NIHRDataInsights/HRCSData huggingface dataset:
Title: novel genetic and neuroimaging biomarkers in the primary tauopathies
Funder: Wellcome Trust

Abstract: Frontotemporal dementia (FTD) is a progressive and ultimately fatal disorder characterised by changes in behaviour, personality, language and occasonally movement, for which there is currently no cure. In the 45-65 year age range FTD has a similar prevalence to Alzheimer’s Disease. Pathological studies suggest that abnormal proteins accumulate in vulnerable brain regions, and then spread along anatomical connections . Tau protein, which is also important in Alzheimer’s disease pathogenesis, accounts for 40% of all cases of FTD. With potential therapeutic treatments targeting Tau on the horizon, there is an urgent need to develop biomarkers to correctly identify the underlying pathological protein in life, as well as well to monitor the effects of these treatments on disease progression. My PhD aims to identify genetic risk factors that make particular regions of the brain vulnerable to tau pathology, and study how the disease progresses over time in the different subtypes (Picks Disease, MAPT mutations, Progressive Supranuclear Palsy and Cortico-Basal Degeneration). Understanding the influence of genetics on the neuro-anatomical vulnerability of the brain to tau pathology may provide not only biological insight into the onset and progression of these disorders, but also biomarkers to better stratify patients in future disease modifying clinical trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Exploring the role of early-life vascular risk factors linking heart and brain health
Funder: Alzheimer's Research UK

Abstract: Heart disease and dementia represent two of the most common causes of disability and death in the world today. Although distinct conditions, growing evidence suggests that similar risk factors may underlie both diseases and that prevention strategies designed to protect the heart may also benefit the brain. Scientists and doctors have long known that the heart disease process starts very early in life, and that poor health choices from as young as childhood can result in early changes to the heart and blood vessels which increase the risk of a heart attack in later life. Growing evidence now suggests that the same may apply to dementia, with its occurrence in late-life possibly also occurring as the result of decades of damage sustained across the lifespan. How early this damage starts, however, and therefore at what age policies aimed at preventing it should be targeted, remains unclear. Using data from three large population studies covering childhood to old age, I aim to investigate whether factors which are known to cause damage to the heart and blood vessels in early life are also associated with early changes within the brain which may cause problems with thinking and memory skills later in life.

Lay abstract: Heart disease and dementia represent two of the most common causes of disability and death in the world today. Although distinct conditions, growing evidence suggests that similar risk factors may underlie both diseases and that prevention strategies designed to protect the heart may also benefit the brain. Scientists and doctors have long known that the heart disease process starts very early in life, and that poor health choices from as young as childhood can result in early changes to the heart and blood vessels which increase the risk of a heart attack in later life. Growing evidence now suggests that the same may apply to dementia, with its occurrence in late-life possibly also occurring as the result of decades of damage sustained across the lifespan. How early this damage starts, however, and therefore at what age policies aimed at preventing it should be targeted, remains unclear. Using data from three large population studies covering childhood to old age, I aim to investigate whether factors which are known to cause damage to the heart and blood vessels in early life are also associated with early changes within the brain which may cause problems with thinking and memory skills later in life.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: NEUROLOGICAL
Title: Targeting Amyloid-beta Toxic Oligomers in Alzheimer's Disease
Funder: Alzheimer's Research UK

Abstract: Small aggregates of the amyloid-β protein (Aβ), designated as oligomers, are emerging as potent neurotoxic species in the pathogenesis of Alzheimer’s disease (AD). The detailed characterisation of the structure and dynamics of Aβ oligomers is necessary to develop oligomer-specific therapeutic agents. However, Aβ oligomers exist transiently, which complicates their structural analysis. The goal of this proposal is to obtain a structural and mechanistic characterisation of a range of Aβ oligomers formed upon interaction with metabolites that are physiological in neurons. These Aβ oligomers are associated with different levels of cytotoxicity and the comparison of their molecular and structural properties will be crucial to reveal the underlying mechanism of the toxicity of Aβ aggregates. We will achieve this ambitious goal for AD research by using a cutting-edge structural approach, recently successful in revealing the mechanism of toxicity of α-synuclein oligomers in Parkinson’s disease (Fusco et al, Science 2017 358:1440-43). The results will be analysed to suggest structural targets for future developments of new strategies of molecular intervention to suppress the toxicity of Aβ oligomers, which will be tested in the final part of the project using neuronal cultures (primary cortical neurons and neuroblastoma cells) and Caenorhabditis elegans animal models of AD.

Lay abstract: Small aggregates of the amyloid-β protein (Aβ), designated as oligomers, are emerging as potent neurotoxic species in the pathogenesis of Alzheimer’s disease (AD). The detailed characterisation of the structure and dynamics of Aβ oligomers is necessary to develop oligomer-specific therapeutic agents. However, Aβ oligomers exist transiently, which complicates their structural analysis. The goal of this proposal is to obtain a structural and mechanistic characterisation of a range of Aβ oligomers formed upon interaction with metabolites that are physiological in neurons. These Aβ oligomers are associated with different levels of cytotoxicity and the comparison of their molecular and structural properties will be crucial to reveal the underlying mechanism of the toxicity of Aβ aggregates. We will achieve this ambitious goal for AD research by using a cutting-edge structural approach, recently successful in revealing the mechanism of toxicity of α-synuclein oligomers in Parkinson’s disease (Fusco et al, Science 2017 358:1440-43). The results will be analysed to suggest structural targets for future developments of new strategies of molecular intervention to suppress the toxicity of Aβ oligomers, which will be tested in the final part of the project using neuronal cultures (primary cortical neurons and neuroblastoma cells) and Caenorhabditis elegans animal models of AD.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Studying alterations in tau release during tauopathy development
Funder: Alzheimer's Research UK

Abstract: In Alzheimer’s disease and other tauopathies, aggregated tau forms inside neurons, and is extruded into the spaces between brain cells before being taken up by connected neurons where it can cause “normal” tau to aggregate. This is responsible for the progressive spread of tau pathology across Alzheimer’s brain. Tau is also released from neurons under physiological conditions, where it is thought to play important functional roles. Our preliminary data suggests that the pathways of tau release from healthy neurons differs from the release of tau aggregates in disease. If we can understand the routes involved, we may be able to specifically modify abnormal tau release without affecting tau function, and this is the purpose of our proposal. We will use brain slice cultures that mimic some aspects of Alzheimer’s brain to understand if tau release mechanisms change during disease development, how tau release relates to alterations in the connections between neurons (known as synapses), and how we can modify different pathways of tau release. We hope that this knowledge can be used in the future to inform the development of treatments aimed at stopping the spread of tau and progression of Alzheimer’s disease and related disorders.

Lay abstract: In Alzheimer’s disease and other tauopathies, aggregated tau forms inside neurons, and is extruded into the spaces between brain cells before being taken up by connected neurons where it can cause “normal” tau to aggregate. This is responsible for the progressive spread of tau pathology across Alzheimer’s brain. Tau is also released from neurons under physiological conditions, where it is thought to play important functional roles. Our preliminary data suggests that the pathways of tau release from healthy neurons differs from the release of tau aggregates in disease. If we can understand the routes involved, we may be able to specifically modify abnormal tau release without affecting tau function, and this is the purpose of our proposal. We will use brain slice cultures that mimic some aspects of Alzheimer’s brain to understand if tau release mechanisms change during disease development, how tau release relates to alterations in the connections between neurons (known as synapses), and how we can modify different pathways of tau release. We hope that this knowledge can be used in the future to inform the development of treatments aimed at stopping the spread of tau and progression of Alzheimer’s disease and related disorders.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mobile Sensing of Altered EveryDay Function in Early Alzheimer's Disease (MEDEA)
Funder: Wellcome Trust

Abstract: Wearable technologies such as smarlwatches and smartphones and are now widely used in the general population. The aim of this study is to develop a suite of wearables and mobile based apps for passive sensing of everyday behaviours in order to detect behavioural changes that occur in brain disorders such as Alzheimer's disease. This suite would have the potential to meet the global need for low cost scalable tests for early diagnosis and monitoring of disease progression, and additionally will expand phenotypic understanding of disease and deliver ecologically valid outcome measures for future treatment trials. This Award will allow us to complete development of apps for sensing sleep, navigation and social engagement through language use and to apply new modelling approaches to the sensed data to maximise diagnostic accuracy, comparing against existing disease measures. We will also explore privacy-enhancing methods such as use of on-device analytics to minimise leakage of personally-sensitive information.

Lay abstract: This project will develop and validate a suite of app-based tests for detecting the effect of early Alzheimer’s disease (AD) on everyday functions (sleep, navigation and spoken communication). This suite will transform clinical practice by i) basing diagnosis on ecologically valid, real life outcomes rather than clinic tests with limited real-world relevance and ii) delivering a low cost, scalable method for detecting early AD in the ageing population. The project will be divided into separate Work Packages (WPs). The WP1 objective will be to finalise test suite development and undertake feasibility studies in patients and controls. WP2 will focus on benchmarking of MEDEA for future clinical usage, in terms of operational (user acceptability, compliance and adherence) and diagnostic (classification accuracy, sensitivity and specificity, validation against AD biomarkers) properties. WP3 will focus on privacy, using on-device analytical approaches to maintain user privacy. Project success will additionally benefit AD research. It will deliver real life outcome measures determine the effect of interventions in clinical trials. Application of machine learning and computational statistics to the datasets produced by the test suite will aid disease modelling and uncover new phenotypic features, generating new testable hypotheses on associations between pathophysiology and real world outcomes.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Dissecting neural networks with optogenetic functional MRI (opto-fMRI)
Funder: Wellcome Trust

Abstract: We seek to establish a state-of-the-art laboratory for combined optogenetics and fMRI in rodent models of disease. The simultaneous combination of these techniques will enable us to dissect specific neural circuits (optogenetics), monitor their activity in vivo (electrophysiology) and map global patterns of brain activity that result from the selective control of specific neuronal populations (fMRI). We will also be able to visualise the central effects of drugs on a micro- and macroscopic scale for direct translation to clinical disorders of major socioeconomic impact, including autism, schizophrenia, dementia, stroke and spinal cord injury. In addition to being highly beneficial to local neuroscientists, this approach complements research initiatives at the Crick Institute, and the Wellcome Trust’s strategy entitled ‘Understanding the Brain’. The requested equipment will complement our existing portfolio of neuroimaging modalities already available within the recently established BRAIN (Biomarker Research and Imaging for Neuroscience) Centre for preclinical imaging at Denmark Hill campus (https://brain-imaging.org/), which has been created following the recent successful HEFCE-UK Research Partnership Investment Fund which contributed to the purchase of a high field 9.4T Bruker preclinical scanner, and will enable our translational, preclinical imaging at KCL to become internationally competitive in both psychiatry and neurology-related applications.

Lay abstract: How does our brain generate and control our emotions, cognition and behaviour? How do changes in brain activity result in psychiatric and neurological disorders? Recent technological advances in fields such as brain imaging and genetics have enabled us to begin answering these important questions. Development of functional magnetic resonance imaging (fMRI) has allowed us to visualise the active brain but with limited ability to manipulate its workings. On the other hand, emergence of optogenetics (a combination of optical and genetic methods) has enabled us to manipulate functions of specific brain cells but without knowing how this affects the rest of the brain. A combination of these two technologies, termed optogenetic fMRI (opto-fMRI), will allow us to determine connections between the inner workings of the brain and behaviour. With opto-fMRI we will gain unprecedented insights into brain circuits, their interactions and how their malfunction results in pathology.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of FUS phase transition in axonal mRNA localisation and translation
Funder: Wellcome Trust

Abstract: The neuropathological hallmark of the two closely related neurodegenerative diseases, ALS and FTD, is the presence of poorly soluble intracellular protein aggregates consisting of low-complexity domain-bearing RNA-binding proteins (RBPs). Intriguingly, these proteins are also key components of liquid-like ribonucleoproteins (RNPs) mediating diverse physiological processes, including transporting mRNAs to distal neurites to promote local protein synthesis (LPS). Interestingly, LPS in disease-affected neurons is often perturbed raising the possibility that the phase transition property of RBPs is critical for regulating the local supply of proteins that promote axon maintenance. Using the ALS/FTD-associated protein FUS as an example, I will investigate the effects of liquid-liquid phase separation and liquid-to-solid phase transition on axonal mRNA localisation, LPS and axon maintenance. Xenopus retinal neurons and mouse cortical neurons will be used as complementary models, in combination with optogenetic tools to achieve precise spatiotemporal control of localised FUS phase transition. A major goal is to understand the mechanisms by which aberrant intra-axonal phase transition of FUS leads to impaired LPS and axon degeneration. As effective treatments for ALS/FTD are currently unavailable, identifying differential mRNA interactors of physiological and pathological FUS and determining their translational status in axons may provide insights for clinical therapeutic options for ALS/FTD.

Lay abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases leading to behavioural and cognitive impairments. Many essential proteins are produced locally in axons (neuronal extensions), and in disease-affected axons, protein aggregation interferes with local protein synthesis and causes neuronal death. However, it remains unclear whether these aberrant aggregates are the direct cause of defective protein synthesis and axon death. I will investigate this question using a light-controlled tool to induce protein assemblies in one of the two forms, stable aggregates found in disease cells, or less stable granules present in normal cells. I will compare the differences in local protein synthesis and axon survival in neurons carrying different forms of protein assemblies. I also intend to identify novel disease-associated proteins, the synthesis of which is affected by the presence of aggregates. My findings will potentially provide new opportunities for the development of effective treatments, which is currently unavailable.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Making advanced characterisation of tissue microstructure clinically practical: a data-driven approach to efficient microstructural MRI
Funder: Wellcome Trust

Abstract: Diffusion MRI (dMRI) is the preferred tool for quantifying tissue microstructure, but current technology prohibits comprehensive assessment. Even in the extensively-studied brain white matter (WM), state-of-the-art measurements invalidate commonly-applied biophysical model constraints, and parameter estimates are unreliable. Moreover, models disregard myelin, a key WM-component typically considered ‘off-limits’ with dMRI. We have reached a hiatus in advancing tissue characterisation by dMRI alone, motivating multi-contrast MRI including myelin-sensitive contrasts. Simultaneously varying multiple experimental variables is now possible through ultra-strong gradients. However, as the dimensionality of the accessible MRI acquisition space increases, efficient data acquisition and representation become challenging, hampering the clinical translation of microstructural MRI. I will develop methods to optimise the execution and data representation of multi-contrast MRI experiments, with the goal of comprehensive tissue-characterisation in a clinically-applicable time. I will employ 1) a top-down approach that considers that the tissue properties most important to characterise are known, and assumes that analytical models exist that can be optimised to maximise precision per unit acquisition time; 2) a bottom-up approach that considers that the dimensionality of the analysis-space is unknown. Starting with rich multi-contrast data, I will develop data-driven approaches to characterise the measurement information-content and to select the most relevant measurements.

Lay abstract: MRI provides information on the structure of the microscopic building-blocks of living tissue. Combining different MRI techniques is crucial to achieve a comprehensive quantitative picture, but as the dimensionality of the MRI acquisition space increases, acquisition-times and analysis-complexity become prohibitive. I will design methods to collect the most relevant MRI measurements in the shortest possible time to make quantitative microstructural MRI clinically-viable. I will employ a ‘top-down and bottom-up’ strategy: The top-down approach considers that it is known which tissue parameters are relevant and how they relate to measured signals; the acquisition can then be optimised to maximise precision per unit acquisition time. The bottom-up approach considers that it is unknown how many and which features are relevant; this may differ from assumptions in mathematical models. Starting with rich multicontrast data, I will develop data-driven approaches to characterise the measurement information-content and use this to select the most relevant measurements.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Revealing microstructural pathology in Parkinson's disease with super-resolution MRI
Funder: Wellcome Trust

Abstract: Parkinson’s disease (PD) is diagnosed by a clinical examination which typically comes 20 years after the initial symptoms. By this time approximately 70% of vulnerable dopaminergic neurons in the substantia nigra (SN) have already been lost. The nigrosomes (small clusters of dopaminergic cells in the SN) have differential histopathological features which make them ideal targets for detecting and monitoring PD. MRI is highly sensitive to the pathological iron accumulation in the nigrosomes, which is a hallmark of the earliest stages of PD, but quantitative imaging on this sub-millimetre scale is beyond the limits of traditional techniques. I have developed a non-traditional approach to MRI, based on super-resolution approaches from optical microscopy, which can surpass these limitations and rapidly generate quantitative images of the nigrosomes in vivo. I will develop this as an accurate measure of iron accumulation in PD. The aims of this fellowship are: 1. Producing accurate microstructural maps at sub-millimetre resolution 2. Modelling and correcting for subject motion 3. Testing the hypothesis that microstructural MRI measures in the nigrosomes distinguish PD subjects from healthy controls If successful, this would enable PD diagnosis in its earliest stages, and maximise the likelihood of finding an effective therapy.

Lay abstract: Parkinson’s disease (PD) is the fastest growing of all neurological disorders, and its symptoms develop gradually. By the time of diagnosis, at least 20 years after the first symptoms, approximately 70% of vulnerable nerve cells in key brain regions are already lost. Many are clustered in tiny structures called nigrosomes, where iron accumulates in the earliest stages of PD. Magnetic resonance imaging (MRI) is highly sensitive to iron accumulation but the nigrosomes are too small to be reliably detected with traditional imaging techniques: even small head motions during a scan can render them invisible. I have developed a non-traditional approach to MRI which overcomes these fundamental technical barriers to reach ultra-high resolutions. This provides new opportunities to both visualise the nigrosomes and measure their iron content. I will develop this as an accurate measure of PD, creating a new path for early diagnosis and rapid clinical trials.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL