NIHRDataInsights/HRCSData huggingface dataset:
Title: The development of gene therapy for Niemann-Pick type C disease
Funder: Medical Research Council

Abstract: NPC is a prematurely fatal autosomal recessive metabolic disorder. A diagnosis is usually made in infancy with approximately half the patients having increased liver bile acid levels. 10% of these patients will die of liver failure within six months of life and those that survive infancy will face progressive neurodegeneration leading to cerebellar ataxia, dysphagia, dementia and death usually in the second decade of life. Most NPC cases are caused by mutations in the NPC1 gene that encodes a late-endosome/lysosome transmembrane protein. The exact role of NPC1 is unknown although it probably has a role in trafficking of cholesterol and sphingolipids as these lipids accumulate in lysosomes of NPC patients and mice. There is currently no major specific disease modifying therapy for patients with NPC and there is an overwhelming need to develop more effective treatments. This project aims to conduct a proof-of-concept pre-clinical study to evaluate the efficacy of AAV9-mediated gene therapy to rescue a mouse model of NPC from neurological and visceral symptoms. We have constructed an AAV9 vector that carries the full-length therapeutic version of the NPC1 gene (AAV9-NPC1). Our preliminary data shows that intracerebroventricular injection of AAV9-NPC1 to newborn NPC1 mice provides significant therapeutic benefit and improves the weight and behaviour compared to uninjected NPC mice. However, more studies are required and our main objectives are to conduct survival, behavioural, biochemical, histological, neuropathology and imaging assessments to ascertain whether: (i) intracerebroventricular; (ii) intravenous or; (iii) a combination of intracerebroventricular and intravenous routes of administration prevent neurological and visceral symptoms and rescue the NPC mice from premature death. Finally, (iv) we will use the most therapeutically efficacious route of administration to treat progressively older and symptomatic NPC mice to evaluate the effect of age on outcome.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Pathfinder: An experimental medicine study of the 18 kD translocator protein as a novel neuroimmunodulatory target for multiple sclerosis
Funder: Medical Research Council

Abstract: Within several years of diagnosis, disability progression in the absence of relapses is observed in most people with multiple sclerosis (secondary progressive MS, SPMS). Current disease-modifying therapies have had little impact on SPMS, therapy for which is a major unmet medical need in neurology. We (and others) hypothesise that therapeutic down- regulation of chronically activated, pro-inflammatory brain microglia will slow or stop the neurodegeneration responsible for progressive forms of MS. However, safe and effective, targeted immunotherapy for microglia has not been identified to test this hypothesis in the human disease. The 18kd Mitochondrial Translocator Protein (TSPO) is highly expressed in microglia and macrophages. There is an extensive literature documenting the innate immune modulatory effects mediated by TSPO in isolated cells and in a variety of acute and more chronic animal disease models. We hypothesise that TSPO ligands constitute a novel class of immune modulators acting primarily through effects on pro-inflammatory microglia (and macrophages). We propose now to test this more fully with human experimental medicine for the first time. Previously, we discovered the genetic basis for variable TSPO interactions of ligands in the human population and have extensive experience with the pharmacology of this target. We now will test for immunomodulation by a TSPO ligand, XBD173, in humans, in people with MS and in human immune cells. While there are 11 licensed medicines currently available for treating relapses in MS, these disease-modifying drugs primarily target the adaptive immune system (T- and B-cells). With validation of TSPO as a novel immunomodulatory target through our experimental medicine studies, we intend to progress towards development of novel TSPO ligands (with improved pharmacological characteristics relative to those available now) for therapeutic modulation of innate immune responses in progressive forms of MS.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Stratifying Chronic Pain Patients By Pathological Mechanism- A Multimodal Investigation Using Functional MRI, Psychometric And Clinical Assessment
Funder: Medical Research Council

Abstract: Chronic pain remains an area of considerable unmet need. Up to 20% of the population suffer psychological distress and poor health status. Classification remains disease-based, despite evidence that multiple pathophysiological processes underpin diseases, and that patients with similar symptoms can have different aetiologies. As most current pharmacotherapies target only one mechanism, it is not perhaps surprising that many offer only moderate pain relief. Mechanism-based patient stratification should facilitate timely, appropriate and cost-effective treatments. We will use multimodal techniques to stratify patients according to their underlying pain mechanisms, examining patients with intractable painful osteoarthritis, orofacial pain and pain-free controls. Evoked-response and resting-state functional and perfusion magnetic resonance imaging will be employed to investigate brain, brainstem and spinal cord structures underpinning mechanisms of ongoing peripheral drive, central sensitisation, descending pain modulation (DPM) and functional connectivity. We will decouple peripheral from central phenomena using anaesthetic blocks. Gold-standard subjective report, psychometric and sensory testing data will also be acquired. We will use multimodal machine learning across all data to predict the mechanisms underlying patients' persistent pain, namely: (i) does persistent pain originate peripherally, centrally or as a combined state? (ii) is the DPM system functioning? We will determine which data types contribute most to patient stratification, deriving simple, identifiable fingerprints of each pathophysiological state for clinical use. Success in this project should impact on clinical practice. Diagnostic uncertainty is associated with poor outcomes, distress and suffering. Delivery of new mechanistic insights should catalyse treatment development; better identification of aetiologies should expedite implementation of treatments tailored to individual patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND BRain Imaging, cognition, Dementia and next generation GEnomics
Funder: Medical Research Council

Abstract: we propose to explore the genetic and epigenetic determinants of quantitative MRI-markers of brain aging that are powerful predictors of dementia/AD risk, and to examine the clinical significance of the markers in a population-based setting. Leveraging the extensive information collected within the largest European population-based cohort studies with neuroimaging data, we will first search for genetic variants associated with established and novel MRI-markers of brain aging, focusing particularly on rare variants, using both an agnostic and candidate locus approach (loci identified through genome-wide association studies [GWAS] as associated AD or with MRI-markers of brain aging). In contrast with GWAS signals, rare variants may lead to the discovery of causal variants, and have hardly been explored in association with structural MRI-markers. Second, we will take an original lifetime perspective, through examination of samples in various age categories spanning from young adulthood to older age, many of which with repeated MRI and blood sampling. Indeed, there is increasing evidence that early-life factors play an important role in the occurrence of late-onset neurodegenerative diseases. We propose an innovative exploration of lifetime changes in methylation associated with structural brain alterations using a novel bisulfite sequencing technology, to help identify functional and disease relevant variants. We will also study the modifying effect of vascular risk factors and socio-economic status on genetic/epigenetic determinants of brain aging. Third, we will explore the clinical significance of genetic and epigenetic markers we identify by examining their association with cognitive performance, cognitive decline and risk of dementia/AD, capitalizing on the elaborate cognitive testing and prospective dementia surveillance available in all studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Is xenon combined with cooling an effective treatment for traumatic brain injury?
Funder: Medical Research Council

Abstract: Need: Traumatic brain injury (TBI) affects young & elderly populations throughout the world and results in a significant global healthcare burden. TBI patients often suffer from costly long-term neurological and cognitive problems, affecting family life & ability to work. Current clinical practice for TBI patients is largely supportive, centred on non-specific endpoints e.g. management of tissue oxygenation, cerebral perfusion pressure & intracranial pressure(ICP). There are no drug treatments aimed specifically at preventing neuronal loss and secondary injury following TBI. Proposed Solution: Treatment with the noble gas xenon combined with cooling will be an effective treatment to improve outcome after TBI. Rationale: We have recently shown for the first time in an animal model of TBI that treatment with xenon alone reduces secondary injury & improves short- and long-term outcome & survival. Xenon is a novel NMDA receptor antagonist and general anaesthetic, and is currently undergoing clinical trials as a treatment for ischemic brain injury (neonatal asphyxia & brain damage after cardiac arrest). Cooling is routine for ischemic brain injury in neonates, & used in adults with brain injury after cardiac arrest. Technology for delivery of xenon (eg AirLiquide Felix anaesthetic machine) and cooling (intravascular cooling devices, cooled blankets) is already available and approved for medical use. Development plan: Xenon combined with cooling may be particularly effective. Before this can be used in TBI patients it is crucial that there is preclinical data on the safety and efficacy of the combination of xenon and cooling in an animal model of TBI. This project will produce a preclinical data package on safety and efficacy, including the optimum xenon concentrations, cooling temperatures and timing of treatment. This preclinical validation data, including any new IP generated, will support a route to commercialisation & use of xenon & cooling in TBI patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: JPND: Targeting epigenetic dysregulation in the brainstem in Alzheimer's Disease (EPI-AD)
Funder: Medical Research Council

Abstract: Alzheimer's disease (AD) is a neurodegenerative disease that affects brain integrity and functioning, resulting in progressive cognitive deterioration. Previous work indicates that epigenetic mechanisms including DNA (hydroxy)methylation represent critical factors in the pathogenesis of AD. Moreover, the early occurrence of various neuropsychological symptoms and novel neuropathological findings suggest a key role for the brainstem, particularly serotonin (5-HT)- and noradrenaline (NA)-specific neurons. Therefore, we hypothesise that epigenetic dysregulation in the brainstem has a critical role in the early pathogenesis of AD and aim to elucidate the exact role of DNA (hydroxy)methylation within the brainstem in the development and progression of AD. Our objectives will be addressed within our cross-disciplinary network, through the use of established large human cohorts. The consortium will link the epigenetic profiles with cognitive dysfunction, AD-related neuropathology, gene variants regulating 5-HT and NA-function (Objectives I & II). For biomarker discovery, blood epigenetic signatures of aging individuals will be linked to subsequent cognitive decline, MCI-AD conversion and depression (Objective III). The putative signatures will also be compared to established (more invasive) biomarkers to determine their validity. By making use of iPSCs (Objective IV), the project will furthermore test whether i) neurons derived from iPSCs of AD patients develop an AD-characteristic molecular/epigenetic and cellular phenotype when exposed to AD brain extracts or glucocorticoids (GCs), and ii) epigenetic editing of candidate genes (from Objectives I and II) within 5-HT and NA neurons generated from iPSCs can reverse AD-specific phenotypes. The comprehensive approach of this project will fill the vital gap in our understanding of the links between epigenetic dysregulation and the 5-HT and NA neurotransmitter systems in the pathophysiology of AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND Genomic Instability in Alzheimer's Disease and Related Disorders: a Single-Cell Approach
Funder: Medical Research Council

Abstract: To study the nature and extent of genomic instability in human AD and primary Tauopathy brains, we will sequence the genomes of ~1500 single neurons obtained from frozen frontal cortex brain tissue of 10 normal, 10 AD, and 10 Tauopathy brains. Computational methods will reveal DNA-copy number landscapes and structural rearrangements from the single-cell sequences. To study the nature and extent of transcriptomic instability in human AD and primary Tauopathy brains, we will apply single-cell resolution spatial transcriptomics to tissue sections of those same brains. Spatial transcriptomics enables molecular imaging of the full mRNA transcriptome in a tissue section by sequencing. To identify somatic mutations in cells that may cause neuropathology, we will employ whole genome (and targeted) sequencing approaches on single neurons isolated from different areas of a subject's brain. Specifically, we will analyse subjects with no family history of AD or Tauopathies, and no causal germline mutation. To determine the role of Tau/Tau pathology in (i) transcription regulation, we will apply spatial transcriptomics to brains of WT, KOTau and THY-Tau22 mice; and (ii) mitochondrial and genomic DNA integrity and repair, as well as (iii) chromatin organization, we will apply a diversity of techniques as e.g. immunostaining on brain. To determine the molecular mechanism by which Tau induces genomic instability, we will (i) characterize the human Tau-induced mitotic aberrations in Drosophila larval neuroblasts and developing photoreceptor neurons, (ii) identify genetic suppressors of hTau-induced spindle defects and genomic instability in Drosophila, (iii) characterize the human Tau-induced mitotic aberrations in a Tau inducible neuroblastoma cell line, (iv) characterize human Tau-induced mitotic aberrations in embryonic brains in the humanized genomic Tau mouse model, and (v) subject brain tissue from Drosophila and mouse models to single cell genome sequencing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND GBA1 mutations in Parkinson disease: clinical and biochemical prodrome, risk profile and pathogenetic modelling for therapeutic intervention.
Funder: Medical Research Council

Abstract: Mutations of the glucocerebrosidase gene (GBA1) are the most important risk factor for Parkinson disease (PD). In Europe, at least 5-10% of all PD patients carry GBA1 mutations. A GBA1 mutation increases PD risk by 20-30x. GBA1-related PD is clinically, radiologically, pharmacologically and pathologically indistinguishable from idiopathic PD, except that age of onset is slightly younger, cognitive deficit more common and progression more rapid. A primary goal of this project is the standardization of clinical and experimental practices for studying GBA1-linked PD, as a critical step toward the definition of diagnostic biomarkers, pathogenetic pathways and therapeutic strategies. The established and web-based cohorts will be used to provide a: - Harmonised international longitudinal evaluation of GBA1 carriers in the established clinic based cohorts to determine prodromal clinical features (olfaction, motor function, bradykinesia, sleep disorder (RBD), cognition, anxiety, depression), biochemical phenotype (blood, urine, CSF) and identify those at high risk for conversion to PD. - Assessment of the web-based group for signs and symptoms including anxiety (HADS), depression (BDI), bradykinesia (peg board), cognitive decline (MoCA, Wesnes), reduced sense of smell (UPSIT), abnormal sleep behaviours (RBD-Q) associated with the very early stages of PD. Participants will be required to undertake a questionnaire and a number of interactive assessments that includes the above, and which are designed to identify risk factors and early clinical signs of PD. - Resource for cell models (fibroblasts, lymphoblasts, inducible pluripotent stem cells and adipose-derived neural crest stem cells). - Genetically stratified group of individuals suitable for future clinical trials of agents targeted for those with GBA1 mutations with PD or at risk of PD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND coFUND ADAGE
Funder: Medical Research Council

Abstract: UCL has recently developed a multiplexed, MRM-based UPLC-MS/MS assay for the simultaneous quantitation of 27 biomarkers in 100 ul of CSF in under 10 min (figure below). Using this assay in the analyses of CSF, it was possible to distinguish correctly between patients with Parkinson's disease, Alzheimer Disease, Lewy Body Dementia (LBD) and age-matched controls (figure 2 and 3). This test was developed on a triple quadrupole based mass spectral platform which allows the translation of this test into any large hospital. Preliminary metabolomic profiling of CSF in the UCL laboratories have identified potential biomarkers and differences in metabolite expression in patients with Lewy Body Dementia, Parkinson's Disease and age-matched controls (Figure below). These results indicate that there are changes in the metabolome and potentially the lipidome (brain is 60% lipid) of patients with neurodegenerative conditions. Cutting edge 'omic' techniques, a full translational test capability and well defined clinical patient samples included in WP3, will allow us to identify new biomarkers, potential disease mechanisms and therapeutic targets for neurodegenerative conditions. Ageing, Single-Carbon Metabolism, and Total Brain Atrophy in Non-Demented Elders: Ageing (table 1a), hyperhomocysteinemia (>10.53)(table Xb), and low folate (<18.67)(table xc) increase risk for total brain atrophy (Bowman et al., 2012; Bowman et al., 2013). Virtually all brain regions atrophy with age and these structural changes increase risk for cognitive decline and Alzheimer's disease. These data suggest that single-carbon metabolism has a role in brain aging.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative
Funder: Medical Research Council

Abstract: Imaging (P. Giunti, UCL) Our EUROSCA data suggest that brainstem, cerebellar and basal ganglia volumes measured by MRI are more sensitive markers of disease progression than clinical scales [Reetz et al. 2013]. To validate this, we will apply an automated brain segmentation pipeline, Learning Embeddings for Atlas Propagation (LEAP), developed by IXICO (London, UK) [Wolz et al. 2010]. LEAP is currently used for hippocampus segmentation where it performs robustly across different imaging platforms and MRI field strengths as well as across morphological variations found in healthy subjects and patients. The method is integrated into the regulatory approved medical device Assessa to provide automated segmentation of brain structures and was used as an exemplar method for the qualification of low hippocampal volume as enrichment biomarker in clinical trials in Alzheimer's disease with the European Medicines Agency. LEAP has been successfully applied to segmenting the brain into 134 structures including the ones relevant for SCA3. To adapt the method for the specific needs of SCA3 research, we will subcontract IXICO. In a first step, existing MRI data will be used to further optimize the automated segmentation technique. In a second step, the optimized method will be applied to the prospectively collected MRIs. Findings will be compared to matched controls of the Assessa database. Recent diffusion tensor imaging (DTI) studies detected widespread microstructural white matter pathology in the cerebellum, brainstem, and additional brain regions suggesting that DTI can be used as a highly sensitive MRI biomarker [Guimaraes et al. 2013]. We will therefore include DTI in our MRI protocol. Data will be analysed with tract-based spatial statistics (TBSS). We will put particular emphasis on studying whether white matter abnormalities can be detected in preclinical mutation carriers. We will collect also biomaterial for the establishment of biomarkers (Human Biol. sample section)


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND:A European DNA bank for deciphering the missing heritability of Alzheimer's disease
Funder: Medical Research Council

Abstract: Our objective is to significantly increase the generation of Genome Wide Association Study-based population data via the creation of a European Alzheimer's Disease DNA BioBank (EADB). We shall be able to collate 31,911 AD cases (of which 24,049 have yet to be genotyped) and 40,802 controls (of which 15,638 have yet to be genotyped) from 11 countries. GWASs and complementary statistical studies (based on genotype and imputation data) will be performed, in order to capture the missing heritability and identify potential disease pathways. This initiative will increase the number of AD samples available for genetic studies in Europe by more than 4-fold and worldwide by almost 2-fold. In parallel, the EADB will collect DNA samples from Europe's largest longitudinal cohort of MCI cases, with a view to identifying genetic markers that modulate the rate of disease progression and cognitive decline. At present, we have compiled approximately 9,109 MCI cases (of which 6,952 have yet to be genotyped) and have data on AD conversion, neuropsychological parameters, cerebrospinal fluid biomarkers and neuroimaging for most of these samples. We shall investigate the influence of genetic risk factors for AD in a genome-wide- or hypothesis-based manner. From a translational perspective, the identification of genetic factors in pathways that modulate the AD risk and increase the rate of disease progression/cognitive decline in MCI will be pivotal for the development and testing of therapeutic approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL