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EPILEPSY AND NEURODEGENERATION: DISEASE MECHANISMS AND EARLY DETECTION


   UCL Queen Square Institute of Neurology

  Prof Maria Thom  Wednesday, September 01, 2021  Funded PhD Project (Students Worldwide)

About the Project

Department of Neuropathology and Clinical and Experimental Epilepsy,

UCL Queen Square Institute of Neurology

This three-year PhD studentship is in in the field of Epilepsy Neuropathology starting in February 2022 based at the UCL Queen Square Institute of Neurology in the department of neuropathology.

Background to the study

Epilepsy is the most common serious neurological disorder, affecting over 600,000 people in the UK and cognitive deficits occur across all domains in 1/3 of patients with temporal lobe epilepsy (TLE), and in 70-80% of those aged over 65. Refractory epilepsy can lead to cognitive dysfunction similar to the incipient states of Alzheimer’s disease with a 6-fold higher prevalence of dementia in older adults with epilepsy. Cross-sectional MRI studies in the ENIGMA-epilepsy consortium (meta-analysis of 2149 cases) show syndrome-specific patterns of cortical volume loss and in the largest longitudinal MRI study to date, we observed progressive cortical thinning in epilepsy in excess of normal aging, which normalises after successful surgery. However, the pathology correlates of neuroimaging changes and cognitive decline are poorly understood. Proposed mechanisms include seizure-dependent degenerative alterations, accelerated aging, cumulative minor traumatic injuries and degenerative vascular pathology that may act synergistically, creating a “perfect storm”. Mixed neurodegenerative disease processes may interact synergistically to explain the observed clinical heterogeneity in the severity and trajectories of cognitive impairment in epilepsy. Our hypothesis is that neuroimaging abnormalities in focal epilepsy, ranging from progressive cortical thinning and diffusion weighted imaging, abnormalities, correlate with specific neurodegenerative changes in resected samples and are predictive of cognitive decline.

Methods that will be used (in summary): This will be both a retrospective and prospective study of patients with focal epilepsy and varied pathologies undergoing epilepsy surgery in addition to post-mortem cases from the epilepsy brain bank at UCL. Quantitative neuropathology methodologies for neurodegenerative disease process and (single cell) gene expression data (using NanoString) will be correlated with clinical features (genetics, psychometry, CSF biomarkers and neuroimaging). In addition, human slice culture experimental studies will be established to explore molecular pathways (eg mTOR pathway) that promote neurodegeneration.  The work will be conducted in the modern neuropathology laboratory facilities in the Institute of Neurology Queen Square. The project will be supervised within the neuropathology department by Professor Maria Thom and Dr Joan Liu (MThom). This PhD research will form part of a multi-disciplinary project and there will be close interaction and collaboration with the clinical and experimental teams in the department of epilepsy, particularly with neuroimaging (led by Professor Matthias Koepp). In addition, a six month component of the study will be under the supervision of Dr Javier Alegre Abarrategui at Imperial College to set up proximity ligation assays for degenerative proteins.

Eligibility

Students must have achieved at least an upper 2:1 in their undergraduate degree specialising in Neuroscience or related disciplines. An MSc is not a pre-requisite. Overseas students may apply if eligible. Previous experience in (multiomics) data analyses and cell/slice cultures are preferred, but not essential.  

How to Apply

An application is made by emailing your CV, two letters of support with institutional letterhead from academic referees (REF), academic transcripts and a personal statement to  References directly sent to the above email addresses using referees’ institutional emails are also accepted.

Your personal statement should be no longer than two sides of A4. We require a minimum of FIVE documents as PDF files (or all documents in one merged PDF file SURNAME_FIRST NAME) labelled as SURNAME_FIRST NAME_CV, SURNAME_FIRST NAME_REF1, SURNAME_FIRST NAME_REF2, SURNAME_FIRST NAME_TRANSCRIPTS and SURNAME_FIRST NAME_STATEMENT.)

No other documents will be accepted.

All enquiries regarding the PhD should be made to


Funding Notes

Funding
This is a fully-funded three year PhD with stipend, funded by the Wellcome Trust and includes project consumables. Overseas students are eligible to apply but will receive funding at the UK tuition fee rate only. Evidence will be required to show the student’s ability to pay the fee shortfall for the full three years of study and should be included as part of the application (as guidance only, this is currently approximately £21,000 per year).

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