Publications by authors named "Leonard H van den Berg"

428 Publications

A Road Map for Remote Digital Health Technology for Motor Neuron Disease.

J Med Internet Res 2021 Sep 22;23(9):e28766. Epub 2021 Sep 22.

Department of Neuroscience, Sheffield Institute for Translational Neuroscien, University of Sheffield, Sheffield, United Kingdom.

Despite recent and potent technological advances, the real-world implementation of remote digital health technology in the care and monitoring of patients with motor neuron disease has not yet been realized. Digital health technology may increase the accessibility to and personalization of care, whereas remote biosensors could optimize the collection of vital clinical parameters, irrespective of patients' ability to visit the clinic. To facilitate the wide-scale adoption of digital health care technology and to align current initiatives, we outline a road map that will identify clinically relevant digital parameters; mediate the development of benefit-to-burden criteria for innovative technology; and direct the validation, harmonization, and adoption of digital health care technology in real-world settings. We define two key end products of the road map: (1) a set of reliable digital parameters to capture data collected under free-living conditions that reflect patient-centric measures and facilitate clinical decision making and (2) an integrated, open-source system that provides personalized feedback to patients, health care providers, clinical researchers, and caregivers and is linked to a flexible and adaptable platform that integrates patient data in real time. Given the ever-changing care needs of patients and the relentless progression rate of motor neuron disease, the adoption of digital health care technology will significantly benefit the delivery of care and accelerate the development of effective treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/28766DOI Listing
September 2021

Current practices and barriers in gastrostomy indication in amyotrophic lateral sclerosis: a survey of ALS care teams in The Netherlands.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Sep 6:1-10. Epub 2021 Sep 6.

Department of Rehabilitation, Physical Therapy Science and Sports, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, the Netherlands.

Objective: To describe current practices and barriers and support needs in gastrostomy indication and decision-making amongst rehabilitation physicians of ALS care teams in the Netherlands. : Cross-sectional online survey of rehabilitation physicians of ALS care teams in the Netherlands. Survey items covered current practices in (i.e. indicators and criteria), , , and criteria for preferred ; and and in indication and decision-making. Descriptive analysis was used for quantitative responses, thematic, and content analysis for qualitative data. : Twenty-nine physicians (41%) of 27 ALS care teams (71%) responded. : physicians agreed on important indicators but not cutoff values/criteria. : optimizing nutritional status (100%), ensuring safe food-intake (72%), and reducing effort of meals (59%). : 52% introduces the topic early after diagnosis, 48% at indication. Criteria for included physician preference (69%), availability of service (21%), lower complication risk (17%), contraindication (59%), and patient preference (24%). Reported (69% of respondents) were: patient readiness (52%), timing of indication (31%), and organizational barriers (18%). (62%): evidence-based timing of indication (35%) and tailored patient education (31%). : There is practice variation in the timing of first introduction of gastrostomy and preferred method of placement, but agreement on goals and indicators . More evidence on optimal timing of gastrostomy placement is needed. However, until then early and regular discussion of the topic of gastrostomy and better patient information may promote patient readiness and support patient choice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2021.1973505DOI Listing
September 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Aug 30. Epub 2021 Aug 30.

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
August 2021

Informal Caregivers in Amyotrophic Lateral Sclerosis: A Multi-Centre, Exploratory Study of Burden and Difficulties.

Brain Sci 2021 Aug 20;11(8). Epub 2021 Aug 20.

Academic Unit of Neurology, School of Medicine, Trinity College Dublin, D02 PN40 Dublin, Ireland.

Amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) is a systemic and fatal neurodegenerative condition for which there is currently no cure. Informal caregivers play a vital role in supporting the person with ALS, and it is essential to support their wellbeing. This multi-centre, mixed methods descriptive exploratory study describes the complexity of burden and self-defined difficulties as described by the caregivers themselves. Quantitative and qualitative data were collected during face-to-face interviews with informal caregivers from centres in the Netherlands, England, and Ireland. Standardised measures assessed burden, quality of life, and psychological distress; furthermore, an open-ended question was asked about difficult aspects of caregiving. Most caregivers were female, spouse/partners, and lived with the person with ALS for whom they provided care. Significant differences between national cohorts were identified for burden, quality of life, and anxiety. Among the difficulties described were the practical issues associated with the caregiver role and emotional factors such as witnessing a patient's health decline, relationship change, and their own distress. The mixed-methods approach allows for a more nuanced understanding of the burden and difficulties experienced. It is important to generate an evidence base to support the psychosocial wellbeing and brain health of informal caregivers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci11081094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394559PMC
August 2021

Innovating Clinical Trials for Amyotrophic Lateral Sclerosis: Challenging the Established Order.

Neurology 2021 Sep 27;97(11):528-536. Epub 2021 Jul 27.

From the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000012545DOI Listing
September 2021

Venous creatinine as a biomarker for loss of fat-free mass and disease progression in patients with amyotrophic lateral sclerosis.

Eur J Neurol 2021 Jul 3. Epub 2021 Jul 3.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.

Background And Purpose: To establish the utility of venous creatinine as a biomarker to monitor loss of fat-free mass in patients with amyotrophic lateral sclerosis (ALS).

Methods: In this multicenter natural history study, body composition and venous creatinine were assessed in 107 patients with ALS and 52 healthy controls. Longitudinal patterns of venous creatinine and its association with the risk of death during follow-up were determined in a cohort of patients with ALS from Australia (n = 69) and the Netherlands (n = 38).

Results: The mean levels of venous creatinine were 75.78 ± 11.15 μmol/L for controls, 70.25 ± 12.81 μmol/L for Australian patients, and 59.95 ± 14.62 μmol/L for Dutch patients with ALS. The relationship between measures of venous creatinine and fat-free mass was similar between all groups (r = 0.36, p < 0.001). Within patients, fat-free mass declined by 0.31 (95% confidence interval [CI]: 0.22-0.40) kg/month, and venous creatinine declined by 0.52 (95% CI: 0.38-0.66) μmol/L/month, with a longitudinal correlation of 0.57 (95% CI: 0.35-0.76, p < 0.001). Lower levels of venous creatinine were associated with increased risk for earlier death in patients with ALS (hazard ratio = 0.94, 95% CI: 0.90-0.98, p = 0.007).

Conclusions: Venous creatinine is decreased in ALS and declines alongside a decline in fat-free mass over the course of the disease, and may serve as a practical marker to monitor the change of fat-free mass in patients with ALS. This could inform clinical care and provide an alternative endpoint for the evaluation of therapeutic interventions that focus on slowing the loss of fat-free mass and disease progression in ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ene.15003DOI Listing
July 2021

Duplications Are Associated With Progressive Muscular Atrophy, but Not With Multifocal Motor Neuropathy and Primary Lateral Sclerosis.

Neurol Genet 2021 Aug 22;7(4):e598. Epub 2021 Jun 22.

Department of Neurology and Neurosurgery (J.W.B., E.J.N.G., R.I.W., C.A.D.C., W.L.v.d.P., L.H.v.d.B.), UMC Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands; and MRC Holland (N.N.M., M.Z., P.W.J.v.V., R.S., R.V.), Amsterdam, the Netherlands.

Objective: To assess the association between copy number (CN) variation in the survival motor neuron () locus and multifocal motor neuropathy (MMN), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS) susceptibility and to determine the association of and CN with MMN, PMA, and PLS disease course.

Methods: In this monocenter study, we used multiplex ligation-dependent probe amplification to determine and CN in Dutch patients with MMN, PMA, and PLS and controls. We stratified clinical parameters for and CN. We analyzed and exons 1-6, intron 6, and exon 8 CN to study the genetic architecture of duplications.

Results: and CN were determined in 132 patients with MMN, 150 patients with PMA, 104 patients with PLS, and 956 control subjects. MMN and PLS were not associated with CN variation in or . By contrast, patients with PMA more often than controls carried duplications (≥3 copies, 12.0% vs 5.0%, odds ratio 2.69 (1.43-4.91), 0.0020). and CN status was not associated with MMN, PLS, or PMA disease course. In case of exon 7 duplications, exons 1-6, exon 8, and introns 6 and 7 were also duplicated, suggesting full duplications.

Conclusions: duplications are associated with PMA, but not with PLS and MMN. duplications in PMA are balanced duplications. The results of this study highlight the primary effect of altered CN on lower motor neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220964PMC
August 2021

Prognostic value of nerve ultrasonography: A prospective multicenter study on the natural history of chronic inflammatory neuropathies.

Eur J Neurol 2021 07 14;28(7):2327-2338. Epub 2021 May 14.

Department of Neurology and Clinical Neurophysiology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands.

Background And Objective: Nerve ultrasound is a promising new tool in chronic inflammatory neuropathies. The aim of this study was to determine its prognostic value in a prospective multicenter cohort study including incident and prevalent patients with CIDP and MMN.

Methods: We enrolled 126 patients with CIDP, and 72 with MMN; 71 were treatment-naive. Patients with chronic idiopathic axonal polyneuropathy (CIAP; n = 35) were considered as disease controls. Standardized neurological examination, questionnaires, and nerve ultrasonography were obtained at time of inclusion and 1-year follow-up. Nerve size development over time and correlation between nerve size and clinical outcome measures were determined using linear mixed effects models.

Results: Nerve size development over time was heterogeneous. Only in MMN was there a correlation between C5 nerve root size and deterioration of grip strength (-1.3 kPa/mm (95% confidence interval [CI] -2.3 to -0.2). No other significant correlations between nerve size and clinical outcome measures were found. In MMN, presence of nerve enlargement at inclusion predicted deterioration of grip strength, and MMN patients with enlargement confined to the brachial plexus seemed to have more favorable outcomes. No other predictive effects of sonographic nerve size were found.

Conclusions: The present study indicates that the natural course of nerve size development in CIDP and MMN is heterogeneous, and that the prognostic value of sonographic nerve enlargement is limited. It had some predictive effect in patients with MMN. Further research in specific subgroups of chronic inflammatory neuropathy is necessary to determine the usefulness of nerve ultrasonography after the diagnostic phase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ene.14885DOI Listing
July 2021

Associations between lifestyle and amyotrophic lateral sclerosis stratified by C9orf72 genotype: a longitudinal, population-based, case-control study.

Lancet Neurol 2021 05;20(5):373-384

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands. Electronic address:

Background: Amyotrophic lateral sclerosis (ALS) is considered to be caused by both genetic and environmental factors. The causal cascade is, however, not known. We aimed to assess lifestyle during the presymptomatic phase of ALS, stratified by C9orf72 mutation, and examine evidence supporting causality of lifestyle factors.

Methods: This study was a longitudinal, population-based, case-control study that used data from the Prospective ALS study the Netherlands. We included patients with a C9orf72 mutation (C9+ group), patients without a C9orf72 mutation (C9- group), and controls. Patients fulfilled the revised El Escorial criteria and were recruited through neurologists and rehabilitation physicians in the Netherlands as well as the Dutch Neuromuscular Patient Association and ALS Centrum website. 1322 population-based controls, matched for age and sex, were enrolled via the patients' general practitioners. Blood relatives or spouses of patients were not eligible as controls. We studied the relationship between ALS risk and smoking, alcohol, physical activity, body-mass index (BMI), and energy intake by the use of structured questionnaires. Smoking, physical activity, and BMI were longitudinally assessed up to 50 years before onset (defined as the period before onset of muscle weakness or bulbar symptoms for cases, or age at completing the questionnaire for controls). We calculated posterior probabilities (P(θ|x)) for causal effects of smoking, alcohol, and BMI, using Bayesian instrumental variable analyses.

Findings: Between Jan 1, 2006 and Jan 27, 2016, we included 143 patients in the C9+ group, 1322 patients in the C9- group, and 1322 controls. Compared with controls, cigarette pack-years (C9+ group mean difference from control 3·15, 95% CI 0·36 to 5·93, p=0·027; C9- group 3·20, 2·02 to 4·39, p<0·0001) and daily energy intake at symptom onset (C9+ group 712 kJ, 95% CI 212 to 1213, p=0·0053; C9- group 497, 295 to 700, p<0·0001) were higher in the C9+ and C9- groups, whereas current BMI (C9+ group -2·01 kg/m, 95% CI -2·73 to -1·29, p<0·0001; C9- group -1·35, -1·64 to -1·06, p<0·0001) and lifetime alcohol consumption (C9+ group -5388 units, 95% CI -9113 to -1663, p=0·0046; C9- group -2185, -3748 to -622, p=0·0062) were lower in the C9+ and C9- groups. Median BMI during the presymptomatic phase for the C9+ group was lower (-0·69 kg/m, 95% CI -1·24 to -0·13, p=0·015) and physical activity was similar (-348 metabolic equivalent of task [MET], 95% CI -966 to 270, p=0·27) to controls, whereas both the median BMI during the presymptomatic phase (0·27 kg/m, 95% CI 0·04 to 0·50, p=0·022) and physical activity (585 MET, 291 to 878, p=0·0001) were higher in the C9- group than controls. Longitudinal analyses showed more cigarette pack-years in the C9- (starting 47 years pre-onset) and C9+ (starting 24 years pre-onset) groups, and higher physical activity over time in the C9- group (starting >30 years pre-onset). BMI of the C9+ group increased more slowly and was significantly lower (starting at 36 years pre-onset) than in controls, whereas the BMI of the C9- group was higher than controls (23-49 years pre-onset, becoming lower 10 years pre-onset). Instrumental variable analyses supported causal effects of alcohol consumption (P(θ|x)=0·9347) and smoking (P(θ|x)=0·9859) on ALS in the C9- group. We found evidence supporting a causal effect of increased BMI at younger age (mean 33·8 years, SD 11·7) in the C9- group (P[θ|x]=0·9272), but not at older ages.

Interpretation: Lifestyle during the presymptomatic phase differs between patients with ALS and controls decades before onset, depends on C9- status, and is probably part of the presymptomatic causal cascade. Identification of modifiable disease-causing lifestyle factors offers opportunities to lower risk of developing neurodegenerative disease.

Funding: Netherlands ALS Foundation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(21)00042-9DOI Listing
May 2021

Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

Neurol Clin Pract 2021 Apr;11(2):147-157

Universitair Medisch Centrum Utrecht (EMJB, HSG, JI, MP, LHB, JHV, MAE), Department of Neurology, Utrecht, The Netherlands; Brighton and Sussex Medical School (AWB, ME, RB, PNL), Clinical Imaging Sciences Centre, Brighton, United Kingdom; Hurstwood Park Neurological Centre (AWB, ME, SJA, RB, AN), Haywards Heath, United Kingdom; Hospital Universitari i Politècnic La Fe (JFVC), ALS Unit, Department of Neurology, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (JFVC), Madrid, Spain; Department of Neurology (JP), Rostock University Medical Center and German Center for Neurodegenerative Diseases (DZNE), Germany; Department of Neurology (CAV), Haukeland University Hospital and Department of Clinical Medicine, Bergen, Norway; Department of Neurology (JPF), Hospital Clínico Universitario de Santiago, Santiago, Spain; Department of Neurology (MPP, MAAA), Hospital Universitari de Bellvitge, Barcelona, Spain; ALS/MND Centre (EDB, GL), 3rd Neurology Unit, Fondazione IRCCS Institute Neurologico Carlo Besta, Milan, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco" (GL), University of Milan, Milan, Italy; Department of Neurology and Neurosurgery (WBVRP, PVSS, ASBO), Federal University of São Paulo (UNIFESP), São Paulo, Brazil; National Institutes of Health (CT), National Human Genome Research Institute, Bethesda, United States of America; Memorial Sloan Kettering Cancer Center (OH), NY; King's College Hospital NHS Foundation Trust (AA-C), London, United Kingdom; and Department of Neuroscience (PNL), Brighton and Sussex Medical School, Brighton, United Kingdom.

Purpose Of Review: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN).

Recent Findings: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases.

Summary: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/CPJ.0000000000000834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032419PMC
April 2021

Genotype-phenotype correlations of stalk domain variants.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Apr 8:1-10. Epub 2021 Apr 8.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.

The kinesin family member 5A () motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (), while tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2021.1907412DOI Listing
April 2021

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 03 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

Participation and autonomy in the first 10 months after diagnosis of ALS: a longitudinal study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Mar 8:1-9. Epub 2021 Mar 8.

Department of Rehabilitation, Physical Therapy Science & Sports, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, The Netherlands.

More insight is needed into participation in daily activities and autonomy among patients with amyotrophic lateral sclerosis (ALS). Aims of this study were (1) to describe the course of participation restrictions and autonomy in participation during the first 10 months after diagnosis; (2) to study the influence of the rate of ALS progression on the course of participation. : Secondary analysis of data from the longitudinal multicenter FACTS-2-ALS study. Self-report questionnaires were administered at inclusion (T0;  = 71), at 4 months (T1), 7 months (T2), 10 months (T3) after inclusion. Median duration of follow-up was 10.0 months. Participation restrictions were assessed using the sum of the Mobility Range and Social Behavior subscales of the Sickness Impact profile-68 (SIPSOC). Autonomy in participation was assessed using the Impact on Participation and Autonomy (IPA) Questionnaire. Fast disease progression was defined as an increase of 1.1 points per month or more on the ALS Functional Rating Scale. : Patients reported participation restrictions in all subscales while having mild physical limitations. There was a decrease of participation over time (restrictions and autonomy). This decrease was greatest in patients with fast disease progression. Disease progression negatively influenced movement-related participation more than social interaction domains. Rate of disease progression was more strongly related to SIPSOC scores compared to IPA scores. : Preserving participation may be an important determinant of quality of care for patients with ALS. Rate of progression of the disease should be taken into account as it was found to be significantly associated with the level of participation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2021.1893335DOI Listing
March 2021

High-resolution mapping identifies HLA class II associations with multifocal motor neuropathy.

Neurobiol Aging 2021 05 20;101:79-84. Epub 2021 Jan 20.

UMC Utrecht Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery, Utrecht, the Netherlands. Electronic address:

Objective: To gain further insight in the immunopathology underlying multifocal motor neuropathy (MMN) by exploring the association between MMN and the human leukocyte antigen (HLA) class II DRB1, DQB1, and DQA loci in depth and by correlating associated haplotypes to detailed clinical and anti-ganglioside antibody data.

Methods: We performed high-resolution HLA-class II typing for the DRB1, DQB1, and DQA1 loci in 126 well-characterized MMN patients and assessed disease associations with haplotypes. We used a cohort of 1305 random individuals as a reference for haplotype distribution in the Dutch population.

Results: The DRB1*15:01-DQB1*06:02 haplotype (OR 1.6 [95% CI 1.1-2.2], p < 0.05) and the DRB1*12:01-DQB1*03:01 haplotype (OR 2.7 [95% CI 1.2-5.5], p < 0.05) were more frequent in patients with MMN than in controls. These haplotypes were not associated with disease course, response to treatment or anti-ganglioside antibodies.

Conclusions: MMN is associated with the DRB1*15:01-DQB1*06:02 and DRB1*12:01-DQB1*03:01 haplotypes. These HLA molecules or gene variants in their immediate vicinity may promote the specific inflammatory processes underlying MMN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.014DOI Listing
May 2021

Cross-reactive probes on Illumina DNA methylation arrays: a large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies.

NAR Genom Bioinform 2020 Dec 17;2(4):lqaa105. Epub 2020 Dec 17.

Department of Neurology, UMC Utrecht Brain Center, 3584 CG, Utrecht, the Netherlands.

Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of the repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to the locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nargab/lqaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745769PMC
December 2020

5'ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis.

Brain Commun 2020 28;2(2):fcaa138. Epub 2020 Aug 28.

Department of Physiology and Medical Physics, Royal College of Surgeons In Ireland, St. Stephen's Green, Dublin, D02 YN77, Ireland.

Loss-of-function mutations in the ribonuclease angiogenin are associated with amyotrophic lateral sclerosis. Angiogenin has been shown to cleave transfer RNAs during stress to produce 'transfer-derived stress-induced RNAs'. Stress-induced tRNA cleavage is preserved from single-celled organisms to humans indicating it represents part of a highly conserved stress response. However, to date, the role of tRNA cleavage in amyotrophic lateral sclerosis remains to be fully elucidated. To this end, we performed small RNA sequencing on a human astrocytoma cell line to identify the complete repertoire of tRNA fragments generated by angiogenin. We found that only a specific subset of tRNAs is cleaved by angiogenin and identified 5'ValCAC transfer-derived stress-induced RNA to be secreted from neural cells. 5'ValCAC was quantified in spinal cord and serum from SOD1 amyotrophic lateral sclerosis mouse models where we found it to be significantly elevated at symptom onset correlating with increased angiogenin expression, imbalanced protein translation initiation factors and slower disease progression. In amyotrophic lateral sclerosis patient serum samples, we found 5'ValCAC to be significantly higher in patients with slow disease progression, and interestingly, we find 5'ValCAC to hold prognostic value for amyotrophic lateral sclerosis patients. Here, we report that angiogenin cleaves a specific subset of tRNAs and provide evidence for 5'ValCAC as a prognostic biomarker in amyotrophic lateral sclerosis. We propose that increased serum 5'ValCAC levels indicate an enhanced angiogenin-mediated stress response within motor neurons that correlates with increased survival. These data suggest that the previously reported beneficial effects of angiogenin in SOD1 mice may result from elevated levels of 5'ValCAC transfer RNA fragment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcaa138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850272PMC
August 2020

An old friend who has overstayed their welcome: the ALSFRS-R total score as primary endpoint for ALS clinical trials.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 2;22(3-4):300-307. Epub 2021 Feb 2.

Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, The Netherlands.

The ALSFRS-R is limited by multidimensionality, which originates from the summation of various subscales. This prevents a direct comparison between patients with identical total scores. We aim to evaluate how multidimensionality affects the performance of the ALSFRS-R in clinical trials. We simulated clinical trial data with different treatment effects for the ALSFRS-R total score and its subscales (i.e. bulbar, fine motor, gross motor and respiratory). We considered scenarios where treatment reduced the rate of ALSFRS-R subscale decline either uniformly (i.e. all subscales respond identically to treatment) or non-uniformly (i.e. subscales respond differently to treatment). Two main analytical strategies were compared: (1) analyzing only the total score or (2) utilizing a subscale-based test (i.e. alternative strategy). For each analytical strategy, we calculated the empirical power and required sample size. Both strategies are valid when there is no treatment benefit and provide adequate control of type 1 error. If all subscales respond identically to treatment, using the total score is the most powerful approach. As the differences in treatment responses between subscales increase, the more the total score becomes affected. For example, to detect a 40% reduction in the bulbar rate of decline with 80% power, the total score requires 1380 patients, whereas this is 336 when using the alternative strategy. Ignoring the multidimensional structure of the ALSFRS-R total score could have negative consequences for ALS clinical trials. We propose determining treatment benefit on a subscale level, prior to stating whether a treatment is generally effective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2021.1879865DOI Listing
May 2021

Pattern of muscle strength improvement after intravenous immunoglobulin therapy in multifocal motor neuropathy.

Muscle Nerve 2021 05 9;63(5):678-682. Epub 2021 Feb 9.

Center of Excellence for Rehabilitation Medicine, UMC Utrecht Brain Center, University Medical Center Utrecht, and De Hoogstraat Rehabilitation, Utrecht, The Netherlands.

Introduction: In multifocal motor neuropathy (MMN), knowledge about the pattern of treatment response in a wide spectrum of muscle groups, distal as well as proximal, after intravenous immunoglobulin (IVIg) initiation is lacking.

Methods: Hand-held dynamometry data of 11 upper and lower limb muscles, from 47 patients with MMN was reviewed. Linear mixed models were used to determine the treatment response after IVIg initiation and its relationship with initial muscle weakness.

Results: All muscle groups showed a positive treatment response after IVIg initiation. Changes in SD scores ranged from +0.1 to +0.95. A strong association between weakness at baseline and the magnitude of the treatment response was found.

Discussion: Improved muscle strength in response to IVIg appears not only in distal, but to a similar degree also in proximal muscle groups in MMN, with the largest response in muscle groups that show the greatest initial weakness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.27185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247955PMC
May 2021

Incidence, Prevalence and Geographical Clustering of Motor Neuron Disease in the Netherlands.

Neurology 2021 Jan 20. Epub 2021 Jan 20.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands

Objective: To assess time trends in MND incidence, prevalence and mortality and investigate geographical clustering of MND cases in the Netherlands from 1998 to 2017, we analyzed data from the Netherlands Personal Records database, the Netherlands MND Center and the Netherlands Patient Association of Neuromuscular Diseases.

Methods: In this prospective cohort study, Poisson regression was used to assess time trends in MND risk. We calculated age- and sex-standardized, observed and expected cases for 1,694 areas. Bayesian smoothed risk mapping was used to investigate geographical MND risk.

Results: We identified 7,992 MND cases, reflecting an incidence of 2.64 (95% CI 2.62-2.67) per 100,000 person-years and a prevalence of 9.5 (95% CI 9.1-10.0) per 100,000 persons. Highest age-standardized prevalence and mortality rates occurred at a later age in men than in women (<0.001). Unadjusted mortality rates increased by 53.2% from 2.57 in 1998 to 3.86 per 100,000 person-years in 2017. After adjustment for age and sex, an increase in MND mortality rate of 14.1% (95% CI 5.7%-23.2%, <0.001) remained. MND relative risk ranged from 0.78 to 1.43 between geographical areas; multiple urban and rural high-risk areas were identified.

Conclusions: We found a significant national increase in MND mortality from 1998 through 2017, only partly explained by an ageing Dutch population, and also a geographic variability in MND risk, suggesting a role for environmental or demographic risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055340PMC
January 2021

Impact of stimulus duration on motor unit thresholds and alternation in compound muscle action potential scans.

Clin Neurophysiol 2021 02 2;132(2):323-331. Epub 2020 Dec 2.

Department of Neurology, Brain Centre Utrecht, University Medical Centre Utrecht, Utrecht, the Netherlands.

Objective: To investigate the impact of stimulus duration on motor unit (MU) thresholds and alternation within compound muscle action potential (CMAP) scans.

Methods: The stimulus duration (0.1, 0.2, 0.6, and 1.0 ms) in thenar CMAP scans and individual MUs of 14 healthy subjects was systematically varied. We quantified variability of individual MU's thresholds by relative spread (RS), MU thresholds by stimulus currents required to elicit target CMAPs of 5% (S5), 50% (S50) and 95% (S95) of the maximum CMAP, and relative range (RR) by 100*[S95-S5]/S50. We further assessed the strength-duration time constant (SDTC). Experimental observations were subsequently simulated to quantify alternation.

Results: RS, unaffected by stimulus duration, was 1.65% averaged over all recordings. RR increased for longer stimulus duration (11.4% per ms, p < 0.001). SDTC shortened with higher target CMAPs (0.007 ms per 10% CMAP, p < 0.001). Experiments and simulations supported that this may underlie the increased RR. A short compared to long stimulus duration recruited relative more MUs at S50 (more alternation) than at the tails (less alternation).

Conclusions: The stimulus duration significantly affects MU threshold distribution and alternation within CMAP scans.

Significance: Stimulation settings can be further optimized and their standardization is preferred when using CMAP scans for monitoring neuromuscular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2020.10.026DOI Listing
February 2021

Portable fixed dynamometry: towards remote muscle strength measurements in patients with motor neuron disease.

J Neurol 2021 May 23;268(5):1738-1746. Epub 2020 Dec 23.

Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Background: We aimed to determine (1) the test-retest reliability of a newly developed portable fixed dynamometer (PFD) as compared to the hand-held dynamometer (HHD) in patients with motor neuron disease (MND) and (2) the PFD's ability to reduce possible examiner-induced ceiling effects.

Methods: Test-retest reliability of isometric muscle strength of the quadriceps was measured in patients with MND and non-neurological controls using the HHD and PFD. Reliability was estimated by the intraclass correlation coefficient (ICC) and standard error of measurement (SEM) using linear mixed effects models, and the Bland-Altman method of agreement.

Results: In total, 45 patients with MND and 43 healthy controls were enrolled in this study. The ICC of the PFD was excellent and similar in both patients and controls (ICC 99.5% vs. ICC 98.6%) with a SEM of 6.2%. A strong examiner-induced ceiling effect in HHD was found when the participant's strength exceeded that of examiner. Employing the PFD increased the range of muscle strength measurements across individuals nearly twofold from 414 to 783 N.

Conclusions: Portable fixed dynamometry may significantly reduce examiner-induced ceiling effects, optimize the standardization of muscle strength testing, and maximize reliability. Ultimately, PFD may improve the delivery of care due to its potential for unsupervised, home-based assessments and reduce the burden to the patient of participating in clinical trials for MND or other neuromuscular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-10366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068646PMC
May 2021

Improving clinical trial outcomes in amyotrophic lateral sclerosis.

Nat Rev Neurol 2021 Feb 18;17(2):104-118. Epub 2020 Dec 18.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41582-020-00434-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747476PMC
February 2021

Discussing personalized prognosis in amyotrophic lateral sclerosis: development of a communication guide.

BMC Neurol 2020 Dec 14;20(1):446. Epub 2020 Dec 14.

Department of Rehabilitation, Physical Therapy Science & Sports, UMC Utrecht Brain Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands.

Background: Personalized ENCALS survival prediction model reliably estimates the personalized prognosis of patients with amyotrophic lateral sclerosis. Concerns were raised on discussing personalized prognosis without causing anxiety and destroying hope. Tailoring communication to patient readiness and patient needs mediates the impact of prognostic disclosure. We developed a communication guide to support physicians in discussing personalized prognosis tailored to individual needs and preferences of people with ALS and their families.

Methods: A multidisciplinary working group of neurologists, rehabilitation physicians, and healthcare researchers A) identified relevant topics for guidance, B) conducted a systematic review on needs of patients regarding prognostic discussion in life-limiting disease, C) drafted recommendations based on evidence and expert opinion, and refined and finalized these recommendations in consensus rounds, based on feedback of an expert advisory panel (patients, family member, ethicist, and spiritual counsellor).

Results: A) Topics identified for guidance were 1) filling in the ENCALS survival model, and interpreting outcomes and uncertainty, and 2) tailoring discussion to individual needs and preferences of patients (information needs, role and needs of family, severe cognitive impairment or frontotemporal dementia, and non-western patients). B) 17 studies were included in the systematic review. C) Consensus procedures on drafted recommendations focused on selection of outcomes, uncertainty about estimated survival, culturally sensitive communication, and lack of decisional capacity. Recommendations for discussing the prognosis include the following: discuss prognosis based on the prognostic groups and their median survival, or, if more precise information is desired, on the interquartile range of the survival probability. Investigate needs and preferences of the patients and their families for prognostic disclosure, regardless of cultural background. If the patient does not want to know their prognosis, with patient permission discuss the prognosis with their family. If the patient is judged to lack decisional capacity, ask the family if they want to discuss the prognosis. Tailor prognostic disclosure step by step, discuss it in terms of time range, and emphasize uncertainty of individual survival time.

Conclusion: This communication guide supports physicians in tailoring discussion of personalized prognosis to the individual needs and preferences of people with ALS and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-020-02004-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734773PMC
December 2020

Reconsidering the revised amyotrophic lateral sclerosis functional rating scale for ALS clinical trials.

J Neurol Neurosurg Psychiatry 2021 May 23;92(5):569-570. Epub 2020 Nov 23.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-325253DOI Listing
May 2021

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Nat Genet 2020 12 16;52(12):1303-1313. Epub 2020 Nov 16.

Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116530PMC
December 2020

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

J Neurol Neurosurg Psychiatry 2020 11 11. Epub 2020 Nov 11.

Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding () and unrelated genes (eg, ). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-322983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803890PMC
November 2020

Associations of Occupational Exposures to Electric Shocks and Extremely Low-Frequency Magnetic Fields With Motor Neurone Disease.

Am J Epidemiol 2021 02;190(3):393-402

In a New Zealand population-based case-control study we assessed associations with occupational exposure to electric shocks, extremely low-frequency magnetic fields (ELF-MF) and motor neurone disease using job-exposure matrices to assess exposure. Participants were recruited between 2013 and 2016. Associations with ever/never, duration, and cumulative exposure were assessed using logistic regression adjusted for age, sex, ethnicity, socioeconomic status, education, smoking, alcohol consumption, sports, head or spine injury, and solvents, and was mutually adjusted for the other exposure. All analyses were repeated stratified by sex. An elevated risk was observed for having ever worked in a job with potential for electric shocks (odds ratio (OR) = 1.35, 95% confidence interval (CI): 0.98, 1.86), with the strongest association for the highest level of exposure (OR = 2.01, 95% CI: 1.31, 3.09). Analysis by duration suggested a nonlinear association: Risk was increased for both short duration (<3 years; OR = 4.69, 95% CI: 2.25, 9.77) and long duration (>24 years; OR = 1.88; 95% CI: 1.05, 3.36) in a job with high level of electric shock exposure, with less pronounced associations for intermediate durations. No association with ELF-MF was found. Our findings provide support for an association between occupational exposure to electric shocks and motor neurone disease but did not show associations with exposure to work-related ELF-MF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/aje/kwaa214DOI Listing
February 2021

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of In Patients With ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 24;22(3-4):287-299. Epub 2020 Sep 24.

Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.

Objective: To evaluate safety, dose response, and preliminary efficacy of over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Patients ( = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance ( = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R,  = 0.09; muscle strength mega-score,  = 0.31). Post hoc analyses pooling all active -treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2020.1822410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117790PMC
May 2021
-->