ORCID Profile
0000-0003-0267-3180
Current Organisations
Health Education England Thames Valley
,
University of Oxford
,
Oxford University Hospitals NHS Trust
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Publisher: Informa UK Limited
Date: 18-07-2017
DOI: 10.1080/21678421.2017.1349151
Abstract: Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic has been a multidisciplinary, specialist, tertiary referral centre since 1995 with a large team with integrated palliative and respiratory care since 2006. We hypothesised that these changes would improve survival. In this retrospective observational study, patients diagnosed with El Escorial definite, probable and possible ALS between 1995-1998 and 2008-2011 were followed up. The primary outcome measure was a chi-square test for the proportion of each cohort surviving. Kaplan-Meier survival analysis and Cox multivariate regression were secondary analyses. There was low reporting of some interventions. Five hundred and forty-seven people were included. Survival between the cohorts was significantly different (p = 0.022) with a higher proportion surviving during 2008-2011. Survival time was 21.6 (95% CI 19.2-24.0) months in the 2008-2011 cohort compared to 19.2 years (15.6-21.6) in the 1995-1998 cohort (log rank p = 0.018). Four hundred and ninety-three cases were included in the Cox regression. Diagnostic cohort was a significant predictor variable (HR 0.79 (0.64-0.97) p = 0.023). These results support the hypothesis that integrated specialist clinics with multidisciplinary input improve survival in ALS.
Publisher: JMIR Publications Inc.
Date: 18-01-2019
Abstract: bjective symptom monitoring of patients with Amyotrophic Lateral Sclerosis (ALS) has the potential to provide an important source of information to evaluate the impact of the disease on aspects of real-world functional capacity and activities of daily living in the home setting, providing useful objective outcome measures for clinical trials. his study aimed to investigate the feasibility of a novel digital platform for remote data collection of multiple symptoms—physical activity, heart rate variability (HRV), and digital speech characteristics—in 25 patients with ALS in an observational clinical trial setting to explore the impact of the devices on patients’ everyday life and to record tolerability related to the devices and study procedures over 48 weeks. n this exploratory, noncontrolled, nondrug study, patients attended a clinical site visit every 3 months to perform activity reference tasks while wearing a sensor, to conduct digital speech tests and for conventional ALS monitoring. In addition, patients wore the sensor in their daily life for approximately 3 days every month for the duration of the study. he amount and quality of digital speech data captured at the clinical sites were as intended, and there were no significant issues. All the home monitoring sensor data available were propagated through the system and were received as expected. However, the amount and quality of physical activity home monitoring data were lower than anticipated. A total of 3 or more days (or partial days) of data were recorded for 65% of protocol time points, with no data collected for 24% of time points. At baseline, 24 of 25 patients provided data, reduced to 13 of 18 patients at Week 48. Lower-than-expected quality HRV data were obtained, likely because of poor contact between the sensor and the skin. In total, 6 of 25 patients had mild or moderate adverse events (AEs) in the skin and subcutaneous tissue disorders category because of skin irritation caused by the electrode patch. There were no reports of serious AEs or deaths. Most patients found the sensor comfortable, with no or minimal impact on daily activities. he platform can measure physical activity in patients with ALS in their home environment patients used the equipment successfully, and it was generally well tolerated. The quantity of home monitoring physical activity data was lower than expected, although it was sufficient to allow investigation of novel physical activity end points. Good-quality in-clinic speech data were successfully captured for analysis. Future studies using objective patient monitoring approaches, combined with the most current technological advances, may be useful to elucidate novel digital biomarkers of disease progression.
Publisher: S. Karger AG
Date: 27-11-2008
DOI: 10.1159/000177032
Abstract: i Background: /i Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that causes progressive paralysis and eventually results in death from respiratory failure. Environmental factors that trigger ALS might result in a pattern of geographical clustering of cases. We tested this hypothesis using the South-East England ALS population register, which covers south-east London, Kent and parts of neighbouring counties. i Methods: /i The register’s catchment area was ided into postcode districts and sectors. The expected rates of ALS (adjusted for age and sex) were compared with the observed rates using a standardised residuals method and the SaTScan programme. i Results: /i There were 406 cases of ALS identified in the catchment area during the study period. Four of the 126 postcode districts, all in Greater London, had residuals .5 SDs from the mean. Similarly, there were 15 postcode sectors (out of 420) that had residuals .96 SDs from the mean. Nine of these were in Greater London. SaTScan identified an area that had a 5.61-km radius in which the relative risk of ALS was 1.70 (p = 0.012). This area overlapped with the postcode districts and some of the sectors identified using the residuals method. i Conclusions: /i These findings suggest an excess of ALS cases in some postcode districts in south-east England.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-11-2015
Publisher: BMJ
Date: 09-2005
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.CLINPH.2015.02.003
Abstract: There is growing evidence that mirror neurons, initially discovered over two decades ago in the monkey, are present in the human brain. In the monkey, mirror neurons characteristically fire not only when it is performing an action, such as grasping an object, but also when observing a similar action performed by another agent (human or monkey). In this review we discuss the origin, cortical distribution and possible functions of mirror neurons as a background to exploring their potential relevance in amyotrophic lateral sclerosis (ALS). We have recently proposed that ALS (and the related condition of frontotemporal dementia) may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. This can include loss of the direct projections from the corticospinal tract, and this is at least part of the explanation for impaired motor control in ALS. Since, in the monkey, corticospinal neurons also show mirror properties, ALS in humans might also affect the mirror neuron system. We speculate that a defective mirror neuron system might contribute to other ALS deficits affecting motor imagery, gesture, language and empathy.
Publisher: Oxford University Press (OUP)
Date: 20-04-2005
DOI: 10.1093/BRAIN/AWH509
Abstract: Five to ten percent of amyotrophic lateral sclerosis (ALS) cases are associated with mutations of the superoxide dismutase-1 (SOD1) gene, and the 'D90A' mutation is associated with a unique phenotype and markedly slower disease progression (mean survival time 14 years). Relative sparing of inhibitory cortical neuronal circuits might be one mechanism contributing to the slower progression in patients homozygous for the D90A mutation (homD90A). The GABA(A) receptor PET ligand [11C]flumazenil has demonstrated motor and extra-motor cortical changes in sporadic ALS. In this study, we used [11C]flumazenil PET to explore differences in the pattern of cortical involvement between sporadic and genetically homogeneous ALS groups. Twenty-four sporadic ALS (sALS) and 10 homD90A patients underwent [11C]flumazenil PET of the brain. In addition, two subjects homozygous for the D90A mutation, but without symptoms or signs ('pre-symptomatic', psD90A), also underwent imaging. Results for each group were compared with those for 24 healthy controls of similar age. Decreases in the binding of [11C]flumazenil in the sALS group were found within premotor regions, motor cortex and posterior motor association areas. In the homD90A group of ALS patients, however, decreases were concentrated in the left fronto-temporal junction and anterior cingulate gyrus. In the two psD90A subjects, a small focus of reduced [11C]flumazenil binding at the left fronto-temporal junction was seen, similar to the pattern seen in the clinically affected patients. Within the sALS group, there was no statistically significant association between decreases in cortical [11C]flumazenil binding and revised ALS functional rating scale (ALSFRS-R score), whereas the upper motor neuron (UMN) score correlated with widespread and marked cortical decreases over the dominant hemisphere. In the homD90A group, there was a stronger statistical association between reduced cortical [11C]flumazenil binding and the ALSFRS-R, rather than the UMN, score, and also with disease duration. This study provides evidence for differences in the distribution of reduced cortical [11C]flumazenil binding in homD90A compared with sALS patients. We hypothesize that this might reflect differences in cortical neuronal vulnerability.
Publisher: Oxford University Press (OUP)
Date: 02-02-2005
DOI: 10.1093/BRAIN/AWH428
Abstract: The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each in idual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2014
Publisher: BMJ
Date: 26-07-2018
Abstract: The thalamus is a major neural hub, with selective connections to virtually all cortical regions of the brain. The multisystem neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) has pathogenic overlap with frontotemporal dementia, and objective in vivo markers of extra-motor pathological spread are lacking. To better consider the role of the thalamus in neurodegeneration, the present study assessed the integrity of the thalamus and its connectivity to major cortical regions of the brain in a longitudinal manner. Diffusion-based MRI tractography was used to parcellate the thalamus into distinct regions based on structural thalamo-cortical connectivity in 20 patients with ALS, half of whom were scanned at two time points, and 31 matched controls scanned on a single occasion. At baseline, widespread diffusivity alterations in motor- and extramotor-associated thalamic parcellations were detectable. Longitudinal decline selectively affected thalamic regions associated with frontal and temporal lobe connectivity. Diffusivity measures were significantly correlated with clinical measures of disease burden. Progression of functional disability, as indicated by change on the ALS functional rating scale, was associated with longitudinal change in mean diffusivity of the right frontal lobe thalamic parcellation (r=0.59, p=0.05). Regional thalamic connectivity changes mirror the progressive frontotemporal cortical involvement associated with the motor functional decline in ALS. Longitudinal MRI thalamic parcellation has potential as a non-invasive surrogate marker of cortical dysfunction in ALS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-01-2013
Publisher: BMJ
Date: 22-06-2017
Publisher: BMJ
Date: 09-11-2017
Publisher: Informa UK Limited
Date: 23-06-2020
Publisher: Cold Spring Harbor Laboratory
Date: 26-11-2019
DOI: 10.1101/849570
Abstract: There is a need to understand the histopathological basis of MRI signal characteristics in complex biological matter. Microstructural imaging holds promise for sensitive and specific indicators of the early stages of human neurodegeneration but requires validation against traditional histological markers before it can be reliably applied in the clinical setting. Validation relies on a precise and preferably automatic method to align MRI and histological images of the same tissue, which poses unique challenges compared to more conventional MRI-to-MRI registration. A customisable open-source platform, Tensor Image Registration Library (TIRL) is presented. Based on TIRL, a fully automated pipeline was implemented to align small stained histological images with dissection photographs of corresponding tissue blocks and coronal brain slices, and further with high-resolution (0.5 mm) whole-brain post-mortem MRI data. The pipeline performed three separate deformable registrations to achieve accurate mapping between whole-brain MRI and small-slide histology coordinates. The robustness and accuracy of the in idual registration steps were evaluated using both simulated data and real-life images from 6 different anatomical locations of one post-mortem human brain. The automated registration method demonstrated sub-millimetre accuracy in all steps, robustness against tissue damage, and good reproducibility between experiments. The method also outperformed manual landmark-based slice-to-volume registration, also correcting for curvatures in the slicing plane. Due to the customisability of TIRL, the pipeline can be conveniently adapted for other research needs and is therefore suitable for the large-scale comparison of routinely collected histology and MRI data. TIRL: new framework for prototyping bespoke image registration pipelines Pipeline for automated registration of small-slide histology to whole-brain MRI Slice-to-volume registration accounting for through-plane deformations No need for serial histological s ling
Publisher: JMIR Publications Inc.
Date: 20-12-2019
DOI: 10.2196/13433
Abstract: Objective symptom monitoring of patients with Amyotrophic Lateral Sclerosis (ALS) has the potential to provide an important source of information to evaluate the impact of the disease on aspects of real-world functional capacity and activities of daily living in the home setting, providing useful objective outcome measures for clinical trials. This study aimed to investigate the feasibility of a novel digital platform for remote data collection of multiple symptoms—physical activity, heart rate variability (HRV), and digital speech characteristics—in 25 patients with ALS in an observational clinical trial setting to explore the impact of the devices on patients’ everyday life and to record tolerability related to the devices and study procedures over 48 weeks. In this exploratory, noncontrolled, nondrug study, patients attended a clinical site visit every 3 months to perform activity reference tasks while wearing a sensor, to conduct digital speech tests and for conventional ALS monitoring. In addition, patients wore the sensor in their daily life for approximately 3 days every month for the duration of the study. The amount and quality of digital speech data captured at the clinical sites were as intended, and there were no significant issues. All the home monitoring sensor data available were propagated through the system and were received as expected. However, the amount and quality of physical activity home monitoring data were lower than anticipated. A total of 3 or more days (or partial days) of data were recorded for 65% of protocol time points, with no data collected for 24% of time points. At baseline, 24 of 25 patients provided data, reduced to 13 of 18 patients at Week 48. Lower-than-expected quality HRV data were obtained, likely because of poor contact between the sensor and the skin. In total, 6 of 25 patients had mild or moderate adverse events (AEs) in the skin and subcutaneous tissue disorders category because of skin irritation caused by the electrode patch. There were no reports of serious AEs or deaths. Most patients found the sensor comfortable, with no or minimal impact on daily activities. The platform can measure physical activity in patients with ALS in their home environment patients used the equipment successfully, and it was generally well tolerated. The quantity of home monitoring physical activity data was lower than expected, although it was sufficient to allow investigation of novel physical activity end points. Good-quality in-clinic speech data were successfully captured for analysis. Future studies using objective patient monitoring approaches, combined with the most current technological advances, may be useful to elucidate novel digital biomarkers of disease progression.
Publisher: Wiley
Date: 29-01-2016
DOI: 10.1111/ENE.12959
Abstract: Apathy is the most commonly reported behavioural change in amyotrophic lateral sclerosis (ALS). However, the degree to which it affects prognosis and overlaps with depression in this population is unknown. The present study examined the relationship between level of apathy, mortality and survival time and whether apathy was linked to specific symptom clusters of depression. A cohort of 76 consecutive ALS patients attending specialized multidisciplinary clinics were classified according to level of apathy. The effects of clinical factors and apathy on survival time were analysed using univariate and multivariate methods. The majority of patients with moderate to severe apathy died during the study (P = 0.003) and had a median survival time of 21.7 months, considerably shorter than patients with mild apathy (46.9 months) and no apathy (51.9 months) (P = 0.0001). Apathy remained a significant predictor of survival even after controlling for clinical factors and symptom duration at the time of study entry (hazard ratio 3.8, 95% confidence interval 1.9-7.5, P = 0.0001). Depression with demoralization was not associated with level of apathy (P = 0.172) whereas depression with anhedonia was more common in patients with apathy than in those without apathy (P = 0.006). The presence of severe apathy is an independent, negative prognostic factor in ALS.
Publisher: BMJ
Date: 30-12-2015
Publisher: Informa UK Limited
Date: 05-2012
DOI: 10.3109/17482968.2011.636050
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.
Publisher: Elsevier BV
Date: 07-2011
Publisher: Elsevier BV
Date: 05-2018
Publisher: Springer Science and Business Media LLC
Date: 25-07-2016
DOI: 10.1038/NG.3626
Publisher: Informa UK Limited
Date: 10-04-2014
Publisher: Informa UK Limited
Date: 12-03-2010
Publisher: BMJ
Date: 06-02-2020
Abstract: Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-04-2007
Publisher: Informa UK Limited
Date: 2005
DOI: 10.1080/14660820510035388
Abstract: Patient care and minimizing complications post gastrostomy have to date received little attention in ALS patients. We compare the complications associated with pigtail and mushroom type percutaneous radiological gastrostomy tubes in this patient group. Patients requiring PRG received either Wills-Oglesby or the skin level Entristar. Retrospective review of the clinical notes was performed capturing demographic data, peristomal infection, tube displacement, tube failure, nutritional status, site of disease onset, and survival. Thirty-five patients (Group 1) had the Wills-Oglesby tube of which 14 (40%) tubes required replacement. The Entristar tube was inserted in 29 patients (Group 2) where 8 (28%) required replacement (NS). The incidence of infection was significantly lower with the Entristar tube, (p<0.001). The mean time to tube removal in Group 2 was 223 days (SD 147 range 71-494 days) due to 'buried bumper syndrome'. We conclude that the Entristar skin level gastrostomy tube is associated with a reduction in peristomal infection, tube failure and blockage compared with the Wills-Oglesby tube.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2018
Publisher: Informa UK Limited
Date: 02-11-2020
Publisher: Informa UK Limited
Date: 29-04-2010
Publisher: SAGE Publications
Date: 05-02-2014
Abstract: Neuroinflammation has been identified as a potential therapeutic target in amyotrophic lateral sclerosis (ALS), but relevant biomarkers are needed. The superoxide dismutase (SOD1) G93A transgenic mouse model of ALS offers a unique opportunity to study and potentially manipulate presymptomatic pathology. While T 2 -weighted magnetic resonance imaging (MRI) has been shown to be sensitive to pathologic changes at symptom onset, no earlier biomarkers were previously identified and the underlying histopathologic correlates remain uncertain. To address these issues, we used a multimodal MRI approach targeting structural ( T 2 , T 2 , apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR)), vascular (gadolinium diethylene triamine pentaacetic acid), and endothelial (vascular cell adhesion molecule-microparticles of iron oxide) changes, together with histopathologic analysis from presymptomatic to symptomatic stages of disease. Presymptomatic changes in brainstem nuclei were evident on T 2 -weighted images from as early as 60 days ( P .05). Histologic indices of vacuolation, astro- and microglial activation all correlated with T 2 -weighted changes. Significant reductions in ADC ( P .01) and MTR ( P .05) were found at 120 days in the same brainstem nuclei. No changes in T 1 relaxation, vascular permeability, or endothelial activation were found at any stage of disease. These findings suggest that T 2 -weighted MRI offers the strongest biomarker potential in this model, and that MRI has unique potential for noninvasive and longitudinal assessment of presymptomatically applied therapeutic and neuroprotective agents.
Publisher: Informa UK Limited
Date: 17-06-2015
DOI: 10.3109/21678421.2015.1051987
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.
Publisher: BMJ
Date: 06-2005
Publisher: Oxford University Press (OUP)
Date: 23-01-2012
DOI: 10.1093/BRAIN/AWR351
Publisher: BMJ
Date: 2011
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 in iduals 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.
Publisher: Wiley
Date: 30-09-2014
DOI: 10.1002/ANA.24273
Publisher: Springer Science and Business Media LLC
Date: 09-02-2007
DOI: 10.1007/S00415-006-0482-7
Abstract: Four PLS patients underwent cerebral [(11)C]-flumazenil PET. They were compared firstly with a group of controls, then later directly with a group of sporadic ALS patients and a familial ALS group homozygous for the 'D90A' SOD1 gene mutation. There was a similar pattern of decreased binding in PLS patients when compared to controls as that seen in a previous study of sporadic ALS patients, supporting the concept that PLS is part of the same overall spectrum of MND. However, in direct group comparisons, both sporadic and homD90A ALS patients demonstrated relative decreases in anterior and orbito-frontal binding compared to PLS patients, suggesting that there may be differences in cortical vulnerability between phenotypic groups.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-05-2017
DOI: 10.1126/SCITRANSLMED.AAD9157
Abstract: Annexin A11 mutations, implicated in ALS, prevent binding to calcyclin and induce the formation of cytoplasmic inclusions.
Publisher: American Medical Association (AMA)
Date: 09-2019
Publisher: Springer Science and Business Media LLC
Date: 12-2006
Publisher: Oxford University Press (OUP)
Date: 07-11-2008
DOI: 10.1093/HMG/DDN375
Publisher: Informa UK Limited
Date: 2007
DOI: 10.1080/17482960701538734
Abstract: Patients homozygous for the D90A mutation of the SOD1 gene (homD90A) demonstrate markedly slower progression of disease than those patients with sporadic ALS (SALS). PET studies have demonstrated a different cortical vulnerability in the two groups, reflected also in neurophysiological studies showing reduced cortical excitability in homD90A. Voxel-based morphometric analysis of magnetic resonance images (MRIs) enables the detection of regional differences in grey matter volume, and can be used to localize cortical atrophy in vivo. In this study, segmented, spatially normalized, modulated and smoothed grey matter portions of the MRIs from 23 SALS and seven homD90A patients with similar disability, were compared with those from 28 healthy control subjects. The SALS group showed bilateral areas of atrophy mainly confined to motor and pre-motor cortices. Cortical changes in the homD90A group were more pronounced within the frontal lobes when both were compared with healthy controls. This study provides further evidence for a different pattern of cortical neuronal vulnerability in homD90A versus SALS patients that may provide insight as to their slower rate of disease progression.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Informa UK Limited
Date: 27-10-2017
Publisher: Elsevier BV
Date: 11-2018
Publisher: BMJ
Date: 14-02-2021
Abstract: The clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care. We performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases. 21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074). Routine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.
Publisher: Informa UK Limited
Date: 28-02-2020
Publisher: Elsevier BV
Date: 2009
Publisher: BMJ
Date: 13-02-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-02-2009
Publisher: Elsevier BV
Date: 03-2011
Publisher: Informa UK Limited
Date: 21-01-2019
DOI: 10.1080/21678421.2018.1562554
Abstract: The cerebellum shows neuropathological change in a number of neurodegenerative conditions where clinical involvement is not the primary feature, including amyotrophic lateral sclerosis (ALS). Whether these changes are associated with disruption to the direct cerebellar tract pathways to the motor cortex and spinal cord in ALS is uncertain. Diffusion tensor imaging was used to examine the integrity of two primary cerebellar pathways, the dentato-rubro-thalamo-cortical (DRTC) and spino-cerebellar (SC) tracts. ALS patients with an upper motor neuron (UMN)-predominant phenotype (
Publisher: BMJ
Date: 17-04-2019
Publisher: Elsevier BV
Date: 10-2014
Publisher: American Association for the Advancement of Science (AAAS)
Date: 27-03-2015
Abstract: Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig's disease,” is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Cirulli et al. sequenced the expressed genes of nearly 3000 ALS patients and compared them with those of more than 6000 controls (see the Perspective by Singleton and Traynor). They identified several proteins that were linked to disease in patients. One such protein, TBK1, is implicated in innate immunity and autophagy and may represent a therapeutic target. Science , this issue p. 1436 see also p. 1422
Publisher: Springer Science and Business Media LLC
Date: 18-12-2020
Publisher: Informa UK Limited
Date: 05-01-2017
Publisher: Elsevier BV
Date: 03-2013
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Martin Turner.