Progressive Loss Of Motor Function Research Articles

Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1+ ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.

The burden of disease in metachromatic leukodystrophy: results of a caregiver survey in the UK and Republic of Ireland.

Metachromatic Leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disease characterised by the progressive loss of motor function and severe decline in cognitive function. Limited information is available on the burden MLD places on patients and their families and the medical and social support these patients need. Three UK-based MLD patient organisations commissioned an online survey, and follow-up semi-structured interviews to describe and quantify these burdens across MLD subtypes, stage of disease (including end of life) and treatment status (untreated, gene therapy or hematopoietic stem cell transplant [HSCT]). A total of 24 patients were included in the study: thirteen late infantile (LI), six early juvenile (EJ), two late juvenile (LJ) and three adult onset (AO). Six patients had received gene therapy and one had received an HSCT. MLD patients receiving no disease modifying treatment bore a high symptom burden: 94% were wheelchair dependent, 88% required tube feeding, 88% were incontinent, 82% had lost their speech and all the children were either unable to attend education or needed specialist provision. Patients were reliant on numerous medical interventions and assistive equipment. All early-onset patients (LI and EJ) were wheelchair dependent, and tube fed, with all EJ patients having lost all speech. The caregiving responsibilities of parents impacted their employment, finances, relationships and health. Patients treated with gene therapy or HSCT were more mobile and were able to eat normally and two thirds of the children were able to attend mainstream school. The impact of illness that patients and their caregivers faced was extensive, and the level of care, amount of medication, number of hospital visits and educational support required were substantial. Financial constraints often brought about by inability to work also placed considerable strain on families. The study increases understanding of the burden of MLD on patients and their families, and the level of unmet need in the treatment of the disease.

The onset of motor learning impairments in Parkinson’s disease: a computational investigation

The basal ganglia (BG) is part of a basic feedback circuit regulating cortical function, such as voluntary movements control, via their influence on thalamocortical projections. BG disorders, namely Parkinson’s disease (PD), characterized by the loss of neurons in the substantia nigra, involve the progressive loss of motor functions. At the present, PD is incurable. Converging evidences suggest the onset of PD-specific pathology prior to the appearance of classical motor signs. This latent phase of neurodegeneration in PD is of particular relevance in developing more effective therapies by intervening at the earliest stages of the disease. Therefore, a key challenge in PD research is to identify and validate markers for the preclinical and prodromal stages of the illness. We propose a mechanistic neurocomputational model of the BG at a mesoscopic scale to investigate the behavior of the simulated neural system after several degrees of lesion of the substantia nigra, with the aim of possibly evaluating which is the smallest lesion compromising motor learning. In other words, we developed a working framework for the analysis of theoretical early-stage PD. While simulations in healthy conditions confirm the key role of dopamine in learning, in pathological conditions the network predicts that there may exist abnormalities of the motor learning process, for physiological alterations in the BG, that do not yet involve the presence of symptoms typical of the clinical diagnosis.

Motor Memory Consolidation Deficits in Parkinson's Disease: A Systematic Review with Meta-Analysis.

The ability to encode and consolidate motor memories is essential for persons with Parkinson's disease (PD), who usually experience a progressive loss of motor function. Deficits in memory encoding, usually expressed as poorer rates of skill improvement during motor practice, have been reported in these patients. Whether motor memory consolidation (i.e., motor skill retention) is also impaired is unknown. To determine whether motor memory consolidation is impaired in PD compared to neurologically intact individuals. We conducted a pre-registered systematic review (PROSPERO: CRD42020222433) following PRISMA guidelines that included 46 studies. Meta-analyses revealed that persons with PD have deficits in retaining motor skills (SMD = -0.17; 95% CI = -0.32, -0.02; p = 0.0225). However, these deficits are task-specific, affecting sensory motor (SMD = -0.31; 95% CI -0.47, -0.15; p = 0.0002) and visuomotor adaptation (SMD = -1.55; 95% CI = -2.32, -0.79; p = 0.0001) tasks, but not sequential fine motor (SMD = 0.17; 95% CI = -0.05, 0.39; p = 0.1292) and gross motor tasks (SMD = 0.04; 95% CI = -0.25, 0.33; p = 0.7771). Importantly, deficits became non-significant when augmented feedback during practice was provided, and additional motor practice sessions reduced deficits in sensory motor tasks. Meta-regression analyses confirmed that deficits were independent of performance during encoding, as well as disease duration and severity. Our results align with the neurodegenerative models of PD progression and motor learning frameworks and emphasize the importance of developing targeted interventions to enhance motor memory consolidation in PD.

Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by an abnormal polyglutamine expansion within the ataxin-3 protein (ATXN3). This leads to neurodegeneration of specific brain and spinal cord regions, resulting in a progressive loss of motor function. Despite neuronal death, non-neuronal cells, including astrocytes, are also involved in SCA3 pathogenesis. Astrogliosis is a common pathological feature in SCA3 patients and animal models of the disease. However, the contribution of astrocytes to SCA3 is not clearly defined. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant IP3R in mediating astrocyte somatic calcium signals, and genetically ablation of IP3R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP3R2 in the onset and progression of SCA3. For this, we tested whether IP3R2 depletion and the consecutive suppression of global astrocytic calcium signalling would lead to marked changes in the behavioral phenotype of a SCA3 mouse model, the CMVMJD135 transgenic line. This was achieved by crossing IP3R2 null mice with the CMVMJD135 mouse model and performing a longitudinal behavioral characterization of these mice using well-established motor-related function tests. Our results demonstrate that IP3R2 deletion in astrocytes does not modify SCA3 progression.

Parkinson’s disease detection and classification using EEG based on deep CNN-LSTM model

ABSTRACT The progressive loss of motor function in the brain is a hallmark of Parkinson’s disease (PD). Electroencephalogram (EEG) signals are commonly used for early diagnosis since they are associated with a brain disorder. This work aims to find a better way to represent electroencephalography (EEG) signals and enhance the classification accuracy of individuals with Parkinson’s disease using EEG signals. In this paper, we present two hybrid deep neural networks (DNN) that combine convolutional neural networks with long short-term memory to diagnose Parkinson’s disease using EEG signals, that is, through the establishment of parallel and series combined models. The deep CNN network is utilized to acquire the structural features of ECG signals and extract meaningful information from them, after which the signals are sent via a long short-term memory network to extract the features’ context dependency. The proposed architecture was able to achieve 97.6% specificity, 97.1% sensitivity, and 98.6% accuracy for a parallel model and 99.1% specificity, 98.5% sensitivity, and 99.7% accuracy for a series model, both in 3-class classification (PD patients with medication, PD patients without medication and healthy).

The systemic inhibition of the terminal complement system reduces neuroinflammation but does not improve motor function in mouse models of CMT1A with overexpressed PMP22.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary demyelinating neuropathy. This autosomal, dominantly inherited disease is caused by a duplication on chromosome 17p which includes the peripheral myelin protein 22 (PMP22) gene. There is clinical evidence that the disability in CMT1A is to a large extend due to axonal damage rather than demyelination. Over-expression of PMP22 is recently thought to impede cholesterol trafficking causing a total shutdown of local cholesterol and lipid synthesis in the Schwann cells, thus disturbing their ability to remyelinate. But there is a large variety in disease burden between CMT1A patients with the same genetic defect, indicating the presence of modifying factors that affect disease severity. One of these potential factors is the immune system. Several reports have described patients with co-occurrence of CMT1A with chronic inflammatory demyelinating disease or Guillain-Barré syndrome. We have previously shown in multiple animal models that the innate immune system and specifically the terminal complement system is a driver of inflammatory demyelination. To test the contribution of the terminal complement system to neuroinflammation and disease progression in CMT1A, we inhibited systemic complement C6 in two transgenic mouse models for CMT1A, the C3-PMP22 and C3-PMP22 c-JunP0Cre models. Both models over-express human PMP22, and one (C3-PMP22 c-JunP0Cre) also has a Schwann cell-specific knockout of c-Jun, a crucial regulator of myelination controlling autophagy. We found that systemic inhibition of C6 using antisense oligonucleotides affects the neuroinflammation, Rho GTPase and ERK/MAPK signalling pathways in the CMT1A mouse models. The cholesterol synthesis pathway remained unaffected. Analysis of motor function during treatment with C6 antisense oligonucleotides did not reveal any significant improvement in the CMT1A mouse models. This study shows that the contribution of the terminal complement system to progressive loss of motor function in the CMT1A mouse models tested is limited.

Interrogating the Metabolomic Profile of Amyotrophic Lateral Sclerosis in the Post-Mortem Human Brain by Infrared Matrix-Assisted Laser Desorption Electrospray Ionization (IR-MALDESI) Mass Spectrometry Imaging (MSI).

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease characterized by progressive loss of motor function with an average survival time of 2-5 years after diagnosis. Due to the lack of signature biomarkers and heterogenous disease phenotypes, a definitive diagnosis of ALS can be challenging. Comprehensive investigation of this disease is imperative to discovering unique features to expedite the diagnostic process and improve diagnostic accuracy. Here, we present untargeted metabolomics by mass spectrometry imaging (MSI) for comparing sporadic ALS (sALS) and C9orf72 positive (C9Pos) post-mortem frontal cortex human brain tissues against a control cohort. The spatial distribution and relative abundance of metabolites were measured by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) MSI for association to biological pathways. Proteomic studies on the same patients were completed via LC-MS/MS in a previous study, and results were integrated with imaging metabolomics results to enhance the breadth of molecular coverage. Utilizing METASPACE annotation platform and MSiPeakfinder, nearly 300 metabolites were identified across the sixteen samples, where 25 were identified as dysregulated between disease cohorts. The dysregulated metabolites were further examined for their relevance to alanine, aspartate, and glutamate metabolism, glutathione metabolism, and arginine and proline metabolism. The dysregulated pathways discussed are consistent with reports from other ALS studies. To our knowledge, this work is the first of its kind, reporting on the investigation of ALS post-mortem human brain tissue analyzed by multiomic MSI.

The importance of early diagnosis and views on newborn screening in metachromatic leukodystrophy: results of a Caregiver Survey in the UK and Republic of Ireland

Metachromatic Leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). MLD causes progressive loss of motor function and severe decline in cognitive function, leading to premature death. Early diagnosis of MLD provides the opportunity to begin treatment before the disease progresses and causes severe disability. MLD is not currently included in newborn screening (NBS) in the UK.This study consisted of an online survey, and follow-up semi-structured interviews open to MLD patients or caregivers, aged 18 years and over. The aims of the study were to understand the importance of early diagnosis and to establish the views of families and caregivers of patients with MLD on NBS.A total of 24 patients took part in the survey, representing 20 families (two families had two children with MLD, one family had three children with MLD). Following on from the survey, six parents participated in the interviews. Our data showed diagnostic delay from first symptoms was between 0 and 3 years, with a median of 1 year (n = 18); during this time deterioration was rapid, especially in earlier onset MLD. In patients with late infantile MLD (n = 10), 50% were wheelchair dependent, 30% were unable to speak, and 50% were tube fed when a diagnosis of MLD was confirmed. In patients with early juvenile MLD (n = 5), over half used a wheelchair some of the time, had uncontrollable crying, and difficulty speaking (all 60%) before or at the time of diagnosis. A high degree of support was expressed for NBS among caregivers, 95% described it as very or extremely important and 86% believed detection of MLD at birth would have changed their child’s future. One parent expressed their gratitude for an early diagnosis as a result of familial MLD screening offered at birth and how it had changed their child’s future: “It did and it absolutely has I will be forever grateful for his early diagnosis thanks to his older sister.”The rapid rate of deterioration in MLD makes it an essential candidate for NBS, particularly now the first gene therapy (Libmeldy™) has been approved by the European Medicines Agency. Libmeldy™ has also been recommended as a treatment option in England and Wales by the National Institute for Health and Care Excellence (NICE) and is being made available to patients in Scotland via the Scottish Medicines Consortium’s ultra-orphan pathway.

Mutations in Drosophila tRNA processing factors cause phenotypes similar to Pontocerebellar Hypoplasia.

ABSTRACTMature transfer (t)RNAs are generated by multiple RNA processing events, which can include the excision of intervening sequences. The tRNA splicing endonuclease (TSEN) complex is responsible for cleaving these intron-containing pre-tRNA transcripts. In humans, TSEN copurifies with CLP1, an RNA kinase. Despite extensive work on CLP1, its in vivo connection to tRNA splicing remains unclear. Interestingly, mutations in CLP1 or TSEN genes cause neurological diseases in humans that are collectively termed Pontocerebellar Hypoplasia (PCH). In mice, loss of Clp1 kinase activity results in premature death, microcephaly and progressive loss of motor function. To determine if similar phenotypes are observed in Drosophila, we characterized mutations in crowded-by-cid (cbc), the CLP1 ortholog, as well as in the fly ortholog of human TSEN54. Analyses of organismal viability, larval locomotion and brain size revealed that mutations in both cbc and Tsen54 phenocopy those in mammals in several details. In addition to an overall reduction in brain lobe size, we also found increased cell death in mutant larval brains. Ubiquitous or tissue-specific knockdown of cbc in neurons and muscles reduced viability and locomotor function. These findings indicate that we can successfully model PCH in a genetically-tractable invertebrate.

Ultra-high field (7T) functional magnetic resonance imaging in amyotrophic lateral sclerosis: a pilot study

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the central nervous system that results in a progressive loss of motor function and ultimately death. It is critical, yet also challenging, to develop non-invasive biomarkers to identify, localize, measure and/or track biological mechanisms implicated in ALS. Such biomarkers may also provide clues to identify potential molecular targets for future therapeutic trials. Herein we report on a pilot study involving twelve participants with ALS and nine age-matched healthy controls who underwent high-resolution resting state functional magnetic resonance imaging at an ultra-high field of 7 Tesla. A group-level whole-brain analysis revealed a disruption in long-range functional connectivity between the superior sensorimotor cortex (in the precentral gyrus) and bilateral cerebellar lobule VI. Post hoc analyses using atlas-derived left and right cerebellar lobule VI revealed decreased functional connectivity in ALS participants that predominantly mapped to bilateral postcentral and precentral gyri. Cerebellar lobule VI is a transition zone between anterior motor networks and posterior non-motor networks in the cerebellum, and is associated with a wide range of key functions including complex motor and cognitive processing tasks. Our observation of the involvement of cerebellar lobule VI adds to the growing number of studies implicating the cerebellum in ALS. Future avenues of scientific investigation should consider how high-resolution imaging at 7T may be leveraged to visualize differences in functional connectivity disturbances in various genotypes and phenotypes of ALS along the ALS-frontotemporal dementia spectrum.

Study of metal exposures and amyotrophic lateral sclerosis in Denmark

Background/Aim: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor function. Although several studies have investigated exposures to known neurotoxic metals, including lead and aluminium, to our knowledge there have been no previous studies of chromium, nickel, or iron occupational exposures and risk of ALS.Methods: We conducted a nested case-control study of occupational exposures to chromium, nickel, and iron and ALS diagnosis using population-based data from Denmark. We identified ALS cases from 1982-2013 and age- and sex-matched controls. Based on employment history and validated job exposure matrices (JEMs), we estimated cumulative exposures to these metals for 1639 ALS cases and 168,194 controls. We used sex-stratified unconditional logistic regression to obtain adjusted odds ratios (aOR) and 95% confidence intervals (CI) for quartile-categorized exposures, adjusting for residential location, socioeconomic status, and age. We also conducted multivariable models mutually adjusting for each metal.Results: Cumulative occupational chromium, nickel, and iron exposures were not association with ALS in men individually or mutually adjusted. Although chromium exposures in men showed higher adjusted odds for those with the 5-year lagged exposures in the third quartile (aOR=1.24; 95% CI 0.91, 1.69) and fourth quartile (aOR=1.19; 95% CI: 0.80, 1.76) compared to those with no exposure, differences did not reach statistical significance. We also observed higher odds of ALS in women with nickel exposures in the third quartile (aOR=2.21; 95% CI: 1.14, 4.28), but not for the fourth quartile (aOR=0.61; 95% CI: 0.23, 1.64). There were no other notable results in women.Conclusion: Though previous studies have suggested that levels of chromium, iron, and nickel can contribute to pathogenesis of neurodegenerative diseases, our findings do not suggest associations between occupational exposures to these metals and ALS. However, unavoidable non-differential misclassification from the use of JEMs, may have masked truly increased risk.

Dietary antioxidants associated with slower progression of parkinsonian signs in older adults

ABSTRACT Background and Objective: Progressive loss of motor function including parkinsonian signs is common in older adults. As diet may contribute to the motor decline, we tested the hypothesis that dietary intake of antioxidant nutrients (carotenoids, vitamin E and vitamin C) is related to the progression of parkinsonian signs in older adults. Research Design and Methods: A total of 682 participants without a clinical diagnosis of Parkinson’s Disease from the Rush Memory and Aging Project, were assessed annually over an average of 5.7 (±3.0) years using a 26-item modified version of the United Parkinson’s Disease Rating Scale. The scale assesses the severity of four parkinsonian signs (bradykinesia, gait, tremors, and rigidity) that were averaged to construct a global parkinsonian sign score. Nutrient intakes were assessed at baseline using a validated food frequency questionnaire. The associations between quintiles of antioxidant nutrient intakes and progression of parkinsonian signs were assessed using mixed effects models adjusted for age, sex, education, smoking. Results: In separate adjusted models, a slower rate of progressive parkinsonian signs was observed among those in the highest intake quintiles of total carotenoids (β= −0.06, 95%CI: −0.10 to −0.02,), beta-carotene from foods (β= −0.04, 95% CI:−0.08 to −0.0021), lutein-zeaxanthin (β= −0.05, 95%CI:−0.09 to −0.02), vitamin E from foods (β= −0.04, 95%CI:−0.08 to −0.01,) and vitamin C from foods (β= −0.06, 95%CI:−0.10 to −0.02), when compared to those in the lowest quintiles of intake. Conclusion: A higher level of dietary antioxidant nutrients may slow the rate of parkinsonian sign progression in older adults.

Influence of Aquatic Therapy in Children and Youth with Cerebral Palsy: A Qualitative Case Study in a Special Education School.

Cerebral palsy results in the progressive loss of motor functions, with a negative impact on daily activities and participation. Despite the well described benefits of aquatic therapy in children, little is known about the effects of the same in school settings. This study aimed to describe the experience of children and youth with cerebral palsy participating in an aquatic therapy program within a special education school considering their educational and therapeutic perspectives. A qualitative descriptive case study with embedded units was developed, comprising 27 participants. This study employed purposeful sampling to include children and youth with cerebral palsy from the Asociación Ayuda a la Paralisis Cerebral (APACE) special education school, together with their parents, the special education teachers, and health care professionals. Data were collected via non-participant observation, semi-structured and informal interviews, focus groups, and researcher field notes. A thematic analysis was conducted, revealing the following themes: (a) the connection with the environment; (b) postural improvements and mobility; (c) the opportunity to perform tasks; (d) learning and transfer. A motivating environment leads to physical, cognitive and social benefits, both at school and in the home. Aquatic therapy was viewed as a means for learning and participation. These findings may enhance understanding regarding the potential benefits of implementing multidisciplinary aquatic therapy programs in specialist school settings.

Niacin for Parkinson's disease

AbstractParkinson's disease (PD) is a neurodegenerative disease associated with progressive loss of motor function and cognitive decline occurring in 1% of the USA population. There is no cure for PD, and current treatment regimens are directed towards treating symptoms and not treating the underlying cause of the disease. Chronic neuroinflammation is associated with loss of neuronal cells, leading to motor and cognitive decline. Current clinical trials on drugs and nutraceuticals, such as coenzyme Q10 and niacin, are being carried out to delay progression and reduce damage by inflammatory molecules, such as reactive oxygen species and cytokines, in PD patients. In this review, we present available clinical trials and the role of niacin in reducing neuroinflammation in PD.

Evaluation of speed-accuracy trade-off in a computer task to identify motor difficulties in individuals with Duchenne Muscular Dystrophy - A cross-sectional study

IntroductionIndividuals with Duchenne Muscular Dystrophy (DMD) present with progressive loss of motor function which can impair both control of speed and accuracy of movement. Aimto evaluate movement time during a task at various levels of difficulty and to verify whether the level of difficulty affects the speed and/ or accuracy during the task. Methodsthe DMD group comprised of 17 individuals age matched with 17 individuals with typical development (TD group). The task evaluates the relationship between speed and accuracy, consisting of the execution of manual movements (using the mouse of the computer) aimed at a target at three different levels of difficulty (ID). ResultsA MANOVA demonstrated statistically significant differences in dispersion data and intercept values between the groups with greater movement time in the DMD group. An ANOVA indicated differences between groups for ID, except for when there was a higher accuracy demand (higher ID). In the other IDs that required lower accuracy demand, individuals in the DMD group had significantly longer movement time when compared to the TD group. ConclusionThese results show that the TD and DMD did not differ in the higher ID, therefore it can be concluded that for those with DMD, motor performance is more affected by speed than accuracy of movement.

Study of mixtures of organic solvent exposures and amyotrophic lateral sclerosis in Denmark

TPS 732: Neurological effects in adults, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Background/Aim: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by rapidly progressive loss of motor function. Previous studies of occupational solvent exposure and ALS were conflicting. However, none of these used objective, solvent-specific assessment such as job exposure matrices (JEMs) to estimate cumulative exposures. In this study, we investigate the association between occupational exposures to multiple organic solvents and odds of ALS. Methods: We conducted a nested case-control study of occupational solvent exposures - benzene, methylene chloride (MCH), toluene, trichloroethylene, perchloroethylene, and 1,1,1-trichloroethane - and ALS diagnosis using population-based data from Denmark. We identified ALS cases from 1982 to 2013 and age- and sex-matched controls. Employment history was obtained from the Danish Pension Fund. We estimated cumulative exposure to solvents based on exposure in 1639 ALS cases and 151,974 controls. We used sex-stratified conditional logistic regression to obtain adjusted odds ratios (aOR) and 95% confidence intervals (CI), for exposures categorized into quartiles and adjusting for residential location and socioeconomic status. We used weighted quantile sum (WQS) regression to further explore combined solvent exposures and risk of ALS in men with any solvent exposure. Results: Analysis for benzene and MCH exposures in men revealed higher adjusted odds for those with the highest quartile exposure unlagged: aOR=1.35 (95% CI 1.02, 1.80) and aOR=1.26 (95% CI: 1.01, 1.58), respectively, compared to those with no exposure. We observed no trends or notable results in women. Our WQS analysis revealed a significant increase for all exposure lag periods of 26 to 28% in odds of ALS for every one-unit increase in the derived solvent mixture index. Interestingly, the weights of MCH predominated the solvent mixture index for all lag periods. Conclusion: These findings support those of previously reported associations between ALS and solvent exposures and highlight the need to investigate exposure mixtures.

EP.77Real-world associations between motor function and lean body mass in the arms and legs in patients with Duchenne muscular dystrophy

Patients with Duchenne muscular dystrophy (DMD) have progressive loss of motor function and skeletal muscle mass. This study assessed real-world associations between motor function and % lean body mass in the arms and legs in boys with DMD. Using data from Cincinnati Children's Hospital and Medical Center (CCHMC), 2,514 assessments with data on both the functional motor scale (FMS) and dual energy X-ray absorptiometry (DEXA) lean body mass were available for n=576 patients (ages 2.8-32.5 years).

A Primer of Deuterium in Drug Design

A Primer of Deuterium in Drug Design

Regulation of lymphocyte trafficking in central nervous system autoimmunity.

CD4+ T helper (Th) cells play a central role in orchestrating protective immunity but also in autoimmunity. Multiple Sclerosis (MS) is a human autoimmune disease of the central nervous system (CNS) characterized by the infiltration of inflammatory lymphocytes and myeloid cells into the brain and spinal cord, leading to demyelination, axonal damage, and progressive loss of motor functions. The release of T cells in the circulation and their migration in the central nervous system are key and tightly regulated processes which have been targeted to decrease CD4+ T cell presence in the CNS and limit disease progression. Here, we review two of these pathways and discuss how their blockade modulate different subsets of CD4+ T cells.