NIHRDataInsights/HRCSData huggingface dataset:
Title: Searching for MS-specific biomarkers
Funder: Multiple Sclerosis Society

Abstract: What is the project about? _x000D_ In this study researchers will search for new biological indicators, or â€˜biomarkersâ€™ of MS that could be used in the diagnosis or monitoring of the condition. Identifying reliable and useful biomarkers of MS has so far proven to be very difficult due to the complexities of the condition, but this study could open the door to finding novel biomarkers. The researchers will compare the cerebrospinal fluid (CSF) of people with MS and people who do not have MS, looking for any differences in the samples. They will particularly focus on differences between specialised structures known as extracellular vesicles. These structures could provide clues about the environment inside cells of the central nervous system, and therefore could be a source of MS-specific biomarkers. _x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ MS is a complex and varied condition that isnâ€™t easy to diagnose. If MS-specific biomarkers are identified in this project, they could be investigated further for use in MS diagnosis, as well as in the monitoring of MS progression, or even in monitoring someoneâ€™s response to treatment. The novel methods tested in this study could also inform the work of other research groups trying to identify new biomarkers or potential targets for treatment.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the importance of Natural Killer cells in MS
Funder: Multiple Sclerosis Society

Abstract: What is the project about?_x000D_ _x000D_ The immune attack on myelin in MS was previously thought to be caused by only one class of immune cells. However, there is growing evidence that a wider range of immune cells including a class called Natural Killer cells could also be involved. Researchers will investigate whether Natural Killer cell levels are different between people with or without MS. They will also look at different groups of NK cells, how they differ and how they interact with proteins and other cells in the body. They will also look further into previous findings that the levels of Natural Killer cells are reduced in people who are taking Tysabri. _x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ Understanding the immune system and its role in MS is a key part of planning future treatment strategies for people living with the condition. Understanding the full picture of how these cells relate to MS could help to manage and treat MS more effectively.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Does blocking the NKCC1 transporter help to prevent nerve cell death?
Funder: Multiple Sclerosis Society

Abstract: What is the project about? The death of nerve cells is a key element of the build up of disability in progressive MS. Researchers believe that this is partly caused by too many sodium ions getting into the nerve cells, causing them damage. A number of research studies have attempted to prevent this by blocking specialised transporters present on nerve cells, but this also stops the nerve cell properly functioning. This project aims to address this issue by specifically targeting a transporter called NKCC1. Blocking this could prevent too many sodium ions entering the cell while still allowing the nerve cell to work normally. This team have identified a drug that can block the NKCC1 transporter, and is currently approved for human use in treating heart failure. By using specialised animal models of MS they will investigate if this drug can help to prevent nerve cell death. _x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ This project could be the first step in repurposing an approved drug as a possible neuroprotective therapy for progressive MS. If successful this project could lead to further animal studies and also human trials of this drug in progressive forms of MS.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Could an immune-tolerance strategy prevent damage to nerve cells?
Funder: Multiple Sclerosis Society

Abstract: What is the project about?_x000D_ _x000D_ MS is thought to be an autoimmune condition, and all of the DMTs currently available to treat relapsing remitting MS work by targeting the immune system. Whilst these drugs can be effective, they can have side effects as they also remove immune cells that are needed in the body. The aim of this study is to develop a way to target only the disease causing cells in MS while leaving the rest of the immune system to function normally. Using an animal model of MS, the researchers will temporarily reduce white blood cell levels and then introduce myelin proteins to attempt to â€œre-programmeâ€ the immune system so that the causes damage to myelin is stopped. _x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ If the treatment strategy developed by the group is able to prevent relapses and slow nerve cell damage in an animal model of MS, this treatment could be taken forward to clinical trials in people with MS. This type of â€˜immune toleranceâ€™ strategy has the potential to stop relapses, and also to slow progression.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: The role of mitochondria in progressive MS
Funder: Multiple Sclerosis Society

