NIHRDataInsights/HRCSData huggingface dataset:
Title: Auditory attention in the amnesia of Alzheimer's disease; and the response to a central cholinesterase inhibitor
Funder: Medical Research Council

Abstract: Aims and Objectives My study will investigate whether impairment of the cortical system for attention contributes to poor verbal memory encoding and retrieval in Alzheimer‘s disease (AD). Incorporated into the design is the investigation of the modulatory effect of galantamine, a central cholinesterase inhibitor (CChI), on attention. Background Explicit episodic memory encoding and recall are dependent on attention. AD is associated with impaired episodic memory, but attention and its executive control are impaired early in the course of the disease. The motivation for my study is based on the notion that episodic memory impairment in AD is in part the consequence of reduced attention; and that the benefit of CChIs in AD may be attributed in part to modulation of attention. Design I will determine the functional and anatomical integrity of the right fronto-parietal cortical components of attention in patients with mild AD, using magnetic resonance imaging (MRI) techniques. The imaging data will be correlated with behavioural measures of attention, memory and executive function. Methodology The study will comprise 50 patients and 25 age-matched normal subjects. The control subjects will be scanned once and the patients will be scanned twice, before and six weeks after they have been randomised to treatment or no treatment with galantamine. Inclusion criteria will include: A clinical diagnosis of AD. MMSE <28 and >20 and ACE-R <85. Functional MR images will be obtained using standard echo-planar imaging sequences. The study design will investigate verbal memory encoding and retrieval with differing demands on selective and sustained attention. Anatomical imaging will consist of acquiring data suitable for DTI analysis. Image analysis will be performed with FSL and SPM software packages. Behavioural data will be acquired using CANTAB Alzheimer. Scientific and Medical Opportunities Major advances are being made in the application of symptom- and disease-modifying agents in AD. The ability to visualise, in vivo, the effects of these agents on brain networks, and the future potential to use the same techniques to study the reorganisation that may follow the initiation of disease-modifying drugs, is an important area of clinical neuroscience research. My study is designed to establish imaging biomarkers to investigate the interaction between attention and memory in AD, and its potential restoration with a licensed symptom-modifying agent. This research can, in future, be extended into an investigation of disease-modifying agents, and potential ‘cognitive restoration‘ after their use.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Whole-Exome Sequencing in Autosomal Recessive Parkinson's Disease
Funder: Medical Research Council

Abstract: It is now clear that there is substantial evidence for a genetic component to Parkinson‘s disease. Research to date suggests that rare variants account for a significant fraction of unexplained heritability. Through the neurogenetics clinic I have identified 30 individuals whose pedigrees suggest an autosomal recessive form of Parkinson‘s disease. Previous gene mapping techniques are not suitable for these families. These individuals are either from consanguineous parentages, and have such large areas of homozygosity that autozygosity mapping with positional cloning strategies are not feasible, or they are non-consanguineous and are too small to use linkage based strategies. I propose to carry out whole-exome sequencing (the selective resequencing of all exons in a genome) on an affected individual from each family. As exome sequencing will identify potential causal variants, it can be applied in families that are too small to provide meaningful information using linkage, allowing families and even single probands to be analysed jointly, irrespective of allelic heterogeneity. The literature suggests that we will identify 400-700 coding non-synonymous variants per exome, which are absent from currently available databases. However, exome data generated at UCL suggests that we will identify approximately 2500 coding novel non-synonymous variants per exome. I will identify genes with both alleles bearing a predicted non-synonymous variant (within homozygous areas for consanguineous individuals), I will further then reduce the pool of candidate variants/genes by filtering variants using functional, expression, and evolutionary data, also incorporating the possibility of genetic heterogeneity. A full resolution of the genetic underpinning of PD has yet to be achieved. Rare monogenic variants of common disease contribute eminently to our understanding of complex disorders by helping define and understand pathways that lead to neuronal dysfunction and cell death.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: An alternative retinoid pathway regulating vertebrate neurogenesis
Funder: Medical Research Council

Abstract: Generation of the nervous system is a fundamental process governed by the balance between proliferation and differentiation of neural progenitor cells. Retinoid signalling is well known to drive neuronal differentiation, however, it is also required for proliferation of neural tissue and the molecular mechanism that determines these distinct outcomes is unknown. Using a genome-wide screen we have identified Fatty Acid Binding Protein 5 (Fabp5) as a gene expressed in newly formed neural progenitors and recent findings in keratinocytes have shown that Fabp5 mediates an alternative retinoid pathway, which can promote proliferation. Our preliminary data shows that Fabp5 inhibits neuron production in the chick neural tube and is required for normal proliferation in this tissue supporting a similar function during the generation of vertebrate nervous system. We propose here to investigate the role, regulation and mechanism of action of Fabp5 using gain and loss of function approaches in chick and mouse neural tube and in ES cell derived neural progenitors.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Epigenetic modifications and their contribution to persistent pain states
Funder: Medical Research Council

Abstract: Persistent pain, whether caused through injury, disease or surgery, is usually temporary but involves adaptations in the spinal cord nociceptive circuitry, including central sensitization of dorsal horn neurons. This is a complex process that effectively amplifies incoming signals to prevent further damage while the body is repairing. These changes are supported by specific patterns of gene expression that are dynamic and evolve with time. Sometimes the pain persists after the injury has resolved and becomes a chronic pain state indicating maintained sensitization of spinal cord nociceptive networks. Could this be due to aberrant epigenetic modifications? Epigenetic modifications such as DNA methylation and chromatin remodelling regulate high-order chromatin structure crucial to the regulation of gene expression. Epigenetic processes imprint environmental experiences such as social interactions onto the fixed genome and therefore provide a bridge between the genes and the environment by refining neural networks according to experience. These processes are dynamic and reversible but can also result in stable alterations. Their de-regulation has been associated with a broad spectrum of neurological disorders. I will investigate the epigenetic processes that contribute to gene repression and activation in dorsal horn neurons in a model of joint inflammation. 1) DNA methylation is known to inhibit gene transcription. I will investigate DNA methylation status of a small number of genes previously identified. 2) Post-translational modifications of histone proteins, specifically at residues known to modify neuronal network function, regulate access to DNA. These modifications will be mapped onto nociceptive pathways during different phases of joint inflammation. 3) Descending controls from the brain and early life injury modulate pain behaviour. I will look at how descending controls and early life injury can regulate DNA methylation and histone modifications and I will investigate the correlation between epigenetic changes and pain behaviour. 4) Finally, to strengthen this correlation, I will modulate the expression of selected genes under epigenetic controls during joint inflammation and analyse their contribution to the pain state. This will include the investigation of micro-RNAs predicted by gene expression analysis and thought to fine tune neural circuits. This investigation will provide insights into the complex roles of epigenetics in central nervous system plasticity and set the stage for a deeper understanding of the molecular changes that contribute to chronic pain, an area of immense unmet clinical needs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The impact of systemic viral infections on the innate immune response in the brain in chronic neurodegeneration
Funder: Medical Research Council

Abstract: The defining features of several common neurodegenerative diseases include the accumulation of misfolded protein within the CNS, degeneration of synapses and neurons and the activation of astrocytes and microglia. Microglia, in common with other tissue macrophage populations, can adopt a number of different phenotypes that contribute to the outcome of tissue injury and disease. There is evidence that systemic inflammation, induced by bacterial and viral mimetics, can modulate the microglia phenotype in both the healthy and diseased brain. We aim in this study to test the following hypothesis: Systemic viral infection during chronic neurodegeneration switches the innate immune response of microglia from a relatively neuroprotective phenotype to a tissue damaging phenotype which will exacerbate disease progression. One of the best characterised laboratory models of chronic neurodegenerative disease in which accumulation of misfolded protein leads to activation of microglia and widespread neurodegeneration is prion disease. The locus and timing of the initiation of neurodegeneration is under precise experimental control and rodent models of these diseases display all the features of a chronic inexorable neurodegenerative process with early behavioural changes, loss of cognitive function and loss of motor function. The behavioural changes are associated with synaptic dysfunction and subsequent widespread death of neurones. We will carry out a study of viral infection before and during the course of a prion infection in our well established murine models. A comprehensive panel of readouts will comprise behavioural studies, pathological, biochemical and microarray analysis. We will establish whether viral infections modify the microglia phenotype in the diseased brain and if so how long this switching of phenotype persists and whether this may alter the course of disease. The findings from this study will have an important impact on our understanding as to how systemic viral infections may contribute to cognitive decline and disease progression in patients with chronic neurodegenerative disease. In understanding the exact role of brain macrophage populations we can establish the molecular pathways leading to neuronal damage thus facilitating development of future therapeutic approaches for protein misfolding neurodegenerative diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: An advanced model for neurodegeneration studies in the fruit fly drosophila melanogaster
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: In vivo molecular research in late-onset neurodegenerative diseases necessarily uses animal models, but symptoms in transgenic mice often take weeks to develop, and numbers of individuals required to obtain phenotypic statistical significance can be high. Invertebrate models such as the fruitfly play a significant role in replacing, refining and reducing the emphasis on mice, and have provided considerable molecular insight into these diseases. However, the current fly disease models are constitutive and the relevant transgenes are usually expressed pan-neurally or in specific organs such as the eye. Our aim is to use the unsurpassed molecular genetic ‘toolbox’ of drosophila, to refine the study of neurodegeneration in the fly. Specifically, we shall, 1. Develop a system whereby we can systematically control the expression levels of a disease bearing transgene such as mutant human huntingtin (mHtt) 2. Refine the system so we can examine the onset of neurodegeneration in a specific cell group rather than pan-neuronally or in particular organs. 3. Further refine the system so that the temporal dynamics of the onset of neurodegenerative disease can be studied with the use of inducible transgenes 4. Validate our approach and show proof-of-principle by extending this controlled methodology to studying the temporal dynamics of suppressors of the Huntington’s phenotype that we have previously identified in our laboratories. The experimental design involves modifying the Ga4/UAS inducible Gene Switch system to make it responsive to LexA rather than Gal4, while incorporating promoters to drive expression of mutant Huntingtin (mHtt) in the Pigment Dispersing Factor (PDF) circadian neurons in the brain. We shall induce mHtt at different ages during adult life and quantify neurodegeneration in PDF clock neurons by assessing circadian behaviour and by microscopy, thereby identifying the critical period when the clock neurons pass the point of ‘no return’. We shall then use suppressors of mHtt induced degeneration under Pdf-Gal4_Gene Switch spatio/temporal control, and investigate whether these suppressors can act as prophylactics to prevent subsequent neuronal damage. The impact of this new model shall be in its contribution to the refocusing of efforts on the timing of the critical cellular (and possibly reversible) events that lead to neurodegeneration. This refinement will consequently lead to a reduction in the numbers used, and, hopefully, to a paradigm change in the types of experiments that are done in mice. Our novel method can be generalised to almost any phenotype, and provides significant added value in the 3Rs.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Modified intrinsic excitability in transgenic mouse models of progressive beta-amyloidopathy
Funder: Medical Research Council

Abstract: Alzheimer?s disease (AD) is the major cause of dementia in the elderly. Our laboratory is interested in characterising neurophysiological deficits that arise in AD and understanding their causal mechanisms To do this we apply a variety of electrophysiological methods to study of pre-clinical animal models of AD-related pathology. Much of our work employs transgenic mice which over-produce Abeta peptides, molecules that are widely believed to play a crucial role in the pathophysiology of AD. In recent years, work with such mice, by ourselves and others has begun to reveal significant disturbances to synchronous network activity in the cortex and hippocampus, brain structures with crucial roles in cognitive function. In vivo EEG recordings reveal network hyperexcitability in these areas, which in some laboratories resembles epileptic activity. It is proposed that these disturbed patterns of network activity are likely to contribute to cognitive dysfunction in AD. As well as performing our own in vivo recordings, we have been investigating cellular level neurophysiological factors that could be the cause of these disturbed patterns of neuronal activity. Our work has focussed on modifications to intrinsic neuronal excitability, an aspect of neurophysiology well known to contribute to network hyperfunction in epilepsy. Using patch clamp recording from CA1 pyramidal cells in hippocampal slices, we have identified robust changes to intrinsic neuronal excitability and action potential waveforms in 2 different Abeta overproducing mouse lines. We also used nucleated macropatch recordings to identify a ~50% loss of voltage-gated sodium currents from the cell bodies of these neurones; potassium currents were, in contrast, entirely unaltered. All of these changes were absent in young animals, and their presence seems to parallel Abeta burden since they arise earlier in the more aggressive PSAPP double transgenic line. This application requests funding to follow up these findings in much greater detail. Our goals include: 1) Generating a more detailed understanding of the timecourse with which both altered excitability and sodium current depression arise. 2) Determining if similar changes to those observed in pyramidal cells occur in GABAergic interneurones. 3) Establishing if the changes to either excitability and/or Na+ channels can be reversed by pharmacological interventions that reduce CNS amyloid load. 4) Using dynamic clamp to establish if altered sodium current levels are solely responsible for the altered intrinsic excitability. 5) Examining if related changes to excitability and ion channels levels are seen in the axonal or dendritic compartments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The importance of complex spikes in cerebellar contributions to behaviour.
Funder: Medical Research Council

Abstract: The cerebellum is the largest sensorimotor structure in the brain and is crucial for the regulation of movements. It is a key target of damage in many diseases, including chronic alcoholism, fetal alcohol syndrome, a range of genetic disorders, tumours and stroke. Cerebellar damage causes impairment in motor function characterized by ataxia, dysmetria of voluntary movements and an impaired ability to learn new motor skills. How the cerebellum exerts its influence to control movements remains an issue of considerable uncertainty and debate. Because Purkinje cells are the only output of the cerebellar cortex, and their main target is the cerebellar nuclei, the behavioural consequences of cerebellar cortical damage ultimately must result from the abnormal synaptic control of the cerebellar nuclei by altered Purkinje cell activity. Purkinje cells discharge two types of impulse: simple spikes and complex spikes. In pilot experiments we have found that complex spikes can be further subdivided into two distinct waveforms (?spiking? and ?non-spiking?), and the type of complex spike a Purkinje cell discharges at any given time can influence simple spike firing rate of the cell under study. A fundamental gap in our knowledge of cerebellar information processing is the effect of Purkinje cell activity on nuclear output. Using a range of systems level approaches in anaesthetized, decerebrate and awake behaving animals (rats and cats), our overarching aim is therefore to determine how ?spiking? and ?non-spiking? complex spike activity modifies activity in the cerebellar nuclei. Specifically, we will test the hypothesis that ?spiking? and ?non-spiking? complex spikes exert a distinct inhibitory impact on cerebellar output: (i) indirectly, by differentially altering levels of Purkinje cell simple spike activity; and (ii) directly, by transmitting different amounts of information themselves to shape cerebellar nuclear activity. Acute experiments will study mechanisms in detail while chronic recording experiments will study Purkinje cell-cerebellar nuclear interactions during performance of a reach-retrieval task, including motor adaptation. Overall, the results from this project will significantly advance our understanding of how complex spike activity is translated into activity in the cerebellar nuclei and the behavioural significance of this transform. This should lead to an improved understanding of how movement disorders resulting from cerebellar damage occur.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Determining the genetic aetiology of early onset Parkinson's disease
Funder: Medical Research Council

Abstract: Although Parkinson?s disease (PD) is a common age dependant neurodegenerative condition about 5% of all PD patients develop disease before the age of 50 (Early onset PD ? EOPD). Three autosomal recessive EOPD genes (parkin, PINK1 and DJ1) have been identified and their discovery has led to new diagnostic tests and insights into the pathogenesis of PD. Many groups have developed cell and animal models of PD based on these genes. There is compelling evidence that there are further autosomal recessive (AR) genes to be identified for EOPD, based on segregation analyses, comprehensive mutation screening and on our own work on homozygosity mapping. We have ascertained over 250 UK patients with EOPD and are members of the International Consortium for PD Genomics (ICPDG), which has collated samples and data on 1400 EOPD patients. Previous gene identification has been based on linkage in known consanguineous families. The advances in next generation sequencing (NGS) mean that we are now in a position to resolve the genetic architecture of EOPD, in a ?linkage-free? approach. Our work indicates that a two-stage approach will be the most efficient. We have demonstrated an excess of genomic homozygosity in EOPD, largely contributed to by a subset of 71 patients in our sample set who carry an 8 Mbp or longer run of homozygosity (ROH). In stage 1 we will examine the entire exome of each of these 71 patients to identify genes that contain a homozygous rare putative loss of function (LOF) mutation. We anticipate that this will identify approximately 20 candidate genes. In stage 2 the exonic sequence of each of these 20 genes will be screened for homozygous and compound heterozygous mutations in the remaining 1300 EOPD patients and 4000 controls (via the UK10K and 1000 genomes projects). Case control analysis of rare bi-allelic LOF mutations will identify which loci are new AR PD genes. This two-stage approach provides a powerful (power 0.99) and efficient approach to identifying new genes for EOPD. Identifying the genetic basis of PD in these patients is the first step in understanding disease heterogeneity and appropriately designing and targeting disease modifying therapies. This work will also inform the design and provision of new diagnostic genetic screening panels.


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