Sheffield Experimental Medicine Programmes in Neuroscience
Sheffield Experimental Medicine Programmes in Neuroscience
December 2011
Professor Pamela Shaw, Professor of Neurology University of Sheffield, Honorary Consultant Neurologist Sheffield Teaching Hospitals NHS Foundation Trust and Academic Director Neurosciences Directorate.
Academic Directorate of Neuroscience:
Department of Neuroscience Web-link:
SITraN Web-Link:
The Dementias & Neurodegenerative Diseases Research Network(DeNDRoN) Web-link:
INSIGNEO Institute for Biomedical Imaging and Modelling
Sheffield is a leading national centre for neurological disease research with strengths in the fields of neurodegeneration, cerebrovascular disease, neuro-inflammation, epilepsy and functional neurology. Sheffield Neuroscience investigators have a strong track record of attracting key sponsors; of recruiting patients into clinical research studies and delivering studies to target and on time. We have key roles within topic specific networks eg Stroke and DeNDRoN and good relationships and support from the South Yorkshire Comprehensive Research Network. We have established a pathway of translational research from basic neuroscience through to phase 3 clinical trials in patients in some areas of Neuroscience, especially in neurodegeneration. We have cohorts of patients carefully characterised throughout the disease course and a large collection of optimally prepared biosamples in multiple neurological disease areas. Sheffield has an excellent collaborative environment for interdisciplinary research between clinicians and basic scientists, together with researchers from health services research, public health (ScHARR and CHLARC), engineering, and bioinformatics. Interaction with the University of Sheffield’s newly formed Virtual Physiological Human Institute provides a unique platform for the continuing application of computation modelling to all aspects of clinical neuroscience research.
• Main themes and Investigators
Professor Graham Venables is the Clinical Director and Professor Pamela Shaw is the Academic Director within the Academic Directorate of Neuroscience which has established 5 main research themes each with a theme leader: Neurodegeneration – Dr Oliver Bandmann; Neuroinflammation – Dr Marios Hadjivassiliou; Cerebrovascular disease – Dr Marc Randall and Mr Umang Patel; Epilepsy – Dr Markus Reuber; Clinical Trials- Industry Liaison – Dr Basil Sharrack
Below are examples of translational research achievements in Neuroscience led by Sheffield investigators:
1. Introduction of riluzole, the first disease modifying therapy for a neurodegenerative disorder, into clinical practice. Investigators: Shaw, McDermott Our basic neurodegenerative diseases research team has been one of the major groups world-wide contributing new insights into the emerging concept that glutamatergic toxicity contributes to motor neuron injury in motor neuron disease (MND) including autoradiographic, immunohistochemical and in situ hybridisation studies indicating altered expression of glutamate receptors and re-uptake transporters in MND and perturbations of CSF glutamate levels in a subset of patients [1-14]. In addition, we uncovered cell specific features of motor neurons predisposing this cell type to excitotoxic injury [15-19]. This body of work contributed to the emergence of the anti-glutamate agent riluzole as a neuroprotective agent in the clinical management of MND [20-21]. We were leading researchers in evaluating this therapy in clinical trials and in establishing its place in UK clinical practice by working with NICE and health care funding bodies. In addition, Sheffield investigators have participated in all the major phase II and III trials of potential neuroprotective therapies in MND and through the DeNDroN MND Clinical Studies Group have also led the initiation of academic trials both of potential neuroprotective agents (eg LiCALS) and of approaches for improving symptom management (eg PROGAS).
2. Non-invasive ventilation produces substantial improvements in survival and quality of life in patients with motor neurone disease (MND). Investigators: Shaw, McDermott. We initiated a programme of work to investigate the effects of the new technology of non-invasive ventilation (NIV) on survival and quality of life for patients with MND. This is a particularly important issue as neuromuscular respiratory failure is the predominant cause of death in patients with MND and commonly occurs within 2-3 years of symptom onset. Initial work established the clinical parameters indicating when NIV should be started and the best respiratory and quality of life measures to assess the impact of this intervention [22-24]. A randomised controlled trial of NIV was undertaken which showed that this therapy had major positive effects on survival and quality of life in patients with MND, especially in patients with relatively good bulbar function [25]. This work has already had a significant impact in terms of improved care of patients with MND and has resulted in the publication of the NICE clinical guideline 105 [26]. A survey of the use of NIV in 2000 indicated that only 2 - 3 % of MND patients were offered this intervention [27]. By 2009 there had been a 3.4 fold increase in the number of MND patients using NIV and an improvement in successful use of NIV by referred patients from 54% to 72% [28]. The NICE guideline is expected to have further impact on the general availability of this treatment. This work has been responsible for demonstrating the therapy with the greatest positive impact on survival and quality of life so far demonstrated in MND. The group are now taking forward several other areas of research to improve the pathway of care provided for patients with MND, which will also be applicable to other patient groups with neuromuscular respiratory failure. These include studies of: the factors determining the uptake of and compliance with NIV; developing pathways for optimising respiratory care, including issues relevant to end of life and carer support and a randomised controlled trial of cough assist devices instigated at the time of NIV . Pilot work, with positive results, has been undertaken by the group to evaluate the new technology of diaphragm pacing in MND patients with respiratory compromise and we have been awarded a £1.5m NIHR HTA grant to lead a multi-centre randomised trial of this intervention (DiPALS).
3. Effective gene therapy approaches in models of neurodegeneration and first into man (phase 1) trials Investigators: Azzouz, Ning, Mead, Grierson, Shaw Professor Azzouz (SITraN Professsor of Translational Neuroscience) has an international profile in gene therapy approaches to ameliorate neurodegenerative diseases. Using lentiviral vectors to carry neuroprotective molecules to relevant neuronal populations or to knock down pathogenic genes (eg mutant Cu Zn superoxide dismutase (SOD1)) using siRNA’s this group has shown some of the most dramatic therapeutic effects to date in pre-clinical models of motor system neurodegenerative diseases [29-32]. In a recent study published in Science Translational Medicine, treatment of an spinal muscular atrophy (SMA) type1 mouse model with gene therapy using codon optimised adeno associated viral vectors given by intravenous injection, restored SMN protein expression, reduced MN cell death, and dramatically increased the life expectancy of this pre- clinical model [33-34]. This therapy has been awarded orphan drug designation by the European Medicines Agency and the programme is now being developed towards a first into man experimental medicine trial with funding from MRC and the European Research Council. In addition, Azzouz led a programme of work using gene therapy in Parkinson’s disease (PD) showing that a multicistronic lentiviral vector expressing three genes (tyrosine hydroxylase TH; Aromatic L-Amino Acid Decarboxylase AADC, and GTP Cyclohydrolase I CH1) could be used for dopamine replacement in a rat model of PD [35]. This therapeutic vector has subsequently been shown to achieve significant efficacy in non-human primate models and is now being tested into human PD clinical trials [36]. Several other areas of gene therapy are poised ready for similar clinical translation over the next 3 – 5 years.
4. Utilisation of gene expression profiling and characterization of mitochondrial function and morphology to identify therapeutic targets and biomarkers of disease subtypes in neurodegeneration. Investigators: Bandmann, Mortiboys, Flinn, Shaw, Kirby, Heath, Ferraiuolo, Rattray, Ramesh, Grierson, de Vos . Our basic neuroscience teams have established robust cellular models [37-41] and in vivo (mouse and zebrafish) models [42-45] of neurodegenerative diseases of the motor system including MND and Parkinson’s disease. By correlating key findings emerging from these models with human biosamples including CNS tissue, we have positioned ourselves at the forefront of research elucidating the molecular pathophysiology of these diseases [46-50]. For example, we have identified alterations in the motor neuron transcriptome and proteome indicating biochemical pathways specifically perturbed by SOD1 mutations which are potentially amenable to therapeutic manipulation, including the anti-oxidant response element transcription factor Nrf-2 and the PTEN- AKT neuronal survival pathways [37-39, 47, 51-54]. The first candidate (S-apomorphine) which could be potentially taken forward towards human Phase 1 trials has recently emerged from our drug screening programme ( Patent application number GB 0819530.7) and has been granted orphan drug designation by the European Medicines Agency. Similarly, in basic neuroscience work we have identified distinct profiles of mitochondrial impairment in MND and in early onset and late-onset Parkinson’s disease [55-60]. There are clear translational benefits for patients in the clinic. For example, there are currently two phase II/III clinical trials evaluating therapies which may achieve neuroprotection through ameliorating mitochondrial function (olesoxime and dexpramipexole). In work undertaken involving close collaboration between basic and clinical neuroscientists we recently identified rapamycin as a promising drug for future neuroprotective drug trials in PD [61].
In addition, gene expression profiling of both neurons and astrocytes extracted from CNS tissue and of peripheral tissue (fibroblasts, blood and lymphoblastoid cell lines) from living patients with genetic subtypes of neurodegenerative disease has provided encouraging evidence that this will be a useful approach for subclassifying these heterogeneous diseases more accurately and for identifying biomarkers of disease progression and therapeutic response [40, 46-48, 62,63]. This work will be taken forward with funding from EU Framework 7 Systems Biology in ALS/MND programme and an award for biomarker optimisation and harmonisation in ALS/MND funded by the MRC/European Joint Programme for Neurodegeneration (JPND) initiative.
5. Development of a clinical rating scale for Wilson’s Disease. Investigator: Bandmann. Wilson’s Disease (WD) is an eminently treatable condition. However, it is currently unclear whether the most widely used drug for this condition (penicillamine) should be replaced with other drugs (eg trientine, zinc) due to their potentially better side-effect profiles. Bandmann contributed to the development and systematic evaluation of the first specific clinical rating scale for WD [64]. This rating scale will now facilitate future head-to-head trials of WD drugs to identify the therapeutic approach with the best benefit-risk profile.
6. Pathogenesis of brain ageing and its relationship to neurodegeneration. Investigators: Ince, Wharton, Highley, Simpson, Shaw, Kirby, Heath, Blackburn, Rattray. The neurodegeneration group in Sheffield have been involved, along with partners in Public Health, Primary Care and Biostatistics in the MRC Cognitive Function and Ageing (CFAS) programme. This study has followed a representative sample of more than 18,000 people since 1990 and has collected more than 530 post-mortem brain donations from people aged 69 to 103 [65]. We have investigated the effect of age on the relationship between neuropathological features and dementia and have discovered that, although the relationship between cerebral atrophy and dementia persisted among all the older age groups (from 75 to 95 years), the strength of the association between classical Alzheimer “plaques and tangle” pathology and clinical dementia diminished after age 75. In the age group at greatest risk, having dementia by the time of death is much less related to classical neuropathological biomarkers than it is at younger ages. This work has provided evidence of a more complex relationship between brain function and brain pathology in very elderly age groups than is usually assumed in dementia research and indicates the need for caution about assuming that the presence of particular biomarkers means that the subject will inevitably develop dementia in these age groups [66]. Other work has generated true ‘epidemiological neuropathology’ including the first estimates of Population Attributable Risk for dementia associated with specific burdens of individual pathological features [67,68]. This analysis provides a sound platform from which the cost effectiveness and clinical impact of disease modifying treatments can be estimated at a population level for health care planning.
Several component studies within CFAS have addressed the role of specific pathologies and cell types in brain ageing. As an example, studies of astrocytes have defined their pathology, which occurs early in relation to progression of Alzheimer type pathology, implying that targeting these cells may be a therapeutic avenue to neuroprotection in brain ageing [69,70]. Gene array studies of astrocytes isolated from autopsy brain have shown down-regulation of key pathways related to cell signalling, structure and junctions with progression of Alzheimer type pathology [71,72]. This work has generated hypotheses that are now being explored in experimental systems, targeted at improving astrocyte function and support for neurons.
A further major area of work is in age-related white matter pathology, an important, but under-recognised contributor to age-related cognitive decline. Pathological and gene expression studies have defined the cellular pathology of white matter lesions and injury pathways involved in their pathogenesis, identifying potential novel targets for further investigation [73,74]. A particularly interesting observation is that surrounding, apparently normal white matter in brains with white matter lesions shows similar transcriptome alterations and up-regulation of microglial activity [75] to the lesions, suggesting a field-effect of abnormal white matter. This raises the possibility that targeting protective strategies to non-lesional white matter in individuals with lesions may be a useful approach.
7. Differential diagnosis of the dementias. Investigators: Venneri, Shanks, Harkness, Blackburn, Woodruff, Wilkinson. Early diagnosis and intervention in dementia is cost-effective, yet there is a significant diagnosis gap and only 30-50% of patients ever receive a formal diagnosis. The clinical neuroscience and neuropsychology team have built a set of normative data for cognitive tests used in the evaluation of dementia, from a cohort of 350 normal local volunteers and the data derived from neuropsychological assessment are presented with reference to the local normal ranges [76,77]. This allows increased confidence that performance outside these established normal ranges may be pathological. We have established a diagnostic pathway which also includes 3D MRI scanning, with protocols for structural brain imaging to detect early regional atrophic changes and comorbid small vessel brain disease, together with specific functional MRI paradigms to assist in early diagnosis of patients at risk during the preclinical stage of dementia [78,79]. We have also developed an innovative approach to pharmacological and non- pharmacological treatment effect evaluation and treatment response prediction based on a personalised patient- centred model which will ensure greater long term cost-effectiveness in the treatment of Alzheimer’s disease [80,81].
8. Cerebrovascular complications of coronary bypass (CABG) surgery. Investigator: Shaw Early translational neuroscience research achievements included the first detailed study of neurological and neuropsychological complications of coronary artery bypass (CABG) surgery, together with evaluation of causative factors, functional impact and prognosis for recovery [82-91]. This comprehensive documentation of the spectrum of peri-operative neurological complications was instrumental in promoting the development and evaluation of new neuroprotective strategies which have been successful in reducing post-operative morbidity.
9. Prevention and intervention in stroke. Investigators: Venables, Harkness, Blank, Randall. Sheffield Neuroscience investigators have taken part in most of the major prevention projects in stroke that have translated the theoretical benefits of antiplatelet drugs, anticoagulants, cholesterol lowering agents and surgical technologies into clinical practice for people with stroke [92-99]. In collaboration with members of the Sheffield Vascular Institute (which includes vascular surgeons and interventional radiologists), new technologies have been developed for stroke prevention that include stent design, protection devices and evaluation of the protective effects of drugs during stenting procedures [97,100,101]. We were one of the first Units in the UK to introduce, through participation in clinical trials, the evaluation of neuroprotective agents in stroke and, more recently, streptokinase and then rTPA in the hyper- acute treatment of stroke. Sheffield investigators have conducted a large study evaluating the safety and necessity of carotid intervention prior to CABG with carotid stenting [102].
The Academic Directorate of Neuroscience now leads the hyperacute stroke service presenting an opportunity to contribute through the Clinical Research Facility to other areas of hyperacute research including different thrombolytic regimes, bridging and clot retrieval technologies. Stroke Research is supported with investigator sessions through the Trent Stroke Local Research Network and engagement with the South Yorkshire CLARHC with stroke projects including the development of improved stroke prevention services and refined evaluation of the role of the Stroke Unit. Sheffield Stroke investigators are actively involved in trial development, governance and management at a national level including national coordinator for IST3 and TSC chair (Clots 3 and ENOS)
10. Risk assessment for patients with cerebral aneurysmal disease. Investigators: Patel, Hose, Lawford, Frangi. Sheffield neurovascular neurosurgeons and interventional neuroradiologists played key roles in a multidisciplinary pan-European study on cerebral aneurysmal disease (‘@neurIST’) involving clinicians, scientists and engineers. The @neurIST partners, led in this effort by Sheffield, developed image processing and Computational Fluid Dynamics tools to provide novel, non-observational in vivo measures to characterise the disease, and to predict the risk of rupture for an individual aneurysm. In addition, treatments such as stenting and coiling were simulated in patient-specific cerebrovascular geometries to investigate the influence on critical haemodynamic parameters, such as shear stress and wall strain. Sheffield Teaching Hospitals NHS Trust was a primary site recruiting patients and led the development of data federation for five of the six participating clinical centres [103-109].
11. Disease modifying therapy development for multiple sclerosis (MS) Investigators: Sharrack, Price, Howell
This MS Clinical Trials Unit within the RHH CRF is one of the largest in the UK and has over the last 10 years played a pivotal role in the development and the evaluation of almost all currently available disease modifying therapies for patients with MS, including beta-interferons, glatiramer acetate, natalizumab, fingolimod, as well as multiple other compounds under current investigation [110-124]. The group has developed close collaborative partnerships with industry, linking local expertise in neuro-immunology with the technical expertise of industry. Chemokines are chemoattractant cytokines which are expressed in lesions within the CNS and in the CSF of MS patients and play a key role in cell recruitment to sites of inflammation. In collaboration with Millennium Pharmaceuticals, Sharrack and colleagues developed and tested the biological activity and safety profile of MLN1202, a humanized monoclonal antibody CCR2 antagonist, in a phase 2a study in patients with relapsing-remitting multiple sclerosis. MLN1202 was biologically active, associated with reduction in new Gd-enhancing lesions in the CNS and was clinically well tolerated, supporting further investigation of this agent in MS and other inflammatory conditions [125]. In collaboration with Bayhill Therapeutics, Sharrack and his team conducted the first phase II trial to evaluate the efficacy and safety of a DNA vaccine encoding myelin basic protein (BHT-3009) in relapsing-remitting multiple sclerosis. This therapy almost attained the primary end point for reduction of the rate of new enhancing MRI lesions and achieved positive outcomes on several secondary end points [126].
12. Aetiology of idiopathic intracranial hypertension (IIH) Investigators: Sharrack, Price, Howell, Hickman
IIH is a headache syndrome which mainly affects overweight women and can lead to significant visual morbidity. Its aetiology remains unclear. A large number of small-scale studies assessing multiple potential aetiological factors have been reported in the literature, with inconsistent results. Sharrack and colleagues conducted the first study to investigate the role of pro-inflammatory cytokines, endogenous sex hormones and prothrombotic factors in a large cohort of IIH patients and demonstrated a significantly elevated leptin free index in IIH patients, suggesting that leptin- induced low grade systemic inflammation and/or leptin resistance may play a role in the pathogenesis of IIH [127-129].
13. Gluten – related neurological disease Investigators: Hadjivassiliou, Sanders, Aeschlimann, Grünewald
Sheffield has led the way internationally over the last 15 years in research investigating the neurological manifestations of gluten related diseases. This work identified for the first time neurological dysfunction as a presenting feature of gluten related disease and has characterised a spectrum of neurological dysfunction seen in this context (gluten related ataxia, neuropathy and encephalopathy [130-135]. The Sheffield Gluten/Neurology clinic now cares for over 500 patients with neurological dysfunction related to gluten sensitivity. The linked basic science aspect of this work has characterised the pathophysiology of neural damage and has identified a novel transglutaminase (TG6) that may represent a specific marker for this cohort of patients [136-137].
14. Immune mediated ataxias Investigators: Hadjivassiliou, Hoggard, Grünewald
The Sheffield ataxia clinic is one of only 4 ataxia centres of excellence in the UK. It cares for over 800 patients with different types of ataxia. There is specific interest in immune mediated ataxias and in particular primary autoimmune cerebellar ataxia, a disease entity first proposed and characterised in Sheffield [138]. Research has concentrated on the pathogenesis of gluten ataxia, MR spectroscopy biomarkers for ataxic disorders and the use of MR spectroscopy as a monitoring tool [139]. In addition there is are strong links and collaborations with the other ataxia centres in the field of genetic ataxias.
15. Using linguistic analysis in the differential diagnosis of transient loss of consciousness (TLOC). Investigators: Reuber, Monzoni.The early diagnosis of the three commonest causes of TLOC (syncope, epilepsy, nonepileptic attack disorder, NEAD) is crucial because the choice of treatment depends on an accurate diagnosis. Investigations such as EEG or MRI are of modest value. The history given by patients and witnesses remains the cornerstone of the diagnostic process. We have used Conversation Analysis and other linguistic methodologies (such as metaphor analysis) to identify diagnostic pointers in the patient's history [pic][140-142]. We have demonstrated in a blinded multirater study that these interactional and linguistic pointers can be used prospectively to make accurate diagnoses [143]. Based on these studies we have developed a self-report questionnaire which can be used to quantify the probability of the commonest causes of TLOC [144].
Sheffield Teaching Hospitals NHS Foundation Trust (STH) Academic Directorate of Neuroscience: STH represents an excellent environment for clinical care and research (Dr Foster Trust of the Year in 2005, 2008 and 2011). Since 2010 STH has implemented an Academic Directorate programme with the core aim of integrating clinical service and research to provide an optimal environment in which patients receiving clinical care can participate in translational research. Neuroscience was selected as the flagship specialty for the Academic Directorate programme. Within the Neuroscience Directorate there are 39 consultant staff: 22 neurologists; 12 neurosurgeons and 5 neurophysiologists serving a population of 2.2 million in South Yorkshire, Derbyshire and Lincolnshire. More than 60% of the NHS Consultants within Neuroscience are currently actively involved in research and have invested in the development and care of well characterised patient cohorts who are willing and interested participants in research.
University of Sheffield - Departmental of Neuroscience (DoN) The University of Sheffield represents one of the top ranking universities in the UK (Times Higher Education University of the Year 2011) and offers a superb environment for translational and interdisciplinary neuroscience research. Neuroscience is one of the 5 departments within the Medical School and incorporates interdisciplinary research with other groups across the University as well as collaborations with internationally leading neuroscience disease groups. The Department of Neuroscience, currently headed by Professor Paul Ince, aligns with the development of the Academic Directorate of Neuroscience within STH, facilitating an acceleration of the translational research agenda. The department, which currently includes 91 faculty, research and support staff and 60 graduate students, encompasses Neurology (Head of Unit Professor Pam Shaw), Neuropathology (Head of Unit Professor Paul Ince) and Psychiatry (Head of Unit Professor Peter Woodruff) and is aligned with the Neuroimaging Group in the Academic Unit of Radiology.
Sheffield Institute for Translational Neuroscience – SITraN: Basic neuroscience research supporting the translational neuroscience research programmes takes place within the new £18m 2,800m2 Sheffield Institute of Translational Neuroscience (SITraN). Within SITraN multidisciplinary research teams of clinicians and scientists conduct research on neurodegenerative disorders. The translational research teams have skills in cellular and molecular biology, neuropathology, genetics, pharmacology, gene therapy, RNA processing, glial and mitochondrial biology, computational biology/bioinformatics and electrophysiology, as well as neurology and clinical trials methodology. Several key strategic new appointments relating to the SITraN development will occur over the next 1-2 years including Stem Cell Biology and Therapeutic Targeting senior appointments. The work of the SITraN teams is underpinned by the development of robust cellular models of neurodegeneration, transgenic mouse and zebrafish models, as well as biosamples from human patients including the Sheffield Brain Tissue Bank, DNA, RNA, fibroblast, CFS banks and a repository of lymphoblastoid cell lines for several of the core diseases. The research facilities available include tissue culture suites; facilities for image analysis; live cellular imaging; confocal microscopy and laser capture microdissection as well as gene expression; genetics; proteomics; histology and tissue processing; gene therapy and small molecule drug screening laboratories. Adjacent core facilities include: gene sequencing; FACS; biorepository with robotics; animal house capacity for 40,000 mice (including operating theatres and procedure rooms); crystallography; NMR; mass spectrometry; proteomics; small animal 7T MRI. Several SITraN investigators are also members of the Sheffield MRC Centre for Developmental and Biomedical Genetics where we have access to non-mammalian model organisms (zebrafish and Drosophila) used to analyse the molecular and cellular basis of disease processes exploiting the ease of genetic manipulation, live imaging of fluorescent reporters, and drug screening opportunities from these model systems. Capacity includes 3 zebrafish aquaria, a Drosophila vivarium, confocal and intravital imaging, tissue culture, robotics platforms and siRNA screening.
Neuroscience research support : Within the Joint Clinical Research Office a dedicated senior member of staff (Dr Ramila Patel) is responsible for the Neuroscience research portfolio. The Academic Directorate of Neuroscience has appointed a Research Coordinator (Ms Jodie Keyworth) to support NHS investigators in setting up clinical research studies and delivering studies to time and on target. Dr. Sarah Langridge has been appointed to the UoS post of SITraN Research Manager to support clinical academic investigators in securing research funding for translational research in neuroscience. A team of 13 dedicated research nurses, 12 specialist nurses and 4 therapists with a research component to their roles and 2 clinical studies officers support translational and clinical neuroscience research working between the Academic Directorate of Neuroscience and the Clinical Research Facility. We also have support from the research infrastructure provided by the DeNDRoN and Stroke Clinical Research networks and the South Yorkshire Comprehensive Local Research Network.
The Virtual Physiological Human Institute: Europe is the home of the Virtual Physiological Human (VPH) initiative, in which the emphasis is on personalisation of human models, including representations of patient-specific anatomy and physiology, and on exploitation for clinical benefit. The University of Sheffield Faculties of Engineering and Medicine, Dentistry and Health, in partnership with Sheffield Teaching Hospitals NHS Foundation Trust (STH) have recently set up an Institute dedicated to the development and clinical translation of VPH technology. The VPH initiative in the EU Framework 7 programme has funded research to the tune of €130m to date and the University of Sheffield/STHT participates in projects valued at €70m. Sheffield has recently recruited Professor Alejandro Frangi, who was the scientific co-ordinator of the @neurIST project. Working together with Umang Patel, this opens new opportunities for leadership from Sheffield. Most recently Sheffield leads the € 14m VPH-Share project dedicated to the development of an infrastructure for the management and sharing of anonymised clinical data; this will be of benefit to clinical research in all areas. In addition, the VPH Insititute offers access to state of the art image processing tools.
• Neurodegeneration Research in this theme focuses on translational aspects of neurodegenerative disease research, with clinical research closely linked to strong laboratory programmes within SITraN. Clinical research in the neurodegeneration occurs within the setting of the Dementias and Neurodegenerative Diseases Clinical Research Network (DeNDRoN). Professor Shaw is Associate Director of the Coordinating Centre and Chair of the Clinical Studies Group/Portfolio Management Group for Motor Neuron Disease (MND) within DeNDRoN. Support for the CRF in Sheffield will facilitate the following areas of experimental medicine research some of which will be rolled out on a multi-centre basis into the research activities within DeNDRoN. These studies involve common neurodegenerative disorders including Alzheimer’s disease and other dementias, Parkinson’s disease (PD), Huntington’s disease and MND.
1. Collection of biological materials for clinical research Investigators: Shaw, McDermott, Ince, Wharton, Kirby, Bandmann, Venneri A major Wellcome Trust / MND Association-funded DNA banking programme has collected DNA, established immortalised cell lines and extracted relevant clinical information from >1600 patients with MND, relevant family members and 1600 control subjects. Sheffield is one of 3 hub sites and the resource collected has successfully been used to investigate genetic factors underlying motor neuron degeneration [refs]. An ongoing epidemiology study involving >1000 subjects will investigate environmental risk factors for MND and gene environmental interactions, facilitated by the recent discovery of C9ORF72 hexanucleotide expansions in 11% of MND cases (50% of familial and 7% of sporadic cases) [145-147]. We also have an extensive collection of DNA used in genetic association studies in patients with familial and sporadic movement disorders eg PD, Wilson’s disease, dystonia. The CRF will facilitate systematic collection of biological materials to strengthen our existing DNA, blood RNA, fibroblast and CSF banks and the Sheffield Brain Tissue Bank, which currently contains material from >500 cognitively impaired and healthy elderly adults collected in the MRC Cognitive Function and Ageing (CFAS) study and 170 cases of MND. These biological samples are currently being used in Wellcome, MRC and EU JPND funded projects to identify biomarkers of disease, markers of fast and slow disease progression and therapeutic response using gene expression profiling and biochemical analysis.
2. Evaluation of new neuroprotective therapies Investigators: Shaw, McDermott, Azzouz, Bandmann, Sharrack, Hadjivassiliou Sheffield investigators are involved in clinical trials of potential disease modifying agents in multiple neurodegenerative disorders eg Huntington’s disease (Bandmann), multiple sclerosis (Sharrack, Howell, Price), ataxias (Hadjivassiliou), motor neuron disease and spinal muscular atrophy (SMA) (Shaw , Azzouz). We plan to building on our track record of running both pharma and academic led phase II and III clinical trials, utilising our existing collaborations with the Clinical Trials Research Unit (CTRU) and the CRF. Our pre-clinical drug screening programmes have identified novel therapeutics which we plan to evaluate further. This will involve further toxicology and dose ranging pre-clinical work before commencing first into man studies.
The SITraN programmes headed by Prof. Shaw aim to increase understanding of the genetic and cellular mechanisms of motor neuron injury and investigate potential new therapeutic approaches, initially in experimental models of disease, with the goal of bringing the most promising of these into the clinic. This strategy utilises small molecule screening against defined molecular targets followed by a screening cascade involving patient biosamples to identify compounds with the most promising profile in terms of drug like features (by Lipinski rules), predicted blood brain barrier penetrance as well as neuroprotective and toxicity features [52-54]. The first of the therapeutic agents identified in SITraN are poised for development into first into man studies through the CRF in the next 1 -2 years.
A drug screen carried out at SITraN has identified powerful new compounds which completely rescue mitochondrial function in PD patient tissue systems. The next steps will be to develop a mitochondrial biomarker panel and undertake phase 1 trials of these compounds. Mitochondrial dysfunction has also been implicated in the pathogenesis of multiple sclerosis, MND and stroke. The expertise in mitochondrial biology can be deployed in collaborative studies in relation to these disorders.
3. Gene therapy approaches to neuroprotection Investigators: Azzouz, Shaw, Ning New gene therapy approaches to neuroprotection in several neurodegenerative diseases, including MND and PD have recently been developed. One example is survival motor neuron (SMN) replacement therapy for the treatment of SMA using codon optimised AAV9 viral vectors [33-34]. This agent has received orphan drug status via the EMA and we have MRC DPFS funding to develop this therapy towards phase 1 human trials.
4. Evaluation of improvements in symptomatic therapies Investigators: Shaw, McDermott, Bandmann, Venneri
We have recently demonstrated that non-invasive ventilation has a major positive impact on survival and quality of life in patients with MND resulting in a recent NICE guideline to promote a change in practice [23-26]. The Sheffield MND research team, in collaboration with the DeNDRoN Clinical Studies Group now have funding through NIHR HTA, i4i, and the MNDA to undertake research for patient benefit in several other areas where current symptom control is sub-optimal including: further measures to improve respiratory symptoms including the administration of Cough Assist devices, diaphragm pacing, end of life care for those on non-invasive ventilation; optimal nutritional and secretion management and the development and evaluation of new technologies to support weakened neck muscles. The Sheffield Huntington’s disease (HD) research team with Bandmann as local PI, participated in the MermaiHD trial, which has identified pridopidine as the first symptomatic drug for the motor deficits observed in HD [148].
Recognising the increasing burden on patients with long term neurological conditions, we will continue to harness new technologies to deliver specialist healthcare to the patients in a place of their choosing and in a responsive manner.
5. Experimental Medicine studies in dementia Investigators: Venneri, Shanks, Harkness, Blackburn, Wilkinson. The main goal of the dementia component of the neurodegeneration team is to strengthen dementia clinical research in Sheffield to complement the existing strong molecular neuropathology dementia research programmes. The long term strategy is to attract leading clinical dementia researchers to build capacity and to take advantage of the advanced technology and state of the art imaging facilities available at Sheffield, in order to improve clinical diagnosis and evaluate the effectiveness of interventional strategies. The initial research plans, coupled with the recruitment of several new investigators, include:
i. Expansion of studies in early and differential diagnosis by strengthening the link with basic research and neuropathology, to achieve a better understanding of what might represent a good endophenotype of neurodegenerative dementia due to Alzheimer’s disease.
ii. Exploration of the potential of intensive non- pharmacological treatment to prevent neuropsychological decline in mild cognitive impairment and to prevent cognitive decline following stroke.
• Stroke Investigators: Venables, Harkness, Blank, Randall, Venneri. Stroke research will be strengthened by the forthcoming appointment of a senior academic post in Stroke Medicine. Stroke research will continue to focus on the requirements of the Stroke Research Network, increasing the numbers of studies in the portfolio and recruitment to those studies to time and on target.
i. It is anticipated that the new academic appointment will take forward developments in acute imaging and hyperacute care of people with stroke, as well as providing stronger links with those researching longer term outcomes. We will continue to be involved in enhancing the effectiveness of hyperacute care and the evaluation of new technologies that improve reperfusion and protect the ischaemic penumbra to improve early outcomes after acute ischaemic stroke. This will require increasing collaborative working between stroke neurology, vascular neurosurgery and interventional neuroradiology.
ii. Further work is required to strengthen links with the South Yorkshire CLARHC and to take forward new ways of developing and evaluating the effectiveness of prevention strategies, especially those that impact on minority communities.
iii. With an increasing attention on the surviving stroke population, there will be a focus on the identification of people with long term cognitive disorders arising as a result of their stroke and measures that impact on their disabilities. Project plans will be taken forward in collaboration with the dementia clinical research team.
iv. We will continue to support the evaluation of new techniques and treatment strategies for people with haemorrhagic stroke through involvement in collaborative projects such as the @neurIST project (6th European framework program) that aims for the development of an integrated IT infrastructure to manage and process intracranial aneurysms and subarachnoid haemorrhage, trials of protective drugs following aneurysm surgery (e.g. STASH) and decision making in the treatment of intracranial arteriovenous malformations. (Aruba). In addition we
will continue to develop collaborative working with the Sheffield based National Centre for Stereotactic Radiosurgery and build on its unique experience of managing intracranial arteriovenous malformations. This unit and its experienced staff offers an opportunity to evaluate new technologies in the management of these, often previously untreatable, anomalies.
v. Improved management of intracranial aneurysms using computational modelling Investigators: Patel, Hose, Lawford, Frangi.
Advanced neurovascular treatment planning using virtual interventional tools. In collaboration with INSIGNEO we have developed a number of tools for treatment planning of cerebral aneurysms using virtual treatment techniques including coiling. The tools promise to enable personalised treatment plans that would identify the optimal device and deployment strategy, as well as the ability to predict the embolisation potential of the intervention. The tools have been evaluated both numerically and clinically as a proof-of-concept, but extensive prospective evaluation is still required. Additionally, modelling thrombus formation and virtual treatment will be combined to develop a methodology to predict intraneurysmal thrombosis and recanalisation risk.
Computational studies investigating the mechanisms of aneurysm recanalization. A variety of techniques exist for minimally invasive embolisation of cerebral aneurysm, but virtually all of them have risks associated with aneurysm recanalization which leads to risk of rebleeding . The exact mechanisms and conditions that promote or prevent such events are not fully understood. We have developed an efficient image-based computational haemodynamic workflow that enables patient-specific studies of flow dynamics in silico, allowing investigation of the mechanisms and risk factors of aneurysm recanalisation. This project will study a cohort of patients that have already undergone coiling and develop subject-specific models before and after coiling as well as at various stages during follow-up. Morphological and haemodynamic variables will be followed over time and correlated with the recanalisation events.
Multifactorial aneurysmal rupture risk score. In @neurIST, we collected a large database of cerebral aneurysms with ancilliary data on clinical, genetic, morphological and haemodynamic factors. We also developed the image-based computational workflows to construct the relevant computational models. The pilot retrospective multi-centre project was successful in generating the computational tools underpinning the database. This new assessment technology will now be taken forward and validated in a prospective study aiming to develop a risk score for aneurysm rupture which can be implemented in clinical practice.
• Neuro-inflammation
Investigators Multiple sclerosis: Sharrack, Price, Howell
i. Through the Sheffield CRF we will continue to take part in phase I, II and II clinical trials to assess the efficacy of new therapeutic agents in the treatment of patients with multiple sclerosis. This is likely to be a platform to investigate new potential disease modifying agents which are currently being developed by pharmaceutical companies in collaboration with the Sheffield MS Clinical Trials Unit (Millennium, Apotope).
ii. Role of autologous stem cell transplantation (HSCT) in patients with multiple sclerosis. HSCT has been extensively reported worldwide as a tool for inducing a prolonged restoration of self-tolerance in MS patients. The ideal target patients for this treatment are those with relapsing–remitting disease, who show high inflammatory activity, clinically and by MRI and who are rapidly deteriorating despite the use of one or more conventional disease modifying treatments. In collaboration with the department of Haematology, the neuro-inflammation team has forged links with a number of European centres to set up an investigator led collaborative study to assess the efficacy of HSCT in patients with active aggressive MS.
iii. The role of citrullination of CNS proteins in the pathogenesis of multiple sclerosis: Although MS is mainly T-cell mediated, B-cells have been implicated in its pathogenesis, with increased immunoglobulin levels present in the CSF being an important diagnostic finding. The target of these immunoglobulins has not yet been fully characterised, however, post-translational modifications (PTMs) of CNS-specific proteins are thought to lead to their production. One PTM in particular, the conversion of the amino acid arginine to the non-standard amino acid citrulline appears to play a role in the disease pathogenesis, as an increase of citrullinated proteins are found in post-mortem brain tissue of patients with MS. Sharrack, Woodruff and colleagues are currently working on evaluating the potential of measuring this PTM as a diagnostic biomarker for MS.
iii. MicroRNAs as key modulators of the brain endothelial inflammatory response? Cerebral microvascular endothelial cells (CMECs) constitute the physical and physiological barrier of the CNS. CMECs show distinctive characteristics and express barrier-specific proteins that line and seal the brain and spinal cord microvasculature. A number of transmembrane proteins such as occludin and claudin-5 are integral constituents of tight junctions (TJs) in CMECs and restrict the free passage of molecules from blood to brain and brain to blood. Alterations in the CMEC phenotype leading to blood brain barrier (BBB) dysfunction are a major hallmark of neuroinflammatory diseases such as multiple sclerosis. Increased production of many cellular factors (e.g. TNF-α, IL-ß and) by activated leukocytes and/or brain-resident cells has been shown to alter TJs organization and mediate leukocyte infiltration and increased BBB permeability. Sharrack et al investigated the changes in the pattern of gene expression induced by inflammatory stimuli in an immortalized human cerebral microvascular endothelial cell line, hCMEC/D3, using an Illumina human v8 human microarray. Under basal conditions, hCMEC/D3 cells expressed ~ 11,000 genes out of 24,000 genes tested. Treatment with TNF-α and IFN-γ increased mRNA levels of 464 genes > 2 fold, with the highest increases (>30 fold) observed for chemokines (CCL2, CCL5, CCL8, CXCL8, CXCL9 and CXCL10) and adhesion molecules (VCAM1), and decreased mRNA levels of 242 genes > 2 fold, many of them associated with regulation of TJs. Cytokine-induced changes in mRNA levels correlated with: 1) an increased paracellular permeability of hCMEC/D3 in a time-dependent manner associated with decreased levels of occludin and claudin-5 at the mRNA and protein level, and 2) an increased adhesion of the monocytic THP1 and the T cell Jurkat cell lines to hCMEC/D3 monolayers. We then hypothesised that microRNAs may be involved in the fine tuning of the brain endothelial inflammatory response. The microRNA (miRNA) expression profile of cytokine-activated hCMEC/D3 was analysed by microarray (Agilent v13) and real-time RT-qPCR identifying 10 miRNAs up-regulated and 118 down-regulated at different time points following the inflammatory stimuli. miRNAs might play an important role in altering CMEC properties leading to BBB breakdown, so we are at present investigating whether modulation of miRNA levels may affect endothelial permeability and/or leukocyte adhesion/migration. Understanding the molecular mechanisms leading to cytokine-induced BBB breakdown will constitute an important strategy in the development of new therapeutic targets for the design of drugs aimed at ameliorating BBB dysfunction in neuro-inflammatory conditions such as MS.
iv. Ataxia research Investigators: Hadjivassiliou, Hoggard, Wilkinson, Grünewald
The ataxia research team will be undertaking a number of experimental medicine projects over the next 3-5 years including:
A pilot trial of immunosuppression in primary autoimmune cerebellar ataxia
Transglutaminase 6 (TG6) as a biomarker of gluten related neurological dysfunction. This is an ongoing project funded by Coeliac UK and BRET investigating the TG6 protein and its role in both the diagnosis and the pathogenesis of gluten related neurological dysfunction.
Biomarkers of cerebellar dysfunction using MR spectroscopy. A collaborative project with the Neuroradiology (Hoggard and Wilkinson) investigating the potential of MR spectroscopy as a biomarker of pathology and a measure of treatment response across the spectrum of ataxias.
• Epilepsy
Investigators: Reuber, Monzoni. Sarrigiannis, Billings, Ponnusamy.
i. Using change in heart rate variation (HRV) parameters accurately to predict the transition from the interictal to the ictal state. We have completed two studies which document the biological plausibility of our approach [149,150]. Cyberonics are keen to support further work in this area. Epileptic seizure specific HRV parameter profiles could be useful to detect seizure onset. The aim of this research would be to create automatically seizure-responsive vagal nerve stimulation and deep brain stimulation devices using specific HRV parameters. Similar HRV parameters will be useful in seizure detection algorhythm during video-telemetry monitoring as well as in the interpretation of ictal ECG data from implantable loop recorders which can record ECG data for 18-24 months.
ii. Developing a new quantitative method of EEG analysis that would allow source localisation and measurement of electrical brain activity synchronisation in epilepsy, based on parametric linear and nonlinear time and frequency domain analysis methods. We have pilot data indicating the relevance and potential of this approach [151].
iii. Diagnosis and treatment of accelerated long-term forgetting (ALF) in patients with epilepsy. We have completed several studies which establish and show the potential of a paradigm measuring ALF in epilepsy. We have also completed a pilot study looking at the use of a structured diary or sensecam to reduce the impact of ALF. We are in the process of measuring ALF before and after epilepsy surgery. A more accurate preoperative assessment of subjective postoperative memory impairment would allow us to give more appropriate counselling to patients with epilepsy.
iv. Emotional processing in patients with non-epileptic attack disorder (NEAD). We have pilot data demonstrating abnormalities of emotional processing in patients with NEAD. We have developed and described an individual psychotherapy programme focussing on emotional processing deficits in this patient group and demonstrated the longer term benefits of this treatment. We have developed an fMRI paradigm measuring emotional processing. Our implicit attention task study will probe difficulties with emotional processing. The next stage is to carry out a controlled study of the effectiveness of psychotherapy on subjective and objective measures of emotional processing.
• Research funding supporting experimental medicine
In the last 5 years (2007-2011) Sheffield Neuroscience investigators have generated £30.01m in research funding of which £9.9m has been for experimental studies. Examples of recent important awards for experimental medicine in Neuroscience include:
EUROPEAN UNION FRAMEWORK 7: 2008 -2011 Sheffield component (€797,000). Mitochondrial dysfunction in neurodegenerative diseases: towards new therapeutics. Mitotarget Consortium. PI’s PJ Shaw, AJ Grierson.
DEPARTMENT OF HEALTH/ NIHR CLINICAL RESEARCH NETWORK FOR DEMENTIAS AND NEURODEGENERATIVE DISEASES (DeNDroN) 2006 -2011 (£1,041,280). Supplementary resources for Motor Neuron Disease and Huntington’s disease. PI PJ Shaw.
MEDICAL RESEARCH COUNCIL CENTRE FOR DEVELOPMENTAL AND BIOMEDICAL GENETICS 2007-2012 £2,383,148 PI Prof. Philip Ingham; Co-applicants PJ Shaw, O Bandmann.
MEDICAL RESEARCH COUNCIL 2008 – 2011 (£531,772) TDP-43 and alternative splicing in motor neurone disease. PI’s PG Ince, PJ Shaw, J Kirby.
SHEFFIELD INSTITUTE FOUNDATION FOR MOTOR NEURONE DISEASE 2009-2011 (£10 million) To support the development of the Sheffield Institute for Translational Neuroscience.
EPSRC 2009 – 2012 (£2.4million) Engineering virus like nanoparticles for targeting the CNS. M Azzouz, PJ Shaw, O Bandmann, PG Ince, PI G Battaglia.
WOLFSON FOUNDATION 2010-2011 £600,000 Equipment grant for the Sheffield Institute for Translational Neuroscience (SITraN). PI PJ Shaw.
EU FRAMEWORK 7 HEALTH 2010 TWO STAGE GRANT. 2010 -2015 €8,998,359 (Sheffield component €700,506) Systems Biology in ALS. PI PJ Shaw, co-applicant J Kirby.
NIHR HEALTH TECHNOLOGY ASSESSMENT PROGRAMME and MOTOR NEURONE DISEASE ASSOCIATION: Clinical Evaluation and trials. 2010 -2013 £1,472,060 A controlled adjunct trial in patients with respiratory muscle weakness due to motor neurone disease of the NeuRx/4 diaphragm pacing system (DiPALS). CI C McDermott, PI PJ Shaw.
MEDICAL RESEARCH COUNCIL DEVELOPMENTAL PATHWAY FUNDING SCHEME 2010 – 2012 £656,000 SMN replacement therapy for spinal muscular atrophy. PI M Azzouz.
PARKINSON’S UK 2007-2011 £ 184,000 New strategies to identify disease-modifying therapy for Parkinson’s Disease. PI O Bandmann
PARKINSON’S UK 2010-2012 £ 248,000 A Parkin knockout zebrafish model of Parkinson’s Disease. PI O Bandmann
SAN CAMILLO IRCCS FOUNDATION ITALY 2010 -2011 £ 60,000 Cognitive stimulation, neuroplasticity and its effects on brain functional connectivity in Alzheimer’s disease. PI A Venneri.
MULTIPLE SCLEROSIS SOCIETY 2009 – 2012 £220,000 The effect of exercise on patients with multiple sclerosis. B Sharrack (co-applicant)
MULTIPLE SCLEROSIS SOCIETY 2011 – 2014 £205,122 Role of microRNAs in the cerebral vasculature and multiple sclerosis. B Sharrack (co-applicant)
NIHR STROKE CLINICAL RESEARCH NETWORK 2006-2011 Sheffield has funding for 3 part time stroke research nurses from the Stroke Trent LRN and is fully funded through the national portfolio for all approved trials. PI G Venables.
NIHR SOUTH YORKSHIRE CLARHC 2006-2011 £600,000 in the first funding round allocated to the Stroke portfolio.
• Markers of esteem
Examples of Prizes and awards
AZZOUZ: European Research Council Advanced Investigator award.
PATEL: Young Neurosurgeon Award -2009 American Association of Neurological Surgeons-World Federation of Neurosurgical Societies.
SHAW: Royal College of Physicians Jean Hunter Prize for research into nervous disorders(2006); Fellowship of the Academy of Medical Sciences (2007); The International ALS/MND Forbes Norris Award for excellence in research and clinical care (2007).
VENNERI: 2009 - Career Excellence Award for contribution to Science and Medicine awarded by a joint committee of the Consiglio Nazionale delle Ricerche (National Research Council) and Agenzia Spaziale Italiana (Italian Space Agency), Italy.
