Background
Intrinsic disorders of the small blood vessel of the brain (arterioles, capillaries, venules) are collectively labelled cerebrovascular small vessel disease (cSVD). CSVD is the commonest adult progressive neurological condition, accounting for around 35% of strokes, 80% of intracerebral bleeds and 45% of dementias. Despite the importance of cSVD, our understanding is limited and fundamental questions remain around pathophysiology, diagnosis, and treatment.
Population based imaging studies suggest that up to one fifth of older adults have established cSVD. However, in practice, cSVD tends to be diagnosed only when a person develops a condition requiring medical attention, for example stroke or dementia. A global brain disease such as cSVD is likely to manifest in other, more insidious ways. For example, cSVD has been plausibly associated with mood disorder, incontinence, and gait issues. Understanding the complete cSVD phenotype offers opportunities to better understand the disease, improve diagnosis and design treatment trials.
Aims
The overarching aim is to describe the complete cSVD phenotype. The project comprises distinct projects that together contribute to a coherent research program while still allowing flexibility for the student to pursue methods of particular interest.
Method:The primary analysis will be a Phenome wide analysis study (PheWAS). Using the UK Biobank neuroimaging resource, the student will create a case control experiment identifying those with and without advanced cSVD (top decile of cSVD neuroimaging markers available in UK-biobank). Adopting a hypothesis free approach, they will quantify cSVD associations across the totality of various physical, psychological including cognitive, and functional measures included in UK Biobank. Based on this analyses and literature review, features will be selected for further validation.
UK biobank offers volume of participants, but the richness of assessment data for factors such as mood and physical function is limited. To validate results from the PheWAS, the student will assess for associations between selected phenotypic measures and presence of cSVD in focused cohorts with detailed assessment data. Choice of dataset will be partly informed by the phenotypic features of interest and differing cohorts may be used to assess specific features. Exemplars include cohorts with cSVD data in the dementia context (Dementia Platforms UK); stroke cohorts (VISTA-Cog; R4VaD) and cohorts with a focus on a specific feature of cSVD (mood, EFFECTS trial (Sweden)). Secondary analysis of trial datasets will allow modelling of differential treatment effects in cSVD versus other conditions.
To give context to these finding, the student will collate published and ongoing trials in cSVD. The focus of the data collection will be around the assessments used to characterize cSVD, both inclusion/exclusion criteria and outcome measures.
Results will be presented to focus groups of multidisciplinary clinicians, researchers and people living with cSVD. We have permissions to contact partcipants from the cohorts listed above and benefit from strong links with stroke and dementia charities. This exercise will assess the face validity of our findings and ensure all potential consequences of cSVD have been considered. A final outout will triangulate data on the common cSVD phenotypes, outcomes assessed in cSVD trials and outcomes considered important by stakeholders.
Training outcomes
The project is designed to provide exposure to complementary research methods. Core training includes understanding vascular and neurodegenerative diseases; neuroimaging for research; large scale data analyses; data governance; evidence synthesis and communication of science. There is opportunity for the student to develop greater expertise in a particular method, for example neuroimaging skills or advanced analysis of registry data.
The project benefits from a team of experienced multidisciplinary supervisors (Glasgow and Edinburgh) and collaborators (Sweden). The successful student will join a vibrant research group of PhD and postdoctoral researchers working in applied neurosciences.
Application Instructions:
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.
http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919
Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.
For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine
Application Enquiries:
Susan Mitchell/Maree Hardie
[Email Address Removed]
https://www.ed.ac.uk/usher/precision-medicine/app-process-eligibility-criteria
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