NIHRDataInsights/HRCSData huggingface dataset:
Title: Early functional network instability in tauopathy
Funder: Alzheimer's Research UK

Abstract: Nerve cells in the brain communicate through connections called synapses and abnormal synaptic communication is known to be a key aspect of dementia. However, we do not fully understand what aspects of abnormal synapse function are important, or at what stage of the disease synaptic defects occur. Our latest data suggests that synapses are unstable early on in a tau-based model of frontotemporal dementia. These results reveal that, even before nerve cells start dying, the connections between them are continually being added and lost more rapidly than those in the normal brain. We predict that this instability of synapses would alter the way that nerve cells communicate and hence the way that their combined activity encodes perceptions, thoughts and memories in the brain. The work proposed here will test the idea that this instability in neuronal network activity is found in the early stages of neurodegenerative disease. To do this, we will use the latest microscopy techniques to repeatedly measure the activity of groups of neurons inside the living brain at different stages of disease. Potentially, the findings of the proposed study could identify early disease biomarkers or point towards new targets for early intervention in tauopathy-based dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Combinatorial biomarkers for dementia prodromes, prediction, pathology and progression
Funder: Alzheimer's Research UK

Abstract: A biomarker (a form of test) is urgently required for Alzheimer's disease to make clinical trials more effective and to facilitate early diagnosis and more accurate prognosis. The best biomarkers currently available are from spinal fluid or involve complex radiological brain scans. However, increasing evidence suggests a biomarker in blood might be used, either alone or to supplement other tests. We plan to use advanced protein analysis of blood combined with structural neuroimaging and brain scans measuring brain function to find a ‘combinatorial, multi-modal' biomarker. We will test this for utility as a marker for very early, pre-clinical diagnosis, as a marker for prognosis (or prediction of decline), as a marker reflecting pathological change in the brain and as a marker for measuring disease progression. Having discovered such a biomarker we will then replicate the finding in a larger group of research participants and validate the finding by comparing results in mouse models of disease and in brains of people with dementia. The outcome will be a biomarker ready for processes preceding regulatory approval (‘qualification') and poised for translation into both clinical trials and clinical practice.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Neurovascular dysfunction in Alzheimer’s disease: the search for early biomarkers
Funder: Alzheimer's Research UK

Abstract: More than any other organ of the body, the brain is dependent on a continuous blood supply to deliver nutrients. If blood supply is halted, even temporarily, severe and irreversible damage can occur. Active brain regions have high energy demands, and the brain has important mechanisms that act to increase blood supply to areas that need it most. One theory suggests that a major contributory factor to the development of Alzheimer’s disease (AD) is a breakdown in the control of blood flow, which causes increased stress to vulnerable brain cells. This project will investigate whether blood flow regulation in the brain is failing in a mouse model of AD over the life span of the animal. We will use powerful methods to measure changes in blood flow that can also be used on humans. It is possible that a breakdown in the regulation of blood flow could be happening early in the disease process. If true, we will be able to develop imaging techniques to detect these changes before the patients know they have the disease, similar to the screening done for cervical cancer. In this way treatments could be given much earlier and with a greater chance of success.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The molecular basis of the innate response to oligomers of beta amyloid and alpha synuclein
Funder: Alzheimer's Research UK

Abstract: The innate immune response is our first line of defence against disease and protects the brain from infection. It appears to play an important role in the development of neurodegenerative disease switching from being protective to being destructive. The cells that are responsible for this response are called microglia and the aim of this project is to work out how they respond to the small clumps of proteins that cause Alzheimer’s and Parkinson’s disease as the number of clumps or size of clumps increases. This will be done by directly watching the receptors on the surface of microglia interacting with the protein clumps and then by following how these cells respond and signal. This should enable us to work out the molecular basis of the response, why the response of microglia changes in the disease and how this might be prevented.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: PSK kinases and tau pathology in Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: In nerve cells, tau protein stabilises microtubules, scaffold-like structures which maintain cell shape and function. In Alzheimer’s disease, tau is abnormal because it is chemically modified by the addition of phosphate. Phosphorylated tau cannot stabilise microtubules and instead it becomes tangled and forms clumps in the brain. Tau tangles cause microtubules to be lost from nerve cells, severing their connections to other nerve cells which then die, leading to the onset of dementia. We have identified a family of enzyme catalysts called PSKs, which can add chemical phosphate to tau and which are associated with tangles in Alzheimer’s brains. Unregulated PSK activity could therefore contribute to tangle development, microtubule breakdown and nerve cell death, which would bring on the clinical symptoms of dementia. Our objective is to find out what causes PSKs to add abnormal amounts of phosphate to tau and causes nerve cell death. We have made a new drug that inhibits PSK activity and we will try this out to see if it can reduce or prevent PSK phosphorylation of tau and nerve cell death. Our intention is to aid the development of drugs targeting tau and to ultimately slow or stop the progress of dementia.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Next Generation Sequencing of Alzheimer's Disease (AD) Genes in non-familial early-onset AD (EOAD).
Funder: Alzheimer's Research UK

Abstract: In the last three years our understanding of the genetics of Alzheimer's Disase (AD) has undergone some astonishing developments. We now have nine replicated 'new' AD genes and these discoveries have highlighted novel pathways implicated in the disease process and are thus viable targets for future therapeutic intervention. Currently these new genes, in conjunction with the well known APOE4 associated risk, explain about 30-50% of the genetics of late-onset AD (LOAD). Clearly there is more work to be done to find the 'missing heritability' and there are on-going drives to use next generation sequencing (NGS) approaches using LOAD samples to search for this. In this collaborative grant application (involving in total 10 of the ARUK Network Centres) we plan to fully sequence the nine new genes in EOAD samples that we have in the ARUK DNA Bank; these are samples that currently are not being utilised in any other NGS project. This project will specifically determine if the LOAD genes play a significant role in EOAD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A multi-centre study using a validated high resolution metabolomics methodology to investigate Alzheimer's disease (AD).
Funder: Alzheimer's Research UK

Abstract: Metabolomics is a new tool for studying disease-related metabolite perturbations and offers extremely strong potential for disease prediction/diagnosis. Metabolomics is potentially more powerful than existing diagnostic tools since it considers information about many more biomarkers than most current methods. While its full diagnostic potential has yet to be fully elucidated, we have pilot data that the technique used on brain tissue can distinguish Alzheimer’s Disease (AD) from healthy age-matched controls with >97% accuracy. At present few reliable biomarkers for AD exist making early detection and clinical diagnosis extremely difficult. The proposed co-operative study aims to prove and extend the use of this new technology for the study of AD. It will determine the disturbances in brain chemistry which differentiate mild cognitive impairment (MCI) from AD and healthy subjects as well explore how these disturbances relate to disease severity in human and transgenic mouse brain tissue. The technology will also be used to generate ‘biochemically fingerprints’ of plasma from patients attending local memory clinics which can be compared to profiles derived from brain tissue. This methodology could inform the creation of a much desired blood test to allow early identification of MCI patients and those most likely to later develop AD.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Functional deficits in a novel murine model of frontotemporal lobar degeneration
Funder: Alzheimer's Research UK

Abstract: Frontotemporal dementia (FTD) is the second most common cause of dementia in people below 65. Genetic analysis of families with inherited FTD has revealed that mutations in 7 different genes can result in FTD. Each of these genes encodes for production of a specific protein and the disease-causing mutations cause these proteins to become dysfunctional. By investigating how FTD-causing mutations disturb the function of proteins we will better understand how FTD and related diseases arise. Here we aim to understand how mutations in the CHMP2B gene disturb brain function and thus cause FTD. The UCL group has genetically engineered mice to possess a mutated form of the human CHMP2B gene. This results in age-dependent development of brain pathology reminiscent of FTD. This award funds a link with Bristol scientists who specialise in measuring activity of brain circuits. Using electrical and optical real-time measurements the teams will collaborate to analyse how parts of the brain important in memory and other important functions become disturbed in these disease model mice. This will provide new information about why the brain works poorly in FTD sufferers, and may also shed light on why neurones die in this and related disease such as Alzheimer’s.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Assessment of neuropathological changes associated with vascular dementia: validation of a consensus approach
Funder: Alzheimer's Research UK

Abstract: The over-arching term vascular cognitive impairment (VCI) refers to a group of conditions in which cognitive problems result from inadequate blood flow through the brain. Vascular dementia (VaD) is a severe form of VCI and is the second most common cause of dementia after Alzheimer’s disease (AD). Establishing a definite diagnosis of most diseases that cause dementia depends on post-mortem neuropathological examination. However, in contrast to other types of dementia, such as AD, there are no widely accepted criteria for the post-mortem assessment and diagnosis of VCI or VaD. Over the past 10 months, within the Brains for Dementia Research (BDR) network, the applicants have used the Delphi method to develop a set of Vascular Cognitive Impairment Neuropathology Guidelines (VCING), representing a consensus approach to the post-mortem assessment of cerebral vascular disease in relation to VCI. We now wish to validate and refine these guidelines. Our aim is to (i) evaluate the practicability and reproducibility of the VCING protocol across multiple UK centres, and (ii) by assessing the relationship between cognitive performance and the VCING standardised scores of vascular pathology, to establish objective neuropathological criteria for commenting on the possible or likely contribution of cerebral vascular disease to cognitive impairment.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: The utility of measuring plasma phosphorylated alpha-synuclein levels as a biomarker for Dementia with Lewy bodies
Funder: Alzheimer's Research UK

Abstract: This project between Manchester/Lancaster/Newcastle Universities is focussed on trying to develop a blood diagnostic test that can help to distinguish Dementia with Lewy Bodies (DLB) from Alzheimer’s disease (AD) and other dementias. DLB is characterised pathologically by the accumulation in the brain in the form of Lewy bodies (LBs) of a substance called ‘phosphorylated α-synuclein’. LBs are also found in Parkinson’s disease (PD), but they are more numerous and more widespread in the nervous system in DLB than in PD. We have already discovered that phosphorylated α-synuclein is present in blood plasma, and that the levels of this substance in blood are higher, on average, in patients with PD than in healthy controls. We now wish to follow this up by investigating whether this blood measurement can also distinguish patients with DLB from normal people, and from patients with AD and other dementias. We anticipate that the levels of phosphorylated α-synuclein in blood plasma will be even higher in DLB than in PD. If successful, this would provide an inexpensive, easy to perform, non-invasive test which would improve the early clinical diagnosis of DLB, and could also provide a biomarker to test the efficacy of new drug treatments.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Age-related changes in the basement membranes of cerebral blood vessels: implications for Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: In sporadic Alzheimer's disease associated with ageing, there is deposition of amyloid-β (Aβ) in the walls of arteries, as cerebral amyloid angiopathy (CAA). Aβ is eliminated from the brain along channels named basement membranes, in the walls of arteries. Basement membranes are made up of proteins with different effects on Aβ. We established two novel techniques: 1. Precise measurements of the thickness of basement membranes in mice of young, adult and old ages using new software for electron microscopy; 2. An assessment of approximately1000 proteins that constitute the walls of human old arteries. Our results demonstrate a significant age-related thickening of basement membranes of mice in the areas of the brain with high incidence of CAA. Analysis of human samples shows changes in the proteins that act upon Aβ, suggesting that the composition of basement membranes changes with age, favouring the aggregation of Aβ. We wish to expand our analysis with samples from normal young human brains from the Edinburgh Brain Bank as well as normal aged and CAA brains from the Newcastle Brain Bank. This project will inform on the exact changes in the clearance pathways for Aβ, allowing the development of new treatment strategies preventing its aggregation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Continued maintenance of the ARUK DNA Resource and Database
Funder: Alzheimer's Research UK

Abstract: In the last four years our understanding of the genetics of late onset Alzheimer's Disease (LOAD) has undergone some astonishing developments. We now have 21 replicated 'new' AD susceptibility loci and these discoveries have highlighted novel pathways implicated in the disease process and are thus viable targets for future therapeutic intervention. Currently these new genes, in conjunction with the well-known APOE4 associated risk, explain about 50-60% of the genetics of late-onset AD (LOAD). Identifying the remaining disease heritability and locating the ‘causal’ mutation within the identified loci remains a significant challenge. There are on-going studies using next generation sequencing (NGS) approaches with AD samples in the search for these. Results from NGS studies will increase our understanding of disease pathophysiology and prioritise targets for therapeutic intervention. In this collaborative grant application (involving 8 of the ARUK Network Centres and 2 international groups) we seek funding to maintain and further develop this resource to ensure that its immensely valuable contribution to AD genetics continues.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL
Title: A biological resource for metagenomic studies of dementia
Funder: Alzheimer's Research UK

Abstract: The bacterial composition of the gut (the micobiome) plays an important role in human health. The microbiome is stable complex system existing in a mutually beneficial relationship with its human host. The intestinal bacteria breakdown indigestible food products to produce micronutrients and stimulate the host's immune system which in turn regulates the bacterial composition. Changes in the microbiome have been found to occur not only in disorders of the digestive system such as irritable bowel syndrome and colorectal cancer but also disease such as Type II diabetes and obesity. The complexity of this composition in terms of the number of different kinds of bacteria is usually regarded as relatively stable throughout adulthood but with ageing this complexity is reduced. Aging, diabetes, obesity and are well established risk factors for Alzheimer's disease associated with low level inflammation and are themselves associated with changes in the intestinal microbiome but there have been no studies examining the microbiome and their metabolites in dementia or Alzheimer's disease. We hypothesise that changes in the intestinal microbiome influences risk for Alzheimer’s disease. We propose therefore to collect detailed clincial information and biological samples from elderly individuals with and without dementia to address this hypothesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Evaluation of microglial activation in Alzheimer’s disease and mild cognitive impairment subjects using a novel TSPO marker, GE180
Funder: Alzheimer's Research UK

Abstract: Mild cognitive impairment (MCI) is a transitional stage between normal awareness and Alzheimer’s disease (AD). Brain inflammation has been proposed to be a link between the build-up of amyloid (an abnormal protein in the brains of patients with AD), damage to nerve cells and formation of “tangles” (clumps of proteins). With PET scanning we have demonstrated that AD subjects have significantly increased amyloid build-up and brain inflammation (demonstrated by increased activity of microglial cells). [18F]GE180 is a PET imaging agent that has been developed for the assessment of brain inflammation. The action of [18F]GE180 is based on its ability to bind to the translocator protein (TSPO). TSPO levels in the normal central nervous system are very low, but increase dramatically in microglial cells in response to brain damage and inflammation. Here we would like to evaluate [18F]GE180 in ten AD subjects, ten MCI subjects and ten healthy volunteers. This will be compared with the levels of amyloid imaged with [18F]flutemetamol, allowing us to better define the role of inflammation in AD and MCI subjects and to determine whether [18F]GE180 gives a suitable signal to assess the role of inflammation in disease progression and to evaluate the effect of anti-microglial agents.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Fronto-thalamic effective connectivity in familial Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: Alzheimer's disease (AD) attacks the brain, resulting in disruption of memory, thinking and behaviour. Magnetic resonance imaging (MRI) of the brain is used for AD diagnosis, to detect key changes. The disease, however, begins to develop years before symptoms become evident, potentially altering brain structure and function. Because important functions, such as learning and memory, engage networks of brain regions, changes in their 'wiring' and functioning could result in the characteristic impairments. Familial AD (FAD) is a rare, genetically inherited form of AD. An individual inheriting a mutated gene from an affected parent (with a 50% chance) develops dementia that onsets at a young age, usually in the 40s or 50s. Because this disease runs in families, individuals at risk can be tracked from several years before AD is diagnosable. In this way we can gain unique insights into the earliest disease mechanisms In this study, I will characterise early signs of neurodegeneration in FAD mutation carriers relative to non-carriers, within the Dominantly Inherited Alzheimer Network (DIAN; http://dian-info.org) cohort. Previously acquired MRI data will be analysed using techniques for studying brain network function. In addition to brain imaging abnormalities, I will determine their relevance to impairments of memory and thinking.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Title: Alpha-Synuclein and Cellular Iron Reduction
Funder: Alzheimer's Research UK

Abstract: Brian diseases such as Parkinson’s Disease are likely to be caused by changes to certain brain proteins. While we don’t know how these changes occur we do know what changes occur. In the case of Parkinson’s disease aggregates of a protein called alpha-synuclein can be detected in the brain. One of the difficulties in discovering how these changes occur and how these changes might cause Parkinson’s disease has been not knowing what alpha-synuclein actually does in the brain normally. We have made the first major breakthrough in understanding what alpha-synuclein does. We have shown that it is an enzyme that can change iron to a form more commonly used by cells. This activity known as ferrireductase activity (FR) is likely to have protective effect but increase or loss of this activity might be damaging to cells in the brain. In this project we will study FR activity of alpha-synuclein and see whether it is changed in disease and and how change in this activity affects cells. It is possible that the generation of excess reduced iron because of too high alpha-synuclein levels might explain the loss of dopamine cells in the brain of Parkinson's disease and some other dementias.


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