NIHRDataInsights/HRCSData huggingface dataset:
Title: Exploring endogenous mediators regulating blood brain barrier functionality in Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: Although the main pathological hallmarks found in Alzheimer’s disease (AD) are Aβ plaques, neurofibrillary tangles and neuronal loss, emerging evidence suggests there are also significant changes to the blood brain barrier (BBB). This structure is the principal mechanism separating the brain from circulating molecules and immune cells, and defects in its function could affect the brain’s natural defence systems and its ability to clear Aβ. We have recently shown that the anti-inflammatory protein annexin A1 (ANXA1) is an endogenous regulator of BBB integrity and that treatment with the protein can ameliorate BBB impairments. We hypothesise that ANXA1 is a critical regulator of BBB function in AD, and has the potential for novel therapeutic exploitation. This project has two aims, firstly to assess the integrity of the BBB during disease progression in an animal AD model and to determine the possible relationship between disease progression and decline in ANXA1 expression. Secondly to examine how administered ANXA1 can restore efficient BBB function. Our goal is to provide strong preliminary data allowing us to apply for full funding with the final aim of understanding how to ameliorate/repair the changes seen in the BBB in AD, and hence reduce the vulnerability of the brain


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Rare variants in inflammatory pathways in Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: Recent work has identified rare changes in two closely related genes in some individuals which may cause or increase their risk of developing Alzheimer’s disease. Whilst these changes are rare, they nevertheless affect a lot of people worldwide and can reveal a lot about what goes wrong in the brain to cause degenerative illnesses such as Alzheimer’s disease. Both genes are members of a small well-defined group of genes which control specialist cells in the brain to either defend the brain against foreign invasion or clear the brain of unwanted material in the course of normal healthy brain maintenance. We predict other genes in this functional group may also contain rare changes associated with Alzheimer's disease. We have prioritised six genes within this group to analyse in detail in our very large collection of samples from people with and without Alzheimer’s disease to see if any of them have changes associated with Alzheimer's disease. These results will improve our understanding of how these genes function together to cause disease, establish if these gene changes cause different symptoms from those experienced by other Alzheimer’s disease patients and help us to develop treatments specifically targeting the function carried out by these genes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cortico-striatal contributions to symptomology in dementia: new targets for therapy
Funder: Alzheimer's Research UK

Abstract: The advent of novel disease modifying therapies in Alzheimer’s disease (AD) highlights the urgency to reliably distinguish AD from other dementias. Especially, diseases such as behavioural variant frontotemporal dementia (bvFTD) can present clinically very similar to AD, which can make it difficult to identify the patients’ disease at the earliest time point. The proposed pilot grant will pioneer a new approach which will allow a double-dissociation of AD and bvFTD at a very early disease stage by contrasting for the first time cortical and subcortical contributions to the symptomology of both diseases. Increasing evidence shows that only AD patients present consistently with cortical parietal changes from disease onset, by contrast earliest changes in the subcortical striatum are only present in bvFTD. This pilot project will confirm the specificity of both regions to AD and bvFTD in pathologically confirmed patients. We will further explore the contributions of these regions to the clinical presentation in both diseases and pilot novel specific clinical and cognitive biomarkers for each region. Overall, these findings will greatly improve the diagnostic specificity of both pathologies even at a very early disease stage, which in turn will increase the efficacy of novel upcoming disease modifying therapies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Validation of an O-GlcNAcase inhibitor as a novel therapeutic agent against Alzheimer pathology
Funder: Alzheimer's Research UK

Abstract: The brain requires energy to function properly, supplied to the brain in the form of glucose, a type of sugar. However as we get older there is a decrease in the brain's ability to use glucose, causing a decrease in the memory and conscious function of the brain. The decrease in the brain's ability to use glucose is accelerated in Alzheimer’s disease (AD) where it is evident prior to the diagnosis of dementia, suggesting that glucose related alterations may occur early in the development of AD. One way the brain uses glucose is to attach it to proteins, a modification called glycosylation. Glycosylation alters how proteins work and in AD brain there is a reduction in glycosylation. We have developed a way of preventing this reduction in glycosylation and the next step is to determine if preventing the reduction in the brain prevents the damaging alterations to brain proteins that occur as Alzheimer’s develops.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: CARASIL - a window into Alzheimer's disease?
Funder: Alzheimer's Research UK

Abstract: Cerebral autosomal recessive arteryopathy, with subcortical infarcts and leukoencephalopathy (CARASIL), is a rare, recessive disease characterized by early-onset changes in the white matter of the brain, associated with strokes and progressive dementia. Eight mutations in the HTRA1 gene have been described as causes for CARASIL. Given that several cases do not harbor mutations in this gene, it is very likely that other genes also play a role in this disease. To address this issue, we collaborated with dr Lohmann (Istanbul University and Tübingen University) and collected a cohort of 30 CARASIL-like Turkish cases. We will use recently developed sequencing technology to determine the sequence of the entire coding part of these patients’ genome (the exome) and will determine the genetic causes of the disease. We recently used this same approach to identify TREM2 mutations as the cause of frontotemporal dementia in three Turkish families and subsequently identified a heterozygous variant in the same gene as a risk factor for Alzheimer’s disease (AD). This Pilot Project will allow the identification of novel genes causative of CARASIL. Given the overlap in pathways between CARASIL and AD, these genes will be excellent targets for future genetic analyses of risk factors in AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Interhemispheric processing in Alzheimer Disease
Funder: Alzheimer's Research UK

Abstract: Alzheimer’s disease is one of the pressing concerns of our time. The syndrome is known to be characterised by cerebral anomalies found in the hippocampus and associate cortical areas, which result in memory and high-level cognitive deficits. However, another major brain structure, the corpus callosum, has also been found to be particularly susceptible to atrophy in Alzheimer’s disease. The corpus callosum is the largest white matter structure that connects the two hemispheres and allows the exchange of information between them. What we do not know is whether the atrophy of the corpus callosum has an impact on cognitive processes and whether this can be detected at the early stages of the disease. Our aim is to obtain objective measures pertaining to the functional integrity of the corpus callosum in Alzheimer’s disease. We will measure the speed of the interhemispheric transfer by recording the brains electrical activity during simple lateralised visual presentations. We predict that the interhemispheric transfer time will be significantly longer in probable Alzheimer’s disease patients when compared to healthy age-matched controls. Our findings will lead to the development of new tests of interhemispheric processing that could be used by doctors for more accurate diagnosis of the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identification of unfolded protein response, apoptosis and autophagy markers in human AD
Funder: Alzheimer's Research UK

Abstract: During ageing, a decline in vital neuronal function leaves brain cells vulnerable to the activation of damaging cellular pathways, a process interwoven with accumulation of Alzheimer’s disease (AD) related proteins (amyloid and tau). Mis-folded and toxic proteins trigger an adaptive response known as the ‘unfolded protein response (UPR)’, a process common in a wide range of brain disorders and recently proposed as a break-through key therapeutic target. Whilst initially beneficial, under prolonged stress cells must activate pathways for protein degradation, inflammation and ultimately cell death. In AD these adaptive responses may be hijacked leading to accelerated accumulation of toxic proteins. To confirm the role of this pathway in dementia, we propose to study human brain tissue using protein quantification and visualisation techniques to determine markers for URP and subsequent cellular events. Cellular pathways will be examined in relation to the stage of the dementia, the documented score of pre-mortem cognition, and established AD protein markers. Correlations between these adaptive responses and the stage of AD is critical to confirm their causative role since data so far have been based on experimental models. Deciphering cellular pathways and their role in degenerative processes will be key to develop future therapeutic strategies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Super resolution microscopy in human brain white matter
Funder: Alzheimer's Research UK

Abstract: Understanding of the pathology of common dementias requires detailed examination of human brain tissue, using a microscope. In the Alzheimer’s field it was careful neuropathology studies - using conventional light microscopy - that provided our understanding of amyloid plaques and tau neurofilament tangles. Current on-going studies from our group aim to understand the white matter lesions that are central to dementing illness. Conventional light microscopy is limited in resolution by the wavelength of visible light. Structural resolution at a smaller scale (i.e. higher magnification) has recently become possible using “super resolution microscopy” methods. One such method is called STORM. In this collaborative project between St George’s University of London and the National Physical Laboratory (a centre of excellence for super resolution microscopy) we will use STORM to explore the detailed histological structure of white matter in aged human brain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Understanding oligodendrocyte progenitor dynamics and myelin loss in Alzheimer's Disease
Funder: Alzheimer's Research UK

Abstract: The massive computing power of the brain depends on the insulation of nerve cell connections with a fatty or myelin sheaths, by cells known as oligodendrocytes (OLs). Bundles of these ‘myelinated’ connections form the white matter that is very prominent in the human cortex. Although a loss of cortical white matter and myelin has been documented in dementia, the causes are unknown. There is evidence that OLs are continuously lost and regenerated from a pool of OL progenitors (OPs). It is proposed that OL regeneration may be decreased in dementia, resulting in accelerated myelin loss. OL regeneration is believed to depend on specialised contacts, synapses, formed by OPs with nerve cells. Disruption of signalling is known to occur in Alzheimer’s disease (AD) and might therefore disrupt OP regeneration of OLs, resulting in loss of myelin and cognitive decline. In this project, we aim to analyse the influence of neuronal signalling on OP regeneration and OL/myelin loss, in human AD tissue and in the APP/PS1 mouse model of AD. This will provide new knowledge on an important but neglected component of AD pathology and identify potential cellular targets for protecting myelin and preserving cognitive function.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Developing a new biomarker for the early diagnosis of dementia; a novel nonlinear signal processing approach using resting state EEG.
Funder: Alzheimer's Research UK

Abstract: An accurate early diagnosis of Alzheimer’s disease is crucial in order to provide support for people with dementia and their carers. Tests of memory and other higher-level processes cannot reliably diagnose people with early AD from those due to depression, strokes or other types of dementia. Brain scans can exclude other causes of memory problems (such as a tumour), but cannot make a positive diagnosis because brain shrinkage only occurs after the onset of dementia. Changes in brain connectivity may be a useful early marker of dementia. How well the brain is connected can be measured using magnetic resonance imaging (MRI) brain scans but also with electroencephalography (EEG). EEG is more ‘patient-friendly’ as it only requires electrodes to be placed on the scalp to measure electrical activity. It is commonly used to diagnose epilepsy. EEG has been used to detect changes in connectivity in people with dementia but the methods are not sensitive enough to be used as a clinical diagnostic test. The University of Sheffield has developed new techniques using EEG to examine brain connectivity. This research will study EEG to see if subtle changes in brain-connectivity can help make a diagnosis of AD at an early stage.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Double-blind randomised crossover placebo-controlled pilot trial with intra-nasal Oxytocin to increase social cognitive function and reduce carer burden in frontotemporal dementia.
Funder: Alzheimer's Research UK

Abstract: Loss of empathy and impaired social behaviours are some of the most devastating symptoms in frontotemporal dementia (FTD) and often lead to an alienation of patients and their families. There are currently no effective drug treatment options available to alleviate these symptoms in FTD. We will study whether a drug called Oxytocin can restore social behaviours in patients, and whether these improvements reduce stress in the patients’ carers. Oxytocin is a natural hormone in the brain, which has been shown to improve social behaviour and empathy in autism when given as a simple nasal spray. Similarly, a pilot study in FTD has shown short-term improvements of general behaviour by a single dose of Oxytocin. This study will see if more realistic social functioning can be sustained over several weeks from this drug. This pilot-stage clinical trial of Oxytocin measures changes in realistic social interaction changes as well carer burden in FTD over a 4 week period. If successful, our results would lead to a large multi-centre trial, with potentially a very strong impact on the well-being quality of life for patients and their families.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: The role of TMEM106B and CHMP2B in neuronal lysosomal trafficking in frontotemporal dementia
Funder: Alzheimer's Research UK

Abstract: Frontotemporal dementia (FTD) is the second most common form of dementia in individuals under the age of 65. Mutations in a number of genes can cause FTD. These genes are known to have quite distinct functions. How mutations in these diverse genes contribute to development of the same disease (FTD) is unknown. A recently published paper has shown that TMEM106B, a gene that increases the risk of developing FTD, causes defects in the ability of cellular components to traffic to their correct destination within neurons. Preliminary data from our lab reveals that the FTD-causing gene CHMP2B causes similar defects in the same trafficking pathway. We would like to further characterise this defect, and investigate whether these two genes function in the same pathway. If this is the case, this would be the first data to suggest a common pathway leading to FTD, which would be a significant progression in understanding the mechanism of neurodegeneration in FTD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Molecular Dissection of Human Alzheimer's Disease
Funder: Alzheimer's Research UK

Abstract: This proposal aims to take the first in-depth look at changes across several regions of brains affected by Alzheimer’s disease, to find how disease develops, and identify targets for better diagnosis and treatment. We have studied the metabolic state of seven different regions of human Alzheimer’s brain. In this project, we want to extend this analysis to study the levels of proteins, the most commonly targeted molecules for therapeutic drugs. By measuring over 3000 proteins, and combining this information with our data on metabolism, we can build a picture of what is happening at the functional level in different regions of the brain in Alzheimer’s disease. This allows us to uncover new avenues of research, develop new medicines, or take medicines which target similar changes in other diseases, e.g. diabetes, and ‘reposition’ them in Alzheimer’s care. Diabetes and Alzheimer’s share several features, including insoluble plaques, abnormal copper, high levels of glucose and alterations in metabolism. We currently have experimental therapies which targets some of these in development against diabetes. Identifying further similarities between these related conditions will allow transfer of knowledge and new treatments for testing in Alzheimer’s models, generating new ways of treating the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of the nuclear transport system in frontotemporal dementia.
Funder: Alzheimer's Research UK

