Publications (145)690.11 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: There is no test for amyotrophic lateral sclerosis (ALS) and so attempts have been made to produce standardized diagnostic criteria based on clinical and electrophysiological findings, e.g. El Escorial. However, the phenotypic classification of the subtypes of ALS is also based on clinical features leading to conflation of diagnosis and phenotype. We used a five-question online survey with ALS specialists to explore the range of descriptors and how they are used. Of 101 specialists approached, 72 completed the survey. The most frequently used labels were ‘ALS’, ‘PLS’ and ‘familial’. Labels other than the El Escorial categories were mainly used as clinical descriptors (83%). Approximately 50% of respondents recorded that the El Escorial criteria had no useful role in patient discussion or in the diagnostic process. Only 31% of respondents rated their current classification system above the median for being logical. A more rational system explicitly distinguishing diagnostic and phenotypic criteria is essential.
- [Show abstract] [Hide abstract] ABSTRACT: To develop effective disease-modifying therapies for neurodegenerative diseases, reliable markers of diagnosis, disease activity and progression are a research priority. The fact that neurodegenerative pathology is primarily associated with distinct subsets of cells in discrete areas of the CNS makes the identification of relevant biomarker molecules a challenge. The trafficking of macromolecules from the CNS to the cerebrospinal fluid and blood, mediated by extracellular vesicles (EVs), presents a promising source of CNS-specific biomarkers. EVs are released by almost all cell types and carry a cargo of protein and nucleic acid that varies according to the cell of origin. EV output changes with cell status and reflects intracellular events, so surface marker expression can be used to identify the cell type from which EVs originate. EVs could, therefore, provide an enriched pool of information about core neuropathogenic, cell-specific processes. This Review examines the current knowledge of the biology and function of EVs, discusses the evidence for their involvement in the pathogenesis of neurodegenerative diseases, and considers their potential as biomarkers of disease.
- [Show abstract] [Hide abstract] ABSTRACT: Clinical signs of upper motor neuron (UMN) involvement are an important component in supporting the diagnosis of amyotrophic lateral sclerosis (ALS), but are often not easily appreciated in a limb that is concurrently affected by muscle wasting and lower motor neuron degeneration, particularly in the early symptomatic stages of ALS. Whilst recent criteria have been proposed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains essentially clinical. As a result, there is often a significant diagnostic delay that in turn may impact institution of disease-modifying therapy and access to other optimal patient management. Biomarkers of pathological UMN involvement are also required to ensure patients with suspected ALS have timely access to appropriate therapeutic trials. The present review provides an analysis of current and recently developed assessment techniques, including novel imaging and electrophysiological approaches used to study corticomotoneuronal pathology in ALS.
- [Show abstract] [Hide abstract] ABSTRACT: An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons and performed an extensive phenotypic characterization. In C9orf72 iPSC-derived motor neurons, decreased cell survival is correlated with dysfunction in Ca(2+) homeostasis, reduced levels of the anti-apoptotic protein Bcl-2, increased endoplasmic reticulum (ER) stress and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC-derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signalling and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia (FTD). This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVE: Neurofilaments are leading neurochemical biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigated the effect of preanalytical factors on neurofilament concentrations in cerebrospinal fluid (CSF) in a “reverse” round-robin with 15 centers across Europe/U.S. METHODS: Samples from ALS and control patients (5/5 each center, n = 150) were analyzed for phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) at two laboratories. RESULTS: CSF pNfH was increased (p < 0.05) in ALS in 10 out of 15 centers and NfL in 5 out of 12 centers. The coefficient of variation (CV%) of pNfH measurements between laboratories was 18.7 ± 19.1%. We calculated a diagnostic cut-off of >568.5 pg/mL for pNfH (sensitivity 78.7%, specificity 93.3%) and >1,431pg/mL for NfL (sensitivity 79.0%, specificity 86.4%). CONCLUSION: Values in ALS patients are already comparable between most centers, supporting eventual implementation into clinical routine. However, continuous quality control programs will be necessary for inclusion in the diagnostic work-up. © 2016 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases
- [Show abstract] [Hide abstract] ABSTRACT: The reduction in ALS Functional Rating Score (ALSFRS) from reported symptom onset to diagnosis is used to estimate rate of disease progression. ALSFRS decline may be non-linear or distorted by drop-outs in therapeutic trials, reducing the reliability of change in slope as an outcome measure. The PRO-ACT database uniquely allows such measures to be explored using historical data from negative therapeutic trials. The decline of functional scores was analysed in 18 pooled trials, comparing rates of decline based on symptom onset with rates calculated between interval assessments. Strategies to mitigate the effects of trial drop-out were considered. Results showed that progression rate calculated by symptom onset underestimated the subsequent rate of disability accumulation, although it predicted survival more accurately than four-month interval estimates of δALSFRS or δFVC. Individual ALSFRS and FVC progression within a typical trial duration were linear. No simple solution to correct for trial drop-out was identified, but imputation using δALSFRS appeared least disruptive. In conclusion, there is a trade-off between the drive to recruit trial participants soon after symptom onset, and reduced reliability of the ALSFRS-derived progression rate at enrolment. The need for objective markers of disease activity as an alternative to survival-based end-points is clear and pressing.
- [Show abstract] [Hide abstract] ABSTRACT: Novel biomarker discovery and validation are essential to the development and appraisal of emerging therapies for the devastating cerebral neurodegenerative disorder motor neuron disease (MND), the commonest phenotype of which is amyotrophic lateral sclerosis (ALS). MND pathology (and strong genetic risk of MND prior to symptoms) was hypothesised to be manifested by changes in movement-related cortical neuronal β-oscillations.
- [Show abstract] [Hide abstract] ABSTRACT: Selective vulnerability in the nervous system refers to the fact that subpopulations of neurons in different brain systems may be more or less prone to abnormal function or death in response to specific types of pathological states or injury. The concept has been used extensively as a potential way of explaining differences in degeneration patterns and the clinical presentation of different neurodegenerative diseases. Yet the increasing complexity of molecular histopathology at the cellular level in neurodegenerative disorders frequently appears at odds with phenotyping based on clinically-directed, macroscopic regional brain involvement. While cross-disease comparisons can provide insights into the differential vulnerability of networks and neuronal populations, we focus here on what is known about selective vulnerability-related factors that might explain the differential phenotypic expressions of the same disease-in this case, typical and atypical forms of Alzheimer's disease. Whereas considerable progress has been made in this area, much is yet to be elucidated; further studies comparing different phenotypic variants aimed at identifying both vulnerability and resilience factors may provide valuable insights into disease pathogenesis, and suggest novel targets for therapy.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: Damage to the cerebral tissue structural connectivity associated with amyotrophic lateral sclerosis (ALS), which extends beyond the motor pathways, can be visualised by diffusion tensor imaging (DTI). The effective translation of DTI metrics as biomarker requires its application across multiple MRI scanners and patient cohorts. A multicentre study was undertaken to assess structural connectivity in ALS within a large sample size. Methods: 442 DTI data sets from patients with ALS (N=253) and controls (N=189) were collected for this retrospective study, from eight international ALS-specialist clinic sites. Equipment and DTI protocols varied across the centres. Fractional anisotropy (FA) maps of the control participants were used to establish correction matrices to pool data, and correction algorithms were applied to the FA maps of the control and ALS patient groups. Results: Analysis of data pooled from all centres, using whole-brain-based statistical analysis of FA maps, confirmed the most significant alterations in the corticospinal tracts, and captured additional significant white matter tract changes in the frontal lobe, brainstem and hippocampal regions of the ALS group that coincided with postmortem neuropathological stages. Stratification of the ALS group for disease severity (ALS functional rating scale) confirmed these findings. Interpretation: This large-scale study overcomes the challenges associated with processing and analysis of multiplatform, multicentre DTI data, and effectively demonstrates the anatomical fingerprint patterns of changes in a DTI metric that reflect distinct ALS disease stages. This success paves the way for the use of DTI-based metrics as read-out in natural history, prognostic stratification and multisite disease-modifying studies in ALS.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: To discern presymptomatic changes in brain structure or function using advanced MRI in carriers of mutations predisposing to amyotrophic lateral sclerosis (ALS). Methods: T1-weighted, diffusion weighted and resting state functional MRI data were acquired at 3 T for 12 asymptomatic mutation carriers (psALS), 12 age-matched controls and affected patients with ALS. Cortical thickness analysis, voxel-based morphometry, volumetric and shape analyses of subcortical structures, tract-based spatial statistics of metrics derived from the diffusion tensor, and resting state functional connectivity (FC) analyses were performed. Results: Grey matter cortical thickness and shape analysis revealed significant atrophy in patients with ALS (but not psALS) compared with controls in the right primary motor cortex and right caudate. Comparison of diffusion tensor metrics showed widespread fractional anisotropy and radial diffusivity differences in patients with ALS compared to controls and the psALS group, encompassing parts of the corpus callosum, corticospinal tracts and superior longitudinal fasciculus. While FC in the resting-state sensorimotor network was similar in psALS and controls, FC between the cerebellum and a network comprising the precuneus, cingulate & middle frontal lobe was significantly higher in psALS and affected ALS compared to controls. Conclusions: Rather than structural brain changes, increased FC may be among the earliest detectable brain abnormalities in asymptomatic carriers of ALS-causing gene mutations. With replication and significant refinement, this technique has potential in the future assessment of neuroprotective strategies.
Article: Lou Gehrig and the ALS split hand
- [Show abstract] [Hide abstract] ABSTRACT: Advanced magnetic resonance imaging (MRI) techniques hold the promise to capture upper motor neuron loss and extramotor brain changes in amyotrophic lateral sclerosis (ALS) and as such deliver biomarkers relevant to diagnosis, prognosis and monitoring disease progression. However, a correlation between imaging parameters and clinical metrics has thus far been inconsistent across studies. We discuss the contributing factors to this clinical-imaging correlation gap as well as its implications for future research.
- [Show abstract] [Hide abstract] ABSTRACT: To use an unbiased method to test a previously reported association between cerebral arteriovenous malformation (AVM) embolisation and the subsequent development of amyotrophic lateral sclerosis (ALS). A hospital record linkage database was used to create cohorts of individuals coded as having cerebral and peripheral vessel AVMs, stroke (separately for haemorrhagic and ischaemic), transient ischaemic attack (TIA) and subarachnoid haemorrhage (SAH). The rate ratio for subsequent ALS was compared to a reference cohort. An increased rate ratio for ALS was found in relation to prior AVM (2.69; p=0.005), all strokes (1.38; p<0.001), and TIA (1.47; p<0.001). Cerebrovascular injury from a variety of causes, rather than the presence of AVM or the associated embolisation procedure per se, may be a risk factor for ALS within the context of a more complex multiple-hit model of pathogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
- [Show abstract] [Hide abstract] ABSTRACT: A relative preservation of eye movements is notable in ALS, but saccadic functions have not been studied longitudinally. ALS overlaps with FTD, typically involving executive dysfunction, and eye-tracking offers additional potential for the assessment of extramotor pathology where writing and speaking are both impaired. Eye-tracking measures (including anti-saccade, trail-making and visual search tasks) were assessed at six-monthly intervals for up to two years in a group of ALS (n = 61) and primary lateral sclerosis (n = 7) patients, compared to healthy age-matched controls (n = 39) assessed on a single occasion. Task performance was explored speculatively in relation to resting-state functional MRI (R-FMRI) network connectivity. Results showed that ALS patients were impaired on executive and visual search tasks despite normal basic saccadic function, and impairments in the PLS patients were unexpectedly often more severe. No significant progression was detected longitudinally in either group. No changes in R-FMRI network connectivity were identified in relation to patient performance. In conclusion, eye-tracking offers an objective means to assess extramotor cerebral involvement in ALS. The relative resistance of pure oculomotor function is confirmed, and higher-level executive impairments do not follow the same rate of decline as physical disability. PLS patients may have more cortical dysfunction than has been previously appreciated.
- [Show abstract] [Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is now recognised to be a heterogeneous neurodegenerative syndrome of the motor system and its frontotemporal cortical connections. The development and application of structural and functional imaging over the last three decades, in particular magnetic resonance imaging (MRI), has allowed traditional post mortem histopathological and emerging molecular findings in ALS to be placed in a clinical context. Cerebral grey and white matter structural MRI changes are increasingly being understood in terms of brain connectivity, providing insights into the advancing degenerative process and producing candidate biomarkers. Such markers may refine the prognostic stratification of patients and the diagnostic pathway, as well as providing an objective assessment of changes in disease activity in response to future therapeutic agents. Studies are being extended to the spinal cord, and the application of neuroimaging to unaffected carriers of highly penetrant genetic mutations linked to the development of ALS offers a unique window to the pre-symptomatic landscape.
- [Show abstract] [Hide abstract] ABSTRACT: Neurochemical biomarkers are urgently sought in ALS. Metabolomic analysis of cerebrospinal fluid (CSF) using proton nuclear magnetic resonance (1H-NMR) spectroscopy is a highly sensitive method capable of revealing nervous system cellular pathology. The 1H-NMR CSF metabolomic signature of ALS was sought in a longitudinal cohort. Six-monthly serial collection was performed in ALS patients across a range of clinical sub-types (n = 41) for up to two years, and in healthy controls at a single time-point (n = 14). A multivariate statistical approach, partial least squares discriminant analysis, was used to determine differences between the NMR spectra from patients and controls. Significantly predictive models were found using those patients with at least one year's interval between recruitment and the second sample. Glucose, lactate, citric acid and, unexpectedly, ethanol were the discriminating metabolites elevated in ALS. It is concluded that 1H-NMR captured the CSF metabolomic signature associated with derangements in cellular energy utilization connected with ALS, and was most prominent in comparisons using patients with longer disease duration. The specific metabolites identified support the concept of a hypercatabolic state, possibly involving mitochondrial dysfunction specifically. Endogenous ethanol in the CSF may be an unrecognized novel marker of neuronal tissue injury in ALS.
- [Show abstract] [Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models.
- [Show abstract] [Hide abstract] ABSTRACT: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls. © 2015 American Academy of Neurology.
- [Show abstract] [Hide abstract] ABSTRACT: Objective Diffusion tensor imaging (DTI) is sensitive to white matter tract pathology. A core signature involving the corticospinal tracts (CSTs) has been identified in amyotrophic lateral sclerosis (ALS). Raised neurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) is thought to reflect axonal damage in a range of neurological disorders. The relationship between these two measures was explored.MethodsCSF and serum NfL concentrations and DTI acquired at 3 Tesla on the same day were obtained from ALS patients (n = 25 CSF, 40 serum) and healthy, age-similar controls (n = 17 CSF, 25 serum). Within-group correlations between NfL and DTI measures of microstructural integrity in major white matter tracts (CSTs, superior longitudinal fasciculi [SLF], and corpus callosum) were performed using tract-based spatial statistics.ResultsNfL levels were higher in patients compared to controls. CSF levels correlated with clinical upper motor neuron burden and rate of disease progression. Higher NfL levels were significantly associated with lower DTI fractional anisotropy and increased radial diffusivity in the CSTs of ALS patients, but not in controls.InterpretationElevated CSF and serum NfL is, in part, a result of CST degeneration in ALS. This highlights the wider potential for combining neurochemical and neuroimaging-based biomarkers in neurological disease.
Oxford University Hospitals NHS TrustOxford, England, United Kingdom
University of OxfordOxford, England, United Kingdom