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PubMed | University Hospital Lille, Peking Union Medical College, St George's, University of London, University of Bristol and 13 more.
Type: Editorial | Journal: BMC medicine | Year: 2016

Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease.Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimers disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimers disease, vascular dementia and mixed Alzheimers disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue.Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.


Donaldson I.J.,University of Manchester | Amin S.,University of Manchester | Hensman J.J.,University of Sheffield | Hensman J.J.,Sheffield Institute for Translational Neuroscience | And 8 more authors.
Nucleic Acids Research | Year: 2012

The regulation of gene expression is central to developmental programs and largely depends on the binding of sequence-specific transcription factors with cis-regulatory elements in the genome. Hox transcription factors specify the spatial coordinates of the body axis in all animals with bilateral symmetry, but a detailed knowledge of their molecular function in instructing cell fates is lacking. Here, we used chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) to identify Hoxa2 genomic locations in a time and space when it is actively instructing embryonic development in mouse. Our data reveals that Hoxa2 has large genome coverage and potentially regulates thousands of genes. Sequence analysis of Hoxa2-bound regions identifies high occurrence of two main classes of motifs, corresponding to Hox and Pbx-Hox recognition sequences. Examination of the binding targets of Hoxa2 faithfully captures the processes regulated by Hoxa2 during embryonic development; in addition, it uncovers a large cluster of potential targets involved in the Wnt-signaling pathway. In vivo examination of canonical Wnt-β-catenin signaling reveals activity specifically in Hoxa2 domain of expression, and this is undetectable in Hoxa2 mutant embryos. The comprehensive mapping of Hoxa2-binding sites provides a framework to study Hox regulatory networks in vertebrate developmental processes. © 2012 The Author(s).


Crunelli V.,University of Cardiff | Cope D.W.,University of Cardiff | Terry J.R.,University of Sheffield | Terry J.R.,Sheffield Institute for Translational Neuroscience
Epilepsy Research | Year: 2011

Absence seizures appear to be initiated in a putative cortical 'initiation site' by the expression of medium-amplitude 5-9Hz oscillations, which may in part be due to a decreased phasic GABA A receptor function. These oscillations rapidly spread to other cortical areas and to the thalamus, leading to fully developed generalized spike and wave discharges. In thalamocortical neurons of genetic models, phasic GABA A inhibition is either unchanged or increased, whereas tonic GABA A inhibition is increased both in genetic and pharmacological models. This enhanced tonic inhibition is required for absence seizure generation, and in genetic models it results from a malfunction in the astrocytic GABA transporter GAT-1. Contradictory results from inbred and transgenic animals still do not allow us to draw firm conclusions on changes in phasic GABA A inhibition in the GABAergic neurons of the nucleus reticularis thalami. Mathematical modelling may enhance our understanding of these competing hypotheses, by permitting investigations of their mechanistic aspects, hence enabling a greater understanding of the processes underlying seizure generation and evolution. © 2011 Elsevier B.V..


Alvarez M.A.,Technological University of Pereira | Luengo D.,Technical University of Madrid | Lawrence N.D.,University of Sheffield | Lawrence N.D.,Sheffield Institute for Translational Neuroscience
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2013

Purely data-driven approaches for machine learning present difficulties when data are scarce relative to the complexity of the model or when the model is forced to extrapolate. On the other hand, purely mechanistic approaches need to identify and specify all the interactions in the problem at hand (which may not be feasible) and still leave the issue of how to parameterize the system. In this paper, we present a hybrid approach using Gaussian processes and differential equations to combine data-driven modeling with a physical model of the system. We show how different, physically inspired, kernel functions can be developed through sensible, simple, mechanistic assumptions about the underlying system. The versatility of our approach is illustrated with three case studies from motion capture, computational biology, and geostatistics. © 1979-2012 IEEE.


Cooper-Knock J.,Sheffield Institute for Translational Neuroscience | Frolov A.,University of Sheffield | Highley J.R.,Sheffield Institute for Translational Neuroscience | Charlesworth G.,University of Sheffield | And 10 more authors.
Neurology | Year: 2013

Objective: To determine the histopathologic bases for the observed incidence of parkinsonism in families with C9ORF72 expansions, which typically cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia. Methods: DNA was extracted from 377 brains with the histopathologic diagnosis of idiopathic Parkinson disease or related disorders and analyzed for C9ORF72 expansions. a-Synuclein and p62 immunohistochemistry of the substantia nigra (SN) was undertaken in brains of 17 ALS cases with (C9ORF721) and 51 without (C9ORF722) the C9ORF72 expansion. Results: Only 1 of 338 cases with pathologically confirmed idiopathic Parkinson disease had a C9ORF72 expansion. Similarly, only 1 of 17 C9ORF721 brains displayed features suggestive of a-synucleinopathy. In contrast, p62-positive, TDP-43-negative neuronal cytoplasmic inclusions within the SN were considerably more frequent in C9ORF721 brain tissue than in the C9ORF722 brains (p 5 0.005). Furthermore, there was a more marked loss of dopaminergic neurons in the SN of C9ORF721 ALS brains than C9ORF722 ALS brains (p 5 0.029). Conclusions: SN involvement is common in C9ORF721 ALS but can be clearly distinguished from Parkinson disease-related mechanisms by the presence of p62-positive inclusions and the absence of a-synuclein-positive Lewy bodies or Lewy neurites. © 2013 American Academy of Neurology.


Jenkins T.M.,Sheffield Institute for Translational Neuroscience | Hollinger H.,Sheffield Institute for Translational Neuroscience | McDermott C.J.,Sheffield Institute for Translational Neuroscience
Current Opinion in Neurology | Year: 2014

Purpose of review: Amyotrophic lateral sclerosis (ALS) is a progressive, incurable and fatal neurodegenerative disease. Few interventions significantly alter the disease course, but many symptomatic treatments exist to improve patients' quality of life. In this review, we describe our approach to symptomatic management of ALS and discuss the underlying evidence base. Recent findings: Discussion focuses predominantly on recently published articles. We cover management settings, disease-modifying treatment, vitamin D, respiratory management including noninvasive ventilation and diaphragmatic pacing, secretions, nutrition, dysphagia and gastrostomy, communication problems, mobility, spasticity, pain, cognition, depression and emotional lability, fatigue, sleep disturbance, head drop, prevention of deep venous thrombosis and end-of-life issues. Summary: Multidisciplinary specialist care appears to improve quality of life and survival. Riluzole remains the only available disease-modifying medication and confers a survival advantage of 2-3 months. Noninvasive ventilation improves quality of life and extends survival by approximately 7 months, at least in patients without severe bulbar problems. Nutrition is an independent prognostic factor; whether gastrostomy improves survival and quality of life remains unclear and further studies are underway. Many other symptomatic treatments appear helpful to individuals in clinic, but further randomized clinical trials are required to provide a more robust evidence base. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


Wharton S.B.,Sheffield Institute for Translational Neuroscience | Simpson J.E.,Sheffield Institute for Translational Neuroscience | Brayne C.,University of Cambridge | Ince P.G.,Sheffield Institute for Translational Neuroscience
Brain Pathology | Year: 2015

Cerebral white matter lesions (WML) are common in the aging brain and are associated with dementia and depression. They are associated with vascular risk factors and small vessel disease, suggesting an ischemic origin, but recent pathology studies suggest a more complex pathogenesis. Studies using samples from the population-representative Medical Research Council Cognitive Function and Ageing Study neuropathology cohort used post-mortem magnetic resonance imaging to identify WML for further study. Expression of hypoxia-related molecules and other injury and protective cellular pathways in candidate immunohistochemical and gene expression microarray studies support a role for hypoxia/ischemia. However, these approaches also suggest that immune activation, blood-brain barrier dysfunction, altered cell metabolic pathways and glial cell injury contribute to pathogenesis. These abnormalities are not confined to WML, but are also found in apparently normal white matter in brains with lesions, suggesting a field effect of white matter abnormality within which lesions arise. WML are an active pathology with a complex pathogenesis that may potentially offer a number of primary and secondary intervention targets. © 2014 International Society of Neuropathology.


Zaccai J.,University of Cambridge | Brayne C.,University of Cambridge | Matthews F.E.,Institute of Public Health | Ince P.G.,Sheffield Institute for Translational Neuroscience
Alzheimer's Research and Therapy | Year: 2015

Introduction: Studies with strong selection biases propose that alpha-synucleinopathy (AS) spreads upwards and downwards in the neuraxis from the medulla, that amygdala-dominant AS is strongly associated with Alzheimer's disease (AD), and that a more severe involvement of the cerebral cortex is correlated with increasing risk of dementia. This study examines the association of AS patterns and observed neuropsychological symptoms in brains of a population-representative donor cohort. Methods: Brains donated in 2 out of 6 cognitive function and ageing study cohorts (Cambridgeshire and Nottingham) were examined. Over 80% were >80 years old at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein (using LB509 by Zymed Laboratories) was carried out in 208 brains to establish Braak stage and the pattern and severity of AS following the dementia with Lewy bodies (DLB) consensus recommendations. Dementia, specific neuropsychological measures as measured using the Cambridge cognitive examination, the presence of hallucinations and Parkinson's disease were investigated. Results: Four patterns of AS were observed: no AS pathology (n = 92), AS pathology following the DLB consensus guidelines (n = 33, of which five were 'neocortical'), amygdala-predominant AS (n = 18), and other AS patterns (n = 33). Each group was subdivided according to high/low neurofibrillary tangles (NFT) Braak stage. Results showed no association between dementia and these patterns of AS, adjusting for the presence of NFT or not. The risk of visual hallucinations shows a weak association with AS in the substantia nigra (odds ratio (OR) = 3.2; 95% confidence interval (CI) 0.5 to 15.5; P = 0.09) and amygdala (OR = 3.0; 95% CI 0.7 to 12.3; P = 0.07). The analysis is similar for auditory hallucinations in subcortical regions. Conclusions: Among the whole population of older people, AS does not increase the risks for dementia, irrespective of Braak stage of NFT pathology. There was no evidence that the pattern of AS pathology in cortical areas was relevant to the risk of hallucination. In general, the hypothesis that AS as measured using these methods per se is a key determinant of cognitive clinical phenotypes is not supported. © 2015 Zaccai et al.; licensee BioMed Central.


Cooper-Knock J.,Sheffield Teaching Hospitals | Cooper-Knock J.,Sheffield Institute for Translational Neuroscience | Ahmedzai S.H.,University of Sheffield | Shaw P.,Sheffield Teaching Hospitals
Amyotrophic Lateral Sclerosis | Year: 2011

Sialorrhoea is a recognized complication of bulbar amyotrophic lateral sclerosis (ALS) that leads to an increased risk of potentially harmful aspiration and often prevents patients from tolerating non-invasive ventilation (NIV). A case of treatment-resistant sialorrhoea in bulbar ALS is described where subcutaneous glycopyrrolate was effective without significant side-effects. The patient went on to markedly increase the length of time she could tolerate NIV each night. © 2011 Informa Healthcare.


PubMed | Institute of Public Health, University of Cambridge and Sheffield Institute for Translational Neuroscience
Type: Journal Article | Journal: Alzheimer's research & therapy | Year: 2015

Studies with strong selection biases propose that alpha-synucleinopathy (AS) spreads upwards and downwards in the neuraxis from the medulla, that amygdala-dominant AS is strongly associated with Alzheimers disease (AD), and that a more severe involvement of the cerebral cortex is correlated with increasing risk of dementia. This study examines the association of AS patterns and observed neuropsychological symptoms in brains of a population-representative donor cohort.Brains donated in 2 out of 6 cognitive function and ageing study cohorts (Cambridgeshire and Nottingham) were examined. Over 80% were >80years old at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein (using LB509 by Zymed Laboratories) was carried out in 208 brains to establish Braak stage and the pattern and severity of AS following the dementia with Lewy bodies (DLB) consensus recommendations. Dementia, specific neuropsychological measures as measured using the Cambridge cognitive examination, the presence of hallucinations and Parkinsons disease were investigated.Four patterns of AS were observed: no AS pathology (n=92), AS pathology following the DLB consensus guidelines (n=33, of which five were neocortical), amygdala-predominant AS (n=18), and other AS patterns (n=33). Each group was subdivided according to high/low neurofibrillary tangles (NFT) Braak stage. Results showed no association between dementia and these patterns of AS, adjusting for the presence of NFT or not. The risk of visual hallucinations shows a weak association with AS in the substantia nigra (odds ratio (OR)=3.2; 95% confidence interval (CI) 0.5 to 15.5; P=0.09) and amygdala (OR=3.0; 95% CI 0.7 to 12.3; P=0.07). The analysis is similar for auditory hallucinations in subcortical regions.Among the whole population of older people, AS does not increase the risks for dementia, irrespective of Braak stage of NFT pathology. There was no evidence that the pattern of AS pathology in cortical areas was relevant to the risk of hallucination. In general, the hypothesis that AS as measured using these methods per se is a key determinant of cognitive clinical phenotypes is not supported.

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