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Martin R Turner,
Orla Hardiman,
Michael Benatar,
Benjamin R Brooks,
Adriano Chio,
Mamede de Carvalho,
Paul G Ince,
Cindy Lin,
Robert G Miller,
Hiroshi Mitsumoto,
Garth Nicholson,
John Ravits,
Pamela J Shaw,
Michael Swash,
Kevin Talbot,
Bryan J Traynor,
Leonard H Van den Berg,
Jan H Veldink,
Steve Vucic,
Matthew C Kiernan
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ABSTRACT: Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.
The Lancet Neurology 03/2013; 12(3):310-22. · 23.46 Impact Factor
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ABSTRACT: OBJECTIVE: To demonstrate the sensitivity of a recently developed whole-brain magnetic resonance spectroscopic imaging (MRSI) sequence to cerebral pathology and disability in amyotrophic lateral sclerosis (ALS), and compare with measures derived from diffusion tensor imaging. METHODS: Whole-brain MRSI and diffusion tensor imaging were undertaken in 13 patients and 14 age-similar healthy controls. Mean N-acetylaspartate (NAA), fractional anisotropy, and mean diffusivity were extracted from the corticospinal tract, compared between groups, and then in relation to disability in the patient group. RESULTS: Significant reductions in NAA were found along the course of the corticospinal tracts on whole-brain MRSI. There were also significant changes in fractional anisotropy (decreased) and mean diffusivity (increased) in the patient group, but only NAA showed a significant relationship with disability (r = 0.65, p = 0.01). CONCLUSION: Whole-brain MRSI has potential as a quantifiable neuroimaging marker of disability in ALS. It offers renewed hope for a neuroimaging outcome measure with the potential for harmonization across multiple sites in the context of a therapeutic trial.
Neurology 01/2013; · 8.31 Impact Factor
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Practical Neurology 12/2012; 12(6):396-7.
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Neurology 09/2012; 79(11):e97. · 8.31 Impact Factor
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ABSTRACT: OBJECTIVE To explore the value of diffusion tensor imaging applied to those specific cerebral white matter tracts consistently involved pathologically in amyotrophic lateral sclerosis as a source of prognostic biomarkers. DESIGN Baseline clinical assessment and 3-T diffusion tensor imaging, repeated after approximately 6 months. Tract-based spatial statistics were used to assess voxelwise correlations of just the baseline diffusion tensor imaging indices with the progression rate (change in disability score/time interval) within the corticospinal tract and corpus callosum. PATIENTS The study involved 21 patients with amyotrophic lateral sclerosis and 3 patients with primary lateral sclerosis. RESULTS Correlation was observed between fractional anisotropy and progression rate for a region of the corticospinal tract spanning the posterior limb of the internal capsule, with a left hemisphere emphasis. Posterior limb of the internal capsule fractional anisotropy showed potential to distinguish those patients with rapid progression. Axial diffusivity significantly increased in this region in a paired t test analysis of baseline and follow-up diffusion tensor imaging, in keeping with axonal damage. No correlations were noted for the corpus callosum. CONCLUSIONS Posterior limb of the internal capsule fractional anisotropy is a candidate prognostic marker in amyotrophic lateral sclerosis, with potential to identify incident cases with more rapid progression.
Archives of neurology 08/2012; · 6.31 Impact Factor
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ABSTRACT: There is a wide range of age at initial symptom onset in amyotrophic lateral sclerosis despite a mean age of 65 years in population-based studies. 'Young-onset' amyotrophic lateral sclerosis typically refers to patients younger than ∼45 years and accounts for about 10% of cases in contemporary series. A review of published cases of amyotrophic lateral sclerosis from 1850 to 1950 revealed a far higher proportion of cases with young onset (>50%), with a steady decline to the contemporary figure. It is possible that this is not solely explained by increases in life expectancy. While there is still a rich variation in phenotypes among cases of young-onset amyotrophic lateral sclerosis, bulbar onset was found to be significantly under-represented in analysis of a large patient database, with implications for age-related vulnerabilities pertaining to focality of symptom onset. The timing of initiating pathological processes in relation to the emergence of symptoms is discussed, including the potential role of very early development and the interaction of epigenetic and environmental factors.
Brain 06/2012; 135(Pt 9):2883-91. · 9.46 Impact Factor
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ABSTRACT: The catastrophic system failure in amyotrophic lateral sclerosis is characterized by progressive neurodegeneration within the corticospinal tracts, brainstem nuclei and spinal cord anterior horns, with an extra-motor pathology that has overlap with frontotemporal dementia. The development of computed tomography and, even more so, MRI has brought insights into neurological disease, previously only available through post-mortem study. Although largely research-based, radionuclide imaging has continued to provide mechanistic insights into neurodegenerative disorders. The evolution of MRI to use advanced sequences highly sensitive to cortical and white matter structure, parenchymal metabolites and blood flow, many of which are now applicable to the spinal cord as well as the brain, make it a uniquely valuable tool for the study of a multisystem disorder such as amyotrophic lateral sclerosis. This comprehensive review considers the full range of neuroimaging techniques applied to amyotrophic lateral sclerosis over the last 25 years, the biomarkers they have revealed and future developments.
Biomarkers in Medicine 06/2012; 6(3):319-37. · 0.86 Impact Factor
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ABSTRACT: The objective of this study is to report trends in mortality, as certified on death certificates, from multiple sclerosis
(MS), motor neuron disease (MND), primary Parkinson’s disease (PD), and epilepsy, analysing not only the underlying cause
of death but also all certified causes for each disease. Death records in the Oxford region, 1979–2006, and England, 1996–2006,
were analysed for ascertaining the trends in mortality. The percentage of deaths coded as the underlying cause changed over
time, coinciding with changes to the rules for selecting the underlying cause of death. Changes over time to coding rules
had a large impact on apparent trends in death rates for PD when studied by underlying cause alone. They also had significant,
though smaller, effects on trends in death rates for MS, MND and epilepsy. Nationally, in the last period of the study, underlying
cause mortality identified 64% of deaths with a mention of MS, 88% of MND, 56% of PD, and 48% of epilepsy. In the longstanding
Oxford data from 1979 to 2006, death rates based on all certified causes of death showed no significant change for MS; an
upward trend for MND (notably in women over 75), though only in the last few years of the study; a significant but small decline
for PD; and no significant change for epilepsy. When mortality statistics are analysed by underlying cause only, their value
is reduced. A substantial percentage of neurological deaths are missed. Time trends may be misleading. All certified causes
for each disease, as well as the underlying cause, should be analysed.
KeywordsMultiple sclerosis-Motor neuron disease-Parkinson’s disease-Epilepsy-Mortality-Trends
Journal of Neurology 04/2012; 257(5):706-715. · 3.47 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is typically regarded as a sporadic neurodegenerative disorder that results in a catastrophic failure of the motor system, with characteristically variable involvement of upper and lower motor neuronal populations. A wide range of evidence from clinical, histological, genetic, neurophysiological, neuroimaging and neuropsychological studies, suggests that a loss of central nervous system inhibitory neuronal influence is a contributing factor in ALS pathogenesis. This loss of inhibitory function points intuitively to an 'interneuronopathy', with natural differences in cortical and spinal inhibitory networks reflected in the hitherto unexplained variable compartmentalization of pathology within upper and lower motor neuron populations. An excitotoxic final common pathway might then result from unopposed glutamatergic activity. If correct, therapies aimed specifically at supporting interneuronal function may provide a novel therapeutic strategy.
Amyotrophic Lateral Sclerosis 03/2012; 13(3):245-50. · 3.40 Impact Factor
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Jose C Roche,
Ricardo Rojas-Garcia,
Kirsten M Scott,
William Scotton,
Catherine E Ellis,
Rachel Burman,
Lokesh Wijesekera, Martin R Turner,
P Nigel Leigh,
Christopher E Shaw,
Ammar Al-Chalabi
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ABSTRACT: Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, with a median survival of 2-3 years. Although various phenotypic and research diagnostic classification systems exist and several prognostic models have been generated, there is no staging system. Staging criteria for amyotrophic lateral sclerosis would help to provide a universal and objective measure of disease progression with benefits for patient care, resource allocation, research classifications and clinical trial design. We therefore sought to define easily identified clinical milestones that could be shown to occur at specific points in the disease course, reflect disease progression and impact prognosis and treatment. A tertiary referral centre clinical database was analysed, consisting of 1471 patients with amyotrophic lateral sclerosis seen between 1993 and 2007. Milestones were defined as symptom onset (functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, needing gastrostomy and non-invasive ventilation. Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration. Milestones occurred at predictable proportions of the disease course. Diagnosis occurred at 35% through the disease course, involvement of a second region at 38%, a third region at 61%, need for gastrostomy at 77% and need for non-invasive ventilation at 80%. We therefore propose a simple staging system for amyotrophic lateral sclerosis. Stage 1: symptom onset (involvement of first region); Stage 2A: diagnosis; Stage 2B: involvement of second region; Stage 3: involvement of third region; Stage 4A: need for gastrostomy; and Stage 4B: need for non-invasive ventilation. Validation of this staging system will require further studies in other populations, in population registers and in other clinic databases. The standardized times to milestones may well vary between different studies and populations, although the stages themselves and their meanings are likely to remain unchanged.
Brain 03/2012; 135(Pt 3):847-52. · 9.46 Impact Factor
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ABSTRACT: Non-human models of neurodegenerative diseases have potential for the identification of key pathways in pathogenesis and for the more rapid assessment of therapeutic candidates. While there are legitimate concerns about the physiological differences between the rodent and human motor systems, mice expressing the 'G93A' superoxide dismutase-1 gene mutation are a predictable and robustly-characterized model for amyotrophic lateral sclerosis (ALS). This model has provided evidence for an important role of inflammatory processes during the pre-clinical phase, a stage currently inaccessible for human study in what is largely a sporadic disease. While magnetic resonance imaging is now an established and leading modality for the identification of ALS biomarkers in humans, it can also be increasingly applied to rodent models to probe structural, functional and biochemical changes throughout the course of the disease, with additional potential to generate surrogate markers for the efficacy of therapeutic interventions. Targeted MRI contrast agents, through tagging of various cell types and even individual molecules, will deliver an era of in vivo molecular neuroimaging, with greater specificity for the most relevant pathological processes. These are potentially important steps towards the ultimate goal of human therapeutic translation.
Amyotrophic Lateral Sclerosis 11/2011; 13(3):288-301. · 3.40 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis as a system failure is a concept supported by the finding of consistent extramotor as well as motor cerebral pathology. The functional correlates of the structural changes detected using advanced magnetic resonance imaging techniques such as diffusion tensor imaging and voxel-based morphometry have not been extensively studied. A group of 25 patients with amyotrophic lateral sclerosis was compared to healthy control subjects using a multi-modal neuroimaging approach comprising T(1)-weighted, diffusion-weighted and resting-state functional magnetic resonance imaging. Using probabilistic tractography, a grey matter connection network was defined based upon the prominent corticospinal tract and corpus callosum involvement demonstrated by white matter tract-based spatial statistics. This 'amyotrophic lateral sclerosis-specific' network included motor, premotor and supplementary motor cortices, pars opercularis and motor-related thalamic nuclei. A novel analysis protocol, using this disease-specific grey matter network as an input for a dual-regression analysis, was then used to assess changes in functional connectivity directly associated with this network. A spatial pattern of increased functional connectivity spanning sensorimotor, premotor, prefrontal and thalamic regions was found. A composite of structural and functional magnetic resonance imaging measures also allowed the qualitative discrimination of patients from controls. An integrated structural and functional connectivity approach therefore identified apparently dichotomous processes characterizing the amyotrophic lateral sclerosis cerebral network failure, in which there was increased functional connectivity within regions of decreased structural connectivity. Patients with slower rates of disease progression showed connectivity measures with values closer to healthy controls, raising the possibility that functional connectivity increases might not simply represent a physiological compensation to reduced structural integrity. One alternative possibility is that increased functional connectivity reflects a progressive loss of inhibitory cortical influence as part of amyotrophic lateral sclerosis pathogenesis, which might then have relevance to future therapeutic strategies.
Brain 11/2011; 134(Pt 12):3470-9. · 9.46 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) appears to be a sporadic disorder in 95% of cases. Although few personal characteristics associated with developing ALS are known, identification of those at risk is essential to any vision of early intervention. There is persistent anecdotal observation that those with ALS are premorbidly physically 'fitter', although such observations are susceptible to bias. Hospital admission for coronary heart disease (CHD) might serve as an objective marker of reduced cardiovascular fitness.
A record linkage study of two large databases of hospital admissions, the Oxford Record Linkage Study (ORLS) and an English national record linkage dataset of Hospital Episode Statistics was undertaken. The ratio of the rate of ALS in people without a record of CHD to that in those with a record of CHD was calculated, factoring out premature death in both cohorts. Similar analysis for Parkinson's disease (PD) and multiple sclerosis (MS) was undertaken.
In the English population, the rate ratio for ALS in the non-CHD cohort, compared with the CHD cohort, was 1.14 (95% CI 1.05 to 1.22); for PD it was 0.95 (95% CI 0.93 to 0.98); and for MS 0.95 (95% CI 0.88 to 1.04). The ORLS data yielded similar findings.
Those without a record of CHD were at modestly higher risk of ALS, but not for PD or MS. This lends support to the assertion that ALS arises within a population who may have relatively higher levels of cardiovascular fitness.
Journal of neurology, neurosurgery, and psychiatry 11/2011; 83(4):395-8. · 4.87 Impact Factor
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Practical Neurology 08/2011; 11(4):220-30.
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Karla L Miller,
Charlotte J Stagg,
Gwenaëlle Douaud,
Saad Jbabdi,
Stephen M Smith,
Timothy E J Behrens,
Mark Jenkinson,
Steven A Chance,
Margaret M Esiri,
Natalie L Voets,
Ned Jenkinson,
Tipu Z Aziz, Martin R Turner,
Heidi Johansen-Berg,
Jennifer A McNab
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ABSTRACT: Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and "gold standard" histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.
NeuroImage 07/2011; 57(1):167-81. · 5.89 Impact Factor
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ABSTRACT: Although traditionally regarded as spared, a range of oculomotor dysfunction has been recorded in patients with amyotrophic lateral sclerosis (ALS). Most frequent is ophthalmoparesis, particularly in patients with prolonged survival; however, pursuit, nystagmus, and saccadic impairments have also been reported. The apparent resistance to pathologic involvement of oculomotor (and sphincter) control pathways in most patients with ALS has prompted comparative study to establish the key pathways that underlie motor neuronal vulnerability, with the hope of generating novel therapeutic strategies. Developments in the assessment of oculomotor function, including portable eye-tracking devices, have revealed more subtle impairments in ALS in relation to phenotype, which can now be better understood through parallel elucidation of the normal cerebral oculomotor control network. Given the clinicopathologic overlap between ALS and some types of frontotemporal dementia, the study of oculomotor function has particular value in probing the variable but consistent cognitive impairment seen in ALS and that reflects frontotemporal extramotor cerebral abnormalities. By transcending the requirement to write or speak, loss of which precludes standard neuropsychological testing in some patients with advanced ALS, cognitive tests performed using only oculomotor functions offer additional potential, allowing the study of patients much later in their disease course. The study of oculomotor dysfunction holds significant promise as an additional source of much needed prognostic, monitoring, and mechanistic biomarkers for ALS.
Archives of neurology 07/2011; 68(7):857-61. · 6.31 Impact Factor
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ABSTRACT: The aetiology of apparently sporadic amyotrophic lateral sclerosis (ALS) is unknown, but prenatal factors are known to influence disease development. In both men and women, motor neurons require testosterone for survival and axonal regeneration after injury, and androgen insensitivity leads to a form of motor neuron degeneration in men. Reduction in the ratio of index to ring finger length (2D:4D ratio) is considered a surrogate marker for high prenatal testosterone levels in both men and women. The authors therefore tested the hypothesis that prenatal testosterone irrespective of gender is an independent risk factor for the development of ALS later in life, and that this would be reflected in a lower 2D:4D ratio in both men and women with ALS.
Patients and unrelated control individuals attending a specialist tertiary referral centre for ALS were studied. A digital camera was used to photograph hands. Finger lengths were measured by four independent scorers blind to case-control status, and the mean 2D:4D ratio derived. Analysis was by linear regression and receiver-operator-curve analysis.
Controlling for differences in sex ratio between groups, the 2D:4D ratio was lower for people with ALS (n=47) than for controls (n=63) (r=-0.25, two-tailed p=0.009).
Patients with ALS have a lower 2D:4D ratio, consistent with higher prenatal circulating levels of testosterone, and possibly a prenatal influence of testosterone on motor-neuron vulnerability in later life.
Journal of neurology, neurosurgery, and psychiatry 06/2011; 82(6):635-7. · 4.87 Impact Factor
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Martin R Turner,
Julian Grosskreutz,
Jan Kassubek,
Sharon Abrahams,
Federica Agosta,
Michael Benatar,
Massimo Filippi,
Laura H Goldstein,
Martijn van den Heuvel,
Sanjay Kalra,
Dorothée Lulé,
Bahram Mohammadi
The Lancet Neurology 05/2011; 10(5):400-3. · 23.46 Impact Factor
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ABSTRACT: Studies suggest that seizures may precede the detection of cerebral tumour by several years. Aim To quantify the risk of cerebral tumour after new onset seizures, with particular interest in long term risk.
Using the Oxford Record Linkage Study (ORLS, 1963-1998) and English national linked Hospital Episode Statistics (1999-2005), cohorts of people with a first admission for epilepsy were constructed. Subsequent admissions with cerebral tumour were identified. The rate of occurrence of subsequent cerebral tumour in each epilepsy cohort was compared with that in a comparison cohort and expressed as a rate ratio (RR).
The RR for cerebral tumour after epilepsy, relative to the rate of cerebral tumour in the comparison cohort, was 19.9 (95% CI 17.2 to 22.9) in the ORLS cohort and 19.7 (18.3-21.1) in the England cohort. The RR for malignant tumours were, respectively, 25.6 (21.7 to 30.0) and 27.3 (25.2 to 29.6). The RR for benign tumours were 10.1 (7.38 to 13.6) and 10.4 (9.07 to 11.8), respectively. The risk was highest for those aged 15-44 years at initial admission for epilepsy both in Oxford (24.2, 18.5 to 31.5) and England (38.1, 32.8 to 44.2). The risk of cerebral tumour was still raised several years after initial admission for epilepsy: in the ORLS cohort at 15 years or more, the RR was 3.29 (1.39 to 6.66) and, in the England cohort 5-7 years after initial admission, the RR was 5.27 (3.87 to 7.06).
Seizures may herald the development of cerebral tumour, remote in time as well as soon after onset, with implications for guidelines on continued surveillance of those with new onset seizures.
Journal of neurology, neurosurgery, and psychiatry 03/2011; 82(9):1041-5. · 4.87 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.
The Lancet 02/2011; 377(9769):942-55. · 38.28 Impact Factor