Abstract: Frontotemporal lobar degenerations (FTLDs) are collectively the second most common form of young onset dementia, characterised by progressive nerve cell loss in the frontal and temporal lobes, and neuropathological hallmarks formed from proteins (TAR-DNA binding protein (TDP-43) and fused in sarcoma (FUS)) becoming defective. The normal function of the TDP-43 and FUS proteins are involved in the movement of ribonucleic acid (RNA, genetic information which directs the production of proteins) from the cell nucleus (control centre) to the outer part of the cell, the cytoplasm. We have shown for the first time that additional proteins involved in the movement of RNA are also found in the neuropathological hallmarks of FTLDs, suggesting these may play a role in the disease progression. Utilising our unique collection of post mortem FTLD cases this study aims to identify brain areas that are vulnerable to developing pathology and compare them to areas that are pathologically unharmed. By identifying these additional proteins and the changes in protein levels we hope to highlight pathological events occurring early in the development of FTLDs, which potentially could be targeted for early therapeutic interventions to prevent or slow the progression of the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Selective vulnerability to Alzheimer’s disease – understanding changes in white matter connectivity of the visual system in Posterior Cortical Atrophy
Funder: Alzheimer's Research UK

Abstract: This project will investigate changes in white matter structure in Posterior Cortical Atrophy (PCA), an atypical form of Alzheimer’s Disease (AD) where the back of the brain and individuals’ visual processing are affected first. The brain works through networks of grey-matter (brain cells) connected by white-matter (cabling between cells). Recent evidence suggests that AD might target and spread through the brain via these networks. Whilst many studies have investigated grey matter loss in AD, far fewer have investigated changes in the organisation of white matter, and specific structural brain networks. Investigating PCA provides a unique opportunity to study AD where the network affected is the visual system, due to a different pattern of sensitive and resistant neuronal populations compared with typical AD. This has advantages because it is a very well-understood system in healthy people, and one can investigate structures that are connected to the brain but are known not to be the primary site of onset for AD (optic tract and eye). This can help reveal whether the disease progresses along white matter tracts, and will improve our characterisation and understanding of why people with this unusual form of AD show such different patterns of vulnerability to the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Exercise, the most promising intervention to prevent or delay cognitive decline, dementia and frailty in older adults?
Funder: Alzheimer's Research UK

Abstract: Older adults are at high risk from developing dementia and frailty. In addition to this cognitive decline and frailty often occur together both bringing reductions in quality of life and increasing care needs. As there are no medications to prevent dementia, lifestyle factors are recieving greater attention. Increasing evidence points to exercise as a means to improve cognitive function and reduce risk of cognitive and physical decline. There are issues to consider as most data has been collected in populations that are already impaired rather than examining prevention of decline and there are also important safety issues to consider when recomending exercise regimens. Despite this exercise has huge potential for benefit, particularly in older adults. We propose running a series of talks by key opinion leaders in the field followed by a panel discussion open to academics, students, clinical staff and researchers. This will provide an up to date overview of the research and allow interaction and discussion. We will also publish a summary of the event in the scientific literature and dissemenate information to the patient and public involvement groups with whom we are involved. This event will educate and kick start discussion/generation of research ideas for the future.


Research activity codes: 6.7 PHYSICAL
Health categories: NEUROLOGICAL
Title: Targeting tau to prevent Abeta mediated synapse degeneration in Alzheimer’s
Funder: Alzheimer's Research UK

Abstract: Memory is made possible by the ability of synapses, the connections between neurons in the brain, to change in response to environmental inputs. In Alzheimer’s disease, memory declines because synapses and neurons become dysfunctional and die. In fact, loss of synapses very strongly corresponds to the severity of dementia in Alzheimer’s patients. The goal of this project is to find out whether the two key disease-causing proteins in Alzheimer’s – amyloid beta and tau – act together to cause this synaptic degeneration. Further, we will test whether therapeutic treatments to reduce tau levels in the brain can halt memory and synapse loss. This study is important, as it will provide new insights into mechanisms of synapse loss in Alzheimer’s and should lead to new therapies to treat this debilitating disease.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL