NIHRDataInsights/HRCSData huggingface dataset:
Title: MRC Transition Support Award [CDA] [Maria Jimenez-Sanchez]
Funder: Medical Research Council

Abstract: To date, therapeutic approaches for Alzheimer's disease (AD) have focused on neuron-centric mechanisms of disease, without fully understanding the contribution of other brain cells. The aim of my Career Development Award is to identify mechanisms used by astrocytes to protect neurons, and how these are modulated in disease. I hypothesised that molecular chaperones, typically considered intracellular proteins with protective functions in neurodegeneration, can be secreted from astrocytes to protect neurons in AD. Our research has shown that chaperones of the small heat-shock protein (sHSP) family are secreted from astrocytes when these become reactive, as occurs in AD. Importantly, primary mouse neurons may internalise sHSPs, suggesting that their secretion and transfer constitutes a mechanism that increases chaperone load under conditions when it is most needed. This exciting new data supports my hypothesis and addresses the aims of my CDA. Unforeseen events have caused delays in generating sufficient data to deliver strong research outputs. These delays include unreliable data generated by the postdoctoral researcher who worked on this grant, and difficulties in breeding the htau transgenic mice necessary for this project. The Transition Support Award will enable us to progress the aims and increase the impact of our findings. Through analysis of clinical samples and alternative tauopathy models, we will determine the relevance of our findings for human disease, elucidate the mechanism by which astrocyte-derived sHSPs modulate tau pathology, and examine the potential therapeutic benefits of molecular chaperones for AD. Collaborations and mitigation plans are in place to ensure the research outputs generated will consolidate my leadership position in the field. Importantly, King's College London has committed to support me by offering a tenured position on the successful completion of this Transition Support Award.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: NEUROLOGICAL
Title: Cortical excitability in refractory focal epilepsy treated with novel gene therapy and conventional resective surgery
Funder: Medical Research Council

Abstract: Epilepsy affects around 50 million people worldwide. The pathophysiology reflects altered excitability of cortical networks. Approximately 1/3 of patients have refractory seizures despite optimal medical management, with an annual risk of sudden unexpected death in epilepsy (SUDEP) of 0.5-1%. In some, surgical resection of the epileptogenic zone can result in seizure freedom; however, surgery has risks, in particular, damage to eloquent brain areas. Professor Walker (Co-Investigator) and colleagues have demonstrated successful treatment of an engineered potassium channel gene (KCNA1), packaged into a viral vector in a rodent model. The next step is the first in-human clinical trial in 10 patients from our presurgical cohort. At present, there are no surrogate markers for changes in brain excitability in this trial. Transcranial magnetic stimulation (TMS) uses time-varying magnetic fields to explore cortical physiology non-invasively. In TMS-EMG, following motor cortex stimulation, neuronal excitability is measured indirectly by electromyography. More recently, TMS-EEG (TMS with high-density electroencephalography) has enabled more direct probing of cortical excitability. A few studies have demonstrated 'normalisation' of preoperative excitability using TMS-EMG, following successful epilepsy surgery, and differences in preoperative excitability in patients that became seizure free compared with those who did not. There have been no published studies to date of TMS-EEG. We plan to apply TMS-EMG/ EEG to our patients with drug refractory epilepsy undergoing both novel gene therapy, and conventional resective surgery, in order to gain an insight into the effects on cortical excitability of the novel genetic therapy, using TMS as a biomarker, and to examine how these change post-operatively in both groups and identify predictive factors that may affect seizure freedom outcome. This may ultimately facilitate future patient selection for gene therapy versus surgery.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.4 SURGERY
Health categories: NEUROLOGICAL
Title: Interoception and functional seizures: a mechanistic and diagnostic approach
Funder: Medical Research Council

Abstract: Functional seizures (FS) are paroxysmal, alterations in motor, sensory, autonomic, and/or cognitive signs/symptoms. Superficially, they resemble epileptic seizures (ES), but they are not caused by epileptic brain activity. Of the 1% of the population diagnosed with epilepsy, up to 20% have FS, and they have elevated morbidity/mortality rates. Methods for differentiating FS/ES are limited by availability, sensitivity and specificity. Little scientific progress has been made in the neurobiology of FS, and they are thought of as psychological in nature. Interoception refers to the continuous communication between the viscera and brain. It is critical to homeostatic control, and explicitly/implicitly shapes emotion, cognition and behaviour. Based on our published work and pilot data we propose a novel model of FS. Central to the model are dynamic interoceptive changes, driven by changes in bodily attention or autonomic arousal; FS represent a dysfunctional form of inference of bodily interoceptive change. Based on this we propose two experiments with diagnostic and mechanistic implications. 1) We will acquire EEG during a cardiac interoceptive paradigm before/after a cold pressor stimulus (CPS), and derive a heartbeat-evoked potential (HEP). The HEP represents a measure of interoceptive accuracy and bodily attention. We hypothesise that changes in the HEP after a CPS will be greater in patients with FS compared to ES. 2) We will acquire EEG-fMRI data during a cardiac interoceptive paradigm before and after a CPS. We hypothesise that activation of interoceptive brain regions will be reduced, but the change in activation after a CPS will be greater, in patients with FS compared to healthy controls (HC). The change in fMRI activation will be mediated by a differing ratio of changes in the ratio of attentional mechanisms (as indexed by changes in beta and gamma EEG power) to peripheral arousal (as indexed by ECG heart rate variability changes).


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Metabolomic profiling of cerebrospinal fluid to improve diagnosis and treatment monitoring of patients with inborn or acquired errors of metabolism
Funder: Medical Research Council

Abstract: Our unit analyses around 1000 CSF samples each year. Our current CSF service results in a definitive diagnosis in about 5% of cases. Many of these disorders respond well to treatment (e.g. tyrosine hydroxylase deficiency, vitamin B6 responsive epilepsies, folate deficiencies, pterin defects) and early diagnosis makes a huge difference to families affected by these disorders. However, almost 50% of samples show metabolic abnormalities of unknown significance. If more CSF metabolites could be measured, the number of observed abnormalities is likely to be higher. Many of these patients with metabolic abnormalities could have a treatable but undiagnosed neurometabolic condition. With extra resources to support research, there is huge potential to identify and understand novel and known defects affecting brain and CSF metabolism. This will also help to inform treatment. The aim of this project is to use modern techniques to increase our diagnostic repertoire to help diagnose this group of currently undiagnosed patients. We propose to develop robust and precise, multi-analyte (metabolomics) mass spectrometry assays to investigate inborn and acquired disorders of dopamine, serotonin, vitamin and antioxidant metabolism. These assays will also measure metabolites related to immune activation (neopterin and kynurenine pathway metabolites). These assays will improve on the speed and depth of current HPLC assays and will be able to measure multiple metabolites in small sample volumes. These assays will initially be used for the diagnosis and treatment monitoring of children with neurometabolic conditions but will also be applicable to neurological disorders in adults such as Parkinson's disease (dopamine deficiency), Alzheimer's disease (abnormal 1-carbon metabolism), depression (serotonin dysfunction), motor neurone disease (antioxidant dysfunction) and multiple sclerosis (immune activation).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Precision Modelling of Cortical Variation and its Association with Neurological/Psychiatric disease
Funder: Medical Research Council

Abstract: The purpose of this grant is to develop urgently needed new technologies for image processing of brain scans to support precise comparisons of populations of brain scans and sensitive localisation of pathologies within individual scans. It is motivated by the fact that current methods for brain image analysis largely ignore considerable variation in brain shape and cortical organisation across individuals in order to deliver well-posed optimisations, which allow reliable but coarse scale comparisons of data across populations. Specifically, these compare brains through use of image registration algorithms which support smooth and invertible spatial mappings of all data into a global average space, where images may be directly compared. Alternative approaches, such as deep learning (which avoids this) require enormous data-sets, and return limited explainability (leaving ethical concerns over bias and generalisation). The key problem with image registration to a single, global template is that this typically ignores subtle sources of individual variation leading to (in some circumstances very) low powered studies of complex phenomena. This is because there is nothing inherent in these algorithms constraining atypical variants of brain architecture to be in correspondence. In this proposal, we therefore seek to develop new techniques for brain image registration which seek to learn all clinically or behaviourally relevant patterns of topographic variation, with the intent of matching these during alignment. In this way, images will be brought into much closer correspondence than possible before, allowing precision generative modelling of population variation for detection of cortical abnormalities in small populations. These frameworks will be used to test and validate development of novel explainable deep-learning frameworks.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Microglia in Early Dementia with Lewy Bodies
Funder: Medical Research Council

Abstract: Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia. The aim of this project is to understand the role of microglia in early DLB and determine if microglial toll-like receptors (TLRs) 2 and 4 are appropriate therapeutic targets in early disease. Objective 1: 18F-DPA714 PET 18F-DPA714 is a PET marker of the translocator protein (TSPO). TSPO is expressed on the cell surface of activated microglia, astrocytes and endothelial cells. Participants with mild cognitive impairment with Lewy bodies (MCI-LB) or mild DLB (n=50) and healthy controls (n=20) will have 18F-DPA714 PET-MR at baseline; this will be repeated at 24 months in the MCI-LB/mild DLB group. Clinical evaluation will take place at baseline, 12 months and 24 months. Blood and optional cerebrospinal fluid samples will be taken at baseline and 24 months. Specific 18F-DPA714 binding will be measured using a supervised cluster analysis. Mean cortical binding potential will be compared between MCI-LB/mild DLB and healthy controls. Change in binding over time and association with disease progression will be analysed in the MCI-LB/mild DLB group. Objective 2: Brain tissue Post-mortem brain tissue from people with MCI-LB/mild DLB (n=30) and controls (n=30) will be co-stained with fluorescent DPA714 and markers of microglia, astrocytes and endothelial cells to determine the cellular correlates of DPA714 binding. Microglial density and the expression of TLR2 and TLR4 in will be compared between MCI-LB/mild DLB and controls. The association between TLR2 and TLR4 expression and pro-inflammatory cytokines (IL1-beta, TNF-alpha and IL6), markers of autophagy (LC3B and p62) and alpha-synuclein will be examined using western blotting and RT-qPCR. This project will increase understanding of microglial activity in early DLB and could rapidly lead to early-stage clinical trials investigating the effect of TLR2 and TLR4 antagonists on microglia.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: MICA: Partnership for Assessment and Investigation of Neuropathic Pain: Studies Tracking Outcomes, Risks and Mechanisms (PAINSTORM).
Funder: Medical Research Council

Abstract: Neuropathic pain (NeuP) affects 8% of the population and prevalence is increasing due to the aging population, diabetes epidemic and enhanced cancer survival. It has a major negative impact on quality of life and current management options are inadequate due to poor efficacy and tolerability. PAINSTORM will bring together people living with NeuP, academics from diverse backgrounds, and industry in order to apply an inter-disciplinary approach to improve understanding and management of NeuP. Our focus will be prospective studies of people at risk of NeuP using established as well as new cohorts and harmonising outcomes with national scale community studies. We will identify the demographic, environmental/psychosocial and clinical factors which determine NeuP risk (both vulnerability and protective factors). We will validate and find novel genetic risk factors for NeuP. Tissue samples and patient-derived cells will be used to validate molecular pathways contributing to chronic NeuP and help develop blood biomarkers. We will optimise measures to assess NeuP in a person-centred manner, including sensory profiling, remote monitoring and assessment of psychosocial factors to understand the impact of pain on daily activities (from self-care to work) and important co-morbidities such as depression, anxiety and poor sleep. Functional brain and neural imaging as well as electrophysiology will be used to determine pathophysiological processes underlying NeuP. This multi-dimensional dataset will be integrated in order to understand the interaction between risk and protective factors, develop composite biomarkers, identify and prioritise novel treatment targets as well as improve the targeting of existing therapies. We will engage key stakeholder groups including health professionals, people living with NeuP and industry at the outset and throughout PAINSTORM. Our aim is that PAINSTORM will transform lives through our improved understanding and future management of NeuP.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: NEUROLOGICAL
Title: MICA ADVANTAGE visceral pain consortium: Advanced Discovery of Visceral Analgesics via Neuroimmune Targets and the Genetics of Extreme human phenotype
Funder: Medical Research Council

Abstract: The core purpose of the ADVANTAGE consortium is to enable better treatment for people with severe visceral pain. We will achieve this through three linked endeavours. 1) The establishment of a National Visceral Pain Resource (NVPR) of patients, by assembling expertly curated cohorts of individuals with severe visceral pain arising as a result of painful bladder syndrome, vaginal MESH surgery, endometriosis, inflammatory bowel disease (Crohn's & ulcerative colitis), autosomal dominant polycystic kidney disease or pancreatitis. We will also recruit individuals with lack of expected visceral pain. Each cohort will undergo extensive clinical, psychological and pain phenotyping (including app-based/wearable sensor technologies). 2) Analysis of our NVPR clinical and psychological data will allow sophisticated definitions and classifications of visceral pain types to identify drivers of severity and resilience to visceral pain. We will also probe for genomic and mitochondrial genomic variants and sex specific differences. 3) Our clinical research will be informed by mechanistic studies in mouse. Analysis of human serum samples in mouse models will allow us to test whether auto-antibodies contribute to visceral disease/pain states. Equally, we will define the molecular identity of sensory neurons innervating visceral organs allowing us to fine-tune our human results on gene or sex differences. Our translational and interdisciplinary approach, uniting patient experts, clinical and pre-clinical pain researchers, visceral disease experts, psychologists, engineers and industrial collaborators will allow us to maximise the development of novel study tools, drugs and treatments - specifically tailored for visceral pain. Our platform will be an open resource - designed to encourage data sharing, access to cohorts and links to other relevant clinical databases and platforms (see e.g. p. 2 and p. 12 of our Case for Support).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Consortium to Research Individual, Interpersonal, and Social influences in Pain (CRIISP)
Funder: Medical Research Council

Abstract: The challenge we address is identifying the most promising psychosocial mechanisms underpinning chronic pain, and making them accessible to biomedical research. Our vision is to deliver a transformational contribution to pain science and practice. Our aim is to deliver robust, diverse, and meaningful psychosocial content on the platform for rich phenotyping and behavioural classification. Our objectives are to define the psychosocial pathway(s) to development and maintenance of chronic pain; to identify multidimensional factors that maintain or exacerbate pain across the lifespan; and to identify modifiable psychosocial factors that can prevent or disrupt the pathway to chronic pain. Working together, people with chronic pain and world-leading behavioural scientists will repurpose existing datasets and run quantitative and qualitative studies to collect new data. Our interdisciplinary consortium, across 8 universities and a wider collaborator network, creates synergies across group disciplines, and is consolidated through work structures, membership, governance, and advisory groups. We have embedded people with pain in this consortium from its inception to ensure what matters most to those with pain is reflected in our goals, objectives and work plans. From our PPI Network we will establish work development groups for each research team, and a Consortium Public Advisory Group to oversee and guide. Through the consortium we seek to harness the UK's expertise in psychosocial and biomedical research. The scale of the consortium provides an unprecedented opportunity to draw together the psychosocial and the biomedical to make real progress towards improving the lives of those living with pain. Our primary contribution, and legacy, will be to identify and classify robust candidate psychosocial mechanisms, with guidance about best methods and measures, to inform novel targets for research, prevention, and treatment.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: NEUROLOGICAL
Title: Imaging macroscopic cortical dynamics to understand sensorimotor dysfunction and recovery in a mouse model of Rett Syndrome
Funder: Medical Research Council

Abstract: Rett syndrome is a severe X-linked neurological disorder caused by mutations in the Mecp2 gene and loss of the DNA binding protein MeCP2, leading to disrupted brain development and function. We have recently shown that loss-of-function mutations in Mecp2 affects neuronal excitability in individual cortical areas, but how loss of MeCP2 affects cortex-wide communication and cognitive function during sensorimotor learning remains unknown. Pilot data suggest that high-level brain functions such as visually guided reaching and decision-making are impacted early in development prior to the onset of core Rett-like phenotypes (i.e., loss of motor control, breathing abnormalities and epileptic seizures). We will combine a novel touchscreen-based two-alternative forced choice (2-AFC) reaching task for mice with widefield calcium imaging of the dorsal cortex to explore how loss of MeCP2 affects cortex-wide neural dynamics during learning in Mecp2-mutant mice. Female Mecp2 mice develop a delayed and variable phenotype due to X chromosome inactivation (XCI) and cellular mosaicism for MeCP2. To link cortex-wide MeCP2 expression with functional activity maps, we will use light-sheet imaging and automated 3D cell detection and registration in wild type and Mecp2+/- mice. In parallel, we will ask whether reexpression of MeCP2 can drive cortex-wide reorganisation of neural dynamics and recovery of high-level brain function and behaviour. We have shown through proof-of-concept experiments that MeCP2 reexpression recovers basic body and brain functions such as gross locomotion and respiration, but deficits in higher-order brain functions appear to persist. We will use an optimised method for systemic viral-mediated gene reactivation to drive MeCP2 expression in the brain and will assess the extent of cortex-wide reorganisation of neural dynamics and phenotypic rescue. The outcomes have the potential to influence the design of gene reintroduction strategies for treating Rett syndrome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL