NIHRDataInsights/HRCSData huggingface dataset:
Title: Goal-oriented cognitive rehabilitation in early-stage Alzheimers disease: multi-centre single-blind randomised controlled trial (GREAT)
Funder: Division for Social Care and Health Research (Wales)

Abstract: Design: Multi-centre single-blind RCT comparing cognitive rehabilitation (CR) to treatment as usual (TAU). Outcomes assessed at 3 and 9 months post randomisation.Setting: The study will take place in six centres across the UK with a part-time therapist and a part-time research assistant appointed at each centre. Participant identification will be undertaken by local research network staff. Participants will be recruited from memory clinics old age mental health services and GP practices. Assessments will be conducted and interventions delivered in participants’ own homes with a carer involved where possible.Target population: People with an ICD-10 diagnosis of Alzheimer’s disease (AD) vascular or mixed dementia. For each participant a carer (a family member or close friend who is either co-resident or in regular contact) will also be involved. Inclusion criteria: in the early-stages of dementia (MMSE score of 18 or above); if taking cholinesterase inhibitors receiving a stable dose for 1 month prior to trial entry and with no intention to change the dose over the 9 month period of trial participation unless clinically indicated; availability of a family carer. Exclusion criteria: prior history of stroke brain injury or other neurological condition; inability to speak English. Health technology: CR is an individualized approach for people with dementia (PwD) aimed at reducing functional disability supporting self-management and maximising engagement and social participation. PwD and their carers identify areas in which they would like to improve functioning and performance and work together with a health professional (e.g. occupational therapist psychologist) over a number of sessions to devise and implement strategies for addressing these personally-relevant goals. CR will be delivered in 10 individual sessions over 3 months followed by 4 maintenance sessions over 6 months. There are no established alternative technologies. In the pilot (Am J Geriatr Psychiatry 2010 DOI:10.1097/JGP.0b013e3181d579 2a) CR was compared with TAU and with an attention placebo condition (relaxation therapy). There was no evidence of a difference between the two control groups so treatment as usual is an appropriate comparator.Sample size: Power calculations and attrition rates are based on the pilot trial. For the proposed study intervention length has been increased in order to further strengthen effect sizes. To achieve 80% power to detect a medium effect size of 0.3 with alpha 0.05 in primary and secondary outcomes 175 PwD need to complete the trial in each arm. Attrition was 20% at 6 months in the pilot but is likely to be higher in a longer multi-centre trial; based on evidence from the recently-complete REMCARE trial an attrition rate of 27% has been used. Therefore we will randomise 480 PwD each with a family carer.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Characterisation of newly identified proteins that interact with the MND-causing expanded repeat in C9orf72
Funder: Motor Neurone Disease Association

Abstract: The investigation of genetic factors that cause motor neuron disease has provided valuable insights into how it occurs and potential treatments. Recently a mistake in the C9orf72 gene was identified as by far the most common genetic cause of motor neuron disease. Therefore, identifying how this mistake causes motor neurons to die is an important goal that could lead to new therapies. Currently nothing is known about how the mistake in C9orf72 causes motor neurons to die, but the mistake is similar to mistakes in other genes that cause neurological disease by forming toxic clumps of RNA (RNA is a copy of DNA that is made when a gene is switched on and is important for the generation of proteins). These toxic RNA clumps stick to proteins called RNA-binding proteins whose normal job is to bind to RNA, but only in certain situations when the cell requires it. The RNA-binding proteins get stuck in these clumps and can no longer do their normal job, which stops the neuron functioning properly and ultimately causes it to die. We have recently identified RNA-binding proteins that specifically get stuck in the toxic C9orf72 RNA clumps. We now plan to extend these important and novel findings. Specifically, we will use state-of-the-art technology to investigate the effect on motor neurons of losing these RNA-binding proteins. We will then determine whether re-introducing these RNA-binding proteins can protect motor neurons carrying the C9orf72 mistake from dying. These studies will give new insight into how the mistake in C9orf72 causes motor neurons to die and may identify new targets for therapeutic intervention in motor neuron disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Understanding the early pathological pathways in Parkinson’s
Funder: Parkinson's UK

Abstract: The Oxford Parkinson's Disease Consortium (OPDC) will use the unique interdisciplinary research environment within Oxford to establish a leading centre focussed on understanding the earliest pathological pathways in PD. Internationally-recognised scientists with strengths in genetics and genomics, transgenic rodent models, in vivo neuroanatomy and neuropharmacology of the basal ganglia, magnetic resonance imaging (MRI), and analysis of protein biomarkers, will work closely with experts in the clinical epidemiology and clinical neurology of Parkinson's. We will identify putative causal genetic variants within pathways leading to Parkinson's from bioinformatics analyses of large-scale genomics projects. Variants will be further characterised by resequencing genes in a large clinical cohort of 1700 Parkinson's patients and 300 aged-matched controls. Induced pluripotent stem cells generated from individuals harbouring susceptibility variants will be differentiated into dopaminergic neurons. The effects of genetic variants on genome-wide transcription and cellular dopamine homeostasis in cultured neurons will identify the best candidates to use in improved rodent models. BAC-transgenesis will be used to express causal variants at physiologically-relevant levels preserving temporal and spatial expression. These new models will be analysed for the earliest changes of dopamine neuropharmacology, basal ganglia circuitry and neuropathology, and compared to high-resolution MRI of the midbrain of individuals from the OPDC clinical cohort with Parkinson's or at high risk for Parkinson's. Biomarker studies on microRNAs and proteins will correlate peripheral and neuroanatomical alterations. Our work will lead to improved methods of earlier diagnosis of Parkinson's, identify new molecular targets for therapy, and generate new improved models for testing neuroprotective treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Tracking Parkinson's: Parkinson’s Repository of Biomarkers and Networked Datasets (PROBAND)
Funder: Parkinson's UK

Abstract: There remains a major need to link genetic and biomarker findings with patterns of disease involvement, to understand the diversity and mechanisms of disease development. This programme will study four main areas of diversity in expression of PD will be studied &ndash; motor, cognitive, therapy responsiveness, and non-motor features. A total of 3080 subjects will be recruited from 24 centres. 2000 patients with PD onset within 3 years, and 750 first degree relatives, will be invited to participate. An additional 240 cases with PD onset under 50 years, and 90 of their first degree relatives, will be invited. All participants will be gene tested for LRRK2 and GBA; under 50's will be tested for Parkin and PINK1. Serum will be sampled serially and DNA will be stored long-term. Clinical scoring will adopt common data elements of the NINDS to maximise compatibility with other studies, and will include demographic, cognitive, quality of life, depression, autonomic, and impulse control recordings. Sampling will be repeated every 18 months, allowing between 2 and 4 visits per case. The programme is linked to, and will support, prevailing scientific and clinical studies, including young onset PD, mitochondrial, and neuroimaging studies, as well as serving as a biosample and data resource for future studies. Recruitment of participants to the Parkinson's UK Tissue bank (Imperial College, London) will be encouraged. International linkage of clinical and scientific data will also occur, involving similar cohort studies in the United States, Sweden, Germany, and Italy.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: NEUROLOGICAL
Title: Validation of Ras-ERK inhibitors to treat L-DOPA induce Dyskinesia
Funder: Parkinson's UK

Abstract: L-DOPA remains the most effective treatment for alleviating Parkinson's disease (PD) symptoms but it causes currently untreatable severe motor side effects, collectively known as levodopa-induced dyskinesia (LID). One of the key pathogenic factors for LID, linked to abnormally high dopamine-mediated responses is the hyperactivation in the striatum of the Ras-ERK signalling pathway. The project aims at validating 8 different inhibitors of this pathway as antidyskinetic agents, acting on different targets within this signalling cascade. Four are cell permeable peptides developed by the applicant while the additional four are molecules developed by pharmacompanies which are at a very advanced stage of clinical development for tumour treatment but have never been tested for LID. In this project we will determine the efficacy of all 8 drugs given both alone and in combination, to prevent and revert abnormal involuntary movements (AIM), the rodent correlate of LID, in mice. In order to maximise the effect, these drugs will be first delivered directly in the dorsal striatum, the brain region affected in LID, using osmotic minipumps, in a 6-OHDA neurotoxic unilateral rodent model of PD. Subsequently, only the best drugs will also be administered systemically. Behavioural and histological characterisation will be carried out after evaluation of AIMs in response to an escalating L-DOPA dose regimen and to chronic treatment. At the end of the three years project we will have validated new therapeutic means which could be rapidly tested in PD patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Point of care PD diagnosis and prognosis
Funder: Parkinson's UK

Abstract: A robust biomarker would have enormous impact for clinical treatment of Parkinson's disease, enabling accurate and immediate confirmation of diagnosis, prediction of disease progression, patient stratification and pre-screening of drugs prior to large scale trials. Here we develop a novel and powerful electrochemical sampling technology using microelectrode arrays and fluidic sample delivery to establish a highly sensitive detection platform for key antibodies and proteins whose levels correlate with disease status. In previous studies we have identified a number of potential biomarkers for Parkinson's including autoantibodies against alpha-synuclein and its oligomeric and fibrillar species, insulin, its autoantibodies and the inflammatory proteins S100A8, S100A9 and S100B. These and other biomarkers will be incorporated into multiplexed sensors and used for high throughput screening of the samples collected from the Oxford Discovery Cohort, suitable for the study of biomarkers in early stage Parkinson's, and the complementary Ume&aring; Medical Biobank collection. These cohorts have been carefully clinically documented and are suitable for the study of biomarkers in early stage Parkinson's and for longitudinal validation and correlation with clinical and pathological features including the efficacy of specific therapies. We will use a novel Parkinson's transgenic mouse model which exhibits early-stage dopaminergic dysfunction and late-stage neurodegeneration to address in a longitudinal study the critical question of the correlation between blood biomarkers and neuronal loss. The proposal is underpinned by exciting preliminary data, a strong collaboration between biophysical, pre-clinical and clinical teams and an association with an experienced manufacturer of advanced medical diagnostic hardware.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Identifying the mechanisms of action of a novel 8-hydroxy quinazolinone in models of Parkinson's disease
Funder: Parkinson's UK

Abstract: The current proposal capitalizes on recent publications by the Investigators in Cell and Nature Medicine, as well as other exciting recent findings by our groups, that (A) tau and the amyloid precursor protein (APP) play major physiological roles in the export of neuronal iron, (B) the dysregulation of tau or APP in PD leads to toxic intraneuronal iron accumulation, (C) a new 8-hydroxyquinazolin-4(3H)-one compound called PBT434 is highly effective in neuroprotection. Here we propose an ambitious program to utilize an established PD animal model to understand the significance of these changes in PD, and seek to understand the mechanisms of action of the PBT434 as a new therapeutic candidate for PD. Hypotheses: 1. Failures in the tau, APP and CP ferroxidase regulatory systems drive iron elevation in brain regions, leading to neuronal degeneration, which is then expressed as PD. 2. PBT434 chelates dissociable iron, preventing metal mediated oxidative damage in a model of PD. 3. PBT434 alters expression or function of the ferroxidase regulatory pathway and is a tractable therapeutic target for PD drug discovery. General Aims: Aim 1: To elucidate the role of ferroxidase in nigral and cortical neurodegeneration. Aim 2: To investigate the role of ferroxidases in a model of PD. Aim 3: To understand the mechanism of action of PBT434.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: PaMIR: Parkinson MR Imaging Repository
Funder: Parkinson's UK

Abstract: There is a recognized need for novel biomarkers to improve early diagnosis and monitoring of Parkinson's. Different technologies are currently being researched for identification and qualification of such biomarkers. We, and others have recently shown that magnetic resonance imaging (MRI) at 3 Tesla holds unique promise for direct visualization of substantia nigra (SN) degeneration as well as for the study of dysfunctional brain networks. Our preliminary results suggest that SN depigmentation and altered brain networks correlate with stage, severity and subtype of the disease. We hypothesize that multimodal MRI at 3T is ideally suited to improve diagnosis and to monitor the progression of Parkinson's. MRI biomarker research in Parkinson's is an emerging field with limited and often controversial findings. To overcome this we propose to build a large dedicated MRI imaging repository in early Parkinson's to assess the diagnostic accuracy and predictive power of novel MRI biomarkers. Candidate MRI markers were selected from meta-analyses of published evidence and our own pilot and proof of concept studies. We plan to collect neuromelanin, iron, diffusion tensor and resting state functional MRI at 3T in 300 people with early Parkinson's co-recruited from the Tracking Parkinson's longitudinal cohort study. Control data will be included from 100 age matched healthy controls. 150 people with and 50 without the condition will be rescanned after 18 months to assess progression. This will allow creation of unique virtual Parkinson's Brain Bank, which will be the largest repository of advanced MRI linked to clinical, genetic and potentially proteomic phenotyping.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Tracking Parkinson's with proteomic biomarkers
Funder: Parkinson's UK

Abstract: Biomarkers for Parkinson's are key to further progressing drug discovery with markers suitable for very early detection, predicting outcomes, defining disease subtypes and tracking disease progression being most needed. We propose a four-phase programme in CSF and in blood; discovery, verification, validation and qualification with funding requested only for phases I-III. The study design utilizes in phase I (Discovery) both case control and endophenotype continuous measure approaches with phenotypes as independent variables to include symptom severity, rate of progression and cognitive impairment. In Phase II (Verification) replication will be in large populations bringing together a collaboration of leading sites and major studies in the UK. In phase III (Validation) we will utilize Parkinson's and other brain banks to show biological validity of discovered proteins in Parkinson's brain. To identify biomarkers we propose to combine two leading multiplexed proteomics technologies including gel free mass spectrometry based proteomics coupled with isobaric tags and 1000 plex aptamer based arrays in discovery phase. In verification phase we will scale these technologies for even higher throughput using selective reaction monitoring coupled with isobaric tags and focused aptamer arrays; in both cases performing replication studies on exactly the same analytes discovered in phase I. Biostatistical analysis will utilize multivariate class prediction and the study is powered to show effect sizes above 0.3. To deliver on time and on budget we bring matching resource from industry partners and NIHR funded infrastructure and a timeline milestone driven project management with confidence of progression to phase IV (Qualification).


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 therapeutic potential for RVG9RÃp137 in a disease relevant model of Parkinson's dementia
Funder: Parkinson's UK

Abstract: There is a major clinical need for neuroprotective therapies in Parkinson's Disease (PD). While many experimental therapeutic agents focus on the dopaminergic motor-related symptoms, little is oriented towards dementia which can be a debilitating complication of PD. We have recently demonstrated that a novel RVG9R-p137 treatment is neuroprotective against rotenone and 6-OHDA insults in both in vitro and in vivo models of PD, respectively (Kuan et al, 2012). The RVG9R peptide is derived from the rabies virus glycoprotein, which transports its RNA cargo across the blood-brain barrier and specifically targets acetylcholine receptor-expressing neural cells whilst the active agent is a small non-coding RNA (p137) that selectively binds to complex 1 and rescues its function. The RVG9R system can effectively deliver the p137 RNA into neurons of both dopaminergic and non-dopaminergic systems upon transvascular administration. The mechanism of p137-mediated neuroprotection involves protecting mitochondrial complex I activity as well as restoration of mitochondrial membrane potential and ATP production. Mitochondrial dysfunction and complex I impairment has been implicated in the pathogenesis of PD and causes cell loss to develop over years. This protracted degenerative process, however, is very different to the traditional acute lesioning models. Furthermore, the formation of alpha-synuclein inclusions - the defining pathology of PD - are not seen in models generated by 6-OHDA. Recently in our lab we have established a rat model of PD involving the overexpression of alpha-synuclein using viral vectors. This model offers a slower, more disease-related neurodegeneration. Given that alpha-synuclein has been shown to inhibit mitochondrial complex I function and compromise cell viability, we believe that this model also provides a better means of evaluating the efficiency of the RVG9R-p137 treatment. We aim to test the RVG9R-p137 treatment in alpha-synuclein overexpression models focusing on dementia related symptoms with a view towards clinical translation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Abnormal lysosomal calcium signalling in Parkinson’s disease: clues from lysosomal storage disorders
Funder: Parkinson's UK

Abstract: Although significant progress has been made in understanding the genetic basis of Parkinson's disease, much of the cell biology remains to be elucidated. Substantial evidence implicates mitochondrial dysfunction, which as a likely endpoint in neuronal demise demands definition of defective upstream pathways. Mutation of the GBA1 gene, responsible for the lysosomal storage disorder Gaucher's disease (GD), is one of the most common genetic risk factors for PD. This adds to mounting evidence pointing to lysosome dysfunction in PD but the underlying mechanisms are not established. Here we combine complementary expertise to consider defective lysosomal calcium release as a culprit. This is based on 1) emerging evidence that lysosomes act as sources of calcium to trigger complex calcium signals which are ultimately transmitted to the mitochondria via the ER, and 2) defective calcium signalling in lysosomal storage disorders to which PD is linked. Based on exciting preliminary data, we will test the hypothesis that abnormal lysosomal calcium signalling is a common feature of PD and GD. We aim to 1) establish fibroblast cultures from a range of PD patients and GD patients/carriers and use imaging approaches to compare 2) the calcium content of lysosomes, ER and mitochondria, and 3) the cytosolic calcium signals in response to physiological cues that these interacting organelles ultimately drive. We will provide new insight in to the role of calcium in PD pathology and lay the foundations for future mechanistic and functional analyses with clear scope for the development of novel biomarkers and mechanism-based therapeutic approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Using modified mRNA to direct differentiation of PD patient derived stem cells towards dopamine neurons
Funder: Parkinson's UK

Abstract: Parkinson’s disease (PD) is caused by progressive dopamine (DA) neuron loss particularly in the substantia nigra. The loss of DA producing cells coincides with the movement impairments observed in PD. The molecular mechanisms of the disease progression are still unclear and good cellular models are essential for understanding the disease.Stem cells are revolutionizing PD research and in particular induced pluripotent stem cells now can be generated from patient cells. Several methods have been described to turn these stem cells into DA neurons. The Oxford Parkinson’s disease Centre generates such neurons and they are an invaluable source for PD research as they allow the study of DA neurodegeneration in the lab. Current methods generate limited number of DA cells or a heterogeneous cell population. These methods either use viral vectors that introduce foreign DNA into stem cells or use expensive signalling molecules to produce DA neurons, but also other neuronal cells types. To characterize DA neurons, a homogenous cell population that is solely affected in PD needs to be generated.To address this problem, we are proposing an innovative method to generate DA neurons that: 1) Generates a pure population of DA neurons by transfecting stem cells with modified mRNA encoding transcription factors (TF) crucially involved in brain and DA neuron development. 2) Does not permanently change the genetic material 3) Has advantages over viral-vector or signalling molecule induced differentiation as it will allow a modular and flexible transfection regime that mimics the natural cellular cues that occur during dopamine neuronal differentiation.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL