NIHRDataInsights/HRCSData huggingface dataset:
Title: The pilot clinical validation study of a novel pain scale for Parkinson's.
Funder: Parkinson's UK

Abstract: Pain is common across all stages of Parkinson's and consistently under-reported and under or inappropriately treated in clinical practice.1,2 There are currently no validated bedside scales to characterise and measure the various types of pain experienced in Parkinson's which is essential for high quality epidemiological studies and clinical trials. In this pilot study we will field test the first pain scale specific to Parkinson's based on relevant responses from 500 people with Parkinson's. The items in the scale (which has four dimensions) were thereafter constructed after analysis of the patient responses and advise from pain specialists. The scale will be tested for appropriate clinimetric evaluation of acceptability, internal consistency, reliability, construct validity (convergent validity with other measures of pain, internal and discriminative validity) and precision in a group of 150 people with Parkinson's across all stages and 75 control subjects matched for age and sex (control group). Test-retest reliability will be tested at(baseline and 7-15 days later in 50 patients. Patients will undergo other measures such as assessment of comorbidity, motor and non motor symptoms, quality of life and 'on' versus 'off' period assessment. This will be a multicentre international study led from King's using a protocol similar to development of several other instruments such as the non motor questionnaire which is now used worldwide and recommended by Parkinson's UK.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: The effect of aggresomes on centrosome function
Funder: Parkinson's UK

Abstract: Aggresomes are closely related to Lewy Bodies, structures whose presence in neurons is a hallmark of Parkinson's disease. Lewy Bodies contain substantial amounts of alpha synuclein, the gene for which is mutated in inherited forms of Parkinson's Disease. In experimental systems, mutant and normal alpha synuclein will cause aggresomes to form. One of the standard molecular markers for aggresomes, to see where the aggresome is located in the cell, is gamma tubulin. The normal function of this protein is to nucleate microtubules at the microtubule organising centre, the centrosome. Despite the aggresome being positioned in extremely close proximity to and sharing components with the centrosome, the effect of aggresomes on centrosome function has not really been investigated. If the aggresome does inhibit centrosome function, it could it turn affect intracellular transport and cell polarity both of which are very important for neuronal function and survival. We propose to use a larval fish model to test if aggresomes do affect centrosome function in neurons. We will induce aggresome formation in three-day old zebrafish larvae by microinjection of mRNA encoding alpha synuclein into fertilised eggs. We will then use immunofluorescence microscopy to observe how the centrosome and its microtubules are affected.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Towards the identification of allele-specific effects of the tau gene H1 haplotype that contribute to increased risk of PD
Funder: Parkinson's UK

Abstract: The tau gene, MAPT, H1 haplotype (H1), an important genetic risk factor in sporadic PD, is defined by an unusually large region of linkage disequilibrium on chromosome 17q21 that evolved due to a ~900kb genomic inversion. H1 is also associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and the basis of the increased risk is due to allele-specific elevations of MAPT transcription and changes in splicing of the alternatively spliced exons 2, 3 and 10. However, differences in DNA methylation of H1 and its inverted allelic counterpart, H2, suggest that the haplotypes are subject to different epigenetic modifications due to the different chromatin contexts of the inverted variants. Epigenetic changes in the form of DNA methylation and histone modifications are important regulators of gene expression and, we hypothesise that differences in chromatin context form an important basis of the allelic differences in gene expression. The particular aim of this proof of principle study is to develop quantitative allele-specific chromatin immunoprecipitation (haploChIP) protocols to identify H1/H2 differences in histone modifications that reflect the transcriptionally permissive, unfolded chromatin and the repressive, closed chromatin and how they correlate to rate of transcription and splicing. We will model this study on the H1/H2 heterozygous human neuroblastoma cell lines with focused haploChIP of targets within the MAPT promoter region that we have shown to harbour critical functional SNPs that are important drivers of H1 risk.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Prodromal Parkinson’s disease in primary care. Analysis of a large primary care dataset
Funder: Parkinson's UK

Abstract: The prodromal phase of Parkinson's disease (PD) is thought to last approximately 2-5 years before clinical diagnosis is possible. Large primary care datasets may be useful to examine clinically significant symptoms during this phase. Objectives: 1) Extract data of patients with PD from a large primary care-based UK for future analysis; 2) examine the association of so-called 'pre-diagnostic' features with later diagnosis of PD; 2) determine the time intervals of first and subsequent symptoms leading to eventual diagnosis. Case-control study from a primary care database including 1.6 million patients over age 50. Analysis methodology: 1) Extraction of data on all patients with a new diagnosis of PD who have information recorded of sufficient quality to allow further analysis. 2) Examination of the association of individual, previously identified or proposed pre-diagnostic symptoms with diagnosis of PD. 3) Calculation of time intervals from first recording of each of these features to clinical diagnosis of PD, as recorded in GP records. This study in a large, representative GP database will 1) provide a unique resource for further study of prodromal features of PD recorded in a real-life primary care setting; 2) establish the strength of association of diagnosis of PD with pre-diagnostic features of PD that can be identified in primary care; 3) establish the time line in which these pre-diagnostic features occur. The study will support earlier diagnosis of PD, increase knowledge on the development of PD, and provide a resource for further studies of prodromal and early PD.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Biomarkers of pain in Parkinson's
Funder: Parkinson's UK

Abstract: Pain in Parkinson’s is common and disabling yet under recognised and poorly understood. This study will investigate multiple factors contributing to pain in patients with early Parkinson's. We will collect detailed data on pain in patients recruited into the Proband study. The Tracking Parkinson's study is a large study of patients mainly with early Parkinson's, already funded by Parkinson’s UK. Funding will enable us to recruit over 1000 Proband patients into our pain study. By linking up with Tracking Parkinson's we have a unique opportunity to capture data on pain from a large cohort of well-characterised Parkinson's patients, and to attempt to identify biomarkers which associate with pain in early Parkinson's. We have 3 main aims in this study:- 1. Determine the prevalence, characteristics, associated symptoms and treatment response of pain and in particular neuropathic pain in a large cohort of patients with early Parkinson's. 2. Investigate the role of genetic polymorphisms in the COMT gene on the prevalence of chronic pain in Parkinson's. 3. Evaluate the contribution of small fibre neuropathy to the development of pain in Parkinson's, using a noninvasive method (corneal confocal microscopy). This is a baseline study in patients with early Parkinson's. Following this study we will apply for NIHR funding to expand into a longitudinal study; further dissect out the mechanisms contributing to pain in Parkinson's; explore the causes of neuropathy and small fibre neuropathy in Parkinson's; incorporate a novel Parkinson’s pain scale and trial therapeutic interventions for pain in Parkinson's.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: NEUROLOGICAL
Title: Re-creating the basal ganglia circuitry in a dish: Towards a model for developing therapies for Parkinson's
Funder: Parkinson's UK

Abstract: There is a lack of in vitro models of neurodegeneration in Parkinson’s that allow for functional measurement of the neuronal circuitry involved, and easy, reliable manipulation, to give accurate read-outs for screening new therapies. This innovative project aims to construct a replica of the basal ganglia circuitry affected in Parkinson’s by culturing specific neuronal subtypes within a Bio-MEMS microfluidic device. We will construct a device with separate chambers for four classes of neurons: midbrain dopamine neurons, striatal neurons, pallidal neurons and cortical neurons; each generated from dissected embryonic CNS tissue. The chamber containing striatal neurons will be connected to all other chambers using graduated microchannels, to allow unidirectional axonal afferents to grow in from the cortical and midbrain neurons, and for efferent projections from the striatal neurons to grow out into the chamber containing pallidal neurons. Thus we will create and interconnect the key nuclei of the basal ganglia.We aim to assess the function of this neuronal circuit by measuring neuronal function at the population level, using aluminium microelectrodes embedded within the base of the Bio-MEMS device. We will compare electrical activity with calcium imaging to assess neuronal responses within the circuit, to optimise accuracy/reliability of our system and to assess changes in neuronal activity with pharmacological stimulation/blockade. Establishing this novel in vitro model aims to lay the foundations to investigate neurodegeneration, to develop a more sustainable model using stem cell-derived neurons, and to become a high-throughput screening tool for emerging therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Single-centre open label exploratory phase two pilot study of exogenous oral melatonin for the treatment of nocturia in Parkinson’s
Funder: Parkinson's UK

Abstract: Parkinson's is the second commonest neurodegenerative condition. Although predominantly a motor disorder, Parkinson’s is associated with non-motor symptoms, nocturia being the commonest. The causes for nocturia are poorly understood, but it has a significant impact on sleep and quality of life in patients and also partners/carers. Current treatment options are limited. Nocturia is often associated with other sleep disturbances and recent evidence suggests that both may be associated with impaired circadian regulation. A novel approach is to target circadian disturbances, and preliminary studies have suggested that melatonin may be useful in managing nocturia. However no trials of melatonin have been carried out for nocturia in Parkinson’s. Objectives: The primary objective of this study is to evaluate the effects of melatonin on nocturia-related bother. Secondary objectives are to evaluate: 1) night time urinary frequency, 2) volume of urine at night, 3) incontinence and other lower urinary tract symptoms (LUTS), 4) quality of sleep, 5) quality of life, 6) partners/carer sleep, 7) Melatonin safety profile. Methods: Twenty patients with Parkinson’s reporting nocturia will be invited to join this study. After assessments, they will receive prolonged-release melatonin 2mg nightly for 12 weeks. Symptoms will be evaluated using frequency-volume charts and questionnaires assessing LUTS and sleep. Sleep diary will be kept, and a wrist actigraph will assess sleep efficiency. Partner/carer sleep will be evaluated by questionnaire and sleep diary. Expected outcomes: This preliminary study will help assess whether melatonin benefits nocturia in Parkinson’s, and whether it results in improved quality of sleep and life in patients and their partners/carers.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Biomarkers for dementia and cognitive decline in Parkinson's
Funder: Parkinson's UK

Abstract: Common non-motor features of Parkinson's disease (PD) include mild cognitive impairment (MCI) and dementia (PDD), with a long-term cumulative prevalence of 80% of developing dementia. The onset of PDD is highly variable, occurring 1 to 20 years from the onset of motor symptoms, with few predictive clinical, laboratory or biochemical biomarkers. The impact of PDD is substantial with major consequences for functioning, institutionalisation, psychiatric comorbidity, care-giver burden and mortality. The Discovery Cohort is a large, extensively phenotyped longitudinal cohort of early PD and at-risk subjects. This offers an ideal platform to investigate mechanisms of cognitive impairment in a population at high risk of future dementia. Indeed a substantial proportion (31-42%) of the cohort already fall in the 'Mild Cognitive Impairment (MCI)' range within the first 3.5 years of diagnosis, based on standard neuropsychological assessment alone. These patients are at increased risk of developing PDD, with at least 25% converting to dementia within 3 years. Serum samples have been collected and stored from each of the participants at baseline and each of their subsequent 18 month visits. Vitamin D[5], Apolipoprotein A1, Uric Acid and Epidermal Growth Factor (EGF) have all been proposed as biomarkers for cognitive decline in PD and/or progression, but lack rigorous validation. We will analyse 1000 baseline samples (800 PD patients, 100 at risk and 100 healthy controls) to determine whether they predict the onset of MCI, or conversion to PDD. Potential candidates will then be validated on the independent Tracking early PD cohort in future studies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Establishing Sustainable Knowledge Mobilisation Communities in Dementia Care
Funder: Department of Health (England)

Abstract: I want to know how to embed knowledge mobilisation in the everyday practice of communities of professionals and service users in sustainable ways. I am interested in dementia care and particularly in care transitions and the needs of informal carers. I will work with people in these groups to identify problems, figure out what knowledge they need and where we can get it, and then help incorporate it into what they do. Doing this will not only improve local health services and patient quality of life, it will allow me to improve our understanding of how to sustain knowledge mobilisation


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Defining the disease mechanism(s) in ALS/FTLD with SQSTM1 mutations
Funder: Motor Neurone Disease Association

Abstract: In this project we want to try to work out what is going wrong within the cells of people affected by amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which are closely related conditions. We want to do this in order to allow better treatments for ALS and FTLD to be developed in the future. Recent research has shown that some forms of ALS and FTLD are caused by mistakes in one particular gene which forms part of the DNA in our cells. The faulty gene then goes on to make a faulty form of a protein called p62. Quite how this faulty protein causes cells to malfunction is not known, and this is what we will try to find out. Cells need be able to dispose of their waste and unwanted materials, much in the same way that households do. We have an idea that in these (and probably other) forms of ALS and FTLD, a waste disposal system in the cells doesn't work properly, and it is this that causes the cells to malfunction. We think this because other research has shown that one of the key jobs of the p62 protein in cells is to control the waste disposal system. We will look at the effects of the faulty p62 protein using cell models - cells grown experimentally in the laboratory that we are able to easily manipulate. If we can prove there is a connection between the faulty p62 protein found in patients with ALS and FTLD and changes in the cell's waste disposal system, this could lead to a revolution in how doctors manage the symptoms of the disease. In fact malfunction of the waste disposal system we are investigating is already known to occur in several other diseases, and classes of drugs already exist (and in fact have been used in humans) that have the ability to correct the defects. Hence, this work has the potential to lead to patient benefit in a relatively short time-frame.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL
Title: Modelling ALS/FTD with SQSTM1 mutations in the fly
Funder: Motor Neurone Disease Association

Abstract: In this project we will generate completely new fly models of amyotrophic lateral sclerosis (ALS, motor neurone disease) and the closely related condition frontotemporal lobar degeneration (FTLD). We want to do this in order to understand the cellular processes that go wrong in these conditions and to allow better treatments to be developed in the future. Recent research has shown that some forms of ALS and FTLD are caused by mistakes in one particular gene which forms part of the DNA in our cells. The faulty gene then goes on to make a faulty form of a protein which we call p62. Quite how this faulty p62 protein causes cells to malfunction is not known. In the lab we will generate flies which produce the faulty p62 protein, including specifically just in motor neurones (the cells principally affected in patients). This has been done before for other proteins which are known to be faulty in ALS/FTLD but not yet for p62. We will look at the effects of the faulty p62 protein in the flies. Specifically, we will test whether they show the characteristic changes within their cells that are seen in patients with ALS and FTLD and if they have defects in their movement and lifespan. We would then use the flies as a ‘model’ of the human disease - to work out the biological processes that cause the motor neurones degenerate; to find out if alterations in other genes combine with the faulty p62 to produce the disease; and importantly to test for new drugs that could in the future be used to correct the cellular defects and therefore treat these devastating conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neurite Orientation Dispersion and Density Imaging ('NODDI') - a new approach to understanding cellular pathology in MND.
Funder: Motor Neurone Disease Association

Abstract: It is possible using magnetic resonance imaging (MRI) techniques to measure aspects of damage in the brain of people with MND. However, current techniques have limited scope for assessing damage to ‘neurites’, which are the extensions of nerve cells in the grey matter of the brain. Neurites are of fundamental importance in brain function. We will use a new technique called ‘NODDI’ (Neurite Orientation Dispersion and Density Imaging) to measure, for the first time, early changes in the integrity of key areas of the brain cortex in MND. This requires an MRI scan, identical to a routine MRI scan but lasting about 1 hour rather than 30 minutes. In addition, a research doctor will assess clinical features including muscle strength, activities of daily living, and thinking processes (cognition). In parallel we will study healthy volunteers as controls against which the measurements in MND volunteers can be compared. In order to understand how the predicted changes revealed by NODDI relate to brain function and disease, participants will also have transcranial magnetic stimulation (TMS) and electroencephalography (EEG). These allow us to measure key aspects of nerve cell function relevant to MND. In addition, because MND affects some areas of the brain associated with planning and thinking, we will be including two short tests of participants’ reasoning processes. The analysis of the MRI data will use well-established procedures to measure damage to nerve pathways (e.g., diffusion tensor tractography) plus new mathematical methods developed by our team for the NODDI technique. This approach will open new possibilities for understanding cellular and molecular processes in different forms of MND in the light of advances in the causes of MND, help us to design better trials, and target treatments more effectively to different types of MND.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A targeted proteomic analysis for biomarkers discovery in ALS
Funder: Motor Neurone Disease Association

Abstract: The lack of any substantial progress in the development of treatments that alter significantly the disease course in amyotrophic lateral sclerosis (ALS) depends on the as yet impossible task to measure objectively the degree of treatment response against what may be the natural disease progression. Recently, we have been able to observe that the plasma levels of the building blocks of axons and neurons, the neurofilaments, and of specific molecules that regulate the immune response to neurodegeneration can indicate different trajectories of disease development, distinguishing among patients between fast and slow progressors. The white cell component of the blood and the plasma are likely to contain proteins that could be used as biomarkers of disease progression and the collection of these biological materials from the same patient at different stages of the disease, may allow us to define moleculs which could be used to predict how aggressive the disease is in each affected individual. To uncover these informative markers, we propose the use of an innovative form of proteomics, a technique which provides the fragmentation of the complexes of proteins that constitute tissues into basic constituents, whose modification may explain a pathological state. Our strategy will be based on deciphering the protein composition of blood cells involved in immune activity generated by the loss of motor cells in the brain and spinal cord, taken at different stages of the disease from individuals with an already established speed of disease progression. By comparing patients with a pattern of fast and slow disease progression, we will disclose molecular signals that can be used along-sidethe determination of neurofilaments as main indicators of disease severity and treatment response. The partnership with Proteomic Sciences,a company which has been instrumental in developing soluble biomarkers for other neurodegenerative conditions, will allow access to a novel form of proteomics where proteins are tagged and identified minimizing confounding factors which are normally limiting the usefulness of 0this technique.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL