NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving the presurgical evaluation of patients with refractory focal epilepsy using advanced neuroimaging techniques
Funder: Medical Research Council

Abstract: Research questions: 1. Can arterial spin labelling (ASL) reliably identify interictal hypoperfusion and determine the laterality and broad localisation of epilepsy in comparison to FDG-PET? 2. Can neurite orientation density and dispersion imaging (NODDI) identify subtle structural abnormalities, particularly malformations of cortical development? 3. Are developmental MRI techniques such as sodium MRI and glucose chemical exchange saturation transfer (GlucoCEST) of benefit? 4. Can voxel-based and more advanced analyses of multimodal MRI data, including both conventional structural scans and these new data detect subtle abnormalities? 5. Is higher resolution diffusion tensor imaging (ZOOM-DTI) beneficial for optic radiation tractography? 6. Can automated seed placement and real time probabilistic tractography improve tractography processing? Patients with refractory focal epilepsy undergoing presurgical assessment and conventional MRI will be invited to have additional research scans and healthy age/sex-matched controls will undergo the same scans. Standard postsurgical follow up includes clinical assessment and repeat scans at 4 and 12 months. ASL and NODDI will be processed as in previous literature and software will be developed to perform voxel-based analysis and improve the detection of subtle abnormalities. This will improve the understanding of data from these scans in epilepsy and other conditions and allow a greater proportion of patients to undergo surgery with a cheaper and more streamlined assessment process. Patients with temporal lobe epilepsy will undergo ZOOM-DTI and tractography data will be used to guide surgery with postoperative assessment of visual outcomes. Atlas-based techniques for automated seed point placement will be further developed for the optic radiation and corticospinal tract. Tractography processing will be implemented on a graphical processing unit (GPU) to enable more accurate results to be available more quickly.


Research activity codes: 6.4 SURGERY
Health categories: NEUROLOGICAL
Title: Developing an evidence base for trials in genetic frontotemporal dementia - measures of disease onset and progression
Funder: Medical Research Council

Abstract: Frontotemporal dementia (FTD) is a common cause of young onset dementia, approximately equal in frequency to Alzheimer's disease in people below the age of 65. Its effect particularly on people of working age with young families represents a major health and economic burden on society. The only known risk factors for FTD are genetic, and around a third of FTD is familial. The aim of the study is to understand the ordering and temporal evolution of imaging and fluid biomarker change in genetic FTD and their clinical associations, forming an evidence base for future clinical trials. In particular, through comprehensive longitudinal phenotyping, the key objectives are to: characterise the earliest neuropsychological and behavioural changes; identify the earliest anatomical changes that occur and how these change over time; evaluate how measures of structural and functional connectivity change over time; examine the role of tau PET imaging as a marker of tau pathology; and correlate changes in CSF and serum markers with changes in neuroimaging. The experimental plan uses cross-sectional and longitudinal measures of behaviour, cognition, neuroimaging and both CSF and serum markers to elucidate the patterns of biomarker change in genetic FTD with the overarching hypothesis being that biomarkers can aid in the identification of disease and tracking of disease progression. The study aims to be the foundation for clinical trials in genetic FTD with the key outcomes being identification of markers of disease onset including those including those indicative of optimal time to start disease-modifying therapy and markers of disease progression that can be used as outcome measures in clinical trials, as well as estimations of the sample sizes necessary for those trials.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: MICA: HD-CSF: Studying cerebrospinal fluid to understand key CNS pathobiological targets in Huntington's disease
Funder: Medical Research Council

Abstract: Huntington's disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disease causing motor and psychiatric symptoms and dementia. No disease-slowing treatment exists. HD is caused by an expanded CAG triplet repeat in HTT, resulting in mutant huntingtin protein (mHTT). Promising therapeutic candidates nearing human trials include nucleotide-based huntingtin-lowering drugs and kynurenine mono-oxygenase inhibitors. Huntingtin has never been quantified in the living CNS, limiting our understanding of the role of wild-type and mutant HTT and their cleaved species in patients, and how these roles change over time; and preventing demonstration of target engagement by HTT-lowering drugs. We have developed a novel, ultra-sensitive immunoassay which can quantify mHTT for the first time in patient CSF, completely distinguishing controls, premanifest mutation-carriers and patients. mHTT level correlates with neurofilament light chain, indicating likely neuronal origin. Depending on the activity of KMO, the kynurenine pathway (KP) produces either neurotoxic or neuroprotective metabolites. It is deleteriously deranged in HD but has never been studied using accurate methods in patient CSF. HD-CSF is the first comprehensive longitudinal study of CSF to elucidate key CNS pathobiological targets in HD. CSF, blood and robust phenotypic data including volumetric MRI will be collected from an 80-subject cohort at two timepoints. Samples will be analysed using our novel assays to quantify mHTT and KP metabolites and examine associations with disease progression. These core findings will be enriched through the targeted study of CNS-specific proteins in CSF. Comprehensive longitudinal study of KP metabolites and huntingtin species in patient CSF, linked to robust clinical and MRI atrophy data, will enhance our understanding of HD neuropathobiology in the living patient CNS, and provide pharmacodynamic biomarkers to accelerate therapeutic development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Investigating deficits of axonal RNA metabolism and axonal signalling in amyotrophic lateral sclerosis
Funder: Medical Research Council

Abstract: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a relentlessly progressive neurodegenerative disorder, which causes loss of motor neurons (MN) leading to paralysis and ultimately death. It is currently untreatable, hence there is a desperate need for understanding its underlying mechanisms to develop novel and effective therapeutic strategies. Published research and preliminary data show that: 1) RNA metabolism alterations play a role in ALS; 2) MN axons are affected in the early stages of disease; 3) axonal RNA transport is altered in ALS and deficits in axonal RNA localisation make axons more susceptible to noxious stimuli; 4) key ALS proteins associate with signalling endosomes (SEs), endosomal organelles which are responsible for axonal signalling and transport of survival messages. These observations converge to define my research questions. I will investigate: a) the axonal RNA changes occurring in ALS; b) the mechanisms contributing to these changes, with a focus on RNA stress granules (cytoplasmic bodies, altered in ALS, where RNAs are protected during cell stress); c) the novel link between key ALS proteins and axonal signalling. In order to do so, I will combine the cutting edge tools and unique resources available in my Sponsor's laboratory and through collaborators. I will isolate MNs from a unique novel ALS mouse model which expresses an aggressive ALS-causative FUS mutation at physiological levels. I will then use microfluidic chambers and the UPRT RNA tagging technology in order to specifically isolate axonal RNA from MNs; I will then analyse SEs using magnetic isolation techniques and quantitative proteomics. Finally I will be able to validate my results using differentiated MNs derived from human iPSC isolated from ALS patients. These findings will be further tested in patient tissue and will be paramount for the identification of novel pathways and potential therapeutic targets in ALS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Steroid Receptors as targets for myelin regeneration by endogenous adult neural stem cells
Funder: Medical Research Council

Abstract: In this project the UK and China research groups with complementary expertise in remyelination biology will continue to further explore the remyelination enhancing properties of a plant steroid diosgenin. Using a combination of in vivo (toxin and immune-mediated rodent [transgenic] models of demyelination) and in vitro (primary OPC culture and myelinating co-cultures) approaches we will: 1) test whether diosgenin accelerates remyelination via oestrogen receptors, 2) explore the downstream processes mediating the pro-remyelination effects, and 3) test the affects of diosgenin on experimental autoimmune encephalomyelitis (EAE). The in vivo models we will use are 1) focal injection of lysolecithin into spinal cord white matter of adult mice, using conditional and genomic knockouts of oestrogen receptors and downstream mediating factors identified, 2) focal injection of ethidium bromide into the rat cerebellum peduncle, and 3) EAE, induced in C57BL/6J mice by immunizing with MOG35-55 peptide in complete Freund's adjuvant followed by i.p. injection of pertussis toxin. Animals with be treated with diosgenin at 20mg/kg, or corn oil as control. To compare the effect of knockout and/or treatment, the extent of OPC recruitment, oligodendrocyte differentiation and remyelination will be analysed with controls at 5, 10 and 21 days after lesion induction. In vitro/ex vivo approaches include: 1) primary isolated OPCs to test functions of identified mediating factors of diosgenin with small interference RNA knockdown techniques or lentivirus mediated overexpression (OPC proliferation, viability, differentiation will be examined using specific stage markers of oligodendrocyte lineage), 2) co-culture of OPC with dorsal root ganglion neurons to test the myelinating efficacy of OPCs subjected to various treatments, and 3) cerebellar slice cultures for remyelination studies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Epigenetic mechanisms regulating pluripotency from embryonic to adult neurogeneisis
Funder: Medical Research Council

Abstract: Recently, it was confrmed that the human SVZ continues to be neurogenic throughout life, but that instead of migrating to the olfactory bulbs as in other species, progenitors migrate into the adjacent caudate putamen and become calretinin+ neurons. The human SVZ can be cultured as neurospheres, proving that latent stem cells, which could be stimulated via epigenetic mechanisms, reside in the tissue. These findings make targeting human SVZ stem cells for neural repair more relevant than ever, since it proves that they are stem cells and migrate naturally to clinically relevant areas. This project is designed to uncover epigenetic mechanisms that can be used to control and enhance stem cell-mediated neurogenesis and repair. We have shown that loss of Enhancer of Zeste Homolog 2 (Ezh2) function, the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase, significantly reduces neurogenesis in the adult subventricular zone (SVZ)/olfactory bulb (OB) system. We now plan to extend these data by studying how PRC2 is functionally related to lnRNAs. Genomic analysis indicated that an unanticipated large percentage of genomic DNA encodes for lnRNAs. It has been estimated that about 20% of human lncRNAs bind to PRC2 and help direct them to specific nuclear sites. lncRNA expression in turn can be modulated by PRC2 and PRC1 suggesting recursive functional interactions between these molecules. Because of the large concentration of lncRNAs in the SVZ, we hypothesize that in this system they also functionally interact with PRC2 function. It is becoming increasingly evident that lncRNAs have clinical relevance via lncRNA interactions with PRC2. We will focus on PRC2 and two lncRNAs, RIAN and YSD14/Haunt. The Shen lab has generated both these knockouts. We will use complementary in vivo and in vitro approaches to study their function in ES cells as well as in normal postnatal and adult neurogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating mechanistic causes of C9ORF72-related amyotrophic lateral sclerosis (ALS).
Funder: Medical Research Council

Abstract: ALS is characterised by relentless motor neuron (MN) degeneration causing progressive paralysis and death usually within 3-5 years. Expansion of GGGGCC repeats in intron 1 of C9ORF72 is the commonest genetic cause of ALS, present in 10% of cases. Three potential pathophysiological mechanisms have been proposed: 1. Toxicity of the expanded c9orf72 pre-mRNA; 2. Aberrant synthesis of dipeptide repeat proteins (DPRs); 3. Haploinsufficiency due to decreased levels of C9ORF72 mRNA/protein. However, recent work has shown that C9ORF72 mRNA/protein levels are not significantly altered in C9ORF72-ALS patients. In contrast, a large body of evidence favours a toxic gain-of-function(s) of the expanded pre-mRNA via formation of RNA foci, sequestration of RNA-binding proteins and/or by repeat-associated non-ATG (RAN) translation and cytoplasmic accumulation of DPRs. This proposal aims to identify the contribution and molecular mechanisms of the toxic gain-of-function that causes C9ORF72-related neurodegeneration. To achieve this, we have generated induced pluripotent stem cells derived from control and C9ORF72-ALS patient fibroblasts which are further differentiated into MNs, or astrocytes recently shown to play a toxic role in MN injury. In addition, we have engineered inducible motor neuron-like and lentiviral transduction based cell models of primary MNs/astrocytes that allow controlled expression of either hexanucleotide repeat expansions (RNA toxic gain-of-function) independently of RAN translation, or production of DPRs (protein toxic gain-of function) independently of GGGGCC RNA repeats. These will allow an extensive and in depth examination of altered stress responses, cell survival, metabolic pathways, disease-related gene expression signatures and aberrant nuclear export of mRNAs. This innovative research work is likely to define novel therapeutic strategies for neuroprotection and to characterise much-needed biomarkers of disease progression and therapeutic response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Role of microtubule acetylation in Parkinson's disease
Funder: Medical Research Council

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD). LRRK2 is a multifunctional protein comprising GTPase and kinase activities that affects many cellular processes. How mutations in LRRK2 cause PD is not known. We have found that pathogenic mutations in the LRRK2 Ras of complex proteins (Roc) GTPase domain (R1441C) and the carboxy-terminal of Roc (COR) domain (Y1699C) domain preferentially associate with deacetylated microtubules, and inhibit axonal transport in vitro in primary neurones and in vivo in transgenic Drosophila larvae. Moreover these LRRK2 Roc-COR domain mutants caused locomotor deficits in vivo in adult transgenic Drosophila. Treating neurones with the histone deacetylase inhibitor Trichostatin A (TSA) to increase microtubule acetylation restored axonal transport in vitro and systemic administration of TSA to transgenic mutant LRRK2 flies was able to restore axonal transport in vivo. Furthermore post hoc administration of TSA reversed the locomotor deficits in adult LRRK2 Roc-COR mutant transgenic flies. Thus, our findings reveal a novel pathogenic mechanism for mutant LRRK2 and a potential therapeutic intervention for PD. In this project we will test the hypothesis that disruption of MT acetylation by mutant LRRK2 is a neurotoxic event in PD that leads to neuron death by disrupting axonal transport. Our aims are to investigate: (1) the therapeutic potential of MT acetylation and the (de)acetylase pathways involved in LRRK2 Roc-COR mutant associated familial PD; (2) how LRRK2 regulates MT acetylation; (3) the involvement of MT acetylation and LRRK2 in models of a-synuclein-related familial PD and sporadic PD In summary, this study aims to investigate how LRRK2 regulates MT acetylation and its involvement in PD pathogenesis. This will allow us to pinpoint and test more precise drug targets and to determine the therapeutic potential of MT acetylation drugs in PD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: The link between sequence and language processing in the adolescent brain
Funder: Medical Research Council

Abstract: The relevance of auditory processing to language skills is controversial. The need for acoustic analysis in early language acquisition is a self-evident truth: the controversy concerns what specific aspects of speech over what times scales are particularly relevant to language acquisition and further development , about which knowledge is limited. In this study we propose to carry out a systematic assessment of the perception of pitch, time intervals and timbre over different levels of sequence complexity from single sounds to sequences. The work tests the central hypothesis that there is a critical relationship between sound-sequence analysis and language skill, and examines whether this relationship changes over adolescence, when there are rapid changes in the auditory system. Auditory testing would be carried out on two cohorts aged 12 and 16 (>200 in each) using custom software and hardware in a classroom setting. Language measures would be carried out using a standardised battery of tasks. Analysis would seek correlation between overall auditory and language skill and, specifically, correlation between auditory sequence tasks and language skill. The analysis of two cohorts allows us to test the hypothesis that different types of sequence analysis correlate with language skill at different ages. Additionally we would carry out voxel based morphometry to test the hypothesis that the intraparietal sulcus is a critical substrate for both auditory-sequence skill and language skill, and that the substrate for sequence and language analysis changes over adolescence.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of NMDA receptor dysfunction in epileptic disorders
Funder: Medical Research Council

Abstract: NMDA receptors are key mediators of brain plasticity, converting neuronal activity into long-term changes in synaptic structure and function. Mutations affecting the GluN2A subunit have recently been identified in focal childhood epilepsies ranging from mild, self-limiting rolandic epilepsy to severe epileptic encephalopathies. By contrast, defects in GluN2B subunit have been linked to West syndrome, intellectual disability, autism and schizophrenia. This project aims to understand how different mutations in GluN2A and GluN2B cause such a wide spectrum of neurological disorders, defining pathogenic mechanisms, exploring new therapeutic avenues and generating new acute mouse models of NMDA receptor dysfunction. Our main objectives are to: (i) Use molecular biology to generate a series of GluN2A and GluN2B missense mutants for analysis in cellular trafficking assays. We will also use molecular modelling to predict potential pathogenic impacts of missense changes. These approaches will enable us to prioritise GluN2A and GluN2B mutations for ii) detailed electrophysiological analysis, which will examine changes in agonist binding, modulation by Zn2+, voltage-sensitive Mg2+ blockade, and changes to kinetics of NMDA currents. Preliminary data suggests that many GluN2A and GluN2B missense mutations involve gain-of-function, rather than loss-of-function; (iii) To explore the possibility of developing new treatments for epilepsy, by testing the efficacy of clinically-approved NMDA receptor antagonists such as memantine on mutant NMDARs; iv) To generate and characterise novel gain-of-function knock-in mouse models for GluN2A and GluN2B dysfunction that are defective in voltage-dependent Mg2+ blockade. This programme of research will use an integrated range of biochemical, electrophysiological, molecular biology and genetics techniques and will provide functional insights into the roles of NMDA receptors in health and disease, as well as new potential therapeutic strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the thermoregulatory role of neurovascular coupling and the anti-epileptogenic and neuroprotective effects of focal cerebral cooling
Funder: Medical Research Council

Abstract: This grant application will develop new and existing technology to assess exactly how one of the most promising treatments for focal cortical epilepsy works. The proposed treatment is called focal cooling (FC); essentially it means cooling down the part of the brain affected by epilepsy to stop or reduce seizures. FC offers the opportunity to develop a successful treatment after the initial cerebral event has occurred and therefore is extremely relevant to human patients. To investigate how FC works we will employ an acutely anaesthetised rodent model to achieve the following research objectives: (i) Measure the amount of temperature reduction needed and maximal duration the cerebral cortex and withstand with no side effects and to understand the role played by thermoregulation in neurovascular coupling. We will employ an array of sophisticated imaging and electrophysiological techniques for this research often simultaneously to reduce animal numbers. These include : 2-dimensional optical imaging spectroscopy - To measure hemoglobin changes from the surface of the cortex Laser Doppler Flowmetry to measure blood flow Tissue Oxygen measurements Direct measurement of cerebral cortical temperature changes Multi-channel electrophysiology to measure neural activity as a function of cortical depth. Functional magnetic resonance imaging (fMRI) to measure effects of FC from deep brain regions Thermal imaging to measure the spatial spread of temperature changes produced by physiological stimulation and focal cortical epilepsy Post mortem histology will be performed after each experiment to asses any tissue damage caused by the FC treatment. (ii) Apply the optimised FC method to an acute model of focal cortical epilepsy at time points relative to the clinic. The 4-AP model of focal cortical epilepsy has already been developed in Sheffield and a senior post doc is named on the application.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL