary mechanism responsible for myocardial damage in this condition. The association between amyotrophic lateral sclerosis (ALS) and Takotsubo cardiomyopathy has not been well established. We present a unique case of Takotsubo cardiomyopathy diagnosed in a patient with ALS who presented after a fall with shortness of breath, generalized weakness, and hypotension. She was found to have troponinemia, elevated brain natriuretic peptide, and Osborn waves without ST-segment changes noted on electrocardiography (EKG). The diagnosis of Takotsubo cardiomyopathy was confirmed via transthoracic echocardiography (TTE), which revealed reduced left ventricular ejection fraction, apical ballooning of the LV, akinesis of the ventricular apex, and hyperkinesis of the base of the heart. Coronary angiography revealed no coronary artery disease. She was managed medically and was hemodynamically stable at the time of discharge.

RevDate: 2023-11-29

Xu D, Chu M, Chen Y, et al (2023)

Identification and verification of ferroptosis-related genes in the pathology of epilepsy: insights from CIBERSORT algorithm analysis.

Frontiers in neurology, 14:1275606.

BACKGROUND: Epilepsy is a neurological disorder characterized by recurrent seizures. A mechanism of cell death regulation, known as ferroptosis, which involves iron-dependent lipid peroxidation, has been implicated in various diseases, including epilepsy.

OBJECTIVE: This study aimed to provide a comprehensive understanding of the relationship between ferroptosis and epilepsy through bioinformatics analysis. By identifying key genes, pathways, and potential therapeutic targets, we aimed to shed light on the underlying mechanisms involved in the pathogenesis of epilepsy.

MATERIALS AND METHODS: We conducted a comprehensive analysis by screening gene expression data from the Gene Expression Omnibus (GEO) database and identified the differentially expressed genes (DEGs) related to ferroptosis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to gain insights into the biological processes and pathways involved. Moreover, we constructed a protein-protein interaction (PPI) network to identify hub genes, which was further validated using the receiver operating characteristic (ROC) curve analysis. To explore the relationship between immune infiltration and genes, we employed the CIBERSORT algorithm. Furthermore, we visualized four distinct interaction networks-mRNA-miRNA, mRNA-transcription factor, mRNA-drug, and mRNA-compound-to investigate potential regulatory mechanisms.

RESULTS: In this study, we identified a total of 33 differentially expressed genes (FDEGs) associated with epilepsy and presented them using a Venn diagram. Enrichment analysis revealed significant enrichment in the pathways related to reactive oxygen species, secondary lysosomes, and ubiquitin protein ligase binding. Furthermore, GSVA enrichment analysis highlighted significant differences between epilepsy and control groups in terms of the generation of precursor metabolites and energy, chaperone complex, and antioxidant activity in Gene Ontology (GO) analysis. Furthermore, during the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we observed differential expression in pathways associated with amyotrophic lateral sclerosis (ALS) and acute myeloid leukemia (AML) between the two groups. To identify hub genes, we constructed a protein-protein interaction (PPI) network using 30 FDEGs and utilized algorithms. This analysis led to the identification of three hub genes, namely, HIF1A, TLR4, and CASP8. The application of the CIBERSORT algorithm allowed us to explore the immune infiltration patterns between epilepsy and control groups. We found that CD4-naïve T cells, gamma delta T cells, M1 macrophages, and neutrophils exhibited higher expression in the control group than in the epilepsy group.

CONCLUSION: This study identified three FDEGs and analyzed the immune cells in epilepsy. These findings pave the way for future research and the development of innovative therapeutic strategies for epilepsy.

RevDate: 2023-11-29

Nakamura R, Kurihara M, Kobashi S, et al (2023)

Ideal body weight-based determination of minimum oral calories beneficial to function and survival in ALS.

Frontiers in neurology, 14:1286153.

INTRODUCTION: This study sought to identify the optimal caloric intake to improve function and survival in ALS patients by comparing oral intake per ideal body weight (IBW) and its discrepancy with total energy expenditure (TEE) using the Shimizu formula.

METHODS: A retrospective analysis of 104 ALS patients was conducted, categorizing them based on their average intake during the first week after admission using two primary intake cutoffs: 25 kcal/kgIBW and 30 kcal/kgIBW. The variance between oral intake and TEE was also evaluated using -300 kcal and 0 kcal as reference points.

RESULTS: Oral caloric intake per IBW and functional decline rate (rs = -0.35, p < 0.001), but the variance from TEE was not significantly correlated (-0.11, p = 0.27). Survival data showed that patients consuming less than 25 kcal/kgIBW had a median survival of 24 months, increasing to 38 months for those consuming between 25-30 kcal/kgIBW and 63 months for those consuming 30 kcal/kgIBW or more. Deviations from the TEE did not significantly affect survival (p = 0.36). Among patients consuming less than their TEE, those consuming less than 25 kcal/kgIBW had a shorter median survival (24 months) compared to their counterparts (46 months) (p = 0.022). Consumption of less than 25 kcal/kgBW emerged as a significant negative predictor of patient outcome, independent of factors such as age, gender or disease progression.

DISCUSSION: Intakes of 25 kcal/kgIBW or more are correlated with improved ALS outcomes, and larger, multi-regional studies are recommended for deeper insights.

RevDate: 2023-11-29

de Brito Siqueira ALG, Cremasco PVV, Bahú JO, et al (2023)

Phytocannabinoids: Pharmacological effects, biomedical applications, and worldwide prospection.

Journal of traditional and complementary medicine, 13(6):575-587 pii:S2225-4110(23)00097-4.

Scientific evidence exists about the association between neurological diseases (i.e., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, depression, and memory loss) and oxidative damage. The increasing worldwide incidence of such diseases is attracting the attention of researchers to find palliative medications to reduce the symptoms and promote quality of life, in particular, in developing countries, e.g., South America and Africa. Among potential alternatives, extracts of Cannabis Sativa L. are suitable for people who have neurological disorders, spasticity, and pain, nausea, resulting from diseases such as cancer and arthritis. In this review, we discuss the latest developments in the use of Cannabis, its subtypes and constituents, extraction methods, and relevant pharmacological effects. Biomedical applications, marketed products, and prospects for the worldwide use of Cannabis Sativa L. extracts are also discussed, providing the bibliometric maps of scientific literature published in representative countries from South America (i.e., Brazil) and Africa (i.e., South Africa). A lack of evidence on the effectiveness and safety of Cannabis, besides the concerns about addiction and other adverse events, has led many countries to act with caution before changing Cannabis-related regulations. Recent findings are expected to increase the social acceptance of Cannabis, while new technologies seem to boost the global cannabis market because the benefits of (-)-trans-delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) use have been proven in several studies in addition to the potential to general new employment.

RevDate: 2023-11-29

Du W, Yan M, Yin C, et al (2023)

A novel modified nano-alumina composite sol for potential application in forest firefighting.

RSC advances, 13(48):33820-33825 pii:d3ra03979j.

Herein, modified ammonium polyphosphate wrapped nano-alumina (mAPP@Als) was first synthesized and then dispersed in traditional fire extinguishing solution (FES) to fabricate a FES-mAPP@Als composite sol. It was found that the phosphorus-silica containing units were attached onto the nano-alumina surface, and the mAPP@Als particles showed excellent dispersion level in FES with a single-domain particle size distribution range. Due to the synergistic effects of the phosphorus-nitrogen and silica-alumina flame retardant components, FES-mAPP@Als (5% concentration) coated wood exhibited improved limiting oxygen index (33.2%) and carbonization ability, and depressed heat release (41.9%) and smoke production (10.7%), as compared to the pristine wood. In addition, the FES-mAPP@Als composite sol showed enhanced fire-extinguishing and anti-reignition capacities compared to the FES. This research offers a novel composite sol fire extinguishing agent for fighting forest fires.

RevDate: 2023-11-29

Harley P, Kerins C, Gatt A, et al (2023)

Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons.

Cell reports, 42(12):113509 pii:S2211-1247(23)01521-8 [Epub ahead of print].

Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of in vitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.

RevDate: 2023-11-29

Zhu Y, Li M, Wang H, et al (2023)

Mendelian Randomization Identifies Genetically Supported Drug Targets for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Molecular neurobiology [Epub ahead of print].

Currently, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have no effective treatments. Drug repurposing offers a rapid method to meet therapeutic need for ALS and FTD. To identify therapeutic targets associated with ALS and FTD, Mendelian randomization (MR) analysis and colocalization were performed. Genetic instruments were based on transcriptomic and proteomic data for 422 actionable proteins targeted by approved drugs or clinical drug candidates. The publicly available ALS GWAS summary data (including a total of 20,806 ALS cases and 59,804 controls) and FTD GWAS summary data (including a total of 2154 patients with FTD and 4308 controls) were used. Using cis-expression quantitative trait loci and cis-protein quantitative trait loci genetic instruments, we identified several drug targets for repurposing (ALS: MARK3, false-discovery rate (FDR) = 0.043; LTBR, FDR = 0.068) (FTD: HLA-DRB1, FDR = 0.083; ADH5, FDR = 0.056). Our MR study analyzed the actionable druggable proteins and provided potential therapeutic targets for ALS and FTD. Future studies should further elucidate the underlying mechanism of corresponding drug targets in the pathogenesis of ALS and FTD.

RevDate: 2023-11-29

Rothstein JD, Baskerville V, Rapuri S, et al (2023)

G2C4 targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in human C9orf72 ALS/FTD induced pluripotent stem cell derived neurons.

Acta neuropathologica, 147(1):1.

The G4C2 repeat expansion in the C9orf72 gene is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Many studies suggest that dipeptide repeat proteins produced from this repeat are toxic, yet, the contribution of repeat RNA toxicity is under investigated and even less is known regarding the pathogenicity of antisense repeat RNA. Recently, two clinical trials targeting G4C2 (sense) repeat RNA via antisense oligonucleotide failed despite a robust decrease in sense-encoded dipeptide repeat proteins demonstrating target engagement. Here, in this brief report, we show that G2C4 antisense, but not G4C2 sense, repeat RNA is sufficient to induce TDP-43 dysfunction in induced pluripotent stem cell (iPSC) derived neurons (iPSNs). Unexpectedly, only G2C4, but not G4C2 sense strand targeting, ASOs mitigate deficits in TDP-43 function in authentic C9orf72 ALS/FTD patient iPSNs. Collectively, our data suggest that the G2C4 antisense repeat RNA may be an important therapeutic target and provide insights into a possible explanation for the recent G4C2 ASO clinical trial failure.

RevDate: 2023-11-29

Naylor K, Chrzanowska-Wąsik M, Okońska P, et al (2023)

Adapting to a Pandemic: Web-Based Residency Training and Script Concordance Testing in Emergency Medicine During COVID-19.

Disaster medicine and public health preparedness, 17:e541 pii:S1935789323001957.

OBJECTIVE: The coronavirus disease (COVID-19) pandemic necessitated alternative methods to ensure the continuity of medical education. Our study explores the efficacy and acceptability of a digital continuous medical education initiative for medical residents during this challenging period.

METHODS: From September to December 2020, 47 out of 60 enrolled trainee doctors participated in this innovative digital Continuous Medical Education (CME) approach. We utilized the Script Concordance Test to bolster clinical reasoning skills. Three simulation scenarios, namely Advanced Trauma Life Support (ATLS), Advanced Life Support (ALS), and European Paediatric Life Support (EPLS), were transformed into interactive online sessions via Zoom™. Participant feedback was also collected through a survey.

RESULTS: Consistent Script Concordance Testing (SCT) scores among participants indicated the effectiveness of the online training module. Feedback suggested a broad acceptance of this novel training approach. However, discrepancies observed between formative SCT scores, and summative Multiple-Choice Questions (MCQ) assessments highlighted areas for potential refinement.

CONCLUSIONS: Our findings showcase the resilience and adaptability of medical education amidst challenges like the global pandemic. The success of methodologies such as SCT, endorsed by prestigious bodies like the European Resuscitation Council and the American Heart Association, suggests their potential in preparing health care professionals for emergent situations. This research offers valuable insights for shaping future online CME strategies.

RevDate: 2023-11-29

Monteiro KLC, de Aquino TM, EF da Silva-Júnior (2023)

Natural Compounds as Inhibitors of Aβ Peptide and Tau Aggregation.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-136363 [Epub ahead of print].

Neurodegenerative conditions like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) encompass disorders characterized by the degeneration of neurons in specific circumstances. The quest for novel agents to influence these diseases, particularly AD, has unearthed various natural compounds displaying multifaceted activities and diverse pharmacological mechanisms. Given the ongoing extensive study of pathways associated with the accumulation of neurofibrillary aggregates and amyloid plaques, this paper aims to comprehensively review around 130 studies exploring natural products. These studies focus on inhibiting the formation of amyloid plaques and tau protein tangles, with the objective of potentially alleviating or delaying AD.

RevDate: 2023-11-29

Brown A, Armon C, Barkhaus P, et al (2023)

ALSUntangled #72: Insulin.

Amyotrophic lateral sclerosis & frontotemporal degeneration [Epub ahead of print].

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.

RevDate: 2023-11-29

Li Y, Chen M, Qi J, et al (2023)

Underwater ghost imaging with detection distance up to 9.3 attenuation lengths.

Optics express, 31(23):38457-38474.

Underwater ghost imaging LiDAR is an effective method of underwater detection. In this research, theoretical and experimental investigations were conducted on underwater ghost imaging, combining the underwater optical field transmission model with the inherent optical parameters of a water body. In addition, the Wells model and the approximate Sahu-Shanmugam scattering phase function were used to create a model for underwater optical transmission. The second-order Glauber function of the optical field was then employed to analyze the scattering field degradation during the transmission process. The simulation and experimental results verified that the proposed underwater model could better reveal the degrading effect of a water body on ghost imaging. A further series of experiments comparing underwater ghost imaging at different detection distances was also conducted. In the experimental system, gated photomultiplier tube (PMT) was used to filter out the peak of backscattering, allowing a larger gain to be set for longer-range detection of the target. The laser with a central wavelength of 532 nm was operated at a frequency of 2 KHz, with a single pulse energy of 2 mJ, a pulse width of 10 ns. High-reflective targets were imaged up to 65.2 m (9.3 attenuation lengths (ALs), attenuation coefficient c = 0.1426 m[-1], and scattering coefficient b = 0.052 m[-1]) and diffuse-reflection targets up to 41.2 m (6.4 ALs, c = 0.1569 m[-1], and b = 0.081 m[-1]). For the Jerlov-I (c = 0.048 m[-1] and b = 0.002 m[-1]) water body, the experimentally obtained maximum detection distance of 9.3 ALs can be equivalent to 193.7 m under the same optical system conditions.

RevDate: 2023-11-28

Iyer AK, Schoch KM, Verbeck A, et al (2023)

Targeted ASO-mediated Atp1a2 knockdown in astrocytes reduces SOD1 aggregation and accelerates disease onset in mutant SOD1 mice.

PloS one, 18(11):e0294731.

Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.

RevDate: 2023-11-28

Giometto S, Finocchietti M, Paoletti O, et al (2023)

Adherence to riluzole therapy in patients with amyotrophic lateral sclerosis in three Italian regions-The CAESAR study.

Pharmacoepidemiology and drug safety [Epub ahead of print].

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease. Riluzole may increase survival and delay the need for mechanical ventilation. The CAESAR project ('Comparative evaluation of the efficacy and safety of drugs used in rare neuromuscular and neurodegenerative diseases', FV AIFA project 2012-2013-2014) involves evaluating prescribing patterns, and analysing effectiveness and comparative safety of drugs, in patients with neurodegenerative diseases. The aim of this study is to evaluate adherence to riluzole in patients with ALS during the first year of use, identifying adherence clusters.

METHODS: A retrospective cohort study was conducted using administrative data from Latium, Tuscany, and Umbria. We identified subjects with a new diagnosis of ALS between 2014 and 2019, with the first dispensation of riluzole within 180 days of diagnosis. We considered a two-year look-back period for the characterization of patients, and we followed them from the date of first dispensing of riluzole for 1 year. We calculated 12 monthly adherence measures, through a modified version of the Medication Possession Ratio, estimating drug coverage with Defined Daily Dose. Adherence trajectories were identified using a three-step method: (1) calculation of statistical measures; (2) principal component analysis; (3) cluster analysis. Patient characteristics at baseline and during follow-up were described and compared between adherence groups identified.

RESULTS: We included 264 ALS patients as new users of riluzole in Latium, 344 in Tuscany, and 63 in Umbria. We observed a higher frequency of males (56.2%) and a mean age of 67.4 (standard deviation, SD, 10.4) in the overall population. We identified two clusters in all regions: one more numerous, including adherent patients (60%, 74%, 88%, respectively), and another one including patients who discontinued therapy (40%, 26%, 12%, respectively). In Tuscany patients discontinuing riluzole more frequently died (28.6% vs. 15.4%, p-value <0.01). Additionally, low-adherers had a higher frequency of central nervous system disorders (69.0% vs. 52.5%, p-value 0.01), and a greater use of non-pharmacological treatments (p-values ≤0.01 for invasive ventilation and tracheostomy). We did not observe any differences in Lazio, whereas in Umbria we observed a higher use of drugs for dementia-related psychiatric problems among low-adherers (57.1% vs. 7.8%, respectively, p-value <0.01), although with small numbers.

CONCLUSION: Most ALS patients who start riluzole adhere to therapy during the first year. Patients who discontinue therapy early show greater fragility and mortality.

RevDate: 2023-11-28

Li X, Pura J, Allen A, et al (2023)

DYNATE: Localizing rare-variant association regions via multiple testing embedded in an aggregation tree.

Genetic epidemiology [Epub ahead of print].

Rare-variants (RVs) genetic association studies enable researchers to uncover the variation in phenotypic traits left unexplained by common variation. Traditional single-variant analysis lacks power; thus, researchers have developed various methods to aggregate the effects of RVs across genomic regions to study their collective impact. Some existing methods utilize a static delineation of genomic regions, often resulting in suboptimal effect aggregation, as neutral subregions within the test region will result in an attenuation of signal. Other methods use varying windows to search for signals but often result in long regions containing many neutral RVs. To pinpoint short genomic regions enriched for disease-associated RVs, we developed a novel method, DYNamic Aggregation TEsting (DYNATE). DYNATE dynamically and hierarchically aggregates smaller genomic regions into larger ones and performs multiple testing for disease associations with a controlled weighted false discovery rate. DYNATE's main advantage lies in its strong ability to identify short genomic regions highly enriched for disease-associated RVs. Extensive numerical simulations demonstrate the superior performance of DYNATE under various scenarios compared with existing methods. We applied DYNATE to an amyotrophic lateral sclerosis study and identified a new gene, EPG5, harboring possibly pathogenic mutations.

RevDate: 2023-11-29
CmpDate: 2023-11-29

Yamashita T, Nakano Y, Sasaki R, et al (2023)

Safety and Clinical Effects of a Muse Cell-Based Product in Patients With Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial.

Cell transplantation, 32:9636897231214370.

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients' serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.

RevDate: 2023-11-29
CmpDate: 2023-11-29

Pestelacci S, Hofer-Inteeworn N, Dennler M, et al (2023)

Balloon dilation and transient stenting of unilateral membranous choanal atresia in a British Shorthair cat with chronic purulent rhinitis and ascending meningoencephalitis.

Schweizer Archiv fur Tierheilkunde, 165(12):793-800.

Choanal atresia is a rare congenital anomaly in humans and animals, characterized by the absence of communication of one or both nasal cavities with the nasopharynx. The severity of clinical signs depends on the presence of unilateral versus bilateral stenosis as well as comorbidities. With bilateral atresia, respiration may be severely compromised particularly during sleep, as airflow can only occur when breathing through the open mouth. Various therapeutic modalities have been described in people and adopted for animals. All treatments may be associated with complications, the most important being post-therapeutic scar formation with re-stenosis. This report describes a 10-month-old British Shorthair cat with chronic unilateral serosal nasal discharge that changed to mucopurulent discharge. When acute neurological signs developed, the cat was presented to the veterinary hospital. A diagnosis of primary, membranous right sided choanal atresia was achieved via computed tomography (CT) and nasopharyngeal (posterior) rhinoscopy. Secondary changes included destructive rhinitis with progression to the CNS with a subdural empyema and meningoencephalitis. Retinal changes and aspiration bronchopneumonia were suspected additional complications. After recovery from the secondary infections, the membranous obstruction was perforated and dilated using a valvuloplasty balloon by an orthograde transnasal approach under endoscopic guidance from a retroflexed nasopharyngeal view. To prevent re-stenosis, a foley catheter was placed as a transient stent for 6 days. The cat recovered uneventfully and was asymptomatic after the stent removal. Endoscopic re-examination after 5 months confirmed a persistent opening and patency of the generated right choanal passage. The cat remains asymptomatic 10 months after the procedure. Transnasal endoscopic balloon dilation and transient stenting of choanal atresia is a minimally invasive and relatively simple procedure with potentially sustained success.

RevDate: 2023-11-28

Alvarado CX, Weller CA, Johnson N, et al (2023)

Human brain single nucleus cell type enrichments in neurodegenerative diseases.

Research square pii:rs.3.rs-3390225.

BACKGROUND: Single-cell RNA sequencing has opened a window into clarifying the complex underpinnings of disease, particularly in quantifying the relevance of tissue- and cell-type-specific gene expression.

METHODS: To identify the cell types and genes important to therapeutic target development across the neurodegenerative disease spectrum, we leveraged genome-wide association studies, recent single-cell sequencing data, and bulk expression studies in a diverse series of brain region tissues.

RESULTS: We were able to identify significant immune-related cell types in the brain across three major neurodegenerative diseases: Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Subsequently, putative roles of 30 fine-mapped loci implicating seven genes in multiple neurodegenerative diseases and their pathogenesis were identified.

CONCLUSIONS: We have helped refine the genetic regions and cell types effected across multiple neurodegenerative diseases, helping focus future translational research efforts.

RevDate: 2023-11-28

Wilkins OG, Chien MZYJ, Wlaschin JJ, et al (2023)

Creation of de novo cryptic splicing for ALS/FTD precision medicine.

bioRxiv : the preprint server for biology pii:2023.11.15.565967.

UNLABELLED: A system enabling the expression of therapeutic proteins specifically in diseased cells would be transformative, providing greatly increased safety and the possibility of pre-emptive treatment. Here we describe "TDP-REG", a precision medicine approach primarily for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which exploits the cryptic splicing events that occur in cells with TDP-43 loss-of-function (TDP-LOF) in order to drive expression specifically in diseased cells. In addition to modifying existing cryptic exons for this purpose, we develop a deep-learning-powered algorithm for generating customisable cryptic splicing events, which can be embedded within virtually any coding sequence. By placing part of a coding sequence within a novel cryptic exon, we tightly couple protein expression to TDP-LOF. Protein expression is activated by TDP-LOF in vitro and in vivo , including TDP-LOF induced by cytoplasmic TDP-43 aggregation. In addition to generating a variety of fluorescent and luminescent reporters, we use this system to perform TDP-LOF-dependent genomic prime editing to ablate the UNC13A cryptic donor splice site. Furthermore, we design a panel of tightly gated, autoregulating vectors encoding a TDP-43/Raver1 fusion protein, which rescue key pathological cryptic splicing events. In summary, we combine deep-learning and rational design to create sophisticated splicing sensors, resulting in a platform that provides far safer therapeutics for neurodegeneration, potentially even enabling preemptive treatment of at-risk individuals.

ONE-SENTENCE SUMMARY: We engineer TDP-43-regulated cryptic exons, enabling exceptionally precise activation of gene therapies in diseased neurons.

RevDate: 2023-11-28

Yang S, Wijegunawardana D, Sheth U, et al (2023)

Aberrant splicing exonizes C9ORF72 repeat expansion in ALS/FTD.

bioRxiv : the preprint server for biology pii:2023.11.13.566896.

A nucleotide repeat expansion (NRE) in the first annotated intron of the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While C9 NRE-containing RNAs can be translated into several toxic dipeptide repeat proteins, how an intronic NRE can assess the translation machinery in the cytoplasm remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived cells, we found that C9 NRE was exonized by the usage of downstream 5' splice sites and exported from the nucleus in a variety of spliced mRNA isoforms. C9ORF72 aberrant splicing was substantially elevated in both C9 NRE [+] motor neurons and human brain tissues. Furthermore, NREs above the pathological threshold were sufficient to activate cryptic splice sites in reporter mRNAs. In summary, our results revealed a crucial and potentially widespread role of repeat-induced aberrant splicing in the biogenesis, localization, and translation of NRE-containing RNAs.

RevDate: 2023-11-28

Smith EN, Lee J, Prilutsky D, et al (2023)

Plasma neurofilament light levels show elevation two years prior to diagnosis of amyotrophic lateral sclerosis in the UK Biobank.

Amyotrophic lateral sclerosis & frontotemporal degeneration [Epub ahead of print].

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease with profound unmet need. In patients carrying genetic mutations, elevations in neurofilament light (NfL) have been shown to precede symptom onset, however, the natural history of NfL in general ALS patients is less characterized.

METHODS: We performed a secondary analysis of the UK Biobank Pharma Proteomics Project (UKB-PPP), a subset of the UK Biobank, a population-based cohort study in the United Kingdom, to examine plasma NfL levels in 237 participants subsequently diagnosed with ALS. We applied logistic and Cox proportional hazards regression to compare cases to 42,752 population-based and 948 age and sex-matched controls. Genetic information was obtained from exome and genotype array data.Results and Conclusions: We observed that NfL was 1.42-fold higher in cases vs population-based controls. At two to three years pre-diagnosis, NfL levels in patients exceeded the 95[th] percentile of age and sex-matched controls. A time-to-diagnosis analysis showed that a 2-fold increase in NfL levels was associated with a 3.4-fold risk of diagnosis per year, with NfL being most predictive of case status at two years (AUC = 0.96). Participants with genetic variation that might put them at risk for familial disease (N = 46) did not show a different pattern of association than those without (N = 191).

DISCUSSION: Our findings show that NfL is elevated and discriminative of future ALS diagnosis up to two years prior to diagnosis in patients with and without genetic risk variants.

RevDate: 2023-11-28

Wang Z, Yang H, Han Y, et al (2023)

Screening and identification of key biomarkers associated with amyotrophic lateral sclerosis and depression using bioinformatics.

Medicine, 102(47):e36265.

This study aims to identify common molecular biomarkers between amyotrophic lateral sclerosis (ALS) and depression using bioinformatics methods, in order to provide potential targets and new ideas and methods for the diagnosis and treatment of these diseases. Microarray datasets GSE139384, GSE35978 and GSE87610 were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between ALS and depression were identified. After screening for overlapping DEGs, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software, and hub genes were identified. Finally, a network between miRNAs and hub genes was constructed using the NetworkAnalyst tool, and possible key miRNAs were predicted. A total of 357 genes have been identified as common DEGs between ALS and depression. GO and KEGG enrichment analyses of the 357 DEGs showed that they were mainly involved in cytoplasmic translation. Further analysis of the PPI network using Cytoscape and MCODE plugins identified 6 hub genes, including mitochondrial ribosomal protein S12 (MRPS12), poly(rC) binding protein 1 (PARP1), SNRNP200, PCBP1, small G protein signaling modulator 1 (SGSM1), and DNA methyltransferase 1 (DNMT1). Five possible target miRNAs, including miR-221-5p, miR-21-5p, miR-100-5p, miR-30b-5p, and miR-615-3p, were predicted by constructing a miRNA-gene network. This study used bioinformatics techniques to explore the potential association between ALS and depression, and identified potential biomarkers. These biomarkers may provide new ideas and methods for the early diagnosis, treatment, and monitoring of ALS and depression.

RevDate: 2023-11-27

Asawadethmetakul P, Xie F, Xie C, et al (2023)

Effect of Tuina Combined with Chinese Herbal Compress on Primary Dysmenorrhea with Cold Coagulation and Blood Stasis Syndrome: A Study Protocol for a Randomized Controlled Trial.

Complementary medicine research pii:000534335 [Epub ahead of print].

INDRODUCTION: Primary dysmenorrhea (PD) is a very common issue in young women that reduces the quality of women's lives. Both Western medicine and traditional Chinese medicine (TCM) provide several ways to treat PD; however, TCM treatment exhibits fewer side effects for the patient. Tuina massage and Chinese herbal compresses are considered forms of external TCM therapy that have been widely used to treat PD, especially in China. Therefore, to provide the most effective and safe treatment for PD, we combined Tuina and Chinese herbal compresses together in this observational study.

METHODS: A randomized controlled trial (RCT) consisting of 114 participants from the Shanghai University of Traditional Chinese Medicine who meet inclusion criteria will be divided into two groups in a 1:1 allocation ratio. The intervention group will receive Tuina combined with Chinese herbal compress therapy, while the control group will only receive Chinese herbal compress therapy. The treatment will be given 3 days before menstruation (once per day, 3 times per menstrual cycle). The primary outcome will be measured with the Visual Analog Scale (VAS). The secondary outcomes will be measured by the Dysmenorrhea Symptom Score, the Chinese Medical Dysmenorrhea Symptom Score, the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), and the pain threshold at Guanyuan (CV4).

CONCLUSION: This study will be the first RCT that will entail the combination of Tuina and Chinese herbal compresses to treat PD in the category of cold coagulation and blood stasis syndrome. If the results demonstrate that Tuina combined with a Chinese herbal compress is effective, we posit that this study will provide evidence-based references for a potential alternative treatment to treat PD in the future.

UNLABELLED: EinleitungDie primäre Dysmenorrhoe (PD) ist ein Problem, das bei jungen Frauen sehr häufig auftritt und ihre Lebensqualität beeinträchtigt. Sowohl die westliche Medizin als auch die traditionelle chinesische Medizin (TCM) bieten verschiedene Therapiemöglichkeiten zur Behandlung der PD, allerdings ist die TCM mit weniger Nebenwirkungen für die Patientin verbunden. Tuina-Massage und chinesische Kräuterkompressen gelten als Formen der äußerlichen TCM-Therapie, die besonders in China zur Behandlung der PD weit verbreitet sind. Daher haben wir in dieser Beobachtungsstudie Tuina und chinesische Kräuterkompressen kombiniert, um eine möglichst wirksame und sichere Behandlung der PD bereitzustellen.MethodenEs handelt sich um eine randomisierte kontrollierte Studie (randomized controlled trial, RCT), bei der 114 Teilnehmerinnen der Shanghai University of Traditional Chinese Medicine, die die Einschlusskriterien erfüllen, im Verhältnis 1:1 in zwei Gruppen aufgeteilt werden. Die Interventionsgruppe erhält Tuina in Kombination mit chinesischen Kräuterkompressen, während die Kontrollgruppe nur eine Behandlung mit chinesischen Kräuterkompressen erhält. Die Behandlung erfolgt drei Tage vor der Menstruation (einmal täglich, dreimal pro Menstruationszyklus). Das primäre Zielkriterium wird anhand der visuellen Analogskala (VAS) gemessen. Die sekundären Zielkriterien werden mithilfe des Dysmenorrhoe-Symptom-Scores, des chinesischen medizinischen Dysmenorrhoe-Symptom-Scores, der Self-rating Anxiety Scale (SAS), der Self-rating Depression Scale (SDS) und der Schmerzschwelle am Guanyuan-Akupunkturpunkt (CV4) ermittelt.SchlussfolgerungDiese Studie ist die erste randomisierte kontrollierte Studie, die die Kombination von Tuina und chinesischen Kräuterkompressen zur Behandlung von PD in der Kategorie Kältekoagulation und Blutstauungssyndrom untersucht. Sollten die Ergebnisse zeigen, dass Tuina in Kombination mit chinesischen Kräuterkompressen wirksam ist, erwarten wir, dass diese Studie evidenzbasierte Belege für eine mögliche alternative Behandlung von PD in der Zukunft liefern wird.

RevDate: 2023-11-27

Zhong R, Rua MT, L Wei-LaPierre (2023)

Targeting mitochondrial Ca[2+] uptake for the treatment of amyotrophic lateral sclerosis.

The Journal of physiology [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non-cell autonomous condition with pathology detected in both MNs and non-neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed.

RevDate: 2023-11-27

Hincelin-Mery A, Nicolas X, Cantalloube C, et al (2023)

Safety, Pharmacokinetics, and Target Engagement of a Brain Penetrant RIPK1 Inhibitor, SAR443820 (DNL788), in Healthy Adult Participants.

Clinical and translational science [Epub ahead of print].

SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1). This phase 1 first-in-human healthy participant study (NCT05795907) was comprised of three parts: randomized, double-blind, placebo-controlled single ascending dose (SAD; Part 1a); 14-day multiple ascending dose (MAD; Part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open-label, single-dose Part 1b (PK-CSF) to assess SAR443820 levels in cerebrospinal fluid (CSF). SAR443820 was well-tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram (ECG) parameters. SAR443820 had a favorable PK profile, with plasma half-lives (geometric mean) ranged between 5.7-8.0 h and 7.2-8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF-to-unbound plasma concentration ratio ranged from 0.8-1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at peripheral level. These results support further development of SAR443820 in phase 2 trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547).

RevDate: 2023-11-27

Fateh HR, Askary-Kachoosangy R, Shirzad N, et al (2022)

The effect of energy conservation strategies on fatigue, function, and quality of life in adults with motor neuron disease: Randomized controlled trial.

Current journal of neurology, 21(2):83-90.

Background: Fatigue is one of the most frequent complaints in patients with motor neuron diseases (MNDs), with a significant impact on the quality of life (QOL). There is lack of enough evidence for current pharmacological or non-pharmacological treatments of fatigue in this population to be applied in clinical setting. Energy conservation strategies are one of the key interventions for fatigue management in chronic diseases. We aimed to investigate the effect of applying these techniques in the fatigue management of patients with MND. Methods: This randomized controlled trial (RCT) study was carried out on 28 patients with MND. Participants were randomly assigned to either the intervention or control group. In addition to routine treatment, patients in the intervention group participated in 3 weekly 1-hour energy conservation programs provided by an experienced occupational therapist. The Fatigue Severity Scale (FSS) score, 36-Item Short Form Survey (SF-36), and Canadian Occupational Performance Measure (COPM) were measured at baseline, immediately after the last intervention session, and one month later. Results: FSS and COPM significantly changed after the course in the intervention group (P < 0.001 and P = 0.001, respectively). Both FSS and COPM improved significantly toward the final assessment only in the intervention group. The SF-36 changes were not significant in each of the groups. Conclusion: According to the findings of the present study, using energy conservation strategies could lead to better mid-term fatigue management and occupational performance improvement, but it did not improve QOL in patients with MND.

RevDate: 2023-11-27

Eishi-Oskouei A, K Basiri (2021)

Safety and efficacy of edaravone in well-defined Iranian patients with amyotrophic lateral sclerosis: A parallel-group single-blind trial.

Current journal of neurology, 20(1):1-7.

Background: This parallel-group single-blind trial evaluates the safety and efficacy of Edaravone, as a free radical scavenger, in a highly selective subgroup of Iranian patients with amyotrophic lateral sclerosis (ALS). Methods: The study was registered in ClinicalTrials.gov (registration number: NCT03272802) and Iranian Registry of Clinical Trials (registration number: IRCT20190324043105N). Patients were included into the study, who were diagnosed as probable or definite ALS (according to revised El Escorial criteria), mildly to moderately affected by the disease [according to Amyotrophic Lateral Sclerosis Health State Scale (ALS/HSS)], scored ≥ 2 points on all items of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and had forced vital capacity (FVC) of at least 80%. 20 patients (10 cases, 10 controls) were observed for 12 cycles (each cycle lasted four weeks). Cases received Edaravone for the first 14 days in the first cycle and for the first 10 days in the next cycles. In addition, all patients received Riluzole. The 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), ALSFRS-R, and Manual Muscle Testing (MMT) scores were measured every 3 cycles to evaluate the physical and functional status of the patients. Besides, injection reactions, adverse events (AEs), and serious adverse events (SAEs) were measured during the study. Results: ALSAQ-40, ALSFRS-R, and MMT scores were not significantly different between cases and controls in 5 different time points. During the study, no injection reactions were observed. AEs and SAEs were not significantly different between cases and controls. Conclusion: Our data did not demonstrate efficacy of Edaravone in ALS treatment, but showed its safety for use in patients with ALS. Further studies are necessary to investigate Edaravone efficacy in patients with ALS before prescribing this new drug outside Japan.

RevDate: 2023-11-27

Afrakhteh M, Esmaeili S, Shati M, et al (2021)

Validating the Persian version of the amyotrophic lateral sclerosis-specific quality of life-revised instrument.

Current journal of neurology, 20(1):37-42.

Background: Amyotrophic Lateral Sclerosis-Specific Quality of Life-Revised (ALSSQOL-R) encompasses 50 items which assess quality of life (QOL) in patients with amyotrophic lateral sclerosis (ALS) in six major domains. This study aims to translate the ALSSQOL-R into Persian and evaluate its reliability and validity among Iranian patients. Methods: ALSSQOL-R was translated by the standard multi-step forward-backward method. Content validity was calculated using item content validity index (I-CVI). Three items in the "intimacy" domain were deleted considering Iranian culture. Cronbach's alpha was used for all 6 dimensions to calculate the internal consistency reliability. Test-retest reliability was evaluated using intraclass correlation coefficient (ICC) with one-month interval. Concurrent validity was measured by the validated version of 36-Item Short Form Health Survey (SF-36) questionnaire. Results: Sixty-three patients with ALS were enrolled in the study. I-CVI was 70%, promoted to 85% after modifications (acceptable). Regarding internal consistency reliability, Cronbach's alpha in all six domains was 0.70 and total Cronbach's alpha was 0.89 which is assumed as good. In terms of test-retest reliability, ICC [95% confidence interval (CI)] was 0.91 (91%) and Pearson correlation coefficient (r) was 0.90 (P < 0.001), all indicating an excellent reliability. The concurrent validity was established based on a strong correlation with SF-36 (r = 0.744, P < 0.001). Conclusion: The findings show that the modified Persian version of ALSSQOL-R is a valid and reliable QOL questionnaire which can be used for Iranian patients with ALS in both clinical and research settings.

RevDate: 2023-11-27

Okhovat AA, Fatehi F, Rafiemehr M, et al (2020)

Evaluation of quality of life and mood disorders in caregivers of patients with amyotrophic lateral sclerosis: A single-center cross-sectional study.

Current journal of neurology, 19(4):190-195.

Background: Caregivers of patients with amyotrophic lateral sclerosis (ALS) may suffer from anxiety, depression, and reduced quality of life (QoL). Our goal was to evaluate the QoL and mood disorders in caregivers and their correlation with the patients' demographic, physical, and mental conditions. Methods: We analyzed data from 39 patients with ALS and their caregivers. Patients completed questionnaires of anxiety assessed by Generalised Anxiety Disorder Assessment (GAD-7), depression using the Beck Depression Inventory-II (BDI-II), and QoL via 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Physical impairment was also measured in the patients using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Caregivers were also assessed by BDI-II, GAD-7, and 36-item Short-Form Health Survey questionnaire (SF-36). Results: The prevalence of depression and anxiety in the patients was 82.1% and 71.8%, respectively. Caregivers also had higher rates of anxiety and depression and lower levels of QoL in comparison with the general population (anxiety: 66.7%, depression: 43.6%). Depression and anxiety were considerably associated with worsened QoL in the caregivers. None of the demographic, physical, or mental characteristics of patients with ALS were related to either mood status or QoL of the caregiver population. Conclusion: Caregivers experience higher rates of anxiety and depression and lower QoL in comparison with the general population. The severity of mood disorders is inversely associated with the physical and mental domains of caregivers' QoL. Nonetheless, QoL in the caregivers is not affected by the physical or mental disability of the patients.

RevDate: 2023-11-27

Cykowski MD, Arumanayagam AS, Powell SZ, et al (2023)

Primary visual cortex pathology in ALS patients with C9ORF72 expansion.

Poly-GA and poly-GP immunofluorescence studies show conspicuous dipeptide repeat pathology in layers IV and II of primary visual cortex in C9ALS patients.

RevDate: 2023-11-26

Zhang J, Wang C, Zhou M, et al (2023)

Comprehensive treatment of amyotrophic lateral sclerosis combined with colon cancer: A case report.

RevDate: 2023-11-26

Feng T (2023)

Applications of Artificial Intelligence to Diagnosis of Neurodegenerative Diseases.

Studies in health technology and informatics, 308:648-655.

Artificial Intelligence (AI) is an umbrella term that represents a new technology for simulating and expanding human intelligence by using machines and computer systems. It consists of methods such as machine learning (ML), deep learning (DL), and natural language processing (NLP). In the era of big data, AI has emerged as an essential tool for improving the detection of neurodegenerative diseases, such as Alzheimer's diseases (AD), Parkinson's diseases, amyotrophic lateral sclerosis, etc. AI with its ability to extract critical information from the mass of data has enabled scientists to deal with various types of large-volume data, including genetic data, imaging data, and clinical data, rapidly generated in the course of neurodegenerative disease research. This review provides a comprehensive overview of the literature on current AI applications in the diagnosis of neurodegenerative diseases. Firstly, bioinformatics and AI approaches to identify potential biomarkers for neurodegenerative diseases such as AD are reviewed. Secondly, the use of ML and DL methods to analyze Magnetic Resonance Imaging (MRI) data for a better understanding of disease progression and predicting patient outcomes is discussed. Finally, the use of AI methods including NLP for Electronic Health Record (EHR) data analysis to extract meaningful information and identify patterns that may contribute to early diagnosis and treatment planning are reviewed. The potential benefits of AI-based approaches in improving patient outcomes and the challenges associated with their implementations are also discussed. Overall, this paper highlights the promise of AI in transforming the diagnosis and management of neurodegenerative diseases.

RevDate: 2023-11-25

Wong CH, Rahat A, HC Chang (2023)

Fused in sarcoma regulates glutamate signaling and oxidative stress response.

Free radical biology & medicine pii:S0891-5849(23)01116-4 [Epub ahead of print].

Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor GLR-1. We found that fust-1 ALS mutations act as loss-of-function in SOD-1 and VGLUT/EAT-4 phenotypes, whereas the fust-1 ALS mutations act as gain-of-function in redox homeostasis and the microbe-induced oxidative stress response. We hypothesized that FUST-1 is a link between glutamate signaling and SOD-1. Our results may provide new insights into the human ALS alleles and their roles in pathological mechanisms that lead to ALS.

RevDate: 2023-11-25

Kabir V, Ombelet F, Hobin F, et al (2023)

Prognostic value of motor and extramotor involvement in ALS.

Amyotrophic lateral sclerosis & frontotemporal degeneration [Epub ahead of print].

Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder resulting in upper and lower motor neuron loss. ALS often has a focal onset of weakness, which subsequently spreads to other body regions. Survival is limited to two to five years after disease onset, often due to respiratory failure. Cognitive impairment is present in approximately 30% to 50% of patients and in 10%-15% of patients, the clinical criteria of frontotemporal dementia (FTD) are met. Methods: In this retrospective single-center ALS cohort study, we examined the occurrence of cognitive and behavioral impairment in relation to motor impairment at disease presentation and studied its impact on survival. Results: The degree of lower motor neuron involvement was associated with a worse survival, but there was no effect for upper motor neuron involvement. Patients who were cognitively normal had a significantly better survival compared to patients with cognitive or behavioral impairment and to patients with comorbid FTD. There was no significant difference regarding survival between patients with FTD and patients with cognitive or behavioral impairment. Conclusions: The extent of motor and extramotor involvement in patients with ALS at disease presentation holds complementary prognostic information.

RevDate: 2023-11-27
CmpDate: 2023-11-27

Li J, Liang W, Yin X, et al (2023)

Multimodal Gait Abnormality Recognition Using a Convolutional Neural Network-Bidirectional Long Short-Term Memory (CNN-BiLSTM) Network Based on Multi-Sensor Data Fusion.

Sensors (Basel, Switzerland), 23(22):.

Global aging leads to a surge in neurological diseases. Quantitative gait analysis for the early detection of neurological diseases can effectively reduce the impact of the diseases. Recently, extensive research has focused on gait-abnormality-recognition algorithms using a single type of portable sensor. However, these studies are limited by the sensor's type and the task specificity, constraining the widespread application of quantitative gait recognition. In this study, we propose a multimodal gait-abnormality-recognition framework based on a Convolutional Neural Network-Bidirectional Long Short-Term Memory (CNN-BiLSTM) network. The as-established framework effectively addresses the challenges arising from smooth data interference and lengthy time series by employing an adaptive sliding window technique. Then, we convert the time series into time-frequency plots to capture the characteristic variations in different abnormality gaits and achieve a unified representation of the multiple data types. This makes our signal processing method adaptable to several types of sensors. Additionally, we use a pre-trained Deep Convolutional Neural Network (DCNN) for feature extraction, and the consequently established CNN-BiLSTM network can achieve high-accuracy recognition by fusing and classifying the multi-sensor input data. To validate the proposed method, we conducted diversified experiments to recognize the gait abnormalities caused by different neuropathic diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD). In the PDgait dataset, the framework achieved an accuracy of 98.89% in the classification of Parkinson's disease severity, surpassing DCLSTM's 96.71%. Moreover, the recognition accuracy of ALS, PD, and HD on the PDgait dataset was 100%, 96.97%, and 95.43% respectively, surpassing the majority of previously reported methods. These experimental results strongly demonstrate the potential of the proposed multimodal framework for gait abnormality identification. Due to the advantages of the framework, such as its suitability for different types of sensors and fewer training parameters, it is more suitable for gait monitoring in daily life and the customization of medical rehabilitation schedules, which will help more patients alleviate the harm caused by their diseases.

RevDate: 2023-11-27
CmpDate: 2023-11-27

Lapshina MA, Shevtsova EF, Grigoriev VV, et al (2023)

New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.

Molecules (Basel, Switzerland), 28(22):.

Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.

RevDate: 2023-11-27

Niazi SK (2023)

Non-Invasive Drug Delivery across the Blood-Brain Barrier: A Prospective Analysis.

Pharmaceutics, 15(11):.

Non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive procedures and devices have been developed or are currently being investigated to enhance drug delivery across the BBB. This paper presents a review and a prospective analysis of the art and science that address pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.

RevDate: 2023-11-25

Huang B, Liu X, Zhang T, et al (2023)

Increase in hnRNPA1 Expression Suffices to Kill Motor Neurons in Transgenic Rats.

International journal of molecular sciences, 24(22):.

A dominant mutation in hnRNPA1 causes amyotrophic lateral sclerosis (ALS), but it is not known whether this mutation leads to motor neuron death through increased or decreased function. To elucidate the relationship between pathogenic hnRNPA1 mutation and its native function, we created novel transgenic rats that overexpressed wildtype rat hnRNPA1 exclusively in motor neurons. This targeted expression of wildtype hnRNPA1 caused severe motor neuron loss and subsequent denervation muscle atrophy in transgenic rats that recapitulated the characteristics of ALS. These findings demonstrate that the augmentation of hnRNPA1 expression suffices to trigger motor neuron degeneration and the manifestation of ALS-like phenotypes. It is reasonable to infer that an amplification of an as-yet undetermined hnRNPA1 function plays a pivotal role in the pathogenesis of familial ALS caused by pathogenic hnRNPA1 mutation.

RevDate: 2023-11-25

Toader C, Dobrin N, Brehar FM, et al (2023)

From Recognition to Remedy: The Significance of Biomarkers in Neurodegenerative Disease Pathology.

International journal of molecular sciences, 24(22):.

With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.

RevDate: 2023-11-25

Lovatto M, Gonçalves-Vidigal MC, Vaz Bisneta M, et al (2023)

Responsiveness of Candidate Genes on CoPv01[CDRK]/PhgPv01[CD][RK] Loci in Common Bean Challenged by Anthracnose and Angular Leaf Spot Pathogens.

International journal of molecular sciences, 24(22):.

Anthracnose (ANT) and angular leaf spot (ALS) are significant diseases in common bean, leading to considerable yield losses under specific environmental conditions. The California Dark Red Kidney (CDRK) bean cultivar is known for its resistance to multiple races of both pathogens. Previous studies have identified the CoPv01[CDRK]/PhgPv01[CDRK] resistance loci on chromosome Pv01. Here, we evaluated the expression levels of ten candidate genes near the CoPv01[CDRK]/PhgPv01[CDRK] loci and plant defense genes using quantitative real-time PCR in CDRK cultivar inoculated with races 73 of Colletotrichum lindemuthianum and 63-39 of Pseudocercospora griseola. Gene expression analysis revealed that the Phvul.001G246300 gene exhibited the most elevated levels, showing remarkable 7.8-fold and 8.5-fold increases for ANT and ALS, respectively. The Phvul.001G246300 gene encodes an abscisic acid (ABA) receptor with pyrabactin resistance, PYR1-like (PYL) protein, which plays a central role in the crosstalk between ABA and jasmonic acid responses. Interestingly, our results also showed that the other defense genes were initially activated. These findings provide critical insights into the molecular mechanisms underlying plant defense against these diseases and could contribute to the development of more effective disease management strategies in the future.

RevDate: 2023-11-25

Lombardi M, Corrado L, Piola B, et al (2023)

Variability in Clinical Phenotype in TARDBP Mutations: Amyotrophic Lateral Sclerosis Case Description and Literature Review.

Genes, 14(11): pii:genes14112039.

Mutations in the 43 kDa transactive-response (TAR)-DNA-binding protein (TARDBP) are associated with 2-5% of familial Amyotrophic Lateral Sclerosis (ALS) cases. TAR DNA-Binding Protein 43 (TDP-43) is an RNA/DNA-binding protein involved in several cellular mechanisms (e.g., transcription, pre-mRNA processing, and splicing). Many ALS-linked TARDBP mutations have been described in the literature, but few phenotypic data on monogenic TARDBP-mutated ALS are available. In this paper, (1) we describe the clinical features of ALS patients carrying mutations in the TARDBP gene evaluated at the Tertiary ALS Center at Maggiore della Carità University Hospital, Novara, Italy, from 2010 to 2020 and (2) present the results of our review of the literature on this topic, analyzing data obtained for 267 patients and highlighting their main clinical and demographic features.

RevDate: 2023-11-25

Tourtourikov I, Dabchev K, Todorov T, et al (2023)

Navigating the ALS Genetic Labyrinth: The Role of MAPT Haplotypes.

Genes, 14(11): pii:genes14112023.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by wide clinical and biological heterogeneity, with a large proportion of ALS patients also exhibiting frontotemporal dementia (FTD) spectrum symptoms. This project aimed to characterize risk subtypes of the H1 haplotype within the MAPT (microtubule-associated protein tau) gene, according to their possible effect as a risk factor and as a modifying factor in relation to the age of disease onset. One hundred patients from Bulgaria with sporadic ALS were genotyped for the variants rs1467967, rs242557, rs1800547, rs3785883, rs2471738, and rs7521. Haploview 4.2 and SHEsisPlus were used to reconstruct haplotype frequencies using genotyping data from the 1000 Genomes project as controls. Genotype-phenotype correlation was investigated in the context of age of disease onset and risk of disease development. While the individual variants of the subtypes do not influence the age of onset of the disease, a correlation was found between the specific haplotype GGAGCA (H1b) and the risk of developing sALS, with results showing that individuals harboring this haplotype have a nearly two-fold increased risk of developing sALS compared to other H1 subtypes. The results from this study suggest that fine transcriptional regulation at the MAPT locus can influence the risk of ALS.

RevDate: 2023-11-25

Genin EC, Abou-Ali M, V Paquis-Flucklinger (2023)

Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis.

Genes, 14(11): pii:genes14111981.

Mitochondrial dysfunction occurs in numerous neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), where it contributes to motor neuron (MN) death. Of all the factors involved in ALS, mitochondria have been considered as a major player, as secondary mitochondrial dysfunction has been found in various models and patients. Abnormal mitochondrial morphology, defects in mitochondrial dynamics, altered activities of respiratory chain enzymes and increased production of reactive oxygen species have been described. Moreover, the identification of CHCHD10 variants in ALS patients was the first genetic evidence that a mitochondrial defect may be a primary cause of MN damage and directly links mitochondrial dysfunction to the pathogenesis of ALS. In this review, we focus on the role of mitochondria in ALS and highlight the pathogenic variants of ALS genes associated with impaired mitochondrial functions. The multiple pathways demonstrated in ALS pathogenesis suggest that all converge to a common endpoint leading to MN loss. This may explain the disappointing results obtained with treatments targeting a single pathological process. Fighting against mitochondrial dysfunction appears to be a promising avenue for developing combined therapies in the future.

RevDate: 2023-11-25

O'Day DH (2023)

Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets.

Journal of clinical medicine, 12(22): pii:jcm12227045.

Seven major neurodegenerative diseases and their variants share many overlapping biomarkers that are calmodulin-binding proteins: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD), Huntington's disease (HD), Lewy body disease (LBD), multiple sclerosis (MS), and Parkinson's disease (PD). Calcium dysregulation is an early and persistent event in each of these diseases, with calmodulin serving as an initial and primary target of increased cytosolic calcium. Considering the central role of calcium dysregulation and its downstream impact on calcium signaling, calmodulin has gained interest as a major regulator of neurodegenerative events. Here, we show that calmodulin serves a critical role in neurodegenerative diseases via binding to and regulating an abundance of biomarkers, many of which are involved in multiple neurodegenerative diseases. Of special interest are the shared functions of calmodulin in the generation of protein biomarker aggregates in AD, HD, LBD, and PD, where calmodulin not only binds to amyloid beta, pTau, alpha-synuclein, and mutant huntingtin but also, via its regulation of transglutaminase 2, converts them into toxic protein aggregates. It is suggested that several calmodulin binding proteins could immediately serve as primary drug targets, while combinations of calmodulin binding proteins could provide simultaneous insight into the onset and progression of multiple neurodegenerative diseases.

RevDate: 2023-11-25

Goto S, Maeda N, Uehara K, et al (2023)

Effect of Segmented Optical Axial Length on the Performance of New-Generation Intraocular Lens Power Calculation Formulas in Extremely Long Eyes.

Journal of clinical medicine, 12(22): pii:jcm12226959.

PURPOSE: To evaluate the performance of traditional vergence formulas with segmented axial length (AL) compared to traditional composite AL in extremely long eyes, and to determine whether the segmented AL can be extended to the new-generation formulas, including the Barrett Universal II, Emmetropia Verifying Optical 2.0 (EVO2), Hill-RBF 3.0 (Hill3), Kane, and Ladas Super formula (LSF) formulas in extremely long eyes.

SETTING: National Hospital. Organization, Tokyo Medical Center, Japan.

DESIGN: Retrospective case series.

METHODS: Consecutive patients who underwent uncomplicated cataract surgery implanted with a three-piece intraocular lens between December 2015 and March 2021 were retrospectively reviewed. The composite AL was measured with a swept-source optical coherence tomography (SS-OCT) biometer using a mean refractive index. The segmented AL was calculated by summing the geometric lengths of the ocular segments (cornea, aqueous, lens, and vitreous) using multiple specific refractive indices based on the data obtained by the SS-OCT-based biometer. When refraction was measured at three months postoperatively, the median absolute errors (MedAEs) were calculated with two ALs for each formula.

RESULTS: The study included 31 eyes of 22 patients. The segmented AL (30.45 ± 1.23 mm) was significantly shorter than the composite AL (30.71 ± 1.28 mm, p < 0.001). The MedAEs were significantly reduced when using segmented AL for SRK/T, Haigis, Hill3, and LSF, compared to those obtained using composite AL (0.38 vs. 0.62, 0.48 vs. 0.79, 0.50 vs. 0.90, 0.34 vs. 0.61, p < 0.001 for all formulas, respectively). On the contrary, the MedAE obtained by Kane with segmented AL was significantly worse compared to the one with composite AL (0.35 vs. 0.27, p = 0.03).

CONCLUSION: In extremely high myopic eyes, the segmented AL improves the performance of SRK/T, Haigis, Hill3, and LSF formulas compared to the composite AL, while the segmented AL worsens the prediction accuracy of the Kane formula.

RevDate: 2023-11-25

Yang J, Xin C, Huo J, et al (2023)

Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis.

Brain sciences, 13(11): pii:brainsci13111531.

BACKGROUND: Currently, there is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Many biomarkers have been proposed, but because ALS is a clinically heterogeneous disease with an unclear etiology, biomarker discovery for ALS has been challenging due to the lack of specificity of these biomarkers. In recent years, the role of autophagy in the development and treatment of ALS has become a research hotspot. In our previous studies, we found that the expression of RabGGTase (low RABGGTB expression and no change in RABGGTA) is lower in the lumbar and thoracic regions of spinal cord motoneurons in SOD1G93A mice compared with WT (wild-type) mice groups, and upregulation of RABGGTB promoted prenylation modification of Rab7, which promoted autophagy to protect neurons by degrading SOD1. Given that RabGGTase is associated with autophagy and autophagy is associated with inflammation, and based on the above findings, since peripheral blood mononuclear cells are readily available from patients with ALS, we proposed to investigate the expression of RabGGTase in peripheral inflammatory cells.

METHODS: Information and venous blood were collected from 86 patients diagnosed with ALS between January 2021 and August 2023. Flow cytometry was used to detect the expression of RABGGTB in monocytes from peripheral blood samples collected from patients with ALS and healthy controls. Extracted peripheral blood mononuclear cells (PBMCs) were differentiated in vitro into macrophages, and then the expression of RABGGTB was detected by immunofluorescence. RABGGTB levels in patients with ALS were analyzed to determine their impact on disease progression.

RESULTS: Using flow cytometry in monocytes and immunofluorescence in macrophages, we found that RABGGTB expression in the ALS group was significantly higher than in the control group. Age, sex, original location, disease course, C-reactive protein (CRP), and interleukin-6 (IL-6) did not correlate with the ALS functional rating scale-revised (ALSFRS-R), whereas the RABGGTB level was significantly correlated with the ALSFRS-R. In addition, multivariate analysis revealed a significant correlation between RABGGTB and ALSFRS-R score. Further analysis revealed a significant correlation between RABGGTB expression levels and disease progression levels (ΔFS).

CONCLUSIONS: The RABGGTB level was significantly increased in patients with ALS compared with healthy controls. An elevated RABGGTB level in patients with ALS is associated with the rate of progression in ALS, suggesting that elevated RABGGTB levels in patients with ALS may serve as an indicator for tracking ALS progression.

RevDate: 2023-11-25

Wu CM, Chen YJ, Chen SC, et al (2023)

Creating an AI-Enhanced Morse Code Translation System Based on Images for People with Severe Disabilities.

Bioengineering (Basel, Switzerland), 10(11): pii:bioengineering10111281.

(1) Background: Patients with severe physical impairments (spinal cord injury, cerebral palsy, amyotrophic lateral sclerosis) often have limited mobility due to physical limitations, and may even be bedridden all day long, losing the ability to take care of themselves. In more severe cases, the ability to speak may even be lost, making even basic communication very difficult. (2) Methods: This research will design a set of image-assistive communication equipment based on artificial intelligence to solve communication problems of daily needs. Using artificial intelligence for facial positioning, and facial-motion-recognition-generated Morse code, and then translating it into readable characters or commands, it allows users to control computer software by themselves and communicate through wireless networks or a Bluetooth protocol to control environment peripherals. (3) Results: In this study, 23 human-typed data sets were subjected to recognition using fuzzy algorithms. The average recognition rates for expert-generated data and data input by individuals with disabilities were 99.83% and 98.6%, respectively. (4) Conclusions: Through this system, users can express their thoughts and needs through their facial movements, thereby improving their quality of life and having an independent living space. Moreover, the system can be used without touching external switches, greatly improving convenience and safety.

RevDate: 2023-11-25

Duranti E, C Villa (2023)

Muscle Involvement in Amyotrophic Lateral Sclerosis: Understanding the Pathogenesis and Advancing Therapeutics.

Biomolecules, 13(11): pii:biom13111582.

Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.

RevDate: 2023-11-25

Jauregui C, Blanco-Luquin I, Macías M, et al (2023)

Exploring the Disease-Associated Microglia State in Amyotrophic Lateral Sclerosis.

Biomedicines, 11(11): pii:biomedicines11112994.

BACKGROUND: Neuroinflammation, and specifically microglia, plays an important but not-yet well-understood role in the pathophysiology of amyotrophic lateral sclerosis (ALS), constituting a potential therapeutic target for the disease. Recent studies have described the involvement of different microglial transcriptional patterns throughout neurodegenerative processes, identifying a new state of microglia: disease-associated microglia (DAM). The aim of this study is to investigate expression patterns of microglial-related genes in ALS spinal cord.

METHODS: We analyzed mRNA expression levels via RT-qPCR of several microglia-related genes in their homeostatic and DAM state in postmortem tissue (anterior horn of the spinal cord) from 20 subjects with ALS-TDP43 and 19 controls donors from the Navarrabiomed Biobank.

RESULTS: The expression levels of TREM2, MS4A, CD33, APOE and TYROBP were found to be elevated in the spinal cord from ALS subjects versus controls (p-value < 0.05). However, no statistically significant gene expression differences were observed for TMEM119, SPP1 and LPL.

CONCLUSIONS: This study suggests that a DAM-mediated inflammatory response is present in ALS, and TREM2 plays a significant role in immune function of microglia. It also supports the role of C33 and MS4A in the physiopathology of ALS.

RevDate: 2023-11-25

Seki S, Kitaoka Y, Kawata S, et al (2023)

Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy.

Biomedicines, 11(11): pii:biomedicines11112967.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons.

RevDate: 2023-11-25

Reddy VP (2023)

Oxidative Stress in Health and Disease.

Biomedicines, 11(11): pii:biomedicines11112925.

Oxidative stress, resulting from the excessive intracellular accumulation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other free radical species, contributes to the onset and progression of various diseases, including diabetes, obesity, diabetic nephropathy, diabetic neuropathy, and neurological diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Oxidative stress is also implicated in cardiovascular disease and cancer. Exacerbated oxidative stress leads to the accelerated formation of advanced glycation end products (AGEs), a complex mixture of crosslinked proteins and protein modifications. Relatively high levels of AGEs are generated in diabetes, obesity, AD, and other I neurological diseases. AGEs such as N[e]-carboxymethyllysine (CML) serve as markers for disease progression. AGEs, through interaction with receptors for advanced glycation end products (RAGE), initiate a cascade of deleterious signaling events to form inflammatory cytokines, and thereby further exacerbate oxidative stress in a vicious cycle. AGE inhibitors, AGE breakers, and RAGE inhibitors are therefore potential therapeutic agents for multiple diseases, including diabetes and AD. The complexity of the AGEs and the lack of well-established mechanisms for AGE formation are largely responsible for the lack of effective therapeutics targeting oxidative stress and AGE-related diseases. This review addresses the role of oxidative stress in the pathogenesis of AGE-related chronic diseases, including diabetes and neurological disorders, and recent progress in the development of therapeutics based on antioxidants, AGE breakers and RAGE inhibitors. Furthermore, this review outlines therapeutic strategies based on single-atom nanozymes that attenuate oxidative stress through the sequestering of reactive oxygen species (ROS) and reactive nitrogen species (RNS).

RevDate: 2023-11-25

Fu RH (2023)

Pectolinarigenin Improves Oxidative Stress and Apoptosis in Mouse NSC-34 Motor Neuron Cell Lines Induced by C9-ALS-Associated Proline-Arginine Dipeptide Repeat Proteins by Enhancing Mitochondrial Fusion Mediated via the SIRT3/OPA1 Axis.

Antioxidants (Basel, Switzerland), 12(11): pii:antiox12112008.

Amyotrophic lateral sclerosis (ALS) is considered a fatal progressive degeneration of motor neurons (MN) caused by oxidative stress and mitochondrial dysfunction. There are currently no treatments available. The most common inherited form of ALS is the C9orf72 mutation (C9-ALS). The proline-arginine dipeptide repeat protein (PR-DPR) produced by C9-ALS has been confirmed to be a functionally acquired pathogenic factor that can cause increased ROS, mitochondrial defects, and apoptosis in motor neurons. Pectolinarigenin (PLG) from the traditional medicinal herb Linaria vulgaris has antioxidant and anti-apoptotic properties. I established a mouse NSC-34 motor neuron cell line model expressing PR-DPR and confirmed the neuroprotective effect of PLG. The results showed that ROS production and apoptosis caused by PR-DPR could be improved by PLG treatment. In terms of mechanism research, PR-DPR inhibited the activity of the mitochondrial fusion proteins OPA1 and mitofusin 2. Conversely, the expression of fission protein fission 1 and dynamin-related protein 1 (DRP1) increased. However, PLG treatment reversed these effects. Furthermore, I found that PLG increased the expression and deacetylation of OPA1. Deacetylation of OPA1 enhances mitochondrial fusion and resistance to apoptosis. Finally, transfection with Sirt3 small interfering RNA abolished the neuroprotective effects of PLG. In summary, the mechanism by which PLG alleviates PR-DPR toxicity is mainly achieved by activating the SIRT3/OPA1 axis to regulate the balance of mitochondrial dynamics. Taken together, the potential of PLG in preclinical studies for C9-ALS drug development deserves further evaluation.

RevDate: 2023-11-25

Martinez A, Lamaizon CM, Valls C, et al (2023)

c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.

Antioxidants (Basel, Switzerland), 12(11): pii:antiox12112007.

The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.

RevDate: 2023-11-25

Fröhlich A, Pfaff AL, Bubb VJ, et al (2023)

Transcriptomic profiling of cerebrospinal fluid identifies ALS pathway enrichment and RNA biomarkers in MND individuals.

Experimental biology and medicine (Maywood, N.J.) [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and the most common form of motor neurone disease (MND) which is characterized by the damage and death of motor neurons in the brain and spinal cord of affected individuals. Due to the heterogeneity of the disease, a better understanding of the interaction between genetics and biochemistry with the identification of biomarkers is crucial for therapy development. In this study, we used cerebrospinal fluid (CSF) RNA-sequencing data from the New York Genome Center (NYGC) ALS Consortium and analyzed differential gene expression between 47 MND individuals and 29 healthy controls. Pathway analysis showed that the affected genes are enriched in many pathways associated with ALS, including nucleocytoplasmic transport, autophagy, and apoptosis. Moreover, we assessed differential expression on both gene- and transcript-based levels and demonstrate that the expression of previously identified potential biomarkers, including CAPG, CCL3, and MAP2, was significantly higher in MND individuals. Ultimately, this study highlights the transcriptomic composition of CSF which enables insights into changes in the brain in ALS and therefore increases the confidence in the use of CSF for biomarker development.

RevDate: 2023-11-24

Genge A, Wainwright S, C Vande Velde (2023)

Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.

Amyotrophic lateral sclerosis & frontotemporal degeneration [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.

RevDate: 2023-11-24

Kuan LH, Parnianpour P, Kushol R, et al (2023)

Accurate personalized survival prediction for amyotrophic lateral sclerosis patients.

Scientific reports, 13(1):20713.

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Accurately predicting the survival time for ALS patients can help patients and clinicians to plan for future treatment and care. We describe the application of a machine-learned tool that incorporates clinical features and cortical thickness from brain magnetic resonance (MR) images to estimate the time until a composite respiratory failure event for ALS patients, and presents the prediction as individual survival distributions (ISDs). These ISDs provide the probability of survival (none of the respiratory failures) at multiple future time points, for each individual patient. Our learner considers several survival prediction models, and selects the best model to provide predictions. We evaluate our learned model using the mean absolute error margin (MAE-margin), a modified version of mean absolute error that handles data with censored outcomes. We show that our tool can provide helpful information for patients and clinicians in planning future treatment.

RevDate: 2023-11-24

Ovsepian SV, O'Leary VB, S Martinez (2023)

Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates.

Brain structure & function [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.

RevDate: 2023-11-24

Metcalf JS, Banack SA, PA Cox (2023)

Cyanotoxin Analysis of Air Samples from the Great Salt Lake.

Toxins, 15(11): pii:toxins15110659.

The Great Salt Lake in Utah is the largest saline lake in the Western hemisphere and one of the largest terminal lakes in the world. Situated at the eastern edge of the Great Basin, it is a remnant of the freshwater Lake Bonneville whose water level precipitously lowered about 12,000 years ago due to a natural break in Red Rock pass to the north. It contains a diverse assemblage of cyanobacteria which vary spatially dependent on salinity. In 1984, the waters of the Great Salt Lake occupied 8500 km[2]. Nearly four decades later, the waters occupy 2500 km[2]-a reduction in surface area of 71%. With predominantly westerly winds, there is a potential for the adjacent metropolitan residents to the east to be exposed to airborne cyanobacteria- and cyanotoxin-containing dust. During the summer and fall months of 2022, air and dried sediment samples were collected and assessed for the presence of BMAA which has been identified as a risk factor for ALS. Collection of air samples equivalent to a person breathing for 1 h resulted in BMAA and isomers being found in some air samples, along with their presence in exposed lakebed samples. There was no clear relationship between the presence of these toxins in airborne and adjacent lakebed samples, suggesting that airborne toxins may originate from diffuse rather than point sources. These findings confirm that continued low water levels in the Great Salt Lake may constitute an increasing health hazard for the 2.5 million inhabitants of communities along the Wasatch Front.

RevDate: 2023-11-24

Violi JP, Pu L, Pravadali-Cekic S, et al (2023)

Effects of the Toxic Non-Protein Amino Acid β-Methylamino-L-Alanine (BMAA) on Intracellular Amino Acid Levels in Neuroblastoma Cells.

Toxins, 15(11): pii:toxins15110647.

The cyanobacterial non-protein amino acid (AA) β-Methylamino-L-alanine (BMAA) is considered to be a neurotoxin. BMAA caused histopathological changes in brains and spinal cords of primates consistent with some of those seen in early motor neuron disease; however, supplementation with L-serine protected against some of those changes. We examined the impact of BMAA on AA concentrations in human neuroblastoma cells in vitro. Cells were treated with 1000 µM BMAA and intracellular free AA concentrations in treated and control cells were compared at six time-points over a 48 h culture period. BMAA had a profound effect on intracellular AA levels at specific time points but in most cases, AA homeostasis was re-established in the cell. The most heavily impacted amino acid was serine which was depleted in BMAA-treated cells from 9 h onwards. Correction of serine depletion could be a factor in the observation that supplementation with L-serine protects against BMAA toxicity in vitro and in vivo. AAs that could potentially be involved in protection against BMAA-induced oxidation such as histidine, tyrosine, and phenylalanine were depleted in cells at later time points.

RevDate: 2023-11-24

Metcalf JS, Banack SA, Wyatt PB, et al (2023)

A Direct Analysis of β-N-methylamino-l-alanine Enantiomers and Isomers and Its Application to Cyanobacteria and Marine Mollusks.

Toxins, 15(11): pii:toxins15110639.

Of the wide variety of toxic compounds produced by cyanobacteria, the neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) has attracted attention as a result of its association with chronic human neurodegenerative diseases such as ALS and Alzheimer's. Consequently, specific detection methods are required to assess the presence of BMAA and its isomers in environmental and clinical materials, including cyanobacteria and mollusks. Although the separation of isomers such as β-amino-N-methylalanine (BAMA), N-(2-aminoethyl)glycine (AEG) and 2,4-diaminobutyric acid (DAB) from BMAA has been demonstrated during routine analysis, a further compounding factor is the potential presence of enantiomers for some of these isomers. Current analytical methods for BMAA mostly do not discriminate between enantiomers, and the chiral configuration of BMAA in cyanobacteria is still largely unexplored. To understand the potential for the occurrence of D-BMAA in cyanobacteria, a chiral UPLC-MS/MS method was developed to separate BMAA enantiomers and isomers and to determine the enantiomeric configuration of endogenous free BMAA in a marine Lyngbya mat and two mussel reference materials. After extraction, purification and derivatization with N-(4-nitrophenoxycarbonyl)-l-phenylalanine 2-methoxyethyl ester ((S)-NIFE), both L- and D-BMAA were identified as free amino acids in cyanobacterial materials, whereas only L-BMAA was identified in mussel tissues. The finding of D-BMAA in biological environmental materials raises questions concerning the source and role of BMAA enantiomers in neurological disease.

RevDate: 2023-11-24

Barker MS, Ceslis A, Argall R, et al (2023)

Verbal and nonverbal fluency in amyotrophic lateral sclerosis.

Journal of neuropsychology [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is a multi-system disorder that commonly affects cognition and behaviour. Verbal fluency impairments are consistently reported in ALS patients, and we aimed to investigate whether this deficit extends beyond the verbal domain. We further aimed to determine whether deficits are underpinned by a primary intrinsic response generation impairment (i.e., a global reduction across tasks), potentially related to apathy, or an inability to maintain responding over time (i.e., a 'drop off' pattern). Twenty-two ALS patients and 21 demographically-matched controls completed verbal and nonverbal fluency tasks (phonemic/semantic word fluency, design fluency, gesture fluency and ideational fluency), requiring the generation of responses over a specified time period. Fluency performance was analysed in terms of the overall number of novel items produced, as well as the number of items produced in the first 'initiation' and the remaining 'maintenance' time periods. ALS patients' overall performance was not globally reduced across tasks. Patients were impaired only on meaningful gesture fluency, which requires the generation of gestures that communicate meaning (e.g., waving). On phonemic fluency, ALS patients showed a 'drop off' pattern of performance, where they had difficulty maintaining responding over time, but this pattern was not evident on the other fluency tasks. Apathy did not appear to be related to fluency performance. The selective meaningful gesture fluency deficit, in the context of preserved meaningless gesture fluency, highlights that the retrieval of action knowledge may be weakened in early ALS.

RevDate: 2023-11-23

López-Erauskin J, Bravo-Hernandez M, Presa M, et al (2023)

Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation.

Nature neuroscience [Epub ahead of print].

The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases.

RevDate: 2023-11-23

Del Pozo Vegas C, Zalama-Sánchez D, Sanz-Garcia A, et al (2023)

Prehospital acute life-threatening cardiovascular disease in elderly: an observational, prospective, multicentre, ambulance-based cohort study.

BMJ open, 13(11):e078815.

OBJECTIVE: The aim was to explore the association of demographic and prehospital parameters with short-term and long-term mortality in acute life-threatening cardiovascular disease by using a hazard model, focusing on elderly individuals, by comparing patients under 75 years versus patients over 75 years of age.

DESIGN: Prospective, multicentre, observational study.

SETTING: Emergency medical services (EMS) delivery study gathering data from two back-to-back studies between 1 October 2019 and 30 November 2021. Six advanced life support (ALS), 43 basic life support and five hospitals in Spain were considered.

PARTICIPANTS: Adult patients suffering from acute life-threatening cardiovascular disease attended by the EMS.

The primary outcome was in-hospital mortality from any cause within the first to the 365 days following EMS attendance. The main measures included prehospital demographics, biochemical variables, prehospital ALS techniques used and syndromic suspected conditions.

RESULTS: A total of 1744 patients fulfilled the inclusion criteria. The 365-day cumulative mortality in the elderly amounted to 26.1% (229 cases) versus 11.6% (11.6%) in patients under 75 years old. Elderly patients (≥75 years) presented a twofold risk of mortality compared with patients ≤74 years. Life-threatening interventions (mechanical ventilation, cardioversion and defibrillation) were also related to a twofold increased risk of mortality. Importantly, patients suffering from acute heart failure presented a more than twofold increased risk of mortality.

CONCLUSIONS: This study revealed the prehospital variables associated with the long-term mortality of patients suffering from acute cardiovascular disease. Our results provide important insights for the development of specific codes or scores for cardiovascular diseases to facilitate the risk of mortality characterisation.

RevDate: 2023-11-23

Ayoubi R, Ryan J, Biddle MS, et al (2023)

Scaling of an antibody validation procedure enables quantification of antibody performance in major research applications.

eLife, 12: pii:91645.

Antibodies are critical reagents to detect and characterize proteins. It is commonly understood that many commercial antibodies do not recognize their intended targets, but information on the scope of the problem remains largely anecdotal, and as such, feasibility of the goal of at least one potent and specific antibody targeting each protein in a proteome cannot be assessed. Focusing on antibodies for human proteins, we have scaled a standardized characterization approach using parental and knockout cell lines (Laflamme et al., 2019) to assess the performance of 614 commercial antibodies for 65 neuroscience-related proteins. Side-by-side comparisons of all antibodies against each target, obtained from multiple commercial partners, have demonstrated that: (i) more than 50% of all antibodies failed in one or more applications, (ii) yet, ~50-75% of the protein set was covered by at least one high-performing antibody, depending on application, suggesting that coverage of human proteins by commercial antibodies is significant; and (iii) recombinant antibodies performed better than monoclonal or polyclonal antibodies. The hundreds of underperforming antibodies identified in this study were found to have been used in a large number of published articles, which should raise alarm. Encouragingly, more than half of the underperforming commercial antibodies were reassessed by the manufacturers, and many had alterations to their recommended usage or were removed from the market. This first study helps demonstrate the scale of the antibody specificity problem but also suggests an efficient strategy toward achieving coverage of the human proteome; mine the existing commercial antibody repertoire, and use the data to focus new renewable antibody generation efforts.

RevDate: 2023-11-24

Ragagnin AMG, Sundaramoorthy V, Farzana F, et al (2023)

ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation.

Scientific reports, 13(1):20467.

Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative condition that is part of the same disease spectrum as frontotemporal dementia (FTD). Mutations in the CCNF gene, encoding cyclin F, are present in both sporadic and familial ALS and FTD. However, the pathophysiological mechanisms underlying neurodegeneration remain unclear. Proper functioning of the endoplasmic reticulum (ER) and Golgi apparatus compartments is essential for normal physiological activities and to maintain cellular viability. Here, we demonstrate that ALS/FTD-associated variant cyclin F[S621G] inhibits secretory protein transport from the ER to Golgi apparatus, by a mechanism involving dysregulation of COPII vesicles at ER exit sites. Consistent with this finding, cyclin F[S621G] also induces fragmentation of the Golgi apparatus and activates ER stress, ER-associated degradation, and apoptosis. Induction of Golgi fragmentation and ER stress were confirmed with a second ALS/FTD variant cyclin F[S195R], and in cortical primary neurons. Hence, this study provides novel insights into pathogenic mechanisms associated with ALS/FTD-variant cyclin F, involving perturbations to both secretory protein trafficking and ER-Golgi homeostasis.

RevDate: 2023-11-22

Wu F, Malek AM, Buchanich JM, et al (2023)

Exposure to ambient air toxicants and the risk of amyotrophic lateral sclerosis (ALS): A matched case control study.

Environmental research pii:S0013-9351(23)02523-9 [Epub ahead of print].

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with few risk factors identified and no known cure. Gene-environment interaction is hypothesized especially for sporadic ALS cases (90-95%) which are of unknown etiology. We aimed to investigate risk factors for ALS including exposure to ambient air toxics.

METHODS: This population-based case-control study included 267 ALS cases (from the United States [U.S.] Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry National ALS Registry and Biorepository) and 267 age, sex, and county-matched controls identified via a commercial database. Exposure assessment for 34 ambient air toxicants was performed by assigning census tract-level U.S. Environmental Protection Agency (EPA) 2011 National Air Toxics Assessment (NATA) data to participants' residential ZIP codes. Conditional logistic regression was used to compute adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for individual compounds, chemical classes, and overall exposure. Sensitivity analyses using both conditional logistic regression and Bayesian grouped weighted quartile sum (GWQS) models were performed to assess the integrity of findings.

RESULTS: Using the 2011 NATA, the highest exposure quartile (Q4) compared to the lowest (Q1) of vinyl chloride (aOR = 6.00, 95% CI:1.87-19.25), 2,4-dinitrotoluene (aOR = 5.45, 95% CI: 1.53-19.36), cyanide (aOR = 4.34, 95% CI: 1.52-12.43), cadmium (aOR = 3.30, 95% CI: 1.11-9.77), and carbon disulfide (aOR = 2.98, 95% CI:1.00-8.91) was associated with increased odds of ALS. Residential air selenium showed an inverse association with ALS (second quartile [Q2] vs. Q1: aOR = 0.38, 95% CI: 0.18-0.79). Additionally, residential exposure to organic/chlorinated solvents (Q4 vs Q1: aOR = 2.62, 95% CI: 1.003-6.85) was associated with ALS.

CONCLUSIONS: Our findings using the 2011 NATA linked by census tract to residential area provide evidence of increased ALS risk in cases compared to controls for 2,4-dinitrotoluene, vinyl chloride, cyanide, and the organic/chlorinated solvents class. This underscores the importance of ongoing surveillance of potential exposures for at-risk populations.

RevDate: 2023-11-22

Li L, Lei T, Xing C, et al (2023)

Advances in microfluidic chips targeting toxic aggregation proteins for neurodegenerative diseases.

International journal of biological macromolecules pii:S0141-8130(23)05207-8 [Epub ahead of print].

Neurodegenerative diseases (NDs) are characterized by nervous system damage, often influenced by genetic and aging factors. Pathological analysis frequently reveals the presence of aggregated toxic proteins. The intricate and poorly understood origins of these diseases have hindered progress in early diagnosis and drug development. The development of novel in-vitro and in-vivo models could enhance our comprehension of ND mechanisms and facilitate clinical treatment advancements. Microfluidic chips are employed to establish three-dimensional culture conditions, replicating the human ecological niche and creating a microenvironment conducive to neuronal cell survival. The incorporation of mechatronic controls unifies the chip, cells, and culture medium optimizing living conditions for the cells. This study provides a comprehensive overview of microfluidic chip applications in drug and biomarker screening for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Our Lab-on-a-Chip system releases toxic proteins to simulate the pathological characteristics of neurodegenerative diseases, encompassing β-amyloid, α-synuclein, huntingtin, TAR DNA-binding protein 43, and Myelin Basic Protein. Investigating molecular and cellular interactions in vitro can enhance our understanding of disease mechanisms while minimizing harmful protein levels and can aid in screening potential therapeutic agents. We anticipate that our research will promote the utilization of microfluidic chips in both fundamental research and clinical applications for neurodegenerative diseases.

RevDate: 2023-11-24

Yang C, Qian C, Singh N, et al (2022)

ATD: Augmenting CP Tensor Decomposition by Self Supervision.

Advances in neural information processing systems, 35:32039-32052.

Tensor decompositions are powerful tools for dimensionality reduction and feature interpretation of multidimensional data such as signals. Existing tensor decomposition objectives (e.g., Frobenius norm) are designed for fitting raw data under statistical assumptions, which may not align with downstream classification tasks. In practice, raw input tensor can contain irrelevant information while data augmentation techniques may be used to smooth out class-irrelevant noise in samples. This paper addresses the above challenges by proposing augmented tensor decomposition (ATD), which effectively incorporates data augmentations and self-supervised learning (SSL) to boost downstream classification. To address the non-convexity of the new augmented objective, we develop an iterative method that enables the optimization to follow an alternating least squares (ALS) fashion. We evaluate our proposed ATD on multiple datasets. It can achieve 0.8% ~ 2.5% accuracy gain over tensor-based baselines. Also, our ATD model shows comparable or better performance (e.g., up to 15% in accuracy) over self-supervised and autoencoder baselines while using less than 5% of learnable parameters of these baseline models.

RevDate: 2023-11-22

Shimizu M, Shiraishi N, Tada S, et al (2023)

RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.

Science advances, 9(47):eadg3193.

Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.

RevDate: 2023-11-22

Yu L, Xu G, Zhou Q, et al (2023)

Biomechanical properties of the ascending aorta in patients with arterial hypertension by velocity vector imaging.

The international journal of cardiovascular imaging [Epub ahead of print].

Aortic stiffness is an important risk factor for cardiovascular events and morbidity. Increased aortic stiffness is associated with an increase in cardiac and vascular hypertension-related organ damage. To evaluate the biomechanical properties of the ascending aorta (AA) in patients with arterial hypertension (AH) by velocity vector imaging (VVI). Ninety-five patients with AH and 53 normal healthy control participants were prospectively enrolled. AA biomechanical properties, i.e., ascending aortic global longitudinal strain (ALS), ascending aortic global circumferential strain (ACS), and fractional area change (FAC), were evaluated by VVI. Relative wall thickness (RWT) and left ventricular mass (LVM) were calculated. Pulsed Doppler early transmitral peak flow velocity (E), early diastolic mitral annular velocity (e'), left ventricular global longitudinal strain (GLS), distensibility (D) and stiffness index (SI) of AA were also obtained. The ALS, ACS and FAC were significantly lower in the AH patients, especially in those with ascending aorta dilatation (AAD), than in the normal healthy control subjects. The patients with AAD had a higher E/e' ratio, RWT, LVM and SI and a lower GLS and D than patients without AAD and normal healthy volunteers (p < 0.05). There were significant associations between biomechanical properties and D, SI, E/e' and GLS (ALS and D: r = 0.606, ALS and SI: r = - 0.645, ALS and E/e': r = - 0.489, ALS and GLS: r = 0.466, ACS and D: r = 0.564, ACS and SI: r = - 0.567, ACS and E/e': r = - 0.313, ACS and GLS: r = 0.320, FAC and D: r = 0.649, FAC and SI: r = - 0.601, FAC and E/e': r = - 0.504, FAC and GLS: r = 0.524, respectively, p < 0.05). The biomechanical properties of AA were impaired in patients with AH, especially patients with ascending aorta dilatation. Hypertension is associated with a high prevalence of diastolic and systolic dysfunction and increased arterial stiffness. Further study is needed to evaluate the clinical application of AA biomechanical properties by VVI.

RevDate: 2023-11-22

Ng SC, McCombie A, Frizelle F, et al (2023)

Influence of the type of anatomic resection on anastomotic leak after surgery for colon cancer.

ANZ journal of surgery [Epub ahead of print].

INTRODUCTION: Anastomotic leak (AL) after colon cancer resection is feared by surgeons because of its associated morbidity and mortality. Considerable research has been directed at predictive factors for AL, but not the anatomic type of colonic resection. Anecdotally, certain types of resection are associated with higher leak rates although there remains a paucity of data on this. This study aimed to determine the AL rate for different types of colon cancer resection to inform decisions regarding the choice of operation.

METHODOLOGY: Retrospective analysis of Bowel Cancer Outcome Registry (BCOR) for all colonic cancer resections with anastomosis between January 2007 and December 2020. Demographic, patient, tumour and outcome data were analysed. AL rates were compared among the different colonic procedures with both univariate and multivariate analysis.

RESULTS: 20 191 patients who underwent resection with anastomosis for cancer were included in this study. Of these 535 (2.6%) suffered ALs. While the univariate analysis found male sex, procedure type, symptomatic cancers, emergency surgery, unsupervised registrars, conversion to open surgery, medical complications and higher TNM staging were associated with AL, multivariate analysis, found only procedure type remained a significant predictor of AL (total colectomy (OR 4.049, P<0.001), subtotal colectomy (OR 2.477, P<0.001) and extended right hemicolectomy (OR 2.171, P < 0.001)).

CONCLUSION: AL is more common in extended colonic resections. With growing evidence of similar oncological outcomes between subtotal colectomy and left hemicolectomy for splenic flexure cancers, more limited resections should be considered. The type of colonic resection should be integrated into prediction tools for AL.

RevDate: 2023-11-21

Basith S, Manavalan B, G Lee (2023)

Unveiling local and global conformational changes and allosteric communications in SOD1 systems using molecular dynamics simulation and network analyses.

Computers in biology and medicine, 168:107688 pii:S0010-4825(23)01153-8 [Epub ahead of print].

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disorder affecting nerve cells in the brain and spinal cord that is caused by mutations in the superoxide dismutase 1 (SOD1) enzyme. ALS-related mutations cause misfolding, dimerisation instability, and increased formation of aggregates. The underlying allosteric mechanisms, however, remain obscure as far as details of their fundamental atomistic structure are concerned. Hence, this gap in knowledge limits the development of novel SOD1 inhibitors and the understanding of how disease-associated mutations in distal sites affect enzyme activity.

METHODS: We combined microsecond-scale based unbiased molecular dynamics (MD) simulation with network analysis to elucidate the local and global conformational changes and allosteric communications in SOD1 Apo (unmetallated form), Holo, Apo_CallA (mutant and unmetallated form), and Holo_CallA (mutant form) systems. To identify hotspot residues involved in SOD1 signalling and allosteric communications, we performed network centrality, community network, and path analyses.

RESULTS: Structural analyses showed that unmetallated SOD1 systems and cysteine mutations displayed large structural variations in the catalytic sites, affecting structural stability. Inter- and intra H-bond analyses identified several important residues crucial for maintaining interfacial stability, structural stability, and enzyme catalysis. Dynamic motion analysis demonstrated more balanced atomic displacement and highly correlated motions in the Holo system. The rationale for structural disparity observed in the disulfide bond formation and R143 configuration in Apo and Holo systems were elucidated using distance and dihedral probability distribution analyses.

CONCLUSION: Our study highlights the efficiency of combining extensive MD simulations with network analyses to unravel the features of protein allostery.

RevDate: 2023-11-21

Teplansky KJ, Wisler A, Goffman L, et al (2023)

The Impact of Stimulus Length in Tongue and Lip Movement Pattern Stability in Amyotrophic Lateral Sclerosis.

Journal of speech, language, and hearing research : JSLHR [Epub ahead of print].

PURPOSE: This study aimed to investigate the effect of stimulus signal length on tongue and lip motion pattern stability in speakers diagnosed with amyotrophic lateral sclerosis (ALS) compared to healthy controls.

METHOD: Electromagnetic articulography was used to derive articulatory motion patterns from individuals with mild (n = 27) and severe (n = 16) ALS and healthy controls (n = 25). The spatiotemporal index (STI) was used as a measure of articulatory stability. Two experiments were conducted to evaluate signal length effects on the STI: (a) the effect of the number of syllables on STI values and (b) increasing lengths of subcomponents of a single phrase. Two-way mixed analyses of variance were conducted to assess the effects of syllable length and group on the STI for the tongue tip (TT), tongue back (TB), and lower lip (LL).

RESULTS: Experiment 1 showed a significant main effect of syllable length (TT, p < .001; TB, p < .001; and LL, p < .001) and group (TT, p = .037; TB, p = .007; and LL, p = .017). TB and LL stability was generally higher with speech stimuli that included a greater number of syllables. Articulatory variability was significantly higher in speakers diagnosed with ALS compared to healthy controls. Experiment 2 showed a significant main effect of length (TT, p < .001; TB, p = .015; and LL, p < .001), providing additional support that STI values tend to be greater when calculated on longer speech signals.

CONCLUSIONS: Articulatory stability is influenced by the length of speech signals and manifests similarly in both healthy speakers and persons with ALS. TT stability may be significantly impacted by phonemic content due to greater movement flexibility. Compared to healthy controls, there was an increase in articulatory variability in those with ALS, which likely reflects deviations in speech motor control.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24463924.

RevDate: 2023-11-22

Nusrath S, Kalluru P, Shukla S, et al (2023)

Current status of indocyanine green fluorescent angiography in assessing perfusion of gastric conduit and esophago-gastric anastomosis.

International journal of surgery (London, England) pii:01279778-990000000-00793 [Epub ahead of print].

Anastomotic leak (AL) remains a significant complication after esophagectomy. Indocyanine green fluorescent angiography (ICG-FA) is a promising and safe technique for assessing gastric conduit (GC) perfusion intraoperatively. It provides detailed visualization of tissue perfusion and has demonstrated usefulness in esophageal surgery. GC perfusion analysis by ICG-FA is crucial in constructing the conduit and selecting the anastomotic site and enables surgeons to make necessary adjustments during surgery to potentially reduce ALs. However, anastomotic integrity involves multiple factors, and ICG-FA must be combined with optimization of patient and procedural factors to decrease AL rates. This review summarizes ICG-FA's current applications in assessing esophago-gastric anastomosis perfusion, including qualitative and quantitative analysis and different imaging systems. It also explores how fluorescent imaging could decrease ALs and aid clinicians in utilizing ICG-FA to improve esophagectomy outcomes.

RevDate: 2023-11-21

Simmonds E, Levine KS, Han J, et al (2023)

Sleep disturbances as risk factors for neurodegeneration later in life.

medRxiv : the preprint server for health sciences pii:2023.11.08.23298037.

UNLABELLED: The relationship between sleep disorders and neurodegeneration is complex and multi-faceted. Using over one million electronic health records (EHRs) from Wales, UK, and Finland, we mined biobank data to identify the relationships between sleep disorders and the subsequent manifestation of neurodegenerative diseases (NDDs) later in life. We then examined how these sleep disorders' severity impacts neurodegeneration risk. Additionally, we investigated how sleep attributed risk may compensate for the lack of genetic risk factors (i.e. a lower polygenic risk score) in NDD manifestation. We found that sleep disorders such as sleep apnea were associated with the risk of Alzheimer's disease (AD), amyotrophic lateral sclerosis, dementia, Parkinson's disease (PD), and vascular dementia in three national scale biobanks, with hazard ratios (HRs) ranging from 1.31 for PD to 5.11 for dementia. These sleep disorders imparted significant risk up to 15 years before the onset of an NDD. Cumulative number of sleep disorders in the EHRs were associated with a higher risk of neurodegeneration for dementia and vascular dementia. Sleep related risk factors were independent of genetic risk for Alzheimer's and Parkinson's, potentially compensating for low genetic risk in overall disease etiology. There is a significant multiplicative interaction regarding the combined risk of sleep disorders and Parkinson's disease. Poor sleep hygiene and sleep apnea are relatively modifiable risk factors with several treatment options, including CPAP and surgery, that could potentially reduce the risk of neurodegeneration. This is particularly interesting in how sleep related risk factors are significantly and independently enriched in manifesting NDD patients with low levels of genetic risk factors for these diseases.

HIGHLIGHTS: Sleep disorders, particularly sleep apnea, are associated with the risk of Alzheimer's disease, amyotrophic lateral sclerosis, dementia, Parkinson's disease, and vascular dementia in national scale biobanks.These sleep disorders imparted significant risk up to 15 years before the onset of a neurodegenerative disease.The cumulative number of sleep disorders in the electronic health records were associated with a higher risk of neurodegeneration related to dementia and vascular dementia.Sleep related risk factors are independent of genetic risk for Alzheimer's and Parkinson's, potentially compensating for low genetic risk in overall disease etiology.Significant multiplicative interaction exists regarding the combined risk of sleep disorders and Parkinson's disease.

RevDate: 2023-11-21

Glineburg MR, Yildirim E, Gomez N, et al (2023)

Stress granule formation helps to mitigate neurodegeneration.

bioRxiv : the preprint server for biology pii:2023.11.07.566060.

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP (rin in Drosophila) and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.

RevDate: 2023-11-21

Fan C, Hahn N, Kamdar F, et al (2023)

Plug-and-Play Stability for Intracortical Brain-Computer Interfaces: A One-Year Demonstration of Seamless Brain-to-Text Communication.

ArXiv pii:2311.03611.

Intracortical brain-computer interfaces (iBCIs) have shown promise for restoring rapid communication to people with neurological disorders such as amyotrophic lateral sclerosis (ALS). However, to maintain high performance over time, iBCIs typically need frequent recalibration to combat changes in the neural recordings that accrue over days. This requires iBCI users to stop using the iBCI and engage in supervised data collection, making the iBCI system hard to use. In this paper, we propose a method that enables self-recalibration of communication iBCIs without interrupting the user. Our method leverages large language models (LMs) to automatically correct errors in iBCI outputs. The self-recalibration process uses these corrected outputs ("pseudo-labels") to continually update the iBCI decoder online. Over a period of more than one year (403 days), we evaluated our Continual Online Recalibration with Pseudo-labels (CORP) framework with one clinical trial participant. CORP achieved a stable decoding accuracy of 93.84% in an online handwriting iBCI task, significantly outperforming other baseline methods. Notably, this is the longest-running iBCI stability demonstration involving a human participant. Our results provide the first evidence for long-term stabilization of a plug-and-play, high-performance communication iBCI, addressing a major barrier for the clinical translation of iBCIs.

RevDate: 2023-11-20

Slyne AD, SC Ó Murchú (2023)

Persistent inward currents: PICking apart the temporal changes in intrinsic motor neuron excitability in amyotrophic lateral sclerosis.

The Journal of physiology [Epub ahead of print].


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Amyotrophic Lateral Sclerosis, or ALS, is a rare, incurable neuro-degenerative disease, of unknown etiology. With this disease, both upper (brain) and lower (spinal cord) motor neurons progressively degenerate and die, rendering immobile the muscles that they innervated. For anyone with a need or desire to appreciate what is known about ALS, this book provides a good foundation. R. Robbins

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Collection of publications by R J Robbins

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