Examples of Panel membership
AZZOUZ: Member of the Scientific Advisory Board, French Muscular Dystrophy Association (AFM) 2009- present; Member of the Research Council of Norway 2011- present; advisor to the UK Government Department for Environment, Food and Rural Affairs (DEFRA).
BANDMANN: Editorial Board of NEUROLOGY, Vice-chair of Research Advisory Panel of Parkinson’s UK.
HADJIVASSILIOU: is a member of the research advisory panel for Ataxia UK, Coeliac UK and The Neuropathy Trust.
INCE: Panel member MRC Neuroscience and Mental Health Board 2008-2012; Research Advisory Panel of Parkinson’s UK 2004-2008; MRC Brain Bank Network Steering Committee 2010-present.
KIRBY: MND Association Research Advisory panel.
MCDERMOTT: Member of NIHR Research for Patient Benefit grant panel.
SHAW: Advisor to the Department of Health Medicines Control Agency/ Committee on Safety of Medicines from 2005; Medical Advisor to the Motor Neurone Disease Association; Chairman of the ALS/MND International Scientific Programme Committee 2004 -2010; Member of the UK Medical Research Council College of Experts 2005-2010; Member of HEFCE Senior Lectureship awards panel 2006 -2009; Associate Director of the Dementia and Neurodegenerative Diseases (DeNDRoN) UK Clinical Research Network 2004 -2011; Chair of the DeNDRoN Clinical Studies Group for Motor Neuron Disorders 2004 -2011; Member of UKCRN Experimental Medicine Committee 2007-2009; Member of the Academy of Medical Sciences Fellowship Panel 2007-2010; Member of the Academy of Medical Sciences Clinical Academic Training Panel 2008-2009; Wellcome Trust / Academy of Medical Sciences New Lecturer Awards panel 2009-2010; Member of MRC Strategic Group for Neurodegeneration 2008; Member of European Joint Programme for Neurodegeneration development panel 2011.
VENABLES: UK National Coordinator IST3, Chair TSC – CLOTS3 and ENOS trials. Member TSC – ICSS, TARDIS. Reviewer NIHR HTA. Member Stroke Research Network Prevention Clinical Study Group.
VENNERI: 2005-2010 Member and Deputy Chair of the Medical Research Council (MRC) Biomedical Informatics Training and Career Development Panel. Member of the panel of reviewers for the joint MRC/ESRC fellowship/studentship panel and for the MRC capacity building studentship scheme.
WHARTON: 2007-current. Editor-in-Chief, Neuropathology and Applied Neurobiology. Member of the Site Specific Reference Group for CNS Tumours of the National Cancer Intelligence Network (2009-current). Member of the British Neuropathological Society General Finance and Purposes Committee (and it predecessor, 2007-current). Member of Peer Review Panel for the UK Multiple Sclerosis and Parkinson’s Disease Tissue Bank (2009-current).
Pharmaceutical company steering committees/ advisory boards
AZZOUZ: Member of the Scientific Advisory Board of Oxford BioMedica Ltd; Scientific Advisor for BioMarin Pharmaceutical Inc.
INCE: Novartis Dementia Advisory Panel from 2012.
SHARRACK: Medical advisor and steering committee member for Biogen Idec, Novartis, Teva, Merc Serono.
SHAW: Medical advisor to Novartis, Oxford Biomedica, ONO Pharma, Biogen Idec, Sanofi Aventis.
VENNERI: Scientific advisor to Novartis
VENABLES: Advisory Boards for Novo-Nordisk ‘Tiagabine’ ; Novo-Nordisk Drugs for acute stroke salvage;
Wellcome: ‘Lamotrigine’ ; Parke Davies ‘Gabapentin’ Safety Monitoring Group; Janssen ‘Lubelazole’; Boehringer Ingleheim ‘Dipyramidole’; Sanofi – Clopidogrel.
Neuroscience researchers in Sheffield have excellent links with multiple pharmaceutical companies to investigate potential disease modifying therapies for neurological diseases. The Academic Directorate of Neuroscience currently delivers approximately 35-40% of all commercial trials in Sheffield Teaching Hospitals NHS Foundation Trust (STH). Sheffield investigators are members of advisory boards, trial management groups and steering committees for the following companies: Biogen Idec; Trophos; Novartis, Teva, Merck Serono.
In experimental medicine specifically we have active Neuroscience collaborations with industrial partners in the following areas:
Neurodegeneration: We have collaborative projects with Lilly (CASE studentship) and TROPHOS (EU Framework7 MITOTARGET) to investigate mitochondrial dysfunction in biosamples from patients with Parkinson’s disease and motor neurone disease (MND) and develop strategies for neuroprotection. Sanofi-Aventis are collaborating in investigating biomarkers of the neuroprotective action of riluzole in MND. Glaxo-Smith-Kline have agreed in principle to collaborate on the development of activators of the Nrf2-anti-oxidant response element pathway for neurodegenerative disorders. We are collaborating with Synapse Biomedical and Timantech in the investigation of diaphragm stimulation as a new technology for the treatment of neuromuscular respiratory failure. We have a long-standing partnership with Novartis for the early testing of compounds for the treatment of Alzheimer’s disease using pharmacological MRI methods.
Neuroinflammation: Collaborative work is being undertaken with a German diagnostics company Zediva to develop a diagnostic kit for TG6, a biomarker for gluten related neurological dysfunction. We are also collaborating with the team of Professor Male and Dr. Romero at the Open University to assess the function of BBB in patients with MS; Professor Nicola Woodroofe at Hallam University to assess the role of citrullination of CNS proteins in the pathogenesis of multiple sclerosis aiming to develop a diagnostic test and a number of leading pharmaceutical companies to test new agents in phase two studies.
Epilepsy: The epilepsy team are collaborating with Cyberonics in the creation of automatically seizure-responsive vagal nerve stimulation devices using specific hear rate variation parameters.
Stroke: Through @neurIST we have collaborations with several industrial partners including Philips Medical Systems, Super Computing Solution s.r.l., GridSystems S.A., ANSYS Europe Ltd / ANSYS UK, InferMed Ltd, Advanced Simulation & Design GmbH IDAC Ireland Ltd.
Neuroscience researchers in Sheffield benefit from opportunities to engage with patient groups and the public because of the vibrant PPI policies in the Academic Directorate within STH Trust and the University of Sheffield Department of Neuroscience. Neuroscience investigators are active in outreach to local, national and international meetings in collaboration with neurological disease charities.
The SITraN development required major public support and awareness to raise £10m through the Sheffield Institute Charitable Foundation, including high profile fund raising projects and regional and national media interest. Within SITraN, we have a regular Open Day to allow patients and family members to hear about our research programmes and to talk directly to the clinicians and scientists working within the Institute. The last Open Day on 15th April 2011 attracted 150 members of the public. Members of SITraN also participate in the University of Sheffield outreach programme for local schools. We frequently host site visits from disease charities and patient self-help organisations such as Parkinson’s UK, the Alzheimer Research UK network, the MND Association, the Multiple Sclerosis Society, Ataxia UK and engage to speak at their local, regional and national meetings. As part of these networks we periodically organise scientific as well as public meetings to increase public awareness of neurological disorders and communicate advances in diagnosis and treatment and available care pathways.
An example of a local PPI development which can be applied in the future to other neurological disease areas is the Sheffield Motor Neurone Disorders Research Advisory Group (SMNDRAG) which was established in 2009, guided by NIHR principles, with the following aims: 1. To include patient and carer perspectives in research strategy and priorities; 2. To assist with the success of ongoing research studies in terms of recruitment and provision of information helping to ensure that studies are delivered on time and to target; 3. To assist in the writing of lay summary documents; 4. To raise awareness and the profile of research in this disease area and build public confidence and trust; 5. To assist in the dissemination of research findings. Members of the SMND RAG have formed part of the application team for multiple recent projects including the present application. In addition, Sheffield neuroscience researchers have direct access to the DeNDRoN and Stroke Network Public and Patient Involvement group, linked to INVOLVE, to maximise opportunities to increase awareness, understand lay concerns, and manage public expectations.
Clinical academic research training programme The University of Sheffield, Yorkshire Deanery and Sheffield Teaching Hospitals Trust has developed an integrated clinical academic training programme. This comprises an intercalated BMedSci in Neuroscience during the MBChB degree, Academic Foundation Doctors posts, Academic Clinical Fellow posts and Clinical Lecturer posts. Currently we have 14 academic trainees and have trained 21 in total since 2006, of which 12 NIHR funded. Trainees from this programme have had success in obtaining external fellowships (MRC, Wellcome) and establishing themselves as independent clinician scientists. Complementing the clinical research training programme we have developed several taught postgraduate courses.
MSc in Translational Neuroscience The MSc in Translational Neuroscience aims to provide theoretical and practical training into fundamental aspects of contemporary neuroscience encompassing molecular, cellular, anatomical and behavioural levels and draws on examples from model organisms and patient-based studies. The course combines the expertise in Neuroscience from across the University of Sheffield, with researchers contributing from the departments of Neuroscience, Biomedical Science and Psychology as well as the Clinical Units of Neurology, Neuropathology, Psychiatry and Neuroimaging, which allows us to offer excellent research and teaching facilities in multiple areas of contemporary neuroscience. The taught part of the course consists of lectures, seminars, tutorials, and practical sessions, whilst the 20 week research project, worth 75 credits, offers the students the opportunity to apply appropriate laboratory based techniques to test a specific scientific hypothesis and write up their research in a scientific manner, culminating in the submission of their dissertation. Students doing the MSc in Molecular Medicine also have the option of undertaking a specialised Neuroscience Pathway within this course.
MSc in Clinical Neurology : This course teaches the fundamentals of Neuroscience and integrates this with in depth knowledge of neurological disease. The course is aimed at scientists and clinicians who want to link the scientific area they are researching with clinical aspects, fostering a truly translational approach to neurological disease research. The course benefits from the close links between the Regional Clinical Neuroscience Unit and SITraN –a new purpose built translational neuroscience research institute. The University of Sheffield is the only provider of such an MSc course outside of London.
• Specialist nurse and technician support for the neuroscience research themes. Nursing and technician support for bio-sample collection, management and co-ordination. We also wish to optimise and harmonise protocols for biosample collection and processing in line with other neurological research centres nationally and internationally.
Increased clinical research co-ordination support for the neuroscience research themes on top of what is already in place, with the bigger move into translational medicine and the requirements to get studies set up quickly and through all the governance mechanisms, as well as monitoring and QC and meeting the key goals of delivering experimental medicine studies to time and on target.
• Specialist radiographer or image analysis support for imaging biomarker studies in neurodegeneration, stroke, neuro-inflammation and epilepsy.
• Increased support to underpin biomarker identification in CNS tissue to determine clinico-pathological phenotypes using state-of-the-art markers in one of the largest collections of post mortem tissue for neurodegenerative diseases. In addition to improved subclassification of disease, this work facilitates target identification and validation for neuroprotective therapy development and underpins a wide range of studies using this tissue, both in-house and collaboratively.
• To stimulate further the Experimental Medicine activity in Neuroscience in Sheffield, we request some research PA’s for capacity building in particular for NHS consultants who wish to devote more time to translational research and who have a proven track record of research in one of the strategic themes.
•
1. The quantitative autoradiographic distribution of [3H] MK-801 binding sites in the normal human spinal cord. PJ Shaw, PG Ince, M Johnson, EK Perry, J Candy. Brain Research 539:164-168; 1991.
2. The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human brainstem in relation to motor neuron disease. PJ Shaw, PG Ince, M Johnson, EK Perry, JM Candy. Brain Research 572:276-280; 1992
3. Excitatory amino acid neurotransmission, excitotoxicity and excitotoxins. PJ Shaw. Current Opinion in Neurology and Neurosurgery 5:383-390; 1992.
4. Autoradiographic comparison of the distribution of [3H]MK-801 and [3H]CNQX binding in the human cerebellum during development and ageing. M Johnson, EK Perry, PG Ince, PJ Shaw, RH Perry. Dev Brain Res 615:259-266; 1993.
5. Autoradiographic distribution of binding sites for the non-NMDA receptor antagonist [3H]CNQX in the human motor cortex, brainstem and spinal cord. RM Chinnery, PJ Shaw, PG Ince, M Johnson. Brain Research 630:75-81; 1993.
6. Excitatory amino acid receptors, excitotoxicity and the human nervous system. PJ Shaw. Current Opinion in Neurology and Neurosurgery 6:414-422; 1993.
7. N-methyl-D-aspartate (NMDA) receptors in the spinal cord and motor cortex in motor neuron disease: a quantitative autoradiographic study using [3H]MK-801. PJ Shaw, PG Ince, JNS Matthews, M Johnson, JM Candy. Brain Research 637:297-302; 1994.
8. A quantitative autoradiographic study of [3H]kainate binding sites in the normal human spinal cord, brainstem and motor cortex. PJ Shaw, PG Ince. Brain Research, 641:39-45; 1994.
9. Non-NMDA receptors in motor neuron disease: a quantitative autoradiographic study in spinal cord and motor cortex using [3H]CNQX and [3H]kainate. PJ Shaw, PG Ince, RM Chinnery. Brain Research 655:186-194; 1994.
10. [3H]D-aspartate binding sites in the normal human spinal cord and changes in motor neuron disease: a quantitative autoradiographic study. PJ Shaw, RM Chinnery, PG Ince. Brain Research 655:195-201; 1994.
11. CSF and plasma amino acid levels in motor neurone disease: elevation of CSF glutamate in a subset of patients. PJ Shaw, V Forrest, PG Ince, J Richardson, H Wastell. Neurodegeneration 4:209-216;1995.
12. An immunocytochemical study of the distribution of AMPA selective glutamate receptor subunits in the normal human motor system. TL Williams, PG Ince, AE Oakley, PJ Shaw. Neuroscience 74:185-198;1996.
13. The expression of the glial glutamate transporter EAAT2 in motor neurone disease: an immunohistochemical study. AE Fray, PG Ince, SJ Banner, ID Milton, M Cookson, PA Usher, PJ Shaw. European Journal of Neuroscience 10:2481-2489;1998.
14. The immunohistochemical expression of the glial glutamate transporter EAAT-2 in the human CNS. ID Milton, SJ Banner, PG Ince, ID Millon, NH Piggott, AE Fray, N Thatcher, CHW Horne, PJ Shaw. Molecular Brain Research 52:17-31;1997.
15. Role of excitotoxicity in neurological disease. PG Ince, C Eggett, PJ Shaw. Reviews in Contemporary Pharmacotherapy 8:195-212;1997.
16. Excitotoxicity and motor neurone disease: a review of the evidence. PJ Shaw. J Neurol Sci 123 (Suppl):6-13; 1994.
17. Glutamate, excitotoxicity and amyotrophic lateral sclerosis (ALS). PJ Shaw, PG Ince. Journal of Neurology 244 (Suppl 2):3-14;1997.
18. Calcium permeable (- amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. TL Williams, NC Day, PG Ince, RK Kamboj, PJ Shaw. Annals of Neurology 42:200-207;1997.
19. Low expression of GluR2 AMPA receptor subunit protein by human motor neurones. PJ Shaw, JY Slade, TL Williams, PG Ince. NeuroReport 10:261-265;1999.
20. A dose-ranging study of riluzole in amyotrophic lateral sclerosis. L Lacomblez, G Bensimon, PN Leigh, P Guillet, V Meninger and the ALS/ Riluzole study group including PJ Shaw. Lancet 347:1425-1431;1996.
21. Riluzole: anti-glutamate therapy for motor neurone disease. PJ Shaw. Drugs and Therapeutics Bulletin 35:11-12;1997.
22. Respiratory muscle weakness versus sleep disordered breathing as predictors of quality of life in ALS. SC Bourke, PJ Shaw, GJ Gibson. Neurology 57:2040-2044;2001.
23. Non-invasive ventilation in ALS: indications for treatment and effects on quality of life. SC Bourke, M Tomlinson, RJ Bullock, TL Williams, PJ Shaw, GJ Gibson. Neurology 61:171-177; 2003.
24. Validation of quality of life instruments in amyotrophic lateral sclerosis. SC Bourke, E McColl, PJ Shaw, GJ Gibson. Amyotrophic Lateral Sclerosis 5:55-60; 2004
25. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomized controlled trial. SC Bourke, M Tomlinson, TL Williams, RE Bullock, PJ Shaw*, GJ Gibson* (Joint Senior Authors). Lancet Neurology 5:140-147;2006.
26. NICE guideline 105. Motor neurone disease. The use of non-invasive ventilation in the management of motor neurone disease. Issue date July 2010.
27. Non-invasive ventilation in motor neurone disease: current UK practice. SC Bourke, GJ Gibson, T Williams, PJ Shaw. ALS and related Motor Neuron Disorders 3:145-149;2002.
28. Non-invasive ventilation in motor neurone disease: an update of current UK practice. C O’Neill, TL Williams, ET Peel, CJ McDermott, PJ Shaw, GJ Gibson, SC Bourke. J Neurol Neurosurg Psychiatry 2011 (In Press).
29. Rabies-G envelope pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Mazarakis ND, Azzouz M, et al. Human Molecular Genetics 10: 2109-2121;2001.
30. Silencing of mutant SOD1 using interfering RNA induces long term reversal of ALS in a transgenic mouse model. Ralph GS, Radcliffe PA, Bilsland L, Leroux MA, Greensmith L, Mitrophanous KA, Kingsman SM, Mazarakis ND, & Azzouz M. Nature Medicine 11(4):429-33;2005.
31. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Azzouz M, et al. Nature, 429: 413-417;2004.
32. PTEN depletion rescues axonal growth defect and improve survival in SMN-deficient motor neurons. Ning K, Drepper C, Valori C, Wyles M, Higginbottom A, Shaw P, Azzouz M*, Sendtner M*. Human Molecular Genetics, 19(16):3159-68;2010. (* joint senior authors).
33. LentiVector-Mediated SMN Replacement in a Mouse Model of spinal Muscular Atrophy. Azzouz M et al. Journal of Clinical Investigation 114: 1726-1731;2004.
34. Systemic Delivery of scAAV9 expressing SMN Prolongs Survival in a Model of Spinal Muscular Atrophy. Valori F.C, Ning K, Wyles M, Mead R., Grierson A., Shaw PJ., Azzouz M. Science Translational Medicine. 2, 35ra42;2010.
35. Multicistronic Lentiviral Vector-Mediated Striatal Gene Transfer of Aromatic L-Amino Acid Decarboxylase, Tyrosine Hydroxylase and GTP Cyclohydrolase I Induces Sustained Transgene Expression, Dopamine Production and Functional Improvement in a Rat Model of Parkinson's Disease. Azzouz M, et al. J. Neurosci 22:10302-10312; 2002.
36. Dopamine Gene Therapy for Parkinson’s Disease in a Nonhuman Primate Without Associated Dyskinesia. Jarraya B, Boulet S, Ralph S, Jan C, Bonvento G, Azzouz M, et al. Science Translational Medicine, 1(2), P 2ra4; 2009.
37. Differential gene expression in a cell culture model of SOD1 related familial motor neurone disease. J Tomkins, FM Menzies, MR Cookson, K Bushby, PJ Shaw. Hum Mol Genet 11:2061-2075; 2002.
38. Impairment of mitochondrial anti-oxidant defence in SOD1related motor neuron injury and amelioration by ebselen. C Wood Allum, SC Barber, J Kirby, P Heath, H Holden, S Allen, T Beaujeux, SHE Alexson, PG Ince, PJ Shaw. Brain 129:1693-1709;2006.
39. Analysis of the cytosolic proteome in a cell culture model of familial amyotrophic lateral scleosis reveals alterations to the proteasome, anti-oxidant defences and nitric oxide synthetic pathways. S Allen, PR Heath, J Kirby, S Wharton, MR Cookson, FM Menzies, R Banks, PJ Shaw. J Biol Chem 278:6371-6383; 2003.
40. Amyotrophic lateral sclerosis-causing TARDBP (TDP-43) mutations cause widespread dysregulation of mRNA splicing in cell lines from human patients. JR Highley, C Hewmadduma, JA Jansweijer , J Kirby, PR Heath, , A Kalaitzis, A Higginbottom, R Raman, L Ferraiuolo, SP Allen, CJ McDermott, N Lawrence, J Cooper-Knock, M Milo, SA Wilson, P G Ince*, PJ Shaw* . PLOS One 2011 (Under review).
41. Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, Abou-Sleiman P, Olpin S, Wood NW, Willems PH, Smeitink JA, Cookson MR, Bandmann O. Ann Neurol 64:555-65; 2008.
42. Optimisation of pre-clinical pharmacology studies in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS) . RJ Mead, E Bennett, A Kennerly, P Sharp, C Sunyach, P Kasher, J Berwick, B Pettmann, G Battaglia, M Azzouz, AJ Grierson, PJ Shaw. PLOS One 2011 (epub October 2011).
43. A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease. Ramesh T, Lyon AN, Pineda RH, Wang C, Janssen PM, Canan BD, Burghes AH, Beattie CE. Dis. Models. Mech. (9–10):652–62; 2010.
44. A progressive stress response cascade in the spinal cord neuronal circuitry of a sod1 zebrafish model of amyotrophic lateral sclerosis culminates in loss of neuromuscular junction volume and denervation. A McGown, A Al Mashadi, N Redhead, A Lyon, CE Beattie, PJ Shaw, T Ramesh. 2011 (Under review )
45. Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). Flinn L, Mortiboys H, Volkmann K, Köster RW, Ingham PW, Bandmann O. Brain 132:1613-23; 2009.
46. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). LE Cox, L Ferraiuolo, PR Heath, A Higginbottom, H Mortiboys, H Nixon, JA Hartley, A Brockington, CE Burness, SB Wharton, AJ Grierson, PG Ince, J Kirby, PJ Shaw. PloS One 5: e9872 ;2010 (ePub March 24).
47. PTEN/AKT pathway linked to motor neuron survival in human SOD1-related amyotrophic lateral sclerosis (ALS). J Kirby*, K Ning*, L Ferraiuolo, PR Heath, A Ismail, S-W Kuo, L Cox, CF Valori, LE Cox, B Sharrack, SB Wharton, PG Ince, PJ Shaw*, M Azzouz*. Brain 134:506-517;2011.
48. Dysregulation of astrocyte-motor neuron cross-talk in mutant SOD1 related amyotrophic lateral sclerosis. L Ferraiuolo, A Higginbottom, PR. Heath, S Barber, D Greenald, J Kirby & PJ. Shaw. Brain 134:2627-2641; 2011.
49. Pathogical TDP-43 distinguishes sporadic ALS from ALS with SOD1 mutations. IRA Mackenzie, EH Bigio, PG Ince, F Geser, M Neumann, NJ Cairns, LK Kwong, MS Forman, J Ravits, H Stewart, A Eisen, L McClusky, HA Kretzschmar, CM Monoranu, R Highley, J Kirby, T Siddique, PJ Shaw, VMY Lee, J Q Trojanowski. Ann Neurol 61:427-435;2007.
50. Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. J Cooper-Knock*, C Hewitt*, J R Highley*, A Brockington, A Milano, S Man, J Martindale, JA Hartley, T Walsh, C Gelsthorpe, L Baxter, G Forster, M Fox, K Mok, CJ McDermott, B Traynor, J Kirby, SB Wharton, PG Ince, J Hardy, PJ Shaw. *Equal contribution. Brain 2011 (In Press).
51. Mutant SOD1 alters the motor neurone transcriptome: implications for familial amyotrophic lateral sclerosis. J Kirby, PR Heath, S Allen, E Halligan, C A Loynes, C Wood-Allum, H Holden, J Lunec, PJ Shaw. Brain 128:1686-1706;2005.
52. An in vitro screening cascade for anti-oxidant drugs in motor neuron disease models. SC Barber, A Higginbottom, RJ Mead, S Barber, PJ Shaw. Free Radical Biology and Medicine 46:1127-1138;2009.
53. Oxidative stress in ALS: key role in motor neuron injury and a therapeutic target. SC Barber, PJ Shaw. Free Rad Biol Med 2010;48:629-641.
54. Pharmacological NRF2-ARE pathway activation is protective in mouse and patient fibroblast models of amyotrophic lateral sclerosis. RJ Mead, A Higginbottom, E Bennett, J Kirby, E Bennett, SC Barber, SP Allen, PR Heath, A Coluccia, A Brancale, AJ Grierson, PJ Shaw. 2011 (Under review)
55. Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Mortiboys H, Johansen KK, Aasly JO, Bandmann O. Neurology Nov 30;75(22):2017-20; 2010.
56. Mitochondrial involvement in amyotrophic lateral sclerosis. FM Menzies, PG Ince, PJ Shaw Neurochemistry International 40:543-551;2002.
57. Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. FM Menzies, MR Cookson, RW Taylor, DM Turnbull, L Dong, DA Figlewicz, PJ Shaw. Brain 125:1522-1533;2002.
58. Motor neurone disease (MND) phenotype in a patient with a mitochondrial tRNA (Ile) mutation. GM Borthwock, RW Taylor, T Walls, K Tonsca, GA Taylor, PJ Shaw, PG Ince, DM Turnbull. Ann Neurol 59:570-574;2006.
59. Familial amyotrophic lateral sclerosis –linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondrial content. KJ de Vos, A Chapman M Tennant, , C Manser, , E Tudor, KF Lau, J Brownlees, S Ackerley, PJ Shaw, DM McLoughlin, PN Leigh, CCJ Miller, AJ Grierson,. Hum Mol Genet 16:2720-2728;2007.
60. Impairment of mitochondrial anti-oxidant defence in SOD1-related motor neuron injury and amelioration by ebselen. C Wood Allum, SC Barber, J Kirby, P Heath, H Holden, S Allen, T Beaujeux, SHE Alexson, PG Ince, PJ Shaw. Brain 129:1693-1709;2006.
61. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Tain LS, Mortiboys H, Tao RN, Ziviani E, Bandmann O, Whitworth AJ. Nat Neurosci 12:1129-35; 2009.
62. Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS. L Ferraiuolo, PR Heath, H Holden, PR Kasher, J Kirby, PJ Shaw. J Neuroscience 27:9201-9219;2007.
63. Gene expression profiling and its application in amyotrophic lateral sclerosis. J Cooper-Knock, JJ Bury, L Ferraiuolo, EF Goodall, PJ Shaw and J Kirby. InTech Open access publisher 2011 (In press).
64. Evaluation of the Unified Wilson’s Disease Rating Scale (UWDRS) in German patients with treated Wilson’s disease. Leinweber B, Möller JC, Scherag A, Reuner U, Günther P, Lang CJ, Schmidt HH, Schrader C, Bandmann O, Czlonkowska A, Oertel WH, Hefter H. Mov Disord (2011) 23(1):54-62; 2008.
65. Epidemiological neuropathology: the MRC Cognitive Function and Ageing Study experience. Wharton S, Brayne C, Savva G, Matthews F, Forster G, Simpson J, et al. J Alzheimer Dis. 25:359-72;2011.
66. For the Medical Research Council Cognitive Function and Ageing Study. Age, neuropathology, and dementia. Savva G, Wharton S, Ince P, Forster G, Matthews F, Brayne C. N Engl J Med. 360:2302-9;2009.
67. Epidemiological pathology of dementia: attributable-risks at death in the MRC Cognitive Function and Ageing Study. Matthews F, Brayne C, Lowe J, McKeith I, Wharton S, Ince P. PLOS Med. 6:e1000180. doi:10.1371/journal.pmed;2009.
68. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. MRC-CFAS. Lancet. 357:169-75;2001.
69. On behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group. Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain. Simpson J, Ince P, Haynes L, Theaker R, Gelsthorpe C, Baxter L, et al.Neuropathol Appl Neurobiol. 36:25-40;2010.
70. Simpson J, Ince P, Lace G, Forster G, Shaw P, Matthews F, et al. on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group. Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging. 31:578-90;2010.
71. Simpson J, Ince P, Shaw P, Heath P, Raman R, Garwood C, et al. On behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group. Microarray analysis of the astrocyte transcriptome in the ageing brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol Aging. 32:1795-807;2011.
72. Fernando M, Simpson J, Matthews F, Brayne C, Lewis C, Barber R, et al. White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 37:1391-8;2006.
73. Simpson J, El-Sayad O, Wharton S, Heath P, Holden H, Fernando M, et al. Medical Research Council Cognitive Function and Ageing Study Neuropathology Group. Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways. Stroke. 40:369-75;2009.
74. Simpson JE, Fernando M, Clark L, Ince P, Matthews F, Forster G, et al. White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses. . Neuropathol Appl Neurobiol. 33:410-9;2007.
75. Simpson J, Ince P, Higham C, Gelsthorpe C, Fernando M, Matthews F, et al. On behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group. Microglial activation in white matter lesions and nonlesional white matter of ageing brains. . Neuropathol Appl Neurobiol. 33:670-83;2007.
76. Patterns of brain activity during a semantic task differentiate normal aging from early Alzheimer's disease. McGeown WJ, Shanks MF, Forbes-McKay KE, Venneri A. Psychiatry Research: Neuroimaging. 173: 218-227;2009.
77. Responders to ChEI treatment of Alzheimer’s disease show restitution of normal regional cortical activation. Venneri A, McGeown WJ, Shanks MF. Current Alzheimer Research.6; 97-111;2009.
78. Influence of APOE status on lexical-semantic skills in Mild Cognitive Impairment. Biundo R, Gardini S, Caffarra P, Concari L, Martorana D, Neri TM, Shanks MF, Venneri A. Journal of the International Neuropsychological Society. 17: 423-430;2011.
79. The neuroanatomical substrate of lexical semantic decline in MCI ApoE ε4 carriers and non carriers, Venneri A,
McGeown WJ, Biundo R, Mion M, Nichelli P, Shanks MF. Alzheimer’s Disease and Associated Disorders.25: 230-241;2011.
80. Using MRI neuroimaging methods to detect treatment responses in Alzheimer's disease. Venneri A, Shanks MF. Journal
of Neurodegenerative Disease Management.1: 235-243;2011.
81. Combining neuropsychological and structural neuroimaging indicators of conversion to Alzheimer’s disease in amnestic Mild Cognitive Impairment. Venneri A, Gorgoglione G, Toraci C, Nocetti L, Panzetti P, Nichelli P. Current Alzheimer Research. 8: 789-797;2011.
82. Neurological and neuropsychological complications of coronary artery bypass graft surgery. PJ Shaw, D Bates, NEF Cartlidge, D Heaviside, DG Julian, DA Shaw. Quarterly Journal of Medicine 212:531-532; 1984.
83. Early neurological complications of coronary artery bypass graft surgery. PJ Shaw, D Bates, NEF Cartlidge, D Heaviside, DG Julian, DA Shaw. British Medical Journal 291:1384-1386; 1985.
84. Early intellectual dysfunction following coronary bypass surgery. PJ Shaw, D Bates, NEF Cartlidge, JM French, D Heaviside, DA Shaw. Quarterly Journal of Medicine 255:59-68; 1986.
85. Neurological dysfunction following coronary artery bypass graft surgery. PJ Shaw. Journal of the Royal Society of Medicine 79:130-131; 1986.
86. Natural history of neurological complications of coronary artery bypass graft surgery: a six month follow-up study. PJ Shaw, D Bates, NEF Cartlidge, JM French, D Heaviside, DG Julian, DA Shaw. British Medical Journal 293:165-167; 1986.
87. Long-term intellectual dysfunction following coronary artery bypass graft surgery: a six month follow-up study. PJ Shaw, D Bates, NEF Cartlidge, JM French, D Heaviside, DG Julian, DA Shaw. Quarterly Journal of Medicine 239:259-268; 1987.
88. Neuro-ophthalmological complications of coronary artery bypass graft surgery. PJ Shaw, D Bates, NEF Cartlidge, JM French, D Heaviside, DG Julian, DA Shaw. Acta Neurologica Scandinavica 76:1-7; 1987.
89. Neurological and neuropsychological morbidity following major surgery: a comparison between coronary artery bypass and peripheral vascular surgery. PJ Shaw, D Bates, NEF Cartlidge, JM French, D Heaviside, DG Julian, DA Shaw. Stroke 18:700-707; 1987.
90. The incidence and nature of neurological morbidity following cardiac surgery: a review. PJ Shaw. Perfusion 4:83-91; 1989.
91. An analysis of factors predisposing to neurological injury in patients undergoing coronary bypass operations. PJ Shaw, D Bates, NEF Cartlidge, JM French, D Heaviside, DG Julian, DA Shaw. Quarterly Journal of Medicine, 267:633-646; 1989.
92. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). ECST Trialist Collaborative Group. Lancet 35: 1379 – 87;1998.
93. Randomised controlled trial of streptokinase, aspirin and combination of both in treatment of acute ischaemic stroke. L Candelise et al for the MAST-I group. Lancet 346:1509;1995.
94. The International Stroke Trial: a randomised trial of aspirin, subcutaneous heparin, both or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Study Collaborative Group. Lancet 349. 1569 – 8; 1997
95. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. ESPRIT Study Group; Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Lancet 367:1665-73;2006.
96. How the treatment of carotid artery stenosis affects blood pressure: a comparison of haemodynamic disturbances following carotid endarterectomy and endovascular treatment. McKevitt FM, Sivaguru A, Venables GS, Gaines PA, TJ Cleveland, Beard JD and Channer KS. Stroke 34(11):2576-81;2003.
97. Complications following Carotid Angioplasty and Carotid Stenting in Patients with Symptomatic Carotid Artery Disease. McKevitt, F.M. Macdonald, S. Venables, G.S. Cleveland, T.J. Gaines, P.A.Cerebrovasc Dis 17:28-34;2004.
98. Effects of cholesterol lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high risk conditions. MRC/BHF Heart Protection Study Collaborative Group. Lancet 363 757 – 767;2004.
99. The third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke. Sandercock P, Lindley R, Wardlaw J, Dennis M, Lewis S, Venables G, Kobayashi A, Czlonkowska A, Berge E, Bruins Slot K, Murray V, Peeters A, Hankey G, Matz K, Brainin M, Ricci S, Celani MG, Righetti E, Cantisani T, Gubitz G, Phillips S, Arauz A, Prasad K, Correia M, Lyrer P; the IST-3 collaborative group. Trials 2008 Jun 17;9(1):37.
100. The benefits of combined anti-platelet treatment in carotid artery stenting. McKevitt FM, Randall MS, Cleveland TJ, Gaines PA, Tan KT, Venables GS.Eur J Vasc Endovasc Surg 29(5):522-7;2005.
101. Comparison of neurological outcomes for carotid stenting with and without cerebral protection with the MedNova NeuroShield Filter: A prospective cohort analysis. S Macdonald, FM McKevitt, GS Venables, TJ Cleveland, PA Gaines. Journal of Endovascular Therapy 9(6):777-785;2002.
102. Is there any benefit from staged carotid and coronary revascularisation using carotid stents? A single centre experience highlights the need for a randomised controlled trial. Randall M.S. McKevitt F.M., Cleveland T.J. , Gaines P.A. , Venables G.S. Stroke 2006 37:435-9.
103. Computational haemodynamics in cerebral aneurysms: the effect of modelled versus measured boundary conditions. A Marzo, P Singh, I Larrabide, A Radaelli, S Coley, M Gwilliam, ID Wilkinson, P Lawford, P Raymond, U Patel, A Frangi, DR Hose. Ann Biomed Eng 39:2,884-896;2011
104. Effects of smoking and hypertension on wall shear stress and oscillatory shear index at the site of intracranial aneurysm formation. Singh PK, Marzo A, Howard B, Rufenacht DA, Bijlenga P, Frangi AF, Lawford PV, Coley SC, Hose DR, Patel UJ. Clin Neurol Neurosurg. 112(4):306-13;2010. Epub 2010 Jan 21.
105. The Effects of Aortic Coarctation on Cerebral Hemodynamics and its Importance in the Etiopathogenesis of Intracranial Aneurysms. PK Singh, A Marzo, C Staicu, MG William, I Wilkinson, PV Lawford, DA Rufenacht, P Bijlenga, AF Frangi, R Hose, UJ Patel, S C Coley. Journal of Vascular and Interventional Neurology 3(1) 17-30;2010.
106. The Development of a Calculator to Predict the Risk of Rupture of Unruptured Intracranial Aneurysms-@neuRisk. U Patel. World Neurosurgery 73(4):231-3;2010.
107. Influence of inlet boundary conditions on the local haemodynamics of intracranial aneurysms. A. Marzo, P.K. Singh, P. Reymond, N. Stergiopulos, U.J. Patel and D.R. Hose. Computer Methods in Biomechanics and Biomedical Engineering, 12(4) 431-444; 2009
109. The role of computational fluid dynamics in the management of unruptured intracranial aneurysms: a clinicians' view. PK Singh, A Marzo, SC Coley, G Berti, P Bijlenga, PV Lawford, MC Villa-Uriol, DA Rufenacht, KM McCormack, A Frangi, UJ Patel and DR Hose. Comput Intell Neurosci 760364;2009. (Epub 2009 Aug 19)
109. Analysis of different hemodynamic factors during initiation and rupture of intracranial aneurysms and influence of various drugs on their natural history. P.K. Singh, A. Marzo, H. Tahir, T. Weeratunge, S.C. Coley, P.V. Lawford, U. Patel, and D.R. Hose.Proceedings of XIV Congress of Neurological Surgery, 30 August- 04 September 2009, Boston, USA.
110. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Comi G, Cohen JA, Arnold DL, Wynn D, Filippi M; FORTE Study Group including Sharrack B. Ann Neurol 69(1):75-82;2011.
111. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Comi G, Abramsky O, Arbizu T, Boyko A, Gold R, Havrdová E, Komoly S, Selmaj K, Sharrack B, Filippi M; LAQ/5063 Study Group. Mult Scler. 16(11):1360-6;2010.
112. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ and the CLARITY Study Group including Sharrack B. New England Journal of Medicine 362(5):416-26;2010.
113. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P and the FREEDOMS Study Group including Sharrack B. New England Journal of Medicine 362(5):387-401;2010.
114. Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis. Tappenden P, Saccardi R, Confavreux C, Sharrack B, Muraro PA, Mancardi GL, Kozak T, Farge-Bancel D, Madan J, Rafia R, Akehurst R, Snowden J. Bone Marrow Transplant 45(6):1014-21;2010.
115. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, Elovaara I, Fazekas F, Hartung HP, Hillert J, King J, Komoly S, Lubetzki C, Montalban X, Myhr KM, Ravnborg M, Rieckmann P, Wynn D, Young C, Filippi M and the PreCISe study group including Sharrack B. Lancet 374(9700):1503-11;2009.
116. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O'Neill GN and the BG-12 Phase IIb Study Investigators including Sharrack B. Lancet 372(9648):1463-72;2008.
117. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj K, Sharrack B, Filippi M and the LAQ/5062 Study Group. Lancet 371(9630):2085-92;2008.
118. Short-term combination of glatiramer acetate with i.v. steroid treatment preceding treatment with GA alone assessed by MRI-disease activity in patients with relapsing-remitting multiple sclerosis. De Stefano N, Filippi M, Hawkins C and the 9011 study group including Sharrack B. Journal of Neurological Sciences. 266(1-2):44-50;2008.
119. Haemopoietic stem cell transplantation--an evolving treatment for severe autoimmune and inflammatory diseases in rheumatology, neurology and gastroenterology. Kapoor S, Wilson AG, Sharrack B, Lobo A, Akil M, Sun L, Dalley CD, Snowden JA. Haematology 12(3):179-91;2007.
120. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW and the AFFIRM Investigators including Sharrack B. New England Journal of Medicine 354:899-910;2006.
121. The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Tubridy N, Behan PO, Capildeo R, Chaudhuri A, Forbes R, Hawkins CP, Hughes RA, Palace J, Sharrack B, Swingler R, Young C, Moseley IF, MacManus DG, Donoghue S, Miller DH. Neurology 53(3):466-72; 1999.
122. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T and the Laquinimod in Relapsing MS Study Group including Sharrack B. Neurology 64:987-991;2005.
123. Expression of ADAM-17, TIMP-3 and fractalkine in the human adult brain endothelial cell line, hCMEC/D3, following pro-inflammatory cytokine treatment. Hurst LA, Bunning RA, Couraud PO, Romero IA, Weksler BB, Sharrack B, Woodroofe MN. Journal of Neuroimmunology 210(1-2):108-12;2009.
124. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH and the Ustekinumab MS Investigators including Sharrack B. Lancet Neurology 7(9):796-804;2008.
125. Frequent MRI study of a novel CCR2 antagonist in relapsing-remitting multiple sclerosis. Sharrack B, Leach T, Jacobson E et al. Ann Neurol 62 S11: S74-S75; 2010 .
126. Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Garren H, Robinson WH, Krasulová E, Havrdová E, Nadj C, Selmaj K, Losy J, Nadj I, Radue EW, Kidd BA, Gianettoni J, Tersini K, Utz PJ, Valone F, Steinman L and the BHT-3009 Study Group including Sharrack B. Annals of Neurology 63(5):611-20;2008.
127. Absence of aquaporin-4 antibodies in patients with idiopathic intracranial hypertension. Dhungana S, Waters P, Ismail A, Woodroofe N, Vincent A, Sharrack B. J Neurol 257(7):1211-2;2010.
128. Cytokines and chemokines in idiopathic intracranial hypertension. Dhungana S, Sharrack B, Woodroofe N. Headache 49(2):282-5;2009.
129. IL-1β, TNF and IP-10 in the cerebrospinal fluid and serum are not altered in patients with idiopathic intracranial hypertension compared to controls. Dhungana S, Sharrack B, Woodroofe N. Clin Endocrinol 71(6):896-7;2009.
130. Does cryptic gluten sensitivity play a part in neurological illness? Hadjivassiliou M, Gibson A, Davies-Jones GAB, Lobo AJ, Stephenson TJ, Milford-Ward A. Lancet 347:369-71;1996.
131. Clinical, radiological, neurophysiological and neuropathological characteristics of gluten ataxia. Hadjivassiliou M, Grünewald RA, Chattopadhyay AK, Davies-Jones GAB, Gibson A, Jarratt JA, Kandler RH, Lobo A, Powell T, Smith CML. Lancet 352:1582-1585;1998.
132. Neuropathy associated with gluten sensitivity. Hadjivassiliou M, Grunewald RA, Kandler RH, Chattopadhyay AK, JA Jarratt, Sanders DS, Sharrack B, Wharton S, Davies-Jones GAB. J Neurol Neurosurg Psychiatry 77:1262-1266;2006.
133. Gluten sensitivity: from gut to brain. Hadjivassiliou M, Sandres DS, Grunewald RA, Woodroofe N, Boscolo S, Aeschlimann D. Lancet Neurol 9:318-30;2010.
134. Dietary treatment of gluten neuropathy. Hadjivassiliou M, Kandler RH, Chattopadhyay AK, Davies-Jones GAB, , JA Jarratt, Sanders DS, Sharrack B, Grunewald RA. Muscle and Nerve 34:762-766;2006.
135. Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Hadjivassiliou M, Grunewald R, Sharrack B et al. Brain 126:685-91;2003.
136. Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Hadjivassiliou M, Maki M, Sanders DS, Williamson C, Grunewald RA, Woodroofe N, Korponay-Szabo I. Neurology 66:373-377;2006.
137. Autoantibodies in gluten ataxia recognise a novel neuronal transglutaminase. Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D. Ann Neurol 64:332-343;2008.
138. Cerebellar ataxia as a possible organ specific autoimmune disease. Hadjivassiliou M, Boscolo S, Tongiorgi E, Grunewald RA, Sharrack B, Sanders DS, Woodroofe N, Davies-Jones GAB. Movement Disorders 23(10):1270-1377;2008.
139. MR spectroscopy and atrophy in Gluten, Friedreich’s and SCA6 ataxias. Hadjivassiliou M, Wallis LI, Hoggard N, Grunewald RA, Griffiths PD, Wilkinson ID. Acta Neurol Scand 10.111/j.1600-0404.2011.01620.x;2011.
140. Conversation analysis can help in the distinction of epileptic and non-epileptic seizure disorders: a case comparison. Plug L, Sharrack B, Reuber M. Seizure 18:43-50;2009.
141. Seizure metaphors differ in patients' accounts of epileptic and psychogenic non-epileptic seizures. Plug L, Sharrack B, Reuber M. Epilepsia 50:994-1000;2009.
142. Seizure, fit or attack? The use of diagnostic labels by patients with epileptic and non-epileptic seizures. Plug L, Sharrack B, Reuber M. Applied Linguistics 31:94-114;2009.
143. Using Conversation Analysis to distinguish between epilepsy and non-epileptic seizures: a prospective blinded multirater study. Reuber M, Monzoni C, Sharrack B, Plug L. Epilepsy and Behavior 16:139-144;2009.
144. Psychogenic non-epileptic seizures: seizure manifestations reported by patients and witnesses. Reuber M, Broadhurst M, Grunewald R, Howell S, Koepp M, Sisodia SJ, Walker M. (Submitted) 2011.
145. Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Neuron 2011; E Pub Oct 27.
146. A Hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-Linked ALS-FTD. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR et al.Neuron 2011; Epub Sept 21.
147. Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. J Cooper-Knock*, C Hewitt*, J R Highley*, A Brockington, A Milano, S Man, J Martindale, JA Hartley, T Walsh, C Gelsthorpe, L Baxter, G Forster, M Fox, K Mok, CJ McDermott, B Traynor, J Kirby, SB Wharton, PG Ince, J Hardy, PJ Shaw. Brain 2011 (In Press).
148. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Yebenes JG, Landwehrmeyer B, Squitieri F, Reilmann R, Rosser A, Barker A. Saft C, Magnet MK, Sword A, Rembratt A, Tedroff J and the MermaiHD study investigators including Bandmann O. Lancet Neurol 10:1049-1057; 2011.
149. Heart rate variability measures as biomarkers in patients with psychogenic nonepileptic seizures: Potential and limitations. Ponnusamy A, Marques JLB, Reuber M. Epilepsy & Behaviour 2011 in press.
150. Comparison of heart rate variability parameters during complex partial seizures and psychogenic non-epileptic seizures. Reuber M, Marques JLB, Ponnusamy A. Proceedings of American Epilepsy Society Scientific meeting, Dec 2011.
151. Time-varying model identification for time–frequency feature extraction from EEG data. Yang Li, Hua-Liang Weia, SA. Billings, PG Sarrigiannis. Journal of Neuroscience Methods 196:151–158; 2011.
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1. Name and Title of Academic Director of Neuroscience and relevant web-links
2. Overview of Experimental Medicine Research in Neuroscience
3. Track record in translating basic research findings into improvements in health care.
4. Supporting infrastructure
5. Experimental Medicine Research Strategy in Neuroscience 2012-2017
2. Name and Title of Academic Director of Neuroscience and relevant web-links
6. Key indicators of research standing in experimental medicine
7. Strategic partnerships with industry
8. Track record in and plans for patient and public involvement
9. Strategy for capacity building and the training of new investigators
10. Resources required to support Experimental Medicine Neuroscience programmes
References
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