NIHRDataInsights/HRCSData huggingface dataset:
Title: Assessing the role of the noradrenergic locus coeruleus in healthy ageing and early Alzheimer's disease
Funder: Medical Research Council

Abstract: Pathological studies show that the major source of cortical noradrenergic projections, the locus coeruleus (LC), shows evidence of neurodegeneration during healthy ageing but that this is accelerated in conditions such as Alzheimer's disease (AD). Indeed, volume loss in LC precedes volume loss in earliest affected cortical areas such as entorhinal cortex in AD. However, because the LC has been a technically difficult structure to image in vivo, the role it might play in both the neurobehavioural as well as cognitive changes that accompany healthy and pathological ageing has remained largely unexplored. Our earlier work demonstrated successful and reliable protocols for functional and structural imaging of the LC in younger and older adults. The research outlined in this proposal will use these novel structural and functional imaging protocols, as well as pupillometric recordings, to investigate the contribution of changes in the LC to cognitive and behavioural changes in ageing. We will recruit younger adults, older adults with mild AD and healthy older controls. We will examine how decline in the structure and function of the LC contributes to the declines in episodic memory and decision making seen during healthy ageing and in the early stages of AD. Unlike previously reported paradigms, our task allows us to disentangle the respective roles of noradrenergic and dopaminergic brain structures, both of which are known to decline in dementia and ageing. Finally, we will examine whether a reduction in LC integrity is linked to reduced resting state connectivity and brain atrophy in relevant cortical target areas of LC (entorhinal and anterior cingulate cortex). The project will provide novel translational insights that can drive understanding and development of potential interventions to alleviate the cognitive and behavioural declines seen in healthy and pathological ageing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A new noradrenergic strategy to treat Impulsivity in Progressive Supranuclear Palsy
Funder: Medical Research Council

Abstract: Impulsivity is a distressing and injurious aspect of PSP that is commonly under-recognised and poorly managed, even when coupled with balance and swallowing difficulty, with high risk of falls, injury, and choking. It typically coexists with apathy and bradykinesia, and is not relieved by current dopaminergic therapies. Impulsivity is a complex construct, with dissociable pharmacological and anatomical mechanisms that impair response inhibition, reward sensitivity, and decision making. Our group and collaborators have provided robust evidence that response inhibition in patients with Parkinsonian disorders linked to PSP (e.g., Parkinson's disease and frontotemporal dementia) is modulated by noradrenaline (NA), a key neurotransmitter mainly synthesized by the locus coeruleus (LC). Our overarching hypothesis is that enhancing NA function via NA reuptake inhibitors can improve response inhibition and impulsivity in PSP patients, mediated by the prefrontal cortex and its connections to the caudate and subthalamic nucleus. This study will: (1) provide new quantitative evidence for the degree of loss of neurons in the LC, using post-mortem samples from PSP patients whom we have followed over the last 10 years; (2) apply advances in ultra-high-field MRI to quantify the LC in living PSP patients, together with a battery of behavioural tests of impulsivity and neuropsychology; (3) use formal models of behavior to track decision variables behind impulsive actions, and relate these to neural and disease markers, including brain network connectivity, and (4) test a repurposed drug, atomoxetine, to restore core neurocognitive systems governing the inhibition of motor responses in PSP. Our work will promote bidirectional translational research, between non-clinical and clinical neuroscience, mapping disease states to preclinical models of cognition and behavior; and guide subsequent clinical trials with better outcome measures and patient selection and stratification.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Sub-cortical systems for stopping
Funder: Medical Research Council

Abstract: Instructions for movement are transmitted from the brain to the spinal cord over various descending tracts. In primates, there has been much past emphasis on the corticospinal tract, which is undoubtedly a major pathway. Recently, our group have shown that the reticulospinal tract also is important in primate motor control, even playing a role in precise movements of the hand. All of this work concerns generation of movement; however, in some circumstances it can also be important to inhibit a movement. Previous work has looked at the cortical processes behind stopping a movement, and assumed that these act to prevent corticospinal output from primary motor cortex. However, there is also evidence for a pathway to the reticular formation from basal ganglia which may allow sub-cortical inhibition of output. Very little data exist on this in primates; it is important to understand this system, as deficits in it may underlie a range of clinical problems such as spasticity, rigidity and dystonia. In this project, we will use experiments in anaesthetised monkeys to characterise the different reticulospinal pathways capable of inhibiting spinal motoneurons, determining their input and output connections. We will then train monkeys to perform a reaction time task, in which they must respond to a 'go' cue, but prevent the movement whenever there is a 'stop' cue. We will characterise performance using the well-defined race model, allowing estimation of the stop signal reaction time. Neural recordings will be made from motor and pre-motor cortex, the reticular formation and spinal cord during task performance. Comparing the timing of neural activity with behaviour will show which centres could contribute to stopping. Finally, we will test the impact of stimulating these centres electrically or pharmacologically on behaviour, providing data on their causal contribution.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Functional and genomic analyses of novel epilepsy mutations
Funder: Medical Research Council

Abstract: The identification of genetic variants associated with epilepsy over recent years represents a major breakthrough. However, we now need to understand how mutations in the identified genes contribute to epilepsy and to translate this into potential therapies. This project will address these issues by focusing on STXBP1 - the second most commonly mutated gene in catastrophic infantile epilepsies. Our principal aims are to characterise the functional effects of disease-causing mutations in STXBP1 and to search for genetic modifiers that can ameliorate the consequences of those mutations. This will involve using CRISPR to replace the single copy of the orthologous Caenorhabditis elegans unc-18 gene with wild-type and epilepsy-associated mutant human STXBP1. These humanised animal models will be analysed for alterations in neurotransmission and behaviour, and for genetic suppressor screening. Biochemical interactions of the corresponding human recombinant proteins with functionally important synaptic protein binding partners will be analysed in vitro. Overall, this multi-disciplinary project will illuminate how genetic variation in STXBP1 causes functional changes that lead to epilepsy and may reveal compensatory cellular pathways that could represent novel targets for antiepileptic drug discovery


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Modelling changes in genomic network structure during development and oncogenesis
Funder: Medical Research Council

Abstract: Understanding interactions between genes and their transcriptional regulators is a fundamental question in genomics. Network models are a natural way to represent groups of these interactions. Transcriptional regulation in terminally differentiated cells is characteristic of cell type and environment, and changes in these regulatory interactions are inherent to disease progression. Biomedical science in the high-throughput genomic age has, for over a decade, been developing ever more innovative ways to collect increasingly vast quantities of data. However, the statistical techniques to represent, analyse and interpret such data still lag behind the means to generate them. In particular, there remains a lack of good computational statistical methods to analyse time-varying biological networks, i.e., methods which take account of dynamic changes in gene-regulatory interactions as cells are specified and change state. I will address this point, by developing novel time-varying statistical network methodology, to represent and analyse dynamic genomic interactions in neural development and related oncogenic processes. These models will be implemented as efficient computational algorithms, and will draw on a range of different data-types. They will be implemented as straightforward, freely available and well supported software packages for easy adoption by end-users in basic science biomedical research. In carrying out this research programme, I will develop models at the interface between biology and statistics, in a project involving collaborations with leading names in both fields. In doing so, I will answer important biological questions, and make new computational statistical tools available to others working in the biomedical sciences.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Modelling variability in the social brain across the lifespan
Funder: Medical Research Council

Abstract: New evidence suggests that as we get older our social abilities, such as our ability to understand other people's intentions (Social Understanding) and our willingness to help others (Prosocial Motivation) can change. Yet, we currently know little about the neurobiology of social behaviour across the lifespan. The aim of this fellowship is to use cutting edge techniques in computational modelling to provide a mechanistic framework for understanding individual differences in the social brain across the lifespan and after brain injury. (1)Social abilities change across the lifespan, as indexed by reduced social understanding and increased prosocial motivation. I will perform the first behavioural experiments to quantify and compare social abilities in young and older adults within a computational framework. (2)Activity in hypothesised cortical regions underpins social understanding and prosocial motivation I will use a combination of neuroimaging techniques (fMRI, DTI, rsfMRI) to test anatomically specific hypotheses about the regions that underpin social understanding and prosocial motivation. Using DTI and rsfMRI I will test whether age-related changes in the strength of connections between these regions accounts for age-related changes in task performance. (3)Hypothesised cortical regions are causally involved in social understanding and prosocial motivation To examine causal contributions of specific brain areas, I will test changes in social abilities after brain stimulation and in patients with brain injury. This work will provide the first computational and biological framework to understand individual differences in the social brain across the lifespan and how changes in the brain can lead to changes in social behaviour. This will provide researchers, clinicians and industry with an evidence-based framework from which to design strategies to scaffold healthy social ageing and to aid those with recovery after brain injury.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Life course aetiology of dementia and cognitive decline: improving causal inference
Funder: Medical Research Council

Abstract: Existing evidence for modifiable risk factors for dementia is inconsistent. This is perhaps unsurprising given the , such as the potential for reverse causation and selection bias. The overall aim of the proposed work is to improve understanding of the causal determinants of, and mechanistic pathways to, dementia and cognitive decline, using novel analytical approaches and cross-cohort comparisons. I will improve causal inference in Mendelian randomisation studies of dementia by using simulation analyses to investigate and apply methods for dealing with selection bias. I will assess whether people at increased genetic risk of Alzheimer's (based on a polygenic risk score) have different life course trajectories of cognitive capability than people not at increased genetic risk. I will use novel statistical methods (such as Mendelian randomisation, offspring instrumental variable analysis and bivariate multilevel modelling) to identify causal risk factors for dementia and cognitive decline across the life course and use novel mediation methods (such as network Mendelian randomisation, counterfactual, decomposition and G computation) to assess possible mediation by circulating metabolites. The triangulation of research findings across different analytical methods and across cohorts in different settings is novel and will increase confidence in my findings. I will use data from cohorts within Dementias Platform UK, the Avon Longitudinal Study of Parents And Children (UK), EPIPorto (Portugal) and The HUNT Study. This work has the potential to inform preventive strategies, which is important given the rising economic burden of the ageing population and because current treatments are unable to delay the onset of, or cure, dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: NEUROLOGICAL
Title: From neurotransmitters to dynamic connectivity: A statistical mechanics approach to modelling cortical interactions.
Funder: Medical Research Council

Abstract: Neuroplasticity and neural connectivity are key to development across the lifespan. Plasticity occurs in healthy brains and underpins our ability to learn and form memories. Impaired connectivity has been associated with a range of pathological states. A number of clinical therapies aimed at stimulating plasticity in the brain are currently in use; however optimisation of such techniques has been hindered due to a limited understanding of the underlying biological mechanisms of plasticity. It is thought the neurotransmitters GABA and Glutamate play a key role in facilitating reorganisation of neuronal networks. Despite this, there is currently no mathematical model linking the synaptic elements of plasticity at the microscopic level to the macroscopic scale observed using clinical imaging technologies such as EEG or fMRI. I propose to develop a new biophysical model of neural activation and connectivity incorporating the release of neurotransmitters. I will use Statistical Mechanics to derive the mean field approximation of a neural mass which includes the synaptic dynamics of GABA and Glutamate as well as Hebbian and homeostatic plasticity mechanisms within and between the masses. I will use this model to better understand and improve current clinical interventions intended to stimulate plasticity for the purpose of rehabilitation or neuroenhancement. The proposed model will be validated with empirical data observed using fMRI and MRS data acquired at 7T. I will use a well-established stimulation paradigm (tDCS) which has previously been shown to enhance neuroplasticity and increase functional connectivity as well as affecting neurotransmitter levels. The imaging data will be used to infer the parameters of the model using parameter estimation and Bayesian model selection techniques. As a proof of concept, I will use the model to make predictions about optimising the effectiveness and safety of tDCS paradigms which will be testable by a neuroimaging lab.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Transplantation of "super-OPCs" to improve central nervous system remyelination.
Funder: Medical Research Council

Abstract: Multiple sclerosis (MS) is a common chronic inflammatory, demyelinating and neurodegenerative disease of the CNS which often starts in young adulthood, leads to disability, and as life expectancy is only slightly shortened, has major societal impact. There are now treatments that help reduce the relapses of early disease, but none which slow, stop or reverse disability progression in the later phase of MS. As disability reflects neurodegeneration, one focus of research into therapies to limit progressive disease involves enhancing repair of the demyelinated lesions (remyelination). This not only restores saltatory conduction but also metabolic support to the underlying axon. One such pro-remyelinating therapy is now in phase 2 clinical trial. Remyelination is carried out by endogenous oligodendrocyte precursor cells(OPCs), which differentiate into mature myelinating oligodendrocytes. However, this fails in MS in part due to negative signals released from damaged tissue, preventing either OPC recruitment to areas of damage or blocking OPC differentiation. In this project, we will genetically modify exogenous human OPCs to not respond to negative migration cues. We will then transplant these into a mouse model of demyelination, and determine whether these are better recruited to areas of damage and improve remyelination, with or without a pro-maturation stimulus. As a proof of concept, we will use factors from our previous work which are involved in remyelination: we will abrogate the response to the chemorepellent Sema3A (expressed in MS lesions which fail to repair) by knocking out its receptor, and use 9-cis retinoic acid to activate the Retinoid X receptor as a pro-maturation factor. These proof of concept experiments will be performed with human OPCs in a mouse in vivo model, to determine if this strategy may have future impact as a MS therapy. If successful, we aim to progress down the translational pipeline into first in man studies.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Advanced peptide-oligonucleotide therapy for Myotonic Dystrophy Type 1
Funder: Medical Research Council

Abstract: Myotonic dystrophy type 1 (DM1) is the most common adult form of muscular dystrophy. A severe congenital form affects infants and children resulting in severe disability and shortened life span. No treatment is presently available for DM1. The genetic basis of DM1 is a CTG repeat expansion in the 3'UTR of the DMPK gene. The favoured pathogenic mechanism involves RNA gain-of-function whereby repeat-containing transcripts from the expanded allele accumulate in affected cell nuclei where they sequester nuclear proteins involved alternative splicing regulation. This leads to dysregulated pre-mRNA splicing resulting in a multisystem disorder, affecting muscle, heart and brain. Antisense oligonucleotides (AO) are single-stranded nucleic acids which, when directed toward the repeat expansion, prevent sequestration of nuclear proteins to the CUG repeats. Proof-of-principle has already been demonstrated for this approach, however current generation AOs show poor distribution to muscle, including diaphragm and heart, and do not penetrate the blood brain barrier. This is critically important for disease modification since DM1 life span in is reduced due to respiratory and cardiac failure. Our SOLUTION is an advanced peptide delivery technology allowing development of peptide conjugated AOs of morpholino (PMO) chemistry thereby permitting highly effective systemic peptide-PMO delivery to all DM1 affected tissues. Starting with well-established (CAG)n PMOs, we will select and optimise peptide sequence, building on the well-established Pip peptide series, to identify lead and back-up peptide-PMOs with high efficacy both in vitro and in vivo. The most effective peptide-PMOs will be selected on the basis of efficacy and safety to determine an optimal treatment dose, including multi-dose, long-term treatment regimens, in model DM1 mice. This project will therefore identify an optimised, lead peptide-PMO compound suitable for clinical development and evaluation in DM1 patients.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: MICA Pharmacological, molecular and cellular mechanisms of muscarinic slowing (modification) of neurodegenerative disease.
Funder: Medical Research Council

Abstract: We aim to establish the mechanistic and pharmacological basis of M1 mAChR-mediated modification of neurodegenerative disease by delivering on the following key objectives. 1. Full characterisation of the modification of prion disease mediated by M1 mAChR allosteric and orthosteric ligands. This will involve determination of the biochemical, cellular, histopathological and behavioural impact of M1 mAChR ligands during prion disease progression from the on-set of the accumulation of misfolded prion protein through to end stage disease. 2. Establish the pharmacological and signalling basis of muscarinic modification of prion disease. We will establish the pharmacological properties that define efficacy of M1 mAChR ligands, paying particular attention to the differential action of orthosteric agonists vs. allosteric modulators. We will also investigate the signalling pathways downstream of M1 mAChRs that mediate modification of prion disease and determine the impact of signalling basis. 3. Establish the molecular mechanism by which M1 mAChR ligands modify prion disease. Using both a candidate approach and unbiased strategy as well as a system based techniques we aim to establish the mechanism of M1 mAChR drug action. This will not only include employing our expertise in biochemical techniques, including global proteomic and transcriptional analysis, but also involve engagement with our collaborators to apply neuroimaging, including fMRI and PET. 4. Determine if M1 mAChR-mediated neuroprotection in prion disease can be translated to AD using animal AD models, patient tissue and clinical data. We will employ rodent AD models that show either tauopathy or accumulation of misfolded amyloid protein to evaluate the potential of M1 mAChR ligands to modify AD-like disease progression. Access to AD patient samples (through Eli Lilly) for pharmacological and signalling studies, and clinical neuroimaging data will ensure a translational focus to this programme.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL