NIHRDataInsights/HRCSData huggingface dataset:
Title: JPND Alpha-synuclein pathology propagation in Parkinson's disease and quest for novel protective strategies
Funder: Medical Research Council

Abstract: In the present proposal, we have assembled leading alpha-syn, PD and microbiology research groups in Europe to address major questions. We hypothesize that specific forms of aggregated alpha-syn are key substrates for propagation of synucleinopathy in a first step from the peripheral nervous system to the brain, and then through the different brain regions. In the physiological situation, alpha-syn exists predominantly as a monomer and is enriched in synapses. In pathological states, alpha-syn undergoes structural changes that lead to the formation of oligomers and amyloid fibrils, ultimately leading to the formation of the Lewy Bodies found in PD brains. Accordingly, the initiation and severity of alpha-syn aggregation is highly associated with the levels of alpha-syn (such as in gene multiplications), with mutations, and with different environmental risk factors having a direct or indirect impact on alpha-syn aggregation (such as pesticide exposure or tabacco/caffeine). We will investigate the hypothesis that cell-to-cell propagation of alpha-syn aggregates coupled to the seeding capacity of the aggregates and enironmental impacts play central roles in the spreading of PD pathology and disease progression. The central role of propagation is highlighted by the growing realization that PD may start in the gut and thence spread to the brain via the vagus nerve, though the underlying mechanism remains unresolved. Various post-translational modifications of alpha-syn (such as phosphorylation, truncation, ubiquitination and nitration) not only determine the protein's function, but, more importantly, affect alpha-syn localization, aggregation and spreading between cells. In this complex context, a better understanding of the links between genetic, sequence, biochemical and cellular determinants of alpha-syn oligomerization and amyloid fibril formation, and spreading of the pathology, is essential for the development of novel diagnostic and therapeutic strategies for PD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Deep and Frequent Phenotyping; combinatorial biomarkers for dementia experimental medicine
Funder: Medical Research Council

Abstract: The D&FPhen study follows from a pilot phase that has established technical feasibility and participant acceptability. The study is for a repeated measures observational design in prodromal disease defined as no dementia but presence of episodic memory impairment >1.5SD from age adjusted norms in the context of AD pathology assessed using PET and CSF. Key design points include: - Participant recruitment through pre-existing parent cohorts. Ethical approval for this process, agreement from cohorts, technical platforms and proof of numbers meeting recruitment criteria are all in place - Utilisation of an algorithm established on ADNI data, tested in other datasets and proposed for US GAP-PAD studies to reduce screen failure based on age, cognition and APOE genotype. - Screen by PET amyloid with entry to study on a 4:1 ratio of screen positive and negative to avoid inadvertent disclosure of genotype or biomarker data - Repeated measures of both outcome comparator modalities (cognition and pathology) and assessment modalities between 2 months and 6 months in frequency based on projected one year change and acceptability criteria (see main section for full details) - Protocols harmonised with EPAD where shared and established in pilot phase for structural and functional MRI, electrophysiology by EEG and MEG, optical measures including ultra wide field studies and OCT and connected devices for gait, activity and cognition (see main section for full details) - Participant engagement including a start-up with a track record of increasing participation, a study within a study for participant engagement and burden in precision medicine studies and a process led by the Alzheimer's Society for Patient and Public Engagement (see main section for full details) - Sharing of data with minimal delay and facilitated data-use including building analytical communities through the leading global not-for-profit organisation for scientific data sharing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Sequential surface EMG recordings in motor neurone disease. Fasciculations as a biomarker of motor neurone health.
Funder: Medical Research Council

Abstract: Aims: To record the site, frequency and morphology of muscle fasciculations in MND patients and controls with benign fasciculation syndrome (BFS). We will compare our data on the disease progression within individual muscles and between anatomical regions with standard clinical measures of disease progression used in drug trials. Methodology: Phase 1 - We will conduct a 12-month prospective study, recruiting 24 patients from the King's College Hospital Motor Nerve Clinic, comprising 20 patients with MND and four with BFS. All MND patients recruited will have a diagnosis of probable or definite ALS by the revised El Escorial Criteria. At each monthly visit, we will take simultaneous 60-minute resting HDSEMG recordings from four muscles (biceps brachii and gastrocnemii). Intervals of one month may not capture the dying process of individual motor units. Therefore, we plan to incorporate a nested component, whereby four MND patients will attend weekly for the first two months. We will use two TMSi Refa-64 devices using 4x8-array sensors. Sensor placement will be standardized between visits. We will prune the recording to leave only epochs of total relaxation. We will perform standard clinical measures of disease progression at each visit. Phase 2- Our bioengineer collaborators at Imperial College are currently designing and testing prototypes of the sensors and transmission devices. We hope to validate this new equipment in a small-scale study (six patients), assessed at two time-points three months apart. We hope to test this equipment in our patients' homes and assess the benefit of remote sensing technology. Medical opportunities: If we can prove that HDSEMG parameters are a more sensitive measure of motor neuron health and accurately predict disease progression, then this technique could be used to rapidly identify positive drug effects and accelerate the process of drug discovery.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Understanding the role of DNA repair in Huntington's Disease pathogenesis: towards new therapeutic targets
Funder: Medical Research Council

Abstract: Huntington's Disease (HD) is a life-shortening, progressive, autosomal dominant neurodegeneration characterised by chorea, psychiatric disturbance, and dementia. Although it is rare (1 in 8000), patients often have long-term care needs that lead to considerable emotional and financial strain on families, carers, and healthcare systems. HD is caused by a CAG repeat expansion in the HTT gene that results initially in striatal medium spiny neuronal degeneration in the brain. There are currently no disease-modifying treatments. Previous work has implicated DNA repair processes in triggering CAG repeat expansion in striatal neurons, thereby accelerating the onset of HD. The work proposed here aims to address two questions: 1. Are DNA repair proteins (in particular FAN1) and their variants directly involved in CAG repeat expansion? 2. Can selective inhibition of DNA repair pathways slow or prevent repeat expansion? Genetic, cellular and biochemical approaches will be used to test these hypotheses. Novel variants in DNA repair genes associated with especially early or late disease onset will be identified through exome sequencing of a stratified HD population. A robust system for inducing and measuring CAG repeat expansion and cell viability in model HD cell lines (mouse and human) will be established, and then the effects of repair gene variants analysed. Certain DNA repair proteins of interest (including FAN1) will be expressed and purified, and their activities on CAG repeat-containing DNA assayed in vitro. We will then investigate whether small molecule inhibitors of DNA repair enzymes can abrogate CAG repeat expansion (and hence improve neuronal viability) in our cellular and biochemical assays. If they can, future exploitation of these leads could ultimately yield new drugs with the potential to delay or prevent disease onset. This would represent considerable progress in HD therapy and likely be applicable to the wider family of trinucleotide repeat disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Predicting dementia outcomes using simple, non-invasive assessments: a prospective population-based study
Funder: Medical Research Council

Abstract: Project aim: To develop a model that predicts the risk of developing dementia over a 5-10 year period in an asymptomatic population using simple, readily available, non-invasive measures and brief, touchscreen cognitive assessments Objectives: 1. Obtain and thoroughly explore the UK Biobank (UKB) baseline and follow up data 2. Identify the variables that most strongly predict incident dementia diagnosis (all-cause dementia, Alzheimer's disease and vascular dementia) 3. Create multivariate risk prediction models by combining the independently predictive variables 4. Validate the model using surplus UKB outcomes and data from external sources Methodology: I will obtain the UKB baseline data for all 503,000 participants as well as coded data for the entire cohort from linked health datasets (hospital admissions, death registrations and primary care). I will perform univariate logistic regression to identify the variables that most strongly predict dementia over a 5-10 year period and then use multivariate logistic regression to combine independently predictive variables to create the prediction models. I will investigate the incremental value of the addition of the cognitive testing data in "high risk" participants. Power calculation: It is generally accepted that 10-20 outcomes are required per variable in a multivariate logistic regression analysis, meaning that 100-200 cases would be sufficient for a 10-variable model. Our scoping work has identified a predicted 4000 all-cause dementia cases by 2017. Model validation: I will comprehensively validate the models using surplus UKB outcomes (internal) and using data from Generation Scotland, CPRD and SAIL databases (external). Outputs: My research will fill a key gap in the pathway to development of better interventions for dementia prevention and treatment, and will equip me with research skills that will provide the foundations of an ongoing clinical academic career in dementia research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Resolving the size and nature of neocortical population codes
Funder: Medical Research Council

Abstract: Human cortex has 20 billion neurons, but cortical neurons are typically studied one, or a handful, at a time. The building blocks of cortical function must reside between these extremes - in populations of neurons. Basic questions about cortical populations are unanswered. How many are engaged by a particular task? Are the computational roles they play distinct or overlapping? And how do they emerge over learning? Our aim is to answer these basic questions, using data from Karel Svoboda's lab that exhaustively sampled neuron activity from mice performing a tactile task. Mice learnt to determine the location of liquid reward by detecting the position of a pole with a single spared whisker. Simultaneous multi-plane, multi-photon imaging of somatosensory cortex captured volumes containing the entire layer 2/3 of the "barrel" region representing the spared whisker. With over 10000 neurons per mouse, and up to 1000 active neurons in a single contiguous recording, these data provide a unique snapshot of a well-defined functional bottleneck necessary to perform a task. To answer our questions, we will first use unsupervised, objective algorithms to determine the size and number of cortical populations distributed across the L2/3 region. We will then use combined dimension reduction and decoding model approaches to work out what sensory or behavioural property is encoded by the joint activity of each population. Finally, we will track how identified populations emerge over task learning, along with their encoding properties. Our results will the first to decompose a complete set of cortical populations, the first to show how multiple populations work together on a single computational task, and the first to show how multiple populations are recruited by learning, in what order, and how this predicts behaviour. Together, these will place strong constraints on theories of cortical coding and computation, and the interpretation of cortical activity data.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of circadian mechanisms in migraine-related pain
Funder: Medical Research Council

Abstract: This proposal will identify if dysregulation of circadian regulation impacts directly or indirectly on migraine susceptibility specifically, and chronic pain more generally. The role of circadian genes, their respective proteins, and downstream mechanism including altered glutamatergic signalling, will be investigated. Regional brain measurements will identify if local clocks influence migraine-related pain and cortical excitability leading to enhanced cortical spreading depression (CSD), the experimental correlate of migraine aura. CSD thresholds, head pain trigeminal nociceptive thresholds and trigeminal nociceptive activity (c-Fos) will measure migraine susceptibility. These results will indicate how the underlying pain processing trigeminovascular system is altered in transgenic mice harbouring a human circadian sleep disorder mutation that is comorbid with migraine with aura and the impact of experimental alteration of light-dark cycles as a model of jetlag. Specific mechanisms will be investigated using immunocytochemistry and biochemistry to detect alterations in clock genes (e.g., Per2, Clock & Bmal1), their respective protein products, glutamatergic signalling (e.g., phosphorylated NR1/NR2B NMDA receptor subunits & Eaat1) and important kinases (Casein kinase 1delta/epsilon). This proposal will identify novel knowledge regarding the circadian rhythm of migraine biology and will confirm or refute the role for altered circadian regulation in migraine triggering and other pain disorders. If refuted, efforts will be concentrated on the underlying mechanisms of disruption leading to the comorbidity of familial advanced sleep phases and migraine. Either way, this will open up new avenues for the development of targeted lifestyle interventions and pharmacological therapy to treat this disabling neurological disorder.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: How does neuronal activity regulate central nervous system myelination?
Funder: Medical Research Council

Abstract: The myelination of central nervous system axons by oligodendrocytes is essential for nervous system formation and function. In addition to facilitating rapid nerve impulse conduction, it is now clear that myelin provides metabolic support to axons, and that myelin is an important regulator of learning and memory. Myelin is made well into adult life by newly differentiating oligodendrocytes and remodeling of existing myelin, and the ability to make new myelin is central to our nervous system's capacity to replace myelin lost in diseases such as multiple sclerosis. However, the regeneration of myelin by oligodendrocytes (remyelination) is imperfect and ultimately fails, and thus the promotion of endogenous remyelination is an important goal. It is now clear that neuronal activity regulates myelination and remyelination in the CNS. Using zebrafish as a model, we have shown that activity-driven vesicular release from axons regulates the number and length of myelin sheaths made along single axons. In recent years we have generated a suite of transgenic reporters to directly observe many aspects of myelination in vivo over time, and methods to visualize and manipulate neuronal activity and vesicular release in the living animal. We have recently developed a transgenic system to non-invasively induce oligodendrocyte cell death and demyelination in zebrafish, a model in which we can use our transgenic reporters to visualize remyelination as it happens in vivo. In this proposal we will use live imaging, transgenic manipulation of neuronal activity and genetic analyses to answer three key outstanding questions: 1, How dynamic is myelination along single axons over time and how are distinct stages of myelination regulated by vesicular release? 2, What are the molecular mechanisms by which vesicular release regulates myelination? 3, How does activity-driven vesicular release regulate remyelination? This work will provide insights into brain formation, function, and repair.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The Role of Neural Activity in Enhancing Axon and Presynaptic Regeneration in the Adult Injured Neocortex In Vivo
Funder: Medical Research Council

Abstract: Careful regulation of synaptic connectivity in the adult brain is essential for normal brain function. It is now clear that even mild alterations in synapse morphology and function give rise to cognitive impairment, and pharmacological agents able to counteract these alterations may improve the symptoms of some of such conditions. The neocortex, a brain area unique to mammals, is affected in numerous developmental and degenerative diseases as well as acute injuries, with long-range excitatory projections being particularly vulnerable. While in the periphery damaged nerves are known to mount a regenerative response, this does not successfully happen in the central nervous system and cortical damage usually leads to devastating and irreparable consequences. Devising new strategies to promote the repair of cortical circuits is therefore a major goal. However, due to the challenge of tracking axons and large numbers of bona fide presynaptic terminals over extended periods of time in vivo, profound gaps remain in our understanding of cortical axon and presynaptic regeneration. The objective of this proposal is to determine how neural activity, a critical regulator of neuronal structure and dynamics during development, can enhance axon and presynaptic connectivity in damaged cortical circuits in vivo. To address this issue, I propose to combine high-resolution in vivo 2-photon axonal and presynaptic imaging assays established by my team, strengthened by the ability to manipulate neural activity and gene expression in single neurons in vivo. The project will thus deliver critical insights into how synaptic connectivity and repair are controlled in the living brain. This knowledge is needed to design drugs and stimulation-based treatments that can fine-tune the rate of axonal and synaptic reorganization for neurological intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Recovery from vestibular dysfunction following Traumatic Brain Injury: A prospective behavioural and neuro-imaging study
Funder: Medical Research Council

Abstract: CLINICAL NEED: Traumatic Brain Injury (TBI) is the commonest cause of chronic disability in young adults. We found in 111 consecutive head injury patients (Fig.1), 86% had symptoms and/or signs of imbalance. IMPACT OF TBI-RELATED VESTIBLAR DYSFUNCTION: Post-TBI imbalance is an independent predictor of failure to return to work but the cause of imbalance in chronic TBI patients is unknown in 25%. TBI IMPAIRS THE BRAIN'S PROCESSING OF THE VESTIBULAR SIGNAL: Patients without inner ear vestibular function display a complete loss of vestibular responsivity, from loss of the vestibular reflexes, to a particular type of gait dysfunction ('vestibular ataxia') as well as an absence of any perception of vertigo during stimuli that would ordinarily provoke this sensation. In the 84% of acute TBI patients with NORMAL INNER EAR FUNCTION, we found a normal vestibular reflex responsivity (e.g. vestibular nystagmus) however we found a vestibular ataxia and an impaired perception of vertigo. The combination of preserved vestibular reflexes and impaired perception and balance indicate an impaired brain processing of the inner ear vestibular signals. The loss of vestibular sensation of self-motion could itself lead to falls since there is no indication of excessive sway, especially in the dark. WHAT WE WILL DO: We will prospectively recruit acute TBI patients (and matched controls) and prospectively acquire data on functional outcome, falls, laboratory measures of vestibular function (of reflex, perceptual and balance function) and structural and functional neuro-imaging. We will assess which of the behavioral and neuroimaging factors predict functional outcome and falls at 6 months. EXPECTED OUTPUTS: We hope to reveal the mechanisms mediating TBI-imbalance enabling a prediction of patients at high risk of imbalance, providing putative mechanisms for developing new treatments as well as objective measures to monitor the response to these treatments.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Sensory sequence representation and discrimination in cortical circuits
Funder: Medical Research Council

Abstract: How does the brain represent and decipher sequences? Temporal stimulus patterning over hundreds of milliseconds to seconds is a ubiquitous feature of events and scenes and enables perception of rhythm, speech or textures. How a sequential pattern is reflected in spiking activity across populations of neurons, integrated over time, and classified as a meaningful entity in an intact animal is unknown. We aim to dissect cortical substrates of sequence selectivity by combining a novel behavioural task for tactile sequence recognition in mice with state-of-the-art tools for targeting neuronal populations and recording activity. The experimental design allows precise control of stimulus and behavioural response: a head-fixed mouse receives a reward on licking a spout whenever it recognises a certain target stimulation sequence. The sequence is distinct from non-target ones only in its specific temporal order and patterning. To determine how sequence representations emerge, we will measure sequence selectivity in neurons at initial and later stages of processing in the somatosensory cortex; test whether neuronal selectivity to sequence identity changes during training; uncover representations of sequence identity in the collective activity of neuronal populations along the somatosensory pathway; and establish the causal participation of specific populations in sequence discrimination by optogenetically perturbing their activity while an animal performs the sequence recognition task. Recordings of neuronal activity will be carried out using two-photon imaging of genetically targeted populations and multichannel extracellular electrophysiology. A central neuroinformatics component will come from the application of novel computational methods to the analysis of neuronal responses. These techniques are established in the Maravall lab at the University of Sussex. The project will provide new insight into the neuronal activity underlying sequence perception.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL