About the Project
Dr Emma Dempster, College of Medicine and Health, University of Exeter
Dr Liz Couthard, University of Bristol
Prof Jonathan Mill, College of Medicine and Health, University of Exeter
There is a need for a reliable biomarker for Alzheimers disease (AD). Loss of neurones in the brain is a major feature of AD and precedes symptom onset. This project proposes to use neuron-specific epigenetic signatures to detect and measure the amount of circulating cell-free DNA of neuronal origin and explore its use as an AD biomarker.
There is currently no disease-modifying treatment for Alzheimer’s disease (AD), and current medications simply treat the symptoms of the disease. As AD can only be definitively diagnosed by autopsy, and neuropathology begins many years before clinical symptoms become manifest, there is considerable need for both diagnostic and prognostic biomarkers that can be used to distinguish AD cases early and predict the rate of cognitive decline and progression of pathology. Neuronal cell loss is a prominent pathological feature of AD and plays a key role in cognitive decline and begins early in AD pathogenesis. There is therefore huge potential in developing methods to detect signs of neuronal death early in the disease process to maximise any potential therapeutic intervention. Circulating cell-free DNA (cfDNA) consists of small double-stranded fragments of DNA that are found circulating in blood plasma or serum, and arises primarily from cell apoptosis.
There is considerable interest in using cfDNA as a non-invasive method (a ‘liquid biopsy’) for diagnosis and monitoring of disease. Epigenetic modifications are preserved in cfDNA and recent studies have shown that it is possible to exploit cell-type-specific patterns of epigenetic modification to identify the cellular origin of cfDNA present in the circulating blood plasma, including those of neuronal origin. To elucidate the specific epigenetic signature of distinct neural cell populations and to better understand the molecular aetiology of AD brain our group is currently profiling DNA methylation on purified populations of neuronal and non-neuronal nuclei isolated from post mortem brain tissue. This wealth of neural–cell type specific epigenetic data has enabled us to identify distinct neuronal epigenetic signatures that can be used to detect neural cfDNA fractions. This PhD project will use these neural cell-specific DNA modification signatures to develop assays that robustly detect and quantify cell-free neuronal DNA in circulating plasma. The student will then apply it to an extensive collection of clinical plasma samples collected from individuals with AD and mild cognitive impairment (MCI), comparing these to healthy controls. The approach can then be extended to other types of dementia, and tested in longitudinally-sampled cohorts to examine its utility as a diagnostic and prognostic biomarker. Specific aims are: 1) Design a panel of digital droplet PCR assays which can be used to accurately quantify levels of neuronal DNA in cfDNA samples. 2) Obtain plasma samples from individuals attending Dr Coulthard’s AD clinic in Bristol, quantify neuron-derived cfDNA in each sample and relate these values to clinical phenotype, established CSF biomarkers and outcome measures. 4) Profile cfDNA from a large well-phenotyped longitudinal AD collection of plasma samples obtained from the PROTECT study. 5) Determine the utility of this biomarker in individuals with MCI and other dementias to assess specificity.
To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl by 5pm Friday 25 November 2019.
For further information relating to the funding please see: http://www.gw4biomed.ac.uk/doctoral-students/
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