NIHRDataInsights/HRCSData huggingface dataset:
Title: Predicting dementia in Parkinson’s: A genotypic and phenotypic study
Funder: Parkinson's UK

Abstract: This award is an extension to the ICICLE-PD study. The primary aims are to determine phenotypic and genotypic markers to identify people with Parkinson’s at high risk of developing dementia, and to better understand the anatomical, biochemical and genotypic mechanisms determining the transition from Parkinson’s disease (PD) to dementia associated with PD (PDD). These aims have clinical relevance but will also provide an essential platform for improved targeting of future drug treatments for cognitive impairment associated with PD. Our baseline cohort comprises 263 people with incident PD and 100 age-matched controls. Each participant has undergone a range of tests and assessments at baseline and is being reviewed every 18 months. The reason for the extension is to provide additional time for more study participants to reach the end-point of dementia (or death) which will greatly enhance the power and significance of this study. Whilst some results from ICICLE-PD will validate (or otherwise) previous findings from other studies our dataset is unique in terms of its size, the fact that it encompasses two distinct geographical areas, enrols patients at diagnosis, and its depth and breadth of assessments including cerebrospinal fluid, imaging, neurophysiological, detailed gait and sleep analysis. Ultimately, clinicopathological correlation will also be possible, since brain tissue donation is being requested routinely.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Characterisation of the long-term prognosis of Parkinson's and development of statistical models to predict prognosis
Funder: Parkinson's UK

Abstract: Many aspects of prognosis in Parkinson’s are unclear, including to what degree mortality is increased and which factors influence prognosis. There are no prognostic models available in Parkinson's. Improved understanding of prognosis and in particular the development of prognostic models has important clinical and research benefits. The optimal way to obtain such prognostic data is long-term follow-up of community-based incident cohorts. Aims: 1. To perform systematic reviews of mortality and disability in Parkinson's 2. To identify factors that influence prognosis in an incident cohort 3. To develop prognostic models in Parkinson's Methods: We will perform systematic reviews of previous studies of mortality and disability in PD and metaanalyses where possible to put our new data into context. We will provide new data on the long-term prognosis of Parkinson's by further follow-up of an existing representative community-based incident cohort of 212 patients with Parkinson's, their carers and 266 matched controls. Data on multiple outcomes including mortality, impairment, motor and non-motor complications, disability and quality of life and carer burden are collected annually. We will describe patient and carer prognosis in terms of these outcomes. We will then extend previous work about which factors influence specific outcomes (survival, impairment, dependency in activities of daily living and quality of life) using multivariate regression analyses or Cox proportional hazards modelling and, with judicious selection of variables, develop prognostic models to predict survival and death or dependency. We will perform internal validation and, if possible, external validation in another cohort.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: The role of phosphodiesterase 10A (PDE-10A) in Parkinson’s L-dopa-induced dyskinesias: a proof-of-concept and double-blind, placebo-controlled randomized in vivo PET and clinical study
Funder: Parkinson's UK

Abstract: L-dopa-induced dyskinesias (LIDs) occur up to 90% of Parkinson’s patients after chronic L-dopa treatment. The pathophysiology underlying LIDs in Parkinson's is poorly understood and current treatments generate only minor benefit for the patients. Experimental work on animal models of Parkinson's has indicated that the intracellular protein phosphodiesterase 10A (PDE-10A) is located almost exclusively in brain areas affected from Parkinson's such as the striatum, where it regulates neuronal activity through the second messenger cyclic nucleotides cAMP and cGMP. In dyskinetic Parkinson's rats, plastic changes arising from advanced dopaminergic denervation lead to reduction of second messenger system due to PDE-10A hyperactivation. In our study for the first time we aim to test this mechanism in vivo in human Parkinson's participants, by investigating with positron emission tomography and a novel ligand tagging PDE-10A, the activity of this enzyme in Parkinson's patients with LIDs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: TIGAR, a p53 inducible inhibitor of glycolysis and mitophagy as a novel target for disease-modifying therapy in Parkinson's
Funder: Parkinson's UK

Abstract: Background: Genetic research has provided crucial new insight into the pathogenesis of Parkinson’s but not yet led to any therapeutic advances. PINK1 deficient zebrafish share key biochemical and histopathological features with human Parkinson's, namely mitochondrial dysfunction and loss of dopaminergic neurons. Pilot data: Gene expression analysis in PINK1 mutant zebrafish revealed marked upregulation of the p53 inducible, glycolysis and mitophagy inhibitor TigarB, the zebrafish orthologue of human TIGAR. Importantly, TigarB knockdown completely rescued the dopaminergic neurons in PINK1 mutants. Our data suggest a crucial role of TigarB in the pathogenesis of PINK1-related neuronal cell death. Hypothesis: TIGAR modulation is a promising novel target for disease-modifying therapy in Parkinson's. Objectives (and methods): 1. To determine whether TigarB is upregulated by p53 in PINK1 mutant zebrafish (p53 Western blots, siRNA inactivation of p53 or its antagonist mdm2) 2. To investigate whether TigarB upregulation has a deleterious effect on mitochondrial function via reduced substrate delivery (in vivo assessment of glycolysis, using the XF Seahorse analyser) or attenuation of mitophagy (LC3 I/II and Cox IV Western blots) in PINK1 mutant zebrafish with and without TigarB knockdown 3. To assess whether TIGAR upregulation per se is sufficient to induce neuronal cell death in vitro (TIGAR overexpression in mouse cortical neurons) 4. To evaluate whether TIGAR is upregulated in human Parkinson's patient tissue, namely in PINK1 mutant fibroblasts (Western blots) or Parkinson's post mortem brain tissue (immunohistochemistry). Expected outcome: We will unravel TigarB-related mechanisms in PINK1 deficiency and establish their relevance to human Parkinson's.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Understanding acetylcholine drive of striatal dopamine transmission in an animal model of Parkinson's
Funder: Parkinson's UK

Abstract: Current mainstream pharmacotherapy of Parkinson's involves boosting dopamine release with the precursor l- DOPA. While initially effective, side effects limit its long-term use. It is critical that we identify new therapies. A balance between dopamine and ACh released from cholinergic interneurons (ChIs) has long been thought important to normal movement, but the precise roles for ChIs are only now emerging. New findings suggest that ChIs play critical roles, and show dysfunction in Parkinson's, that could be targeted in PD therapies. Using an optogenetic approach, we recently identified that ChIs operate a direct means of driving striatal DA release: synchronised action potentials in a few ChIs powerfully drives dopamine release by activating presynaptic nicotinic receptors, bypassing activity in dopamine neurons. We propose in this timely project, to understand how this powerful ChI-dopamine axis operates in a new mouse model of Parkinson's. Current ideas about ChI dysfunction have arisen largely from toxin models which do not recapitulate PD progression. Within the Oxford Parkinson’s Disease Centre we have developed a mouse model of human a-synuclein expression which shows age-related motor dysfunction and deficits in striatal DA transmission. We propose to test the hypothesis that ChIs show dysfunction, and to explore whether ChIs can be targeted to drive DA transmission in Parkinson's, using this new model in a pioneering combination with optogenetic technology. By identifying how striatal ChIs function in this model we will understand better whether ChIs can promote dopamine function as a future direction for alternative treatment strategies for Parkinson's.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: PD-HELP: Development of an intervention to increase help-seeking for non-motor symptoms in people with Parkinson’s
Funder: Parkinson's UK

Abstract: Non-motor symptoms (NMS) are common in Parkinson's and contribute significantly to the burden of disease, causing distress and decreasing quality of life. A high rate of non-declaration of NMS by patients means that some NMS remain unrecognized and unmanaged, even in specialist services. The present program of research aims to increase help-seeking for NMS and consequently receipt of clinical care. The study aims to fully define the main barriers which prevent patients seeking medical attention for NMS using both quantitative and qualitative methods. This evidence will be used to develop an online, individualised intervention to provide information-support and increase help-seeking for Nms A feasibility study will be conducted &nbsp;to assess the acceptability of the intervention. The feasibility study will also explore methods of assessment and provide sample size estimates to inform plans for a future controlled trial to assess the efficacy of the intervention. Once efficacy has been demonstrated it is our intention to make the intervention widely available via Parkinson's websites to increase help-seeking and ultimately receipt of clinical care for NMS among patients with Parkinson's.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: The integration of biomedical research, describing the biological processes relevant to Parkinson’s, into the Gene Ontology database
Funder: Parkinson's UK

Abstract: Genome wide association studies, next generation sequencing, proteomics and transcriptomic datasets are currently being employed in many research laboratories to identify the genetic modifiers that regulate the penetrance of Parkinson's and the genetic interactions that cause this polygenic condition. The constructive interpretation of the resulting high-throughput datasets will depend on the quality of annotations that are available for the identified gene products to detect relevant pathways, regulatory networks and biomarkers. Yet, there is a surprising and unacceptable gene annotation deficit within the neurological and immunological domains, both of which are relevant to Parkinson's. We therefore request support to carry out a systematic and comprehensive functional annotation of human proteins in these domains through the generation and population of Gene Ontology (GO) terms that can then be integrated into widely accessed public resources, including the GO Consortium database, UniProt and NCBIGene, as well as freely available functional analysis tools, such as ALIGATOR, BioProfiling and GeneMania. The generation of this resource, at a fraction of the cost of genome wide association studies, will further our understanding of the molecular mechanisms underlying Parkinson's and help researchers identify new targets for therapy. All annotations will be attributed to Parkinson's UK to help raise awareness for Parkinson's.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: NEUROLOGICAL
Title: Alpha-synuclein and ER-mitochondria interactions in Parkinson's
Funder: Parkinson's UK

Abstract: The endoplasmic reticulum (ER) and mitochondria form close associations and these facilitate a number of fundamental physiological processes including Ca2+ exchange between the two organelles. Electron microscopy (EM) studies reveal the presence of tethers that link ER with mitochondria but their biochemical nature is not properly known. We have recently identified the ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 as interacting proteins that form at least some of these tethers. Alpha-synuclein and other Parkinson's insults have recently been shown to disrupt ER-mitochondria associations. Our identification of VAPB and PTPIP51 as ER-mitochondria scaffolding proteins thus facilitates investigations to dissect the mechanisms that underlie these effects. The aim of this project is to test the hypothesis that alpha-synuclein, a protein intimately linked to both sporadic and familial forms of Parkinson's, perturbs ER-mitochondria interactions and that this is via an effect on the VAPB-PTPIP51 interaction. We have already obtained evidence that alpha-synuclein is present within the specialized region of the ER that is associated with mitochondria and that expression of alpha-synuclein disrupts the VAPB-PTPIP51 interaction. The specific objectives are: i) To properly quantify the effect of alpha-synuclein on ER-mitochondria interactions. ii) To determine how alpha-synuclein disrupts the VAPB-PTPIP51 interaction. iii) To establish high throughput assays to screen for agents that modulate the effect of alpha-synuclein on the VAPB-PTPIP51 interaction. Such agents might represent novel lead therapeutics for the treatment of Parkinson's.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Whole genome methylomic profiling in Parkinson's: an integrated genetic-epigenetic approach
Funder: Parkinson's UK

Abstract: Our understanding of idiopathic Parkinson's has recently been enhanced by large genome-wide association (GWA) studies which have collectively identified susceptibility variants at over 18 loci that increase risk for Parkinson's. However, the biological basis for Parkinson's associations identified through GWA studies remain unsolved. In this project we propose to look beyond the traditional aetiology of genetic mutations in Parkinson's by examining the role of epigenetic mechanisms in the idiopathic form of this disorder. We propose that epigenetic mechanisms can mediate an increased risk to Parkinson's, and in particularly, genotype-DNA methylation interactions can facilitate the increased risk carried by genetic susceptibility variants implicated by GWA studies. This proposal will address the paucity of epigenetic studies in Parkinson's by conducting a series of molecularly robust and statistically well powered analyses to establish whether DNA methylation (DNAm) is correlated with Parkinson's susceptibility loci. We will also investigate whether previously implicated biological pathways are enriched for changes in DNAm, directly following-up our previous observation that variants implicated by Parkinson's-GWA studies implicate genes of shared biological function. Finally, we will also perform the largest genome wide investigation of differentially methylated regions that either increase risk to Parkinson's or are correlated with Parkinson's progression. This work has the potential to impact greatly upon the clinical diagnosis, prognosis and future treatment of Parkinson's. Moreover, given the potential reversibility of epigenetic mechanisms it is possible that our analyses will highlight novel targets for the development of therapeutic interventions for Parkinson's.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Testing a combination therapy with Ras-ERK and mTor inhibitors for L-DOPA induced dyskinesia
Funder: Parkinson's UK

Abstract: L-DOPA remains the most effective treatment for alleviating Parkinson's disease (PD) symptoms but causes currently untreatable severe motor side effects, collectively known as levodopa-induced dyskinesia (LID). Recent evidence indicates that a key pathogenic factor for LID, linked to abnormally high dopamine-mediated responses, is the hyperactivation in the striatum of both the Ras-ERK and the mTor signalling pathways. Previous work by the applicant, funded by Parkinson's UK, identified a clinically relevant Ras-ERK inhibitor that, given systemically, is not only able to block cell signalling in a mouse model of PD and LID but also to partially revert already established dyskinesia. Since the inhibition of LID with maximal doses of this Ras-ERK inhibitor is incomplete, we hypothesise that a combination approach with a selected mTor inhibitor may provide a better therapeutic outcome. Hence, in this project we will test 5 distinct mTor inhibitors, already in advanced stage of clinical development for cancer treatment, for their ability to prevent in mice abnormal involuntary movements (AIMs), the rodent correlate of LID.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Over 2 years to investigate improved detection of seizure activity in the neonatal and infant brain using integrated optical imaging and electroencephalography.
Funder: Action Medical Research

Abstract: Background Newborn babies and young infants that are unwell often suffer with epileptic activity (seizures) associated with injury to the developing brain which is a major cause of death and long term disability. Each year in the UK, over 1,000 newborn infants born at term suffer seizures due to a variety of causes and preterm infants have an even higher risk of seizures. Epilepsy is associated with abnormal electrical brain activity and changes in blood flow in different parts of the brain. Seizures in the young can be difficult to identify but prolonged seizures can damage the brain, so it is important to detect and treat them early. Currently doctors routinely measure electrical brain activity using EEG, but this does not detect all seizures and this remains a major unsolved problem in medicine. The research project This project aims to use a new technique to improve our ability to diagnose seizures in this vulnerable patient group. Optical imaging is a safe non-invasive technique which detects changes in blood flow and oxygen levels in the brain. This team has developed a new system combining electrical monitoring and optical imaging. In preliminary studies, this technique has been able to show new information about blood flow in infants with brain injury. The researchers plan to develop this system further to improve our understanding of seizures, allow more accurate diagnosis and more effective treatment. If successful, this technique could be developed for clinical use within three to five years.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Over two years to investigate mapping sensorimotor connectivity in children with cerebral palsy: development of a clinical tool to understand and predict motor function deficits
Funder: Action Medical Research

Abstract: Background_x000D_ Cerebral palsy describes a group of disorders of movement, posture and coordination that are caused by damage to the developing brain before, during or soon after birth. The incidence of cerebral palsy is rising and current estimates from Europe suggest that two in 1,000 live births are affected making the condition a major public health concern. Advanced magnetic resonance neuroimaging techniques can be used to determine how connections in the brain that control movement and sensation are damaged in cerebral palsy. A key question is to determine how the damage is related to loss of movement and coordination. _x000D_The research project_x000D_ This project aims to answer this question by using new techniques that the researchers have recently developed for measuring how the movement and sensation parts of the brain cortex are connected to 'hubs' in the brain known as the sub-cortical structures. This will make it possible, for the first time, to investigate the relationship between these connections and movement in children with cerebral palsy. The team will study a group of 75 children between the ages of six and 12 years. This research could be the first step towards developing a tool that can predict future loss of movement and coordination in children with cerebral palsy. Further studies in younger children are planned which, together with this study, may enable healthcare professionals to determine the most beneficial course of rehabilitation for children with cerebral palsy at an early stage.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Over 30 months for using new quantitative MRI tissue parameter maps to detect and delineate focal cortical dysplasia (FCD) in children
Funder: Action Medical Research

Abstract: Background_x000D_ Epilepsy is a disorder of the brain which causes seizures. Seizures can cause physical injury and even death but they are also strongly associated with behavioural and developmental problems especially when suffered in childhood. Often seizures can be controlled with medication but some children with epilepsy do not respond to drug treatment. Many of these children have epilepsy arising from a single abnormal area (lesion) in the brain - called focal cortical dysplasia (FCD). It is sometimes possible to use surgery as an effective treatment if the FCD lesion can be clearly seen on Magnetic Resonance Imaging brain scans. Doctors often want a positive brain scan before attempting surgery, but 25 per cent of patients with focal epilepsy have a brain scan that looks normal. Although current MRI brain scans in patients being evaluated for epilepsy are fairly sensitive, lesion detection remains difficult. If detection and precise mapping of FCD lesions within the brain can be improved, this should enable more accurate evaluation of patients and lead to better outcomes for epilepsy surgery. _x000D_The research project_x000D_ These researchers aim to use a new MRI scanning technique that provides very detailed information about brain tissue. They will scan the brains of children with FCD and also the brains of healthy children (controls) and then evaluate the ability of radiologists to detect abnormalities using these new scans compared to standard scans. Since young children can find it difficult to remain still during scanning, the researchers will be using new motion correction technology to make sure the scans are of high quality. The team has already generated a database using brain tissue samples from 120 children with FCD collected over the last 20 years. This has allowed them to understand different types of FCD lesion and, more recently, to identify associated genetic markers. It is hoped that the new scanning technique will provide a non-invasive way of identifying lesions, thereby improving diagnosis and benefitting patients.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL