NIHRDataInsights/HRCSData huggingface dataset:
Title: Contextual Modulation of Layer 6 Pyramidal Neurons in Visual Cortex
Funder: Wellcome Trust

Abstract: To successfully navigate through their environment, animals must constantly compare sensory information about the world around them with their own ideas about current location, heading direction and motion status. Precisely which areas of the mammalian brain contribute to this comparison process is unknown, but recent work has shown that information regarding head movements provided by the vestibular system is present in the earliest stage of visual processing in mouse neocortex, specifically, in a group of excitatory neurons residing in its deepest layer.I aim to understand the cellular basis of how vestibular signals, alongside other internally generated inputs, modulate the responses of these neurons to visual input, and how these neurons modulate the response profiles of other neurons in their cortical column.I will design and build a microscope capable of simultaneous volumetric three-photon calcium imaging and two-photon optogenetic stimulation in headfixed mice. I will also implement a modification to the conventional headpost setup which allows mice to make self-generated movements that can be reversibly coupled to visual and vestibular input.These experiments will contribute to our understanding of context-dependent processing in an understudied class of pyramidal neuron.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Karyoptotic Cell Death in Dementia
Funder: Alzheimer's Research UK

Abstract: In Alzheimer’s Disease (AD) nerve cells in the brain die in large numbers in particular in the late stages of the disease, after patients have been diagnosed with the disease. So far, scientists have been unable to understand all the mechanisms though which nerve cells die at this stage. We have recently studied a rare neurodegenerative disease (Dentatorubro-Pallidoluysian-Atrophy, in short DRPLA), a disorder of movement in which some patients also develop dementia. In DRPLA we have reported a new mechanism for nerve cell death. We have reasons to think that this is one of the most important mechanisms by which nerve cells die also in dementia, because of what other scientists have published and because of data we were able to collect in human brain samples of fronto temporal dementia (FTD), the second most common form of dementia. We now wish to understand better this mechanism for nerve cell death and identify possible regulators that may be targets for future treatments aiming at slowing down or blocking this cell death mechanism.

Lay abstract: In Alzheimer’s Disease (AD) nerve cells in the brain die in large numbers in particular in the late stages of the disease, after patients have been diagnosed with the disease. So far, scientists have been unable to understand all the mechanisms though which nerve cells die at this stage. We have recently studied a rare neurodegenerative disease (Dentatorubro-Pallidoluysian-Atrophy, in short DRPLA), a disorder of movement in which some patients also develop dementia. In DRPLA we have reported a new mechanism for nerve cell death. We have reasons to think that this is one of the most important mechanisms by which nerve cells die also in dementia, because of what other scientists have published and because of data we were able to collect in human brain samples of fronto temporal dementia (FTD), the second most common form of dementia. We now wish to understand better this mechanism for nerve cell death and identify possible regulators that may be targets for future treatments aiming at slowing down or blocking this cell death mechanism.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Weight-shift training to overcome freezing of gait in daily life
Funder: Parkinson's UK

Abstract: Freezing can be a common symptom of Parkinson’s. People describe it as feeling like their feet are ‘glued’ to the ground. In order to start walking someone’s balance needs to be adjusted in a specific way but this ‘weight-shift’ adjustment does not occur properly in people who freeze. The team at the University of Exeter have previously shown in a controlled lab environment that helping people to initiate weight shifting allowed them to overcome freezing and continue walking. This research project aims to build on these results to see if people can independently learn the weight-shifting strategy from an instructional video and apply it safely in daily life. If successful, this would provide a simple strategy to benefit people who experience freezing, with the potential to reduce the anxiety that comes with this symptom.


Research activity codes: 6.7 PHYSICAL
Health categories: NEUROLOGICAL
Title: Involvement of the glymphatic system in the propagation of pathological tau
Funder: Alzheimer's Research UK

Abstract: The glymphatic system is a recently discovered pathway thought to be responsible for removing waste products from the brain. Accumulation of one of these waste products, named ‘tau’, is very closely linked to brain cell death, brain shrinkage and, in turn, the development of dementia symptoms. In Alzheimer’s disease, tau accumulates on the inside of nerve cells and becomes extremely toxic towards its host cell. In doing so, tau is ejected from the neuron or released upon death of the cell. Recent discoveries suggest that once tau is released it is often absorbed into neighbouring cells, where this migrant tau acts as a foundation for the building up of additional tau. In this way there is spread and expansion throughout the brain and the rapid advance of dementia symptoms through the death of neurons. In this project I aim to discover if, by altering the function of the glymphatic system (which can clear away toxic tau), I can prevent the spread and accumulation of tau. In doing so, we may be able to thwart brain cell death and the onset of dementia. Potentially, this could provide a new pathway for dementia prevention and the opportunity to develop novel therapies.

Lay abstract: The glymphatic system is a recently discovered pathway thought to be responsible for removing waste products from the brain. Accumulation of one of these waste products, named ‘tau’, is very closely linked to brain cell death, brain shrinkage and, in turn, the development of dementia symptoms. In Alzheimer’s disease, tau accumulates on the inside of nerve cells and becomes extremely toxic towards its host cell. In doing so, tau is ejected from the neuron or released upon death of the cell. Recent discoveries suggest that once tau is released it is often absorbed into neighbouring cells, where this migrant tau acts as a foundation for the building up of additional tau. In this way there is spread and expansion throughout the brain and the rapid advance of dementia symptoms through the death of neurons. In this project I aim to discover if, by altering the function of the glymphatic system (which can clear away toxic tau), I can prevent the spread and accumulation of tau. In doing so, we may be able to thwart brain cell death and the onset of dementia. Potentially, this could provide a new pathway for dementia prevention and the opportunity to develop novel therapies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Prediction of Cognitive Decline Following PostOperative Delirium – Follow Up Of An Observational Cohort Study With Genetic, Cerebrospinal Fluid and Plasma Biomarkers
Funder: Alzheimer's Research UK

Abstract: This research is important because whilst we know that in general there is a relationship between delirium and subsequent memory problems we do not know what this means for individual patients. In this study we will test the idea that people who develop delirium after surgery are more likely to develop memory problems several years later and explore whether this relationship is solely because people who develop delirium have vulnerable brains or whether the delirium itself affects people’s brains in an additional way. We will invite people who were previously in a study of delirium after surgery to be involved in this follow-up research. We will ask people 1) if they have had any new health problems 2) to do a set of memory and concentration tests 3) to volunteer a family member, or someone who knows them well, to speak to the researcher about their memory 4) to provide a blood sample that we will analyse for a protein called neurofilament light. This research will help us advise the estimated 17% of people who develop delirium after planned orthopaedic surgery what to expect from their memory in the years after their delirium.

Lay abstract: This research is important because whilst we know that in general there is a relationship between delirium and subsequent memory problems we do not know what this means for individual patients. In this study we will test the idea that people who develop delirium after surgery are more likely to develop memory problems several years later and explore whether this relationship is solely because people who develop delirium have vulnerable brains or whether the delirium itself affects people’s brains in an additional way. We will invite people who were previously in a study of delirium after surgery to be involved in this follow-up research. We will ask people 1) if they have had any new health problems 2) to do a set of memory and concentration tests 3) to volunteer a family member, or someone who knows them well, to speak to the researcher about their memory 4) to provide a blood sample that we will analyse for a protein called neurofilament light. This research will help us advise the estimated 17% of people who develop delirium after planned orthopaedic surgery what to expect from their memory in the years after their delirium.

Research activity codes: 6.4 SURGERY;7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Diagnostic and prognostic biomarkers for dementia with Lewy bodies
Funder: Alzheimer's Research UK

Abstract: Dementia with Lewy bodies (DLB) is one of the most common dementias, but despite having the poorest prognosis, DLB is under-researched and there are few therapeutic options and no disease modifying treatments available. Recruiting sufficient number of patients is challenging, since DLB patients are referred to different specialities due to their complex clinical phenotype. We will develop a UK DLB research network among centres with expertise and experience in clinical and translational DLB research. A particular focus is to exploit the opportunities in studying cerebrospinal fluid (CSF), as we have successfully done in Scandinavia where we have lead the development of novel biomarkers for Alzheimer’s research. The lack of CSF research in the UK has hampered dementia research. The network will recruit patients to a multicentre longitudinal cohort study. The scientific focus will be the development of novel diagnostic and prognostic biomarkers, as well as increased mechanistic understanding of the disease, with a particular focus on synaptic pathology. An important aim is to use this cohort as a registry for clinical trials, since companies are showing an increased interest in developing new drugs for DLB. The biomarker research will be focused on blood, CSF, EEG, and structural and functional imaging.

Lay abstract: Dementia with Lewy bodies (DLB) is one of the most common dementias, but despite having the poorest prognosis, DLB is under-researched and there are few therapeutic options and no disease modifying treatments available. Recruiting sufficient number of patients is challenging, since DLB patients are referred to different specialities due to their complex clinical phenotype. We will develop a UK DLB research network among centres with expertise and experience in clinical and translational DLB research. A particular focus is to exploit the opportunities in studying cerebrospinal fluid (CSF), as we have successfully done in Scandinavia where we have lead the development of novel biomarkers for Alzheimer’s research. The lack of CSF research in the UK has hampered dementia research. The network will recruit patients to a multicentre longitudinal cohort study. The scientific focus will be the development of novel diagnostic and prognostic biomarkers, as well as increased mechanistic understanding of the disease, with a particular focus on synaptic pathology. An important aim is to use this cohort as a registry for clinical trials, since companies are showing an increased interest in developing new drugs for DLB. The biomarker research will be focused on blood, CSF, EEG, and structural and functional imaging.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: The role of the Wallerian axon-death pathway in neuronal and axonal vulnerability in Parkinson's disease
Funder: Wellcome Trust

Abstract: Parkinson’s disease (PD) involves preferential loss of substantia nigra pars compacta (SNc) dopaminergic neurons and their projecting axons to the striatum. SNc neurons have huge, highly branched and vulnerable axons, whose distal ends are lost first in PD, so preventing this will be essential for any disease modifying therapy. Our preliminary data suggest the involvement of an axon-death pathway in PD shared with the loss of injured axons (Wallerian degeneration). The Wallerian pathway is initiated by loss of the activity of the essential NAD-biosynthetic enzyme NMNAT2 in axons. Crucially, axons expressing lower levels of NMNAT2 are more vulnerable, raising the possibility that SNc neuron and axon susceptibility in PD reflects a particular sensitivity to Wallerian pathway activation. To test this hypothesis, I will use cutting-edge research strategies from three leading laboratories in axon degeneration and Parkinson’s disease, combining expertise in mouse primary neuronal cultures, human iPSC-derived dopaminergic neurons and mouse and zebrafish in vivo models of PD. The proposed research will greatly advance our understanding of mechanisms of SNc neuron and axon death in PD. In the longer term, this work has significant clinical implications since axons are lost early in PD and the Wallerian pathway can be potently blocked.

Lay abstract: The reasons why a specific type of nerve cells, called dopaminergic neurons, is particularly vulnerable in Parkinson’s disease (PD) is unknown. Understanding this is essential to develop effective therapies. Dopaminergic neurons develop huge projections, called axons, which die early in PD. I aim to identify new molecular players that contributes to the vulnerability of dopaminergic neurons and axons in PD. I will tackle these research questions from different angles. I will perform mechanistic studies in dopaminergic neurons derived from humans and use models of PD in fish. I will specifically test the role of a preventable axon-death programme, Wallerian degeneration, since this offers a way to alleviate PD. These studies could greatly advance our understanding of mechanisms of nerve cells death in PD. The project also has important clinical implications since the Wallerian pathway can be potently blocked. Finally, our studies are likely to be relevant to other neurodegenerative conditions.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Dissecting the methylome across FTD pathological subtypes – another path for treatment?
Funder: Alzheimer's Research UK

Abstract: Frontotemporal lobar degeneration (FTLD) is highly incapacitating and incurable, involving behavioural, memory, language and mobility difficulties. Microscopic brain examination shows several FTLD forms. This fellowship project focuses on the commonest subgroup (FTLD-TDP), in which a sticky protein TDP-43, clumps together in nerve cells causing them to die. DNA provides the code for cells to make proteins. A chemical alteration to DNA, called methylation, can change the amount of protein produced and therefore alter how a cell functions. Amounts of DNA methylation can be influenced by environment and lifestyle. I, and others, have shown that this is important in neurodegeneration, including in dementias, but this chemical alteration has not been studied in FTLD-TDP. I will investigate DNA methylation changes specific to FTLD-TDP and those shared with other diseases, including Alzheimer’s disease. This is a new approach in FTLD-TDP research, and will provide new insights into what goes wrong in FTLD brain cells. Findings of this project will help to improve diagnosis, develop new treatment (DNA methylation may be reversible), and develop biomarkers to monitor disease progression in life and response to treatments in drug trials. To promote future research, the data will be made publically available for other researchers to use.

Lay abstract: Frontotemporal lobar degeneration (FTLD) is highly incapacitating and incurable, involving behavioural, memory, language and mobility difficulties. Microscopic brain examination shows several FTLD forms. This fellowship project focuses on the commonest subgroup (FTLD-TDP), in which a sticky protein TDP-43, clumps together in nerve cells causing them to die. DNA provides the code for cells to make proteins. A chemical alteration to DNA, called methylation, can change the amount of protein produced and therefore alter how a cell functions. Amounts of DNA methylation can be influenced by environment and lifestyle. I, and others, have shown that this is important in neurodegeneration, including in dementias, but this chemical alteration has not been studied in FTLD-TDP. I will investigate DNA methylation changes specific to FTLD-TDP and those shared with other diseases, including Alzheimer’s disease. This is a new approach in FTLD-TDP research, and will provide new insights into what goes wrong in FTLD brain cells. Findings of this project will help to improve diagnosis, develop new treatment (DNA methylation may be reversible), and develop biomarkers to monitor disease progression in life and response to treatments in drug trials. To promote future research, the data will be made publically available for other researchers to use.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: How do dysfunctional endothelial cells in cerebral small vessel disease modulate surrounding oligodendroglia through secretion of heat shock protein 90 alpha?
Funder: Wellcome Trust

Abstract: Dementia is becoming an increasingly important disease, affecting vast numbers of people. Disease of the small blood vessels in the brain is the second most common cause of dementia, and is called cerebral small vessel disease. The endothelial cells which line the blood vessels start the disease process and then affect the surrounding brain cells causing the problems we seen in patients with dementia. I will study how endothelial cells cause disruption to the surrounding brain cells and whether it can be reversed, leading the way to potential treatments for small vessel disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: An investigation of white matter fibre tract topology, connectivity and microstructure to uncover the ictogenic network in focal epilepsy
Funder: Wellcome Trust

Abstract: Epilepsy is the most common serious neurological disorder and one-third of those affected continue to experience disabling seizures despite taking regular medications. It is thought that there are abnormal cortical areas in the brain that, together with the white matter connections that join them, form pathological circuits responsible for seizures. These circuits vary between subjects in their properties, location and spread. Modern medical imaging and other investigations do not fully detect the abnormal circuits, leaving the majority of patients unsuitable for surgery or vastly reducing their chances of seizure freedom post-operatively. Using state-of-the-art imaging hardware and methodology I will obtain high quality brain scans of 20 patients with epilepsy. I will look at the multiple qualities that can tell us about the state of the brain connections, producing very detailed maps of abnormalities. I will then test contribution of these abnormalities by mathematically simulating seizures and comparing my simulations with the real seizure activity we record from the same patients. This will help us describe the circuits or give us information about how these circuits work. My approach will allow us better understand the exact mechanisms that drive epilepsy and may help develop better treatments for these patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Optogenetics to model activity-dependent neurodegeneration in amyotrophic lateral sclerosis
Funder: Wellcome Trust

Abstract: Amyotrophic lateral sclerosis (ALS) causes motor neurons, nerve cells which control voluntary movement, to die. The cause is not fully understood but likely involves an interplay between errors in our genetic code (mutations) and the environment. With stem cell technology, patient skin cells can be transformed into motor neurons in the laboratory. Our group has used this technique to identify important disease-related changes. However, in the body, motor neurons are highly electrically active and undergo repetitive 'firing' to activate muscles. Therefore, a complete understanding of motor neuron vulnerability in ALS requires a model in which the activity of these cells can be controlled. In this project I will generate motor neurons from patients with disease-causing mutations, and insert a genetically-engineered light-sensitive 'switch' to control activity using light. I will light-stimulate them, both in isolation and with muscle cells. We hypothesise that stimulation will mature the cells, making them more representative of motor neurons in ALS, which start dying in later life. We also hypothesize that stimulation will drive disease-relevant changes. This impact of this work will be a contribution to our understanding of the causes of ALS, and a novel model of disease for further study and testing possible treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Discovering the Genetic Basis of Epilepsies through Computational Analysis of Clinical Phenotype
Funder: Wellcome Trust

Abstract: Background Epilepsy affects 1% of people and empirical treatment benefits only a third. Seizures and their treatments have serious health and socioeconomic consequences. Over a third of epilepsy is thought to arise from variation in the person’s genetic code. However, currently we can only rarely identify what this is, a necessary step towards using it to improve treatment. Studying people grouped by the symptoms of their epilepsy has successfully defined, and discovered the genetic causes of distinctive but rare epilepsies such as Dravet Syndrome, facilitating research that has improved their treatment. Approach The yield of large genetic studies of epilepsy is currently limited by the challenges of combining and interpreting vast quantities of complex information about participants' epilepsy symptoms. We will develop computational methods to make information about the symptoms of participants in Epi25 (the largest ever epilepsy study) more tractable. We will use these to identify new patterns of symptoms and their associated genetic causes. Expected Impact Identifying new genetic causes of epilepsy could help to us to personalise the selection of existing treatments more successfully within a few years, and to design new, precise treatments based upon newly discovered mechanisms. Our methods may be applicable to other diseases.


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