NIHRDataInsights/HRCSData huggingface dataset:
Title: ACTIFCare: ACces to Timely Formal Care
Funder: Economic and Social Research Council

Abstract: In the absence of a cure that can alter the course of the Neurodegenerative Disorders, including the dementias, an early diagnosis is widely agreed to be important. Early diagnosis is seen as opening the way to future care and treatment, and can help people take control of their lives and plan ahead. Many EU countries have now adopted strategies to promote timely recognition of dementia. Timely access to dementia care services, such as home care, is also important for reducing health care costs, for example by postponing placement in a nursing home. Despite these developments, individuals are often not receiving services of the type, quality and timing that they need. This proposal aims to better understand the reasons for inequalities in access to healthcare. We will assess and compare health care systems giving access to formal home care across Europe using literature review, expert consultation and focus groups, to provide an overview of policies, services and systems At the individual level, we will assess the access to and use of formal care services by people with dementia and their carers in 8 EU countries, and examine how this relates to their (un)met needs and quality of life. A cohort of 400 people with dementia and their carers will be recruited across the 8 countries, and followed up for 12 months. In addition, costs, consequences and novel specific outcome measures will be evaluated. This will lead to the identification of best-practice pathways to formal care, in terms of efficiency and cost-effectiveness. This project will generate knowledge on best-practice with regards to an important stage of the dementia care pathway where there is great potential to impact positively upon quality of life in the short and long term.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: NEUROLOGICAL
Title: Support for carers of people with early onset dementia
Funder: Economic and Social Research Council

Abstract: RHAPSODY aims primarily at analysing the health and social care systems and infrastructures in six European countries that are available to the severely burdened yet underserved group of people with young onset dementia (YOD). YOD affects approximately 100 individuals in the population aged 45-64 years and their carers. In addition, RHAPSODY attempts to improve the management of people with YOD by supporting their carers. The main instrument for this will be an educational, web-based, interactive e-learning programme. A multi-disciplinary team of 8 main investigators from academia and industry representing the fields of psychiatry, neurology, neuropsychology, neuroscience, health economy and information systems as well as a patient and carer advocacy organisation from 6 countries have joined their efforts. They will analyse, evaluate and compare health and social care policies and strategies (macro level) as well as needs and access to service provision and care (individual level). As primary methods documentary analysis, focus groups and qualitative analysis will be employed. Using this evidence an established key component of dementia management will be tailored to the requirements of the target population of carers with regard to content and format of delivery. An internet-based e-learning programme is particularly appropriate in view of barriers related to low prevalence, geographical spread and reduced mobility. A pilot study will evaluate the telemedicine intervention with regard to feasibility, acceptance, cost- effectiveness, most appropriate outcomes and effect sizes in 3 countries.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Adaptive Implementation and Validation of the Meeting Centres Support Programme for people with dementia and their carers in Europe
Funder: Economic and Social Research Council

Abstract: MEETINGDEM aims to implement and evaluate an innovative and inclusive approach to supporting community dwelling people with mild to moderately severe dementia and their family carers, called the Meeting Centres Support Programme (MCSP), in three EU countries: Italy, Poland and United Kingdom. This evidence-based, person-centred, approach has been positively evaluated, and implemented in 90 meeting centers in the Netherlands, and is now well-placed to be trialled and implemented in other EU countries. Demonstrated benefits include high levels of user satisfaction, reduced behavioural and mood problems, delayed admission to residential care, lower levels of caregiving-related stress, higher carer competence, and improved collaboration between care and welfare organizations. Project partners in the three countries will utilise strategies and tools developed in the Netherlands and adapt them to country-specific requirements, establish a group of appropriate organizational collaborators in each country, develop an implementation plan and toolkit, implement MCSP, and evaluate the programme in a controlled trial in terms of its impact on the behaviour, mood and quality of life of people with dementia and carers, its cost effectiveness as a result of changes in use of other (more expensive) services, such as hospitals and residential care, and psychotropic medications. An overall evaluation will draw together findings from the three implementation countries to develop recommendations for successful implementation of the MCSP across the EU and beyond. The project will be carried out over a 36 month period. In Phase One (M1-18) activities will focus on establishing an initiative group of relevant organizations and user representatives in each country, exploring pathways to care and potential facilitators and barriers to implementing the programme, and developing country and context-specific implementation plans and materials. In Phase Two (M19-36) training will be provided to organizations and staff, after which the meeting centres will be established and evaluated for impact, cost-effectiveness, user satisfaction and implementation process


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Quantitative neuroimaging in disorders of consciousness caused by acquired brain injury
Funder: Chief Scientist Office (Scotland)

Abstract: The diagnosis of disorders of consciousness such as coma or vegetative state remains a major challenge for critical care and rehabilitation medicine. Standard clinical tests rely on behavioural assessment and therefore often lead to inaccurate results in unresponsive brain injury patients. In fact, recent research by the Universities of Cambridge and Liege has shown that as many as one in six patients diagnosed as vegetative may be consciously aware. In this study will we employ quantitative neuroimaging techniques such as functional connectivity MRI to address this diagnostic challenge. The primary aim of this pilot study is to identify novel biomarkers of functional impairment based on functional connectivity and integration and to translate this information into novel clinical tests to aid the diagnosis of disorders of consciousness. A further objective is to identify the most suitable connectivity measures and to provide effect size estimates for the use in future cohort studies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Development of disease-specific diagnostic tests for Alzheimer's disease and Lewy body dementia based on RT-QuIC analysis of cerebrospinal fluid.
Funder: Chief Scientist Office (Scotland)

Abstract: Dementia is a major public health concern that will increase in the next decade due to the ageing population. Currently the clinical diagnosis of Alzheimer’s disease (AD), the most common form of dementia, is made using clinical assessment and neuropsychological tests. Real-time quaking induced conversion (RT-QuIC) is an “amyloid seeding assay” which monitors the ability of biological fluids such as cerebrospinal fluid (CSF) to induce the formation of amyloid aggregates of selected proteins in real-time. Using this technique we have recently developed a CSF diagnostic test for sporadic Creutzfeldt-Jakob disease. We now wish to expand on our experience and expertise with this technique to develop RT-QuIC assays for both AD and Lewy body dementia, as these conditions frequently co-exist and may be mistaken for each other. These conditions are ideal candidates for RT-QuIC as they are associated with amyloid aggregates that bind Thioflavin T.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Promoting activity and preventing activity-related falls in Parkinson’s
Funder: Parkinson's UK

Abstract: The aim of this project is to discover how Activity-Related Falls (AR-Falls) contribute to the reduction in activity that accompanies the progression of Parkinson's. AR-Falls are common in PD but the evidence centres on falls at home. Some of the most common Fall-Related Activities (FR-Activities) have been analysed in detail but others remain obscure. Experiencing or anticipating AR-Falls may be among the factors that deter people with Parkinson's from persisting with exercise and active leisure following a diagnosis of Parkinson's. If it is possible to develop strategies that make certain FR-Activities safer and to make exercise and active leisure (with all the inherent benefits) more attractive to people with Parkinson's, the challenge remains to communicate this information to all relevant bodies. A postal survey will expand our understanding of the circumstances surrounding falls in Parkinson's and allow us to compare AR-Falls in contrasting settings. It will also allow us to identify people a) who have fallen tripping, stepping backwards and/or misjudging distances and b) abandoning previously enjoyable activities. We will invite the former to a laboratory-based movement analysis study using newly developed protocols for trips, back steps and misjudgements; we will interview the latter and complete a mobility assessment to explore perceived and actual physical performance. Finally, with people with Parkinson's and health and media professionals we will develop and test new methods of disseminating the study findings.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Modelling Parkinson’s with rat embryonic stem cells and transgenesis
Funder: Parkinson's UK

Abstract: Parkinson’s disease (PD) is a neurodegenerative condition that is clearly progressive. The spreading agent, α-synuclein, is a protein that is normally found to function in nerve cells in the brain. The existence of individuals with elevated amounts of α-synuclein exhibiting a very aggressive form of PD strongly indicate that any factor, whether environmental or genetic, leading to increased α-synuclein protein is crucial in initiating and progressing PD pathology. The mouse has been so far the main animal system used in scientific laboratories to address questions about causes and progression of degenerative diseases because they are amenable to genetic modifications. However, rats display complex behaviour, which make them more similar to humans than mice. For example, rats have complex emotions and cognitive abilities, and can even become depressed. For the same reason, rats constitute a better model system when it comes to testing drugs affecting neuronal functions. Taking advantage of the very recent advances in the genetic engineering of rat embryonic stem cells and zygotes, we aim to make genetically modified neurons and rats, which contain abnormal levels of human α-synuclein. We propose that these modified cells and animals will be able to mimic most aspects typical of human PD and will then be the ideal substrate for investigating the disease progression, and in the future for testing new diseasemodifying strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The Economics of Parkinsons Disease: Advancing the scope of costs and benefits
Funder: Parkinson's UK

Abstract: It is very important to have robust evidence on the costs and benefits of Parkinson's Disease interventions so that decision makers, such as those at the National Institute for Health and Clinical Excellence (NICE) can allocate our scarce health care resources accordingly. In recent years there have been huge advances in economic methodology to assist decision makers in this task. These methodological advances take the form of statistical and economic developments. While many disease areas such as cancer and diabetes have benefited from such advances, Parkinson's Disease, with its complex nature and associated impacts on carers has received little attention from health economists. The aim of this project is to use up to date economic methodology to clearly identify the costs and benefits associated with Parkinson's Disease interventions and health states more generally. The project will initially benefit from analysis of currently available data sets on two large PD trials and this will be followed by development of economic hypotheses and further survey work to explore these hypotheses. The aim being to generate evidence on the true costs and benefits of PD interventions as well as to identify true economic values of PD states of well-being more generally.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: NEUROLOGICAL
Title: Dissecting the molecular basis of LRRK2 Parkinson's Disease
Funder: Parkinson's UK

Abstract: This fellowship aims to investigate the basic biochemistry of LRRK2, mutations in which are the most common genetic cause of Parkinson's disease. Since mutations were described in LRRK2, much research has been directed towards identifying its normal function and how this is altered in the disease state. Despite these efforts, fundamental questions remain including how the enzymatic activities of this protein relate to each other and the nature of the unifying deficit associated with mutations. During this fellowship I will: - Carry out detailed experimental characterization of the biochemical properties of purified wild type and mutant LRRK2 - Identify interacting proteins acting as upstream activators and regulators of LRRK2 and downstream substrates. - Combine data from biochemical characterisation and interacting protein screen to produce in vitro and ex vivo models for LRRK2 function To address these points, I will use biochemical and biophysical techniques to investigate the enzymatic activities, folding, complex formation and interactome of LRRK2 isolated in solution and in a cellular context. At the end of this fellowship we will have a comprehensive picture of the biochemistry of LRRK2, and will have established validated models for testing approaches to target the aberrant activity of this protein.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Further development of a systemic gene therapy treatment for Parkinson's disease
Funder: Parkinson's UK

Abstract: Gene therapy is one of the most promising tools for the treatment of Parkinson's disease (PD), however one of the major challenges facing this approach is the development of a gene therapy vehicle for widespread delivery to the brain. We have developed a gene therapy vehicle based on targeted exosomes which we have shown are capable of selectively targeting the delivery of siRNA to brain resulting in gene silencing after intravenous administration. Alpha-synuclein aggregation plays a central role in PD pathology and increased expression or decreased degradation may be key features in its mechanism. Consequently an obvious initial target is alpha-synuclein. The first aim is to evaluate the efficacy of normal and modified siRNA delivery by RVG-exosomes to silence alpha-synuclein expression in mice. The second aim is to develop this system for long-term silencing within the brain using minicircles expressing shRNA (shRNA MC). As a model system we will target the fluorescent EGFP protein. We will optimise the sequences, constructs and electroporation conditions in SH-SY5Y cells over-expressing EGFP. Subsequently, we will evaluate the efficacy of long-term silencing by shRNA MC delivery by RVG-exosomes to silence EGFP expression in the brain of transgenic EGFP-mice. Finally, we will silence the expression of human WT and phospho-mimic S129D alpha-synuclein expressed in mice using shRNA MC. Alpha-synuclein silencing will be evaluated by qPCR, western blot and immnuhistochemistry throughout the brain. These studies will allow us to continue to develop this gene delivery vehicle and identify its suitability for use in the treatment of PD.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: PREDICT-PD
Funder: Parkinson's UK

Abstract: An Innovation Grant from Parkinson's UK has supported the PREDICT-PD pilot study since April 2011. To date, the pilot study has recruited 1000 subjects who do not have a diagnosis of Parkinson's disease (PD). Each individual has completed an online questionnaire about risk factors for PD. Answers have been stored in a secure online database and will be analysed using an algorithm developed from literature review to estimate individual risk of developing PD. All 1000 have had the opportunity to complete a computer keyboard tapping test, assessing movement speed, and a smell test. Loss of smell sense and REM-sleep behaviour disorder (RBD) will be used as surrogates for future PD and will be used to modify the existing algorithm to further refine it for the purpose of more widespread screening. Individuals at highest risk need to be examined clinically to make sure that they do not already have PD. A proportion of medium and low risk participants will be examined to maintain blinding. These clinical data (questionnaire, smell test, RBD, finger tapping, clinical examination) form the baseline for a follow up study into early PD detection. Subjects will be screened annually using the questionnaire and tapping test online and will be further screened with clinical examination and smell testing at 3 years follow up. In addition, transcranial ultrasound has been shown to be a marker of PD risk and this technique will be explored in the study participants, as well as validating it in established PD and healthy controls.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: NEUROLOGICAL
Title: The role of mitochondrial DNA variation in Parkinson’s disease
Funder: Parkinson's UK

Abstract: Mitochondria are intracellular organelles, whose function is critical to a number of metabolic processes. They are the site of oxidative phosphorylation; the protein components of which are partly encoded by mitochondrial DNA (mtDNA). Variation in mtDNA can affect the efficiency of oxidative phosphorylation. Increasing evidence links mitochondrial dysfunction to Parkinson's disease (PD). PD patients have reduced respiratory chain function, specifically in the substantia nigra (SN), and inhibition of respiratory chain components has been shown to cause dopaminergic neuron loss in humans. Studies linking inherited mtDNA variants to PD have been inconclusive, reporting conflicting associations with common mtDNA haplogroups or with rare pathogenic variants. These studies were often underpowered, dependent on poorly defined haplogroup structures, and failed to link mtDNA variation to the somatic mutations well-described in the post mortem SN of PD patients. My hypothesis is that inherited and somatic mtDNA variation is intrinsically linked, combining to make a significant contribution to the multi-factorial aetiology of PD. I will test this hypothesis in two ways: 1) by defining the inherited variants at the whole mitochondrial genome level, and 2) correlating these findings with somatic mutation load in post mortem PD brains. I will utilise a large sample cohort and NGS to address the first point, subsequently addressing the second point by correlating risk conferring variants to somatic mtDNA mutations in post-mortem PD brains. I anticipate that these findings will identify a key component of the disease mechanism of PD, whilst explaining part of the 'missing heritability' of PD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A novel drug re-positioning strategy for Parkinson's: Simultaneous, high content screening for translatable small molecules which are beneficial for mitochondrial and lysosomal dysfunction in primary fibroblasts from Parkinson's patients
Funder: Parkinson's UK

Abstract: Background: There is still no disease-modifying therapy for Parkinson's. A drug re-positioning strategy has proved successful for other diseases. Pathogenesis of Parkinson's is complex and novel approaches targeting multiple pathways are needed. Mitochondrial and lysosomal dysfunctions are important pathogenic mechanisms in Parkinson's. Hypothesis: I hypothesise that a drug screen (i) in patient tissue encompassing different causes of Parkinson's, (ii) using a compound library designed to only include licensed drugs which have good brain penetrance and (iii) a screen which assesses the effect of the compounds on multiple pathways dysregulated in Parkinson's; will provide lead compounds amenable to rapid translation to the clinic. Objectives: 1. Compile a library of licensed drugs with good brain penetrability. 2. Screen this compound library in fibroblasts from patients with either familial or sporadic Parkinson's to determine the effect on mitochondrial and lysosomal function. 3. Establish optimal concentration exposure time. 4. Determine mechanism of action by analysis of each pathway. 5. Validate compounds&rsquo; effectiveness in neuronal models. Methods: Objective 1: Chemoinformatic data-mining. Objectives 2 and 3: High throughput screening of mitochondrial function (mitochondrial membrane potential (MMP)) and lysosome number. Objective 4: In depth measurement of mitochondrial function using spectrophotometric and oxygen consumption methods. Measurement of lysosomal function using Western blotting and activity assays of cathepsin D processing through the lysosomal pathway. Objective 5: Measurement of MMP and lysosome number in neurons. Expected Outcome: Lead drugs identified using this strategy which are beneficial in patient cells could potentially be progressed rapidly to the clinic.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL