NIHRDataInsights/HRCSData huggingface dataset:
Title: Replacing Alzheimer's disease (AD) - Down syndrome (DS) mice with fly models
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: World-wide ~ 6 million people have Down syndrome (DS), and are at significantly greater risk of developing Alzheimer's disease (AD) than the general population. By the age of 40, almost all people with DS will develop AD pathology, namely amyloid plaques and neurofibrillary tangles within their brain. The vast majority of people who have DS will go on to develop early onset dementia (AD-DS), with a mean age of onset of ~ 57 years. DS is caused by an extra copy of human chromosome 21 (Hsa21), which encodes 231 genes. One of these genes (APP) codes for a protein that is cleaved to form the amyloid-beta (A?) that accumulates in plaques during AD. How the other genes on Hsa21 affect disease is not yet understood. We have recently shown using mouse models that a gene(s) on Hsa21, other than APP, exacerbates the accumulation of A? (Wiseman et al Brain 2018). This suggests that the increase in AD rates in DS individuals is not purely driven by an extra copy of APP.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Identification of the molecular mechanisms underlying disease variation, severity and progression in Parkinson’s disease using cohorts of deeply phenotyped patients and human induced pluripotent stem cell models.
Funder: Welsh Government Office for Science

Abstract: The molecular bioinformatics research programme proposed here involves a multidisciplinary approach that includes bioinformatics, statistical genetics, functional genomics analysis, clinical data exploration and next-generation sequencing methods, as well as the production of human iPSC and genome editing technique and all of which complement the excellent research performed in CU


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Deconvoluting the Dementia Phenotype using Functional Genomics and Computational Approaches
Funder: Welsh Government Office for Science

Abstract: A main achievement of science and medicine in the 20th century is the remarkable increase in life expectancy. Age is one of the main risk factors for a large number of common diseases in humans and as a result, a number of disorders are increasing in prevalence among the elderly population. In this respect, the number of individuals with the most common form of Dementia, Alzheimer's disease, is only set to increase. Understanding the biological processes behind the development of Dementia would lead to understanding the disease risk, development of prevention strategies and design of novel therapies. The aim of this project is to help understand the molecular mechanisms that underlie Alzheimer's disease, using a computational approach that utilises the already generated vast publicly-available data. For this purpose, I am implementing a novel computational


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Cholesterol metabolites in dopamine neuron development and Parkinson's disease diagnosis and therapy.
Funder: Welsh Government Office for Science

Abstract: Liver X receptors (Lxrα/NR1H3 and Lxrβ/NR1H2) are well known regulators of lipid metabolism and inflammation, but they have also recently emerged as key factors for neurogenesis and maintenance of neuronal survival. I and others have previously reported that LXRs control different aspects of midbrain dopamine (mDA) neuron development and that endogenous brain LXR ligands, such as 24(S),25-epoxycholesterol and cholic acid, are an entirely new family of highly selective and potent regulators of midbrain neurogenesis and/or survival. Here I plan to study the effect of several newly-identified cholesterol metabolites that are up- or down-regulated in the CSF and plasma of Parkinson’s disease (PD) patients compared to healthy controls. I will use Nuclear Receptor activation assays and rodent in vitro assays in order to determine the mechanism of action of these compounds in various biological processes such as neurogenesis, survival, toxicity and others, as well as to examine their potential role in the physiopathology of PD. In addition I plan to utilise existing and newly-identified LXR ligands to improve protocols for the generation of mDA neurons from several human or mouse cell types in order to obtain improved cell preparations that are homogeneous and enriched in mDA neurons, without immature or undifferentiated cells and without other neuronal types. These cell preparations will be utilised in vivo to describe their possible effect on the functional recovery in rat models of PD after grafting. PD research is not currently under study in Swansea University and this is a novel expertise that I hope to bring to the University. In addition I have already initiated a collaborative study together with existing groups in Swansea and Cardiff Universities, as well as in Karolinska Institute, and I believe that by utilising the expertise of all the aforementioned groups, we will improve the diagnostic and therapeutic potential for PD patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Expanding the Frontiers of Molecular MRI: Imaging the Inflamed Brain during Neurodegeneration
Funder: The Academy of Medical Sciences

Abstract: The immune system is essential to natural brain health and maintenance, but over-active inflammatory pathways cause untold degenerative damage. Neuroinflammation is now regarded as a significant contributor and aggravator to a broad range of neurodegenerative conditions in patients, from the development of dementia following stroke through to long-term deterioration in multiple sclerosis. While we are aware of the connection between neuroinflammation and neurodegeneration, the exact relationship between the complex pathways at work is poorly understood, limiting the effectiveness of new treatments. My aim is to re-imagine how we look at the inflamed brain through cutting-edge imaging technology. By understanding inflammatory process in situ across the whole brain, we can study neurodegeneration in enhanced detail and, ultimately, develop improved therapeutic interventions in the clinic. My approach will develop magnetic resonance imaging (MRI) contrast agents to detecting, characterising, and monitoring neuroinflammatory pathways. Combination with PARASHIFT MRI, a technique I developed in my PhD, will allow multichannel MR imaging in an analogous fashion to blue/green/red channels in fluorescent microscopy. I will synthesise inflammation-targeted contrast agents that will allow inflammation to be monitored alongside the biochemical signatures of neurodegeneration in vitro, ex vivo, and in vivo (C. elegans) models. The Springboard Award will establish the basis of this approach to build towards subsequent studies of neurodegeneration in more complex rodent models. Through increasing understanding of disease progression and combining with therapeutic intervention studies, my long-term goal is to aid in the development of new treatments and, ultimately, lead to improved outcomes in the clinic.

Lay abstract: The brain’s natural defence system, under certain conditions, becomes too aggressive and begins to cause damage to the brain itself. This condition, neuroinflammation, is linked to the long-term and deteriorating health effects associated with neurodegenerative diseases, such as Alzheimer’s disease. A relationship between neuroinflammation and neurodegeneration is well accepted, but what is less understood is how the two are connected and how they contribute to each other. Very much like the classic chicken and the egg scenario, we are often unsure on which comes first and how that comes to be. Treatments against neuroinflammation have had mixed success, largely because we don’t fully understand these complicated processes at work. Using simplified biological models to start with, I aim to develop new tools for magnetic resonance imaging (MRI) that will allow inflammation to be mapped out and monitored alongside the chemical signatures of neurodegeneration. The goal is, ultimately, to improve the development of new treatments and leading to improved outcomes for patients.

Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Sleep and sleeping for parents and children aged 2-4
Funder: The British Academy

Abstract: This project will examine the understudied area of very young children’s sleep (children aged 2-4 years) from their own and their parents’ perspectives. Its key innovation is that it involves children in the research process, by asking them to take photographs, and co-interviewing them with parents. Its main aim is to develop qualitative, sociological resources on very young children’s sleep; a field so far that has been tipped toward health and policy agendas. The project undertakes three core activities. First: a 'netnography' analysing posts in the Facebook group The Beyond Sleep Training Project. Comprised of 50,000 members posting about infants’ sleep, I will interview participants, and ask them to take photographs of everyday experiences of their young children's sleep. Second: to review literature by organisations such as NCT (National Childbirth Trust), the NHS, and best-selling parenting books. Third: to create a workshop and exhibition about the images, to disseminate findings.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: A special touch to decrease pain: exploring subjective and brain responses “to affective touch” in a model of chronic pain
Funder: The British Academy

Abstract: Chronic pain is a pandemic problem which comes with enormous costs, both for the individual and the society. Pharmacological remedies are not always a viable solution, so an urge to identify drug-free treatments is rising. “Affective touch” is a peculiar and pleasant tactile stimulation which may have pain-relieving properties. However, nothing is known about its potential to alleviate chronic pain. In a recent pilot I discovered that affective touch is able to significantly reduce participants’ pain ratings in a model of chronic pain. Building on this, the present project will test the real effectiveness of this intervention by combining the participants’ subjective ratings with objective measures such as the participants’ brain responses, via electroencephalographic (EEG) recordings. Potential modulating factors like attention, pleasantness of touch, and interoceptive awareness will be also considered. This research will pave the way to future clinical studies and to a new non-pharmacological intervention for chronic pain.


Research activity codes: 5.8 COMPLEMENTARY
Health categories: NEUROLOGICAL
Title: Stigma and discrimination experienced by adults with cerebral palsy: A participatory action research study
Funder: The British Academy

Abstract: We will use participatory action research to co-create a project that helps us to understand the correlates of social stigma and discrimination for adults living with cerebral palsy and co-develop ways to reduce stigma and discrimination in this population. We will involve adults with cerebral palsy as co-producers as investigators and research partners. The project will comprise two main components: a.) a co-designed survey to collect data on the correlates of stigma and discrimination in adults with CP and; b.) a research retreat where adults with CP will come together with the research team to interpret the survey results and co-develop ideas for interventions to reduce stigma and discrimination in this population. These findings will be promoted via a research report, study video and academic paper to people living with cerebral palsy, groups that advocate for people living with cerebral palsy, academics and clinicians.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Recollections May Vary: How Does Sleep Affect False Memory?
Funder: The British Academy

Abstract: Human memory is known to be supported by sleep. However, less is known about the development and maintenance of false memories. Here, we determine how sleep influences this process. In the laboratory, false memories are often induced via the DRM paradigm where participants are presented with semantically related words such as hot, snow, and warm. Subsequently, participants are likely to erroneously recall that a related word such as cold was presented. Multiple studies have examined whether these false memories are influenced by sleep, with contradictory results. A recent meta-analysis suggests that the discrepancy may relate to (i) test type (recall vs. recognition), (ii) number of words presented, and (iii) participants’ memory capacity. We propose a series of high-powered and pre-registered experiments that will conclusively determine how these variables mediate the interplay between sleep and false memory. The results will inform models of memory consolidation and practices concerning (eye)witness testimony.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL
Title: Neural Entrainment of Brain Rhythms to Aid Sleep
Funder: The British Academy

Abstract: Four In ten adults report problems getting to sleep, which can have a major impact on their health and well-being. The prevailing brain rhythm slows during sleep onset, and it may be possible to alleviate insomnia by slowing the brain rhythm at bedtime. This could be achieved with neural entrainment (synchronisation of the prevailing brain frequency with an external signal) by using a simple finger tapping task. However, the importance of visual feedback in this process remains unknown, as well as its efficacy and the effect on subsequent sleep structure. In a two-part project, we will monitor a simple tapping task with EEG first during the day in a MIRAGE box (to answer the visual feedback question by manipulating subjective and objective tempo) and with polysomnography during overnight sleep. We will learn about the basis of neural entrainment and whether such a technique can be used to help combat insomnia.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: NEUROLOGICAL
Title: Harnessing social media to support people living with dementia: A framework to guide training and resource development
Funder: The British Academy

Abstract: Our preliminary research suggests that social media can be a valuable source of post-diagnostic support for people with early-stage dementia. However, the perspectives of other key stakeholders, including carers, dementia organisations, and people with dementia who do not already use social media, are yet to be explored; and there is a notable lack of evidence-based training and resources. We address this gap in our work in which we ask: “How can we support people with early-stage dementia to use social media in a manner that can satisfy the diverse needs of stakeholders”. In Study 1, stakeholders’ attitudes towards people with early-stage dementia using social media will be explored through a combination of an online survey and in-depth interviews. In Study 2, workshops will be conducted with stakeholders to co-produce resources and a training framework. Our work responds to recent calls to support people with dementia to live well.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: Loughborough University Concussion IDentification (LUCID): concussion diagnosis using smartphone-based eye tracking
Funder: The British Academy

Abstract: Sports players are at risk of head injuries and potentially concussion in any contact sport. Existing practice for measuring concussion during sporting events is highly subjective. More objective measures of concussion which provide rapid results are required to establish whether a player is able to continue or needs to be removed from the game. Eye movement tasks are able to distinguish between healthy and unhealthy/abnormal patterns of eye movements. During a concussion, neural pathways are disrupted, leading to measurable deficits in attention. The current study would demonstrate the utility of using a smartphone-based eye tracking system which could effectively measure the attentional deficits which are associated with concussion and provide immediate feedback regarding whether a player can continue playing. By utilising smartphone devices, the concussion tool would be easy to take to any sporting event and be available for all levels of any sport, from professional to amateur grassroots.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Neural interfaces for the understanding and treatment of neurodegenerative conditions
Funder: Royal Academy of Engineering

Abstract: This research will focus on brain-interfacing technologies that could further our understanding of brain circuits and how they are affected by neurological disorders. Using these findings, Professor Mathieson will develop neurotechnologies to treat a number of conditions, including brain disorders, dementia and systems for restoring functional vision to blind people.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);5.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL
Title: Targeting autophagy as a shared mechanism in rare early-onset neurodegenerative diseases (Niemann-Pick type C1 (NPC1) disease and Wolfram syndrome (WS))
Funder: LifeArc

Abstract: There are over 600 rare neurodegenerative diseases, many childhood-onset, with devastating effects on children and families. Finding new treatments is hampered by their rarity, a limited understanding of how they work and a low commercial incentive for investment. This research project targets a mechanism that many of these rare disorders have in common: deregulated autophagy. Autophagy is the process by which cells degrade and recycle their unwanted or damaged components. It is critical for maintaining a healthy cellular balance. Deregulated autophagy, when this process goes wrong, reduces the viability of cells and leads to neurodegeneration. This project targets deregulated autophagy in two exemplar rare disorders: Niemann-Pick type C1 (NPC1) disease and Wolfram syndrome (WS). Induction of autophagy has been beneficial in various transgenic or animal-based disease models. Although several chemical modulators of autophagy have been identified, some research has indicated that drugs identified in immortalized human cells or mouse cells may not be effective in human disease-affected cell types. The research team will be using different models based on pluripotent human stem cells – stem cells that can become any other type of cell – to identify candidate drugs that induce autophagy and that work in relevant tissues such as human neurons. The project’s overarching aim is to determine the most potent inducer of autophagy via drug repurposing that will have therapeutic benefits in patients’ brains and can also be used in other rare early-onset neurodegenerative disorders associated with defective autophagy. The research project aims to provide a robust experimental platform showing that targeting a common disease mechanism such as autophagy can be generalized to more than one neurodegenerative disease; that this can be extended in future to related conditions such as Batten/CLN3 disease; and that the data will support a future proposal for an early phase proof of concept and safety study in children with neurodegenerative disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Gene Replacement Therapy for Spastic Paraplegia 47
Funder: LifeArc

Abstract: Spastic paraplegia type 47 (SPG47), an inherited condition affecting children, is due to loss of neurons in the brain leading to muscle weakness. Patients develop cognitive defects including poor speech and intellectual disability, in addition to loss of movement. A deficiency of the AP4B1 protein causes the loss of neurons. The project aims to restore the AP4B1 gene into cells using virus carriers modified to remove all their harmful properties, making them safe for human use. The team successfully used this approach to restore the level of AP4B1 protein in skin cells donated by an SPG47 child and demonstrated the safety of the approach in healthy mice. These results generated great hope and optimism among patients and their families but further studies are needed before entering clinical application. The project aims to: - test the approach in neurons derived from skin cells donated by SPG47 children - determine the minimal dose of the carrier that generates impact in the animal model - assess potential adverse effects in a research pilot safety study - request advice from the regulatory body in the UK and the USA


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: AAV9-mediated gene targeting of natural antisense transcript as a novel treatment for Dravet Syndrome
Funder: LifeArc

Abstract: Dravet syndrome is a rare neurological condition that is often described as a complex form of epilepsy. Children and adults with this lifelong condition will experience severe seizures that are difficult to control. Individuals with the condition may also suffer from varying degrees of intellectual disability and a spectrum of associated health conditions (known as ‘comorbidities’) – which may include autism, ADHD, challenging behaviours and difficulties affecting their speech, mobility, eating and sleep. 80% of patients with the condition carry a mutation in the SCN1A gene which encodes a sodium ion channel, NaV1.1, which functions to maintain normal firing patterns in neurons. Mutated NaV1.1 channels in Dravet syndrome patients do not function properly, which results in abnormal neuronal activity. There is no cure and current treatments have limited benefit, as well as side-effects. With this funding, Dr Karda aims to develop a gene therapy for Dravet syndrome. The approach involves delivering a gene element, using a viral vector, in order to increase healthy SCN1A expression and thereby restore the number of functional sodium ion channels, which in turn should normalise neuronal excitability. The project will test the novel gene therapy in mice which have a deletion in the Scn1a gene (mouse equivalent gene) and therefore are a model of Dravet Syndrome. The Dravet mice, like the human Dravet patients, contain one functional gene and one non-functional gene and show seizures, cognitive impairment and premature death, which makes it a clinically relevant model of disease. Treatment is expected to upregulate the Scn1a gene, producing more functional sodium ion channels, which should restore normal neuronal activity. The aim is to generate an optimised, clinically relevant gene therapy treatment which has demonstrated robust efficacy and safety in a clinically translatable model of the Dravet syndrome disease. The gene therapy has the potential to treat all patients with an SCN1A mutation that causes loss of function, regardless of the specific mutation. It could potentially reduce or completely stop seizures, cognitive impairment, ataxia (an inability to coordinate muscle movements) and premature death.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL