A5050302490- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Neurological diseases and metabolism
- Prion Diseases and Protein Misfolding
- Epigenetics and DNA Methylation
- Biochemical Acid Research Studies
- Endoplasmic Reticulum Stress and Disease
- Parkinson's Disease Mechanisms and Treatments
- Ubiquitin and proteasome pathways
- Genetic Neurodegenerative Diseases
- Cancer-related gene regulation
- Autophagy in Disease and Therapy
- Genomics and Rare Diseases
- Alzheimer's disease research and treatments
- Human-Animal Interaction Studies
- Telomeres, Telomerase, and Senescence
- Genetic Associations and Epidemiology
- Mitochondrial Function and Pathology
- Pluripotent Stem Cells Research
- Genetics, Aging, and Longevity in Model Organisms
- Animal Behavior and Welfare Studies
- Genetic Syndromes and Imprinting
- Veterinary Orthopedics and Neurology
- Pain Management and Placebo Effect
- Genetics and Neurodevelopmental Disorders
King's College London
2016-2024
Duke University
2022
University of Illinois Chicago
2022
Neuroscience Institute
2017
University of Notre Dame
2017
Queen Elizabeth University Hospital
2016
University of Kentucky
2003-2010
<ns4:p>Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis death from respiratory failure within 2 to 3 years. The peak age of onset 55 70 years, with male predominance. causes amyotrophic are only partly known, but they include some environmental risk factors as well several genes that have been identified harbouring disease-associated variation. Here we review the nature, epidemiology,...
Abstract Increasing evidence suggests that proteasome inhibition plays a causal role in promoting the neurodegeneration and neuron death observed multiple disorders, including Alzheimer's disease (AD) Parkinson's (PD). The ability of severe acute function to induce neuropathology similar AD PD is well documented. However, at present effects chronic low‐level on neural homeostasis has not been elucidated. In order determine homeostasis, we conducted studies individual colonies SH‐SY5Y cells...
Amyotrophic lateral sclerosis (ALS) is a progressive and usually fatal neurodegenerative disease. Survival from diagnosis varies considerably. Several prognostic factors are known, including site of onset (bulbar or limb), age at symptom onset, delay to the use riluzole non-invasive ventilation (NIV). Clinicians patients would benefit practical way using these provide an individualised prognosis.575 consecutive with incident ALS population-based registry in South-East England register for...
Abstract There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up 60%. Both Mendelian and small effect variants have been identified, but in common other conditions, such only explain little the heritability. Genomic structural variation might account for some this otherwise unexplained We therefore investigated association between set 25 ALS genes, risk phenotype. As expected, repeat expansion C9orf72 gene was identified as...
Abstract Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to 20% of cases, family history observed. Although Mendelian disease gene variants are found in apparently sporadic ALS, genetic testing usually restricted those with or younger patients disease. With the advent therapies targeting it important that everyone treatable identified. We therefore sought determine probability clinically actionable ALS test result by age onset, globally, but using UK...
Abstract Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people SOD1 -ALS ALS no recorded variant. We investigate age at symptom onset time from to death censoring using Cox proportional-hazards regression. The dataset reports for 1122...
Background: Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic been a multidisciplinary, specialist, tertiary referral centre since 1995 large team integrated palliative and respiratory care 2006. We hypothesised that these changes would improve survival. Methods: In this retrospective observational study, patients diagnosed El Escorial definite, probable possible ALS between 1995–1998 2008–2011 were followed up....
Objective Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system. The split hand sign in ALS refers to observed preferential weakness muscles, which unexplained. One possibility larger cortical representation compared with medial. Biceps strength usually preserved relative triceps neurological conditions, but biceps has and might be expected show ALS. Methods Using South-East England Register for Lateral Sclerosis, we performed retrospective longitudinal...
Numerous studies suggest that proteasome inhibition may play a causal role in mediating the increased levels of protein oxidation and neuron death observed conditions associated with oxidative stress. In present study we demonstrate administration non‐toxic stress does not result impairment 20S/26S activity, actually increases expression specific subunits. Non‐toxic were to elevate amount presence preserved proteasomal function, suggesting mediate following low‐level Preserving basal...
Objective Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease of motor neurons with median survival 2 years. Familial ALS has younger age onset than apparently sporadic ALS. We sought to determine whether this result ascertainment bias or genetic basis. Methods Samples from people were sequenced for 13 genes. To the effect variation, was compared in carrying pathogenic gene variant and those who do not; family history, we familial Results There 941...
Mutations in the superoxide dismutase 1 (SOD1) gene are second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported people with It was previously proposed that can be broadly classified two groups, 'wild-type like' (WTL) 'metal binding region' (MBR) variants, based on their structural location biophysical properties. MBR but not WTL were associated a reduction enzymatic activity. In this study we used molecular dynamics large...
While motor symptoms are well-known in ALS, non-motor often under-reported and may have a significant impact on quality of life. In this study, we aimed to examine the nature extent ALS.
Objective: To model the effects of demographic change under various scenarios possible future treatment developments in ALS. Methods: Patients diagnosed with ALS at King's College Hospital Motor Nerve Clinic between 2004 and 2017, living within London boroughs Lambeth, Southwark, Lewisham (LSL), were included as incident cases. We also ascertained cases from Canterbury region over same period. Future incidence was estimated by applying calculated age- sex-specific rates to UK population...
Genetic penetrance is the probability of a phenotype when harbouring particular pathogenic variant. Accurate estimates are important across biomedical fields including genetic counselling, disease research, and gene therapy. However, existing approaches for estimation require, instance, large family pedigrees or availability databases people affected not by disease.
To characterize the natural history of revised ALS functional rating scale (ALSFRS-R) over a 24-month period following initial assessment, and to assess its associations with survival. Longitudinal ALSFRS-R measurements survival data were obtained from seven population-based, European cohorts. Different models for trajectory evaluated, including tests linearity between-cohort differences. We employed joint modeling framework factor in mortality, thereby aiming derive more precise estimate...
Amyotrophic Lateral Sclerosis (ALS) remains an incurable disease, with limited treatment options, and riluzole is the most widely available drug. We evaluated survival in a large cohort of patients ALS, comparing those treated to who were not. Using data from PRECISION-ALS database, we retrospectively analyzed ALS 100 mg daily at time diagnosis. ALSFRS-R slope onset diagnosis (ΔFRS) was calculated. Based on ΔFRS distribution, defined fast progressors as having > 1.17, intermediate 1.17 0.31...
To investigate the association between C9orf72, SOD1, FUS and TARDBP variants on clinical trajectory of ALS patients in Europe. Nine centers with population-based registries provided data demographic disease characteristics - at diagnosis longitudinally as part PRECISION ALS. These were harmonized collated for analysis. 21,820 identified, 9,887 underwent genetic testing least one 4 genes interest. 9.8% carried a hexanucleotide expansion C9orf72; 2.9% pathogenic variant SOD1; 1.4% TARDBP;...
To examine the working status of people living with ALS (plwALS), identity their caregivers, amount informal care provided to them, and how these factors change over time. Data from nine specialist European centers previously funded projects, such as ALSCarE, were collated. The cohort was stratified into progression groups based on calculated ΔFRS compared longitudinally. Twenty-one thousand eight hundred twenty patients identified at time data analysis. One one eighty-four had data. Two...
Respiratory function typically deteriorates as ALS progresses and is associated with shorter survival. This study aims to describe respiratory the prevalence of noninvasive ventilation (NIV) along disease trajectory using prospective data from PRECISION project. We included 3449 patients six European population-based cohorts. All had comparable assessments vital capacity, percent predicted (VC%) (58.1% multiple assessments) 56% revised Functional Rating Scale (ALSFRS-R). The were analyzed in...
Map time to key clinical milestones in amyotrophic lateral sclerosis (ALS), highlighting underlying genotypic and phenotypic prognostic factors. Understanding the ALS disease trajectory factors influencing heterogeneous course is important guide care stratify individuals effectively assess therapeutics trials. Population-based datasets from nine European centers were collated. Time-to-event analysis was conducted for milestones: symptom onset, diagnosis, gastrostomy insertion, noninvasive...
The proteasome is a large intracellular protease, composed of multiple subunits, that present in all eukaryotic cells. Proteasome inhibition known to occur during normal aging, and believed contribute towards an age-related increase oxidative stress, although at the mechanisms responsible for mediating agerelated changes activity have not been elucidated. At relationship between subunit expression, activity, protein oxidation aging has In study we observed absence LMP2, specific subunit,...