NIHRDataInsights/HRCSData huggingface dataset:
Title: The Cognitive Function and Ageing Study: a proposal for doctoral training focused on gender
Funder: Alzheimer's Research UK

Abstract: There is mixed and often conflicting evidence as to whether women are at an increased risk of dementia (specifically Alzheimer’s disease (AD)) beyond their greater life expectancy, and whether they are more likely to experience greater cognitive decline in old age. Factors throughout our lifetime can affect our risk of developing dementia: genes, education in early life, occupation, health and lifestyle in midlife, stress and mental health, and social engagement in later life. Many of these have differed greatly by gender over the last century, however research often implicates biological differences without taking such factors into account. There are also several potential sources of bias when addressing gender differences in dementia research which are often overlooked, including selection bias, measurement error and uncontrolled confounding. The main aims and objectives of this PhD research are to: 1. Explore potential sources of bias that may impact on studies of gender differences in dementia risk 2. Explore secular trends in cognition (verbal fluency) and changing patterns of risk factors over time (20-year comparison between CFAS I and II) and their potential role in dementia trends, and the potential for uncontrolled confounding when comparing dementia risk between genders. 3. Use the population-based neuropathology resource to test a prominent but unreplicated finding of differential gender susceptibility for dementia.

Lay abstract: There is mixed and often conflicting evidence as to whether women are at an increased risk of dementia (specifically Alzheimer’s disease (AD)) beyond their greater life expectancy, and whether they are more likely to experience greater cognitive decline in old age. Factors throughout our lifetime can affect our risk of developing dementia: genes, education in early life, occupation, health and lifestyle in midlife, stress and mental health, and social engagement in later life. Many of these have differed greatly by gender over the last century, however research often implicates biological differences without taking such factors into account. There are also several potential sources of bias when addressing gender differences in dementia research which are often overlooked, including selection bias, measurement error and uncontrolled confounding. The main aims and objectives of this PhD research are to: 1. Explore potential sources of bias that may impact on studies of gender differences in dementia risk 2. Explore secular trends in cognition (verbal fluency) and changing patterns of risk factors over time (20-year comparison between CFAS I and II) and their potential role in dementia trends, and the potential for uncontrolled confounding when comparing dementia risk between genders. 3. Use the population-based neuropathology resource to test a prominent but unreplicated finding of differential gender susceptibility for dementia.

Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: NEUROLOGICAL
Title: Using optogenetics to understand memory retrieval in APP overexpressed and in APP knock-in mice
Funder: Alzheimer's Research UK

Abstract: Unable to store, or unable to retrieve, that is the question. Contrary to the common thinking that dementia in Alzheimer’s disease (AD) reflects failure in storing memory, a recent study suggests that memory retrieval is impaired in early AD. The new evidence comes from cutting-edge optogenetics research that allows labelling and stimulating memory cells. Directly stimulating brain cells that are active during learning can lead to recovery of the lost memory in AD mice. However, we do not know if optically stimulated memory is functionally similar to natural memories. Hence, this project will address this question by asking if the stimulated memory in the hippocampus, an important area related to memory loss in AD, can enable meaningful association with subsequent experiences or guide future learning. Second, it will examine if stimulating learning-related brain cells can also recover memory in APP knock-in mice, a mild and more natural AD model. It will examine if pharmacological or behavioural stimulation during a memory test can lead to better memory retrieval. Finally, it will look at how multiple memories are represented in the hippocampus and whether this is affected in AD. These findings will provide understanding of stimulating memory retrieval for cognitive improvement.

Lay abstract: Unable to store, or unable to retrieve, that is the question. Contrary to the common thinking that dementia in Alzheimer’s disease (AD) reflects failure in storing memory, a recent study suggests that memory retrieval is impaired in early AD. The new evidence comes from cutting-edge optogenetics research that allows labelling and stimulating memory cells. Directly stimulating brain cells that are active during learning can lead to recovery of the lost memory in AD mice. However, we do not know if optically stimulated memory is functionally similar to natural memories. Hence, this project will address this question by asking if the stimulated memory in the hippocampus, an important area related to memory loss in AD, can enable meaningful association with subsequent experiences or guide future learning. Second, it will examine if stimulating learning-related brain cells can also recover memory in APP knock-in mice, a mild and more natural AD model. It will examine if pharmacological or behavioural stimulation during a memory test can lead to better memory retrieval. Finally, it will look at how multiple memories are represented in the hippocampus and whether this is affected in AD. These findings will provide understanding of stimulating memory retrieval for cognitive improvement.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The GDNF neurosurgical clinical trial: listening to, and learning from the participant experienceT
Funder: Parkinson's UK

Abstract: The aim of this study is to use a qualitative interview-based approach to explore the subjective experience of participants and their informal caregivers in novel neurosurgical interventional trials and to contextualise this against the experience of the clinical trial team. Objective questionnaire based data will be used alongside this to provide additional information on the participant and impact of the trial.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Investigating the structural signature of Dementia with Lewy Bodies within the human synapse
Funder: The Lewy Body Society

Abstract: A PET-MR study of occipital connectivity in DLB [SPICE] A no cost extension agreed 26/05/22 due to problems with scanner and staff absence.

Lay abstract: A PET-MR study of occipital connectivity in DLB [SPICE] A no cost extension agreed 26/05/22 due to problems with scanner and staff absence.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Investigating Neuron-Microglia Interactions in Alzheimer's Disease
Funder: Wellcome Trust

Abstract: Microglia, the resident immune cells of the brain, play an important role in synapse elimination within specific brain regions at early, pre-plaque stages of Alzheimer’s disease (AD). One such region impacted is the hippocampal formation, which is vital for the production of new memories, a process adversely affected early in AD pathology. Hyperactivity of hippocampal neurons has also been observed during early AD. We hypothesize that this hyperactivity could mobilize microglia toward synaptic elimination in a circuit-specific manner in response to ‘tagging’ of synapses with the AD-associated synaptotoxic protein species, amyloid-beta (A&beta;). In order to address this research question, we will first use immunohistochemistry to visualize synapse loss in AD mouse model hippocampal layers as well as synaptic engulfment by microglia via viral tracing of neurons. We will employ optogenetic techniques in wild type mice to activate specific hippocampal neurons and determine whether these overactive synapses alone are targeted for elimination by microglia. Finally, we aim to elucidate the exact mechanisms by which this microglial activation occurs using knockout genetic mouse models and pharmacological manipulation. These studies will further our understanding of the key role played by microglia during early AD and isolate new potential functions for the A&beta; peptide.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: mGluR1-TRPC3 signalling in dominantly inherited Spinocerebellar Ataxias
Funder: Wellcome Trust

Abstract: The dominantly inherited spinocerebellar ataxias (SCAs) are rare neurodegenerative disorders which primarily affect the cerebellum, the area of the brain responsible for motor coordination. Patients suffering from SCAs experience a progressive loss of coordination as the cerebellum degenerates. Key cerebellar cells known as Purkinje cells (PCs) are particularly affected, but not enough is known about the disease mechanisms and there is currently no cure. This project aims to investigate the role of two key proteins – TRPC3 and mGluR1 – in the molecular pathways underlying these disorders. mGluR1 is a cell-surface membrane protein which responds to the neurotransmitter glutamate at synapses and leads to activation of TRPC3, an ion channel which allows positively charged ions such as calcium into the cell. Mutations in both proteins have been identified in different subtypes of SCA; these mutations lead to increased protein activity and a subsequent toxic increase of intracellular calcium. Using computational techniques, in vitro studies, and a novel mGluR1 mutant mouse model, I will investigate the impact of mutant TRPC3 and mGluR1 on PCs, as well as the effects of novel TRPC3 inhibitors, to better understand the molecular mechanisms underlying SCAs and work towards new therapeutic approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Role of CASPR2 in Neuropathic Pain
Funder: Wellcome Trust

Abstract: Neuropathic pain is a wide-spread, chronic pain condition that affects 7-8% of the general population. It is usually caused by nerve damage or neurological conditions. Patients that suffer from neuropathic pain may feel pain from stimuli that are not normally painful. This can be due to changes in the pain-sensing neurons (nociceptors) in the peripheral nervous system that leads to neuronal hyperexcitability. Evidence suggests several neurological disorders linked to neuropathic pain may be caused by autoantibodies. These autoantibodies target proteins that are a part of the voltage-gated potassium channel complex (VGKCC), which is important in regulating neuronal excitability. Antibodies that target CASPR2 (Contactin-associated protein-like-2), a protein part of the VGKCC, have been shown to enhance pain behaviours when administered in mice. Abolishing CASPR2 expression in mice also led to changes in neuronal excitability and pain hypersensitivity, suggesting the importance of CASPR2 in regulating neuronal excitability. We aim to elucidate the role of CASPR2 in the induction of neuropathic pain using a combined approach of anatomical, electrophysiological, and behavioural methods. A better understanding of the induction and mechanism of neuropathic pain can aide in the development of targeted therapies necessary for efficacious treatment of neuropathic pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the role of microglia in perinatal brain injury and repair
Funder: Wellcome Trust

Abstract: Injury to the infant brain before, during, or after birth can lead to problems with movement, intellect, and sensation, as seen in cerebral palsy. This is due to damage to white matter, areas rich in a fatty substance called myelin that insulates nerves for their health/function. Current treatments are not suitable for all infants, are only moderately effective, and do not support white matter repair. Microglia are immune cells that control white matter repair in adult brain, yet their roles in supporting white matter formation and repair in the developing brain are not clear. I aim to understand how microglia regulate white matter formation and repair, to contribute to the development of therapies for infant brain injury. I will analyse myelin formation and repair following injury in a model where microglia are absent. As microglia are known to be composed of multiple subtypes, I will also assess how these subtypes change in white matter following experimental injury using single cell-sequencing, and examine these in injured human infant brain. Lastly, I will assess the roles of microglia subtypes by transplantation following injury. This project will identify microglia subtypes to target in order to drive white matter repair in injured infant brain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Molecular Mechanisms in PCDH19 Regulation of Cortical Neurogenesis
Funder: Wellcome Trust

Abstract: Genetic changes (mutations) in the gene Protocadherin-19 (PCDH19) - located on the X-chromosome - are associated with Epileptic Encephalopathy Early Infantile 9 (EIEE9), a rare genetic disease that causes early onset epilepsy and cognitive impairment in heterozygous females (females that carry a normal and a mutant copy of PCDH19). To date, little is known about how this phenomenon causes EIEE9, however the early onset of the disorder suggests a neurodevelopmental basis. Using genetically-altered mice, we have shown that Pcdh19 has a critical role in brain development by helping primordial brain cells called progenitors communicate with each other and transition into mature nerve cells, an event called neurogenesis. We also found that progenitors that express Pcdh19 and progenitors that do not express Pcdh19 produce significantly less and more nerve cells, respectively, but only in the developing brains of heterozygous female mice, which may be the underlying factor of EIEE9. To explore this further, we aim to discover the significant molecular pathways that Pcdh19 might be involved in to regulate neurogenesis using candidate and unbiased approaches. The results from this project will provide new insight into the roles of Pcdh19 during brain development and highlight potential targets for EIEE9 therapeutic intervention.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Modelling Dravet syndrome with human iPSC-derived neural circuits
Funder: Wellcome Trust

Abstract: Dravet syndrome is a form of epilepsy caused by mutations in the ion channel NaV1.1. These mutations affect the functionality of inhibitory interneurons in the cortical circuits, resulting in the abnormal hyperexcitation of pyramidal neurons and ultimately causing epileptic seizures. The quality and duration of life of affected individuals is severely compromised by the gravity of the epileptic symptoms and associated cognitive/behavioural disorders and, to date, standard treatments have poor efficacy. We aim to generate a novel human in vitro disease model for Dravet syndrome suitable for testing chemical and gene/cell-based therapies. We will use induced pluripotent stem cells derived from Dravet patients to generate excitatory and inhibitory neurons that will be combined in vitro to generate cortical neural circuits that phenotypically and functionally recapitulate the disease phenotype. Following characterisation and validation, we aim to use this in vitro model as a drug screening platform for the identification of novel treatments and as a potential model for cell therapy-based applications aimed at restoring the excitation/inhibition balance in compromised neural circuits. The establishment of a comprehensive in vitro model for Dravet syndrome would prove invaluable in furthering our understanding of the disease mechanisms and in the development of novel therapeutic approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mechanisms of cell fate plasticity in adult CNS progenitors
Funder: Wellcome Trust

Abstract: Myelin sheaths provide trophic support to the axons and are essential for rapid nerve impulse conduction, so maintaining their integrity is of utmost importance. In response to demyelinating injuries in the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) classically differentiate into oligodendrocytes, which make new myelin sheaths. However, lineage tracing studies have demonstrated that OPCs can also generate Schwann cells (SCs), the myelinating cell of the peripheral nervous system. This is surprising because the progenitors that produce SCs and OPCs separate very early during development, so SCs are considered phylogenetically distinct from OPCs. Therefore, I aim to investigate the transcriptomic mechanisms that underlie this unusual cell fate, and to characterise the functional consequences of SC versus oligodendrocyte myelination in the CNS. I will impose a SC identity onto OPCs using CRISPR/Cas9 gene editing to manipulate the activity of core transcription factors, Olig2 and Sox10, then I will use histological, behavioural and sequencing studies to evaluate the functional impact of Schwann cell myelination in vitro and in vivo. These findings will reveal insights into the mechanisms of OPC cell fate decisions and could represent a new therapeutic approach to promote remyelination.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Oligodendroglial Dysfunction in Huntington's Disease
Funder: Wellcome Trust

Abstract: Huntington’s disease (HD) is a genetic neurodegenerative disease causing long term disability and life-threatening complications. It is well known that the loss of particular types of nerve cells in the brain causes the main symptoms of HD, but there is evidence that a different type of brain cell, oligodendrocytes, are also involved. Recent evidence has shown that human oligodendrocytes are heterogeneous, suggesting that their functions vary and that these are altered in disease. In this project I will investigate whether oligodendrocyte states are different in HD. I will analyse and validate the heterogeneity of oligodendrocytes in post mortem brain tissue from HD patients, as well as in oligodendrocyte cultures generated from human stem cells. Furthermore, I will investigate whether certain dysfunctional oligodendrocyte states are shared across different diseases by comparing the heterogeneity of oligodendrocytes in HD and Multiple Sclerosis. Finally, I will investigate whether targeting the cause of HD, a mutation in the huntingtin gene, can change oligodendrocyte states to become more like healthy cells. Together these approaches will establish whether and how oligodendrocyte dysfunction is a pathological feature of HD and will provide insight into common oligodendrocyte states across disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the role of mitophagy regulators in neuronal cell and Drosophila models.
Funder: Wellcome Trust

Abstract: Mitochondria are the powerhouses of the cell and are crucial for neuronal function and survival. Disruption of mechanisms governing mitochondrial integrity lead to development and progression of different neurodegenerative disorders (NDs) such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). In fact, the accumulation of defective mitochondria in neurons is a hallmark of NDs. Mutations in genes linked to PD lead to a failure in pathways designed to rid the cell of low-quality mitochondria. Restoring this pathway offers an attractive therapeutic option. While this pathway is well characterised in cell models, less is known about this process in living organisms (in vivo). Our laboratory has engineered fruit flies (Drosophila) such that the mitochondria undergoing degradation can be directly visualised. I will develop this model system to characterise the influence of various genetic or pharmacological changes upon the mitochondrial degradation process in flies. I aim to shed light on the interplay between various genes linked to this pathway and discover new factors relevant to the process.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Time Series based dimension reduction methods on scRNA-seq data for Alzheimer's disease
Funder: Wellcome Trust

Abstract: 1 in every 14 of the elderly in the UK has Alzheimer’s disease (AD). Identifying early warning signs of AD can provide great clinical benefits. Recent research suggests there are different possible mechanisms leading to the disease and a long-standing hypothesis that the building up of beta-amyloid proteins is the cause of the disease is shown not to be totally true. The mechanism of AD varies between population and different stages of the disease. Rigorous statistical methods are required to study the heterogeneity of the disease. Existing theory on the pathology of AD suggests physiological cycle involving different types of cells in the brain, suggesting it is important to consider the differences of each cell in identifying candidate genes that are differentially expressed. The research will improve existing dimension reduction and clustering methods on single-cell RNA sequencing data. Time series analysis techniques will be considered so to identify changes of gene expression across different stages of the disease. The research will allow a better understanding of the progression of AD and in another similar neurodegenerative context. Potential therapeutic targets can then be identified with a better understanding of the disease mechanism.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Protein Interactomes of Alzheimer’s Disease Risk Genes in Microglia
Funder: Wellcome Trust

Abstract: Alzheimer's disease is a fatal condition with currently no cure. In our aging population, it is more important than ever to find ways to treat Alzheimer's, or even prevent it. Understanding the biology of Alzheimer's is a key step to understanding the disease and finding the best possible treatment and preventions. Previous research has found mutations in key genes, mostly expressed in microglia (the brain's immune cells) that increase a person's risk of developing Alzheimer's. Our work will focus on 3 of these genes (ABI3, TREM2, and PLCG2) and will look at how the proteins they code for interact with other proteins within cells. We will do this by mapping which proteins interact with our proteins of interest, both the normal and mutant versions, then compare these interactomes. We will then investigate the function of any new proteins found in these results and finally assess if these new proteins also contain mutations that carry a risk for Alzheimer's. This impact of this research will be to broaden our understanding of how these mutations increase the risk of Alzheimer's and may highlight potentially druggable targets to treat or reduce the risk of developing Alzheimer's.


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