Funders: Patrick Berthold Charitable Trust/ABN

Fellowship title: Synaptic loss in primary tauopathies.

University of Cambridge, Department of Clinical Neuroscience

2019-2022

Current position: NIHR Neurology Clinical Lecturer

Bio: I completed my ABN (Patrick Berthoud Charitable Trust) Fellowship in June 2022, and was subsequently appointed as an NIHR Clinical Lecturer at the University of Cambridge. My fellowship focused on assessing in vivo synaptic loss in the primary tauopathies of progressive supranuclear palsy and corticobasal degeneration, using [11C]UCB-J PET/MRI imaging. In a series of publications, I illustrated significant synaptic loss in these neurological disorders, which was progressive over one year, and correlated with the underlying tau pathology, and the patients’ cognitive performance. This work however highlighted that patients significantly vary in their rate of synaptic loss over time. My clinical lectureship therefore focuses on understanding this heterogeneity in primary tauopathies, using disease modelling with multimodal neuroimaging (PET and MRI), and blood biomarkers as input parameters. Alongside my research, I am a neurology registrar in the East of Anglia Deanery, aiming to combine a research and clinical career as an academic neurologist.

Contact: nda26@medschl.cam.ac.uk

Funders: Patrick Berthold Charitable Trust/ABN

Fellowship title: The role of DNA repair in Huntington's disease pathogenesis: towards new therapeutic targets

Cardiff University

2016-2019

Current position: Guarantors of Brain clinical academic Fellow

Bio: I originally studied Biochemistry as an Undergraduate at Cambridge, before completing a D.Phil in DNA recombination and repair at Oxford under the supervision of Prof David Sherratt. Subsequently I trained in Medicine and specialised in Neurology. My research interests are centred on understanding the role of DNA repair genes in modifying the onset and progression of Huntington's disease. I have been generously supported by Fellowships from the MRC and ABN/PBCT and am now starting to translate our basic research discoveries into new treatments.

Contact: MasseyT1@cardiff.ac.uk

Predicting epilepsy following a first unprovoked seizure: blood serum, EEG and MRI biomarkers.

A first unprovoked seizure is a common presentation, 10% of the population will have at least one seizure and approximately 50% will have a recurrence. It remains a major challenge for neurologists to reliably identify those that will have a recurrent seizure, creating uncertainty for both patients and clinicians. This uncertainty is associated with serious physical, psychological and social consequences for patients, with significant impacts on their driving and future employment prospects.

This fellowship will be the first to combine and explore the utility of using serum, quantitative EEG and quantitative MRI biomarkers to predict seizure recurrence. Patients with a first unprovoked seizure will be recruited and serum samples will be collected for measurement of circulating biomarkers, a resting-state EEG will be performed for computational analysis and we will acquire advanced quantitative structural MR imaging sequences to investigate brain connectivity and network dynamics. Patients will then be followed up at various time points to assess for seizure recurrence. The primary outcome event is a seizure recurrence, and the primary analysis will be of time to seizure recurrence using a multivariable regression model.

The identification of reliable biomarkers of seizure recurrence following a first unprovoked seizure will identify potential mechanisms associated with seizure predisposition and epileptogenesis. It will also better inform patient stratification for counselling and treatment decisions as well as optimising the recruitment of high-risk patients to future clinical trials of novel disease modifying agents, with the ultimate goal of improving the natural history of epilepsy.

Blood brain barrier permeability in cerebral small vessel disease

Cerebral small vessel disease (SVD) is an enormous public health problem; it represents 20% of ischaemic strokes and is the most common cause of vascular dementia. Understanding of the pathophysiology is nevertheless incomplete and there are no disease-modifying treatments.

Two related novel pathophysiological mechanisms have recently been proposed, namely that inflammation and increased permeability of the blood-brain barrier (BBB) are implicated in the development of SVD. This might mediate the progression from areas of haemodynamic disturbance to the white matter damage seen in the disease.

Cross-sectional MRI studies have shown increased BBB permeability in SVD, and pilot data from Cambridge using positron emission tomography (PET) has shown glial activation (evidence of neuroinflammation) in patients. The key question of whether these processes are causal or merely secondary phenomenon remains uncertain. I will aim to provide further insight into the roles of these process taking blood and CSF samples from patients with SVD and healthy controls