Abstract: What is the project about? Cells require energy to carry out their specific roles in the body. This energy is generated by specialised structures inside cells called mitochondria. There is some evidence to suggest that these mitochondria are damaged in the nerve cells of people with MS. Researchers believe that this may contribute to the loss of nerve cells that occurs in MS, and there is currently no way to regenerate or replace these nerve fibres. This project will use donated samples of brain and spinal cord tissue from the UK MS Society Tissue Bank and the Cleveland clinic in Ohio to find out more about how the mitochondria in nerve cells become damaged, comparing people with relapsing-remitting, primary and secondary progressive MS and people without MS. The researchers will try to determine if the amount of mitochondria damage is related to the amount of demyelination or the level of nerve cell death._x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ There is currently little understanding about the role of mitochondria in MS. This study could not only help to identify what part mitochondria have to play, but could also determine whether they could be used as possible markers to of MS progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating how FoxO3a functions in remyelination
Funder: Multiple Sclerosis Society

Abstract: What is the project about? _x000D_ In MS damage to the myelin sheath leaves nerve cells exposed and vulnerable to injury. This leads to the gradual accumulation of MS symptoms over time. The cells that produce myelin are known as oligodendrocytes, and should be produced in the brain and spinal cord to help repair any damage that occurs. However, in MS far fewer oligodendrocytes are produced, meaning that myelin repair cannot occur. Progress has been made in understanding how oligodendrocytes are produced, and one key protein called FoxO3a appears to prevent this production. Researchers have found that by blocking FoxO3a activity they can promote oligodendrocyte and myelin production. This project will further investigate what FoxO3a does during the process of remyelination, and how this function might be modulated to promote myelin production._x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ Better understanding of the role of FoxO3a in oligodendrocyte production could identify key processes involved in remyelination. Promoting remyelination could help repair myelin damage, stopping MS from getting worse. This study could help to identify targets that could be used for new remyelination therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: SWIMS: A long-term study of MS from the patient perspective
Funder: Multiple Sclerosis Society

Abstract: What is the project about? This long-term project based in Devon and Cornwall involved more than 1,200 people living with MS._x000D_ _x000D_ Participants are asked to complete regular surveys for up to 10 years. The surveys are aimed at understanding how MS impacts on the lives of people living with it._x000D_ _x000D_ At the end of the project the results from the surveys will be collated to develop a long-term picture of how MS affects people._x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ This project aims to:_x000D_ _x000D_ - promote better understanding of the impact of MS from the perspective of those living with it _x000D_ - develop ways of measuring the impact of MS in order to support clinical trials _x000D_ - develop tools that may predict the future impact of MS on individuals


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: The role of FUS in ALS - New models and human neuropathology
Funder: Motor Neurone Disease Association

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related diseases without any effective treatment. The most common form of ALS/FTD is characterized by pathology of a molecule called TDP-43. Another common form is linked to a molecule called FUS. In both instances, faults in these molecules can trigger the disease. The functions of TDP-43 and FUS are similar, and they probably interact with each other. These are crucial recent discoveries which suggest that the most widely used model for ALS, the SOD1 mouse, is not directly relevant for common forms of ALS/FTD. Faults in the SOD1 gene can cause ALS, but they never cause FTD, and the pathology is very different from common ALS/FTD. Improved models are urgently needed, and any model should be validated in human tissue. We have recently identified an aggressive form of human ALS with a faulty FUS gene and FUS pathology. To date, there is no model for this form of ALS. In this project, we will make a mouse model of FUS disease based on our own genetic and pathologic observations in humans. This model will be made with a technique that replicates as faithfully as possible the regulation of FUS in humans. It is the same approach we are currently using in an MNDA-funded study of TDP-43. We will therefore be able to directly compare the role and interaction of these two key ALS/FTD molecules. This would not be possible if totally different modelling approaches were used. We have further improved this technique which will now allow us to switch the faulty FUS gene off. This is very important, because it will give us an opportunity to test the reversibility of the disease process, even after symptoms have started. This complementary approach will significantly increase the scientific value of each model. We will study the tissue of the models in parallel with that of human TDP-43 and FUS ALS/FTD from the Oxford Brain Bank. This validation step will allow us to focus on those aspects of the models that are relevant for human disease. Together with our clinical and biomarker studies, this will complete a very powerful research set-up in Oxford. A multidisciplinary scientific approach is our best chance of finding new treatments for ALS/FTD, and also provides an excellent environment for training of young scientists in ALS research. At least two DPhil students (one of them MNDA-funded) will immediately benefit from the research proposed in this application.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Genetics of Late-onset Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: This project will maintain, expand and utilise one of the worldâ€™s largest Alzheimerâ€™s disease (AD) DNA collections including samples from both patients and controls. Our collaborating scientists from England (Nottingham, Birmingham, Bristol, Manchester, Oxford, Southampton), Wales (Cardiff) and Northern Ireland (Belfast) will use the DNA source to identify and validate the genetic variations that contribute to the development of late-onset AD. Once identified, ART will launch a public dissemination campaign (print, electronic, media and public talks) to inform Alzheimerâ€™s patients, their families and carers of how genetics affects AD and how this information can be utilised for prevention, treatment and a future cure.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Imaging amyloid and neuroinflammation in subjects "at risk" for Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: There are a number of known risk factors for Alzheimer’s disease (AD). These include the presence of subjective memory impairment (SMI) without cognitive deficit (subjects with self reported memory complaints with objectively normal cognition on detailed memory testing), a positive family history of AD, ApoE4 carriage, a past history of head trauma or stroke, and insulin resistance eg type 2 diabetes. With positron emission tomography (PET) we have demonstrated that AD subjects have significantly increased amyloid deposition and brain inflammation (microglial activity). In our study memory tests correlated with brain inflammation, but not with the amyloid load. Brain inflammation has been proposed to be the link between amyloid deposition, damage to the neurons and the formation of “tangles”. It has been shown that inflammation takes place with the deposition of amyloid in animals but the relative timings have not been studied in humans. We believe that brain inflammation is an early feature in the development of Alzheimer’s disease and will be present in the above at-risk groups. We think that inflammatory proteins called “cytokines” and “chemokines” play a significant role in progressive worsening of memory in these subjects. We plan to research this by performing special PET scans. [11C]PK11195 and [11C]PBR28 are PET markers of brain inflammation while [11C]PIB PET reveals the amyloid load. We will perform a head to head study comparing the efficacy of [11C]PK11195 and [11C]PBR28 PET as inflammatory markers. Depending on the results of this study we will choose either [11C]PK11195 or [11C]PBR28 PET for this study.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Increasing diagnostic specificity in the degenerative dementias: A multi-centre MRI study of post-mortem proven cases
Funder: Alzheimer's Research UK

Abstract: Distinguishing different forms of dementia will become ever more important as specific therapies become available. Brain scanning, using magnetic resonance imaging (MRI), is increasingly being used to help make an accurate diagnosis during life. However few studies have assessed if MRI can accurately predict diagnosis confirmed post mortem. We have identified 230 patients with a range of different dementias who have had MRI during life, have subsequently died and donated their brains for research at three UK university hospitals and the VU Medical Centre, Amsterdam. This sample is a unique resource to determine how best MRI can be used in the diagnostic process. Using the expertise made available through this collaboration, we will assess the relative diagnostic accuracy of (1) simple scan inspection by neurologists and radiologists; (2) using visual scoring systems and algorithms, which can easily be implemented in a clinical setting; (3) incorporating a range of automated computer-based image analysis programs, including: (a) those designed to automatically measure specific brain regions; and (b) techniques designed to allow computer-based "pattern recognition". Once the analysis is complete, we aim to produce definitive guidelines to suggest how MRI scans can best be used to aid the diagnosis of dementia during life.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL
Title: Axon-glial disruption: the link between vascular disease and Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: The brain requires a good supply of blood delivered through a network of blood vessels (cerebrovascular system) to function properly and to maintain good cognitive abilities. Cerebrovascular dysfunction is a major feature of AD and is suggested to contribute to the cognitive decline and degenerative processes but the mechanisms underlying this remain unclear. Previously, we have demonstrated that modest reductions in blood flow results in selective damage to components of the brains ‘wiring' or white matter (critical for communication between brain cells and regions) and that these changes cause memory impairment. We also have evidence that there are changes in the brains white matter in human AD and in models of AD. Furthermore, we have shown that reductions in blood flow precipitate amyloid pathology. This proposal will determine whether specific components of the wiring are disrupted in AD and how local changes in blood flow and amyloid levels contribute to these changes. This project would not only further our understanding of the mechanisms underlying AD and vascular disease but provide a basis on which to develop alternative therapeutic strategies in AD aimed at improving cerebrovascular function and slowing the rate of cognitive decline.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Impairment of Insulin Signalling Pathways in Astrocytes in Brain Ageing and the Progression of Alzheimer-Type Pathology
Funder: Alzheimer's Research UK

Abstract: Whilst damage to nerve cells is a central feature in Alzheimer's, other cell-types are also important in normal brain function and are affected in ageing and dementia. Astrocytes are star-shaped cells that provide support to nerve cells, maintain the contacts between nerve cells, the synapses, and have a role in transmission of nerve impulses. Our studies have shown that astrocytes are damaged in brain ageing at early stages of Alzheimer's. This may affect their ability to support nerve cells and so play a role in declining brain function. Using methods that allow us to examine changes in the genes that are expressed in these cells, we have recently found that key components of the insulin-signalling pathway, which plays a key role in regulating activities in the cell, show reduced levels in astrocytes as AD progresses. In this project, we aim to find out how reduced insulin-signalling pathway activity affects the astrocytes, their ability to respond to the kinds of cell injury that develop in AD, and their ability to support nerve cells. This is potentially important because altering astrocyte functions, e.g., to enhance their supportive and protective functions, is a potential therapeutic approach for AD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Evaluating the relationship between ischaemia and neurodegeneration in post-mortem brain tissue
Funder: Alzheimer's Research UK

Abstract: Dementia is probably the largest healthcare challenge faced by society. Disorders such as high blood pressure and strokes that reduce blood flow to the brain substantially increase the risk of dementia, partly because they cause direct brain damage but also due to exacerbation of the abnormal changes in the brain that cause Alzheimer's disease and possibly other dementias as well. In addition, Alzheimer’s itself causes stroke-like brain damage. Little is known about the ways in which reduced blood flow to the brain contributes to Alzheimer's, or Alzheimer's contributes to stroke-like brain damage. A major obstacle to elucidating these relationships has been the post-mortem detection of evidence of reduced blood flow in human brain tissue. We propose to conduct studies to establish reliable ways to measure the effects of reduced blood flow and to establish the extent and mechanisms of contribution of reduced blood flow to Alzheimer's and other diseases that cause dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of reactive astrocytes in Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: There is growing evidence to suggest that the toxicity of the Aβ peptide found in the brains of patients with Alzheimer’s disease (AD) could be mediated through the triggering of inflammation in the brain. The presence of Aβ in the plaques stimulates the surrounding support cells, the astrocytes and microglia. The activation of these glial cells is initially a protective reaction, because they are able to clear away the Aβ and protect the neurons from further damage, but if the cells remain activated it seems that the inflammatory and toxic chemicals that they release can initiate a cascade of events which could result in further production of Aβ. The purpose of this project is to better understand the role of astrocytes by using a novel mouse model in which reactive astrocytes can be removed by the injection of a specific drug. We plan to cross these mice with a transgenic model of AD and in the offspring investigate how the absence of astrocytes affects the progression of the disease. Our preliminary data indicate that the animals without reactive astrocytes present higher levels of Aβ, therefore accelerating the course of the disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Tau-related cell death and neuroprotection by astrocytes
Funder: Alzheimer's Research UK

Abstract: Intracellular tau protein aggregates constitute one of the major neuropathological features of Alzheimer’s disease (AD) and other tauopathies. The identification of mutations in the Tau gene in familial cases of frontotemporal dementia has led to the production of transgenic mice that show tau aggregates similar to those present in brains from patients with the disease. We have produced transgenic mice that show abundant tau aggregates in both brain and spinal cord. In the brain of these transgenic mice we have identified neurones that form ring-like tau aggregates and then die. In order to see whether stem cell implantation could have an effect on tau-related neuronal death, we transplanted stem cells in the brain of these mice and found that transplantation of these cells prevented death of neurones containing tau-rings. Transplanted cells did not migrate to the area where the neurons die suggesting that their effect is due to secreted protective factors. The aim of this application is to identify the factors produced by the transplanted cells to prevent death of neurones containing tau-rings. The identification of the neuroprotective factors will provide an important clue for the design of novel therapies for untreatable diseases such as AD and other tauopathies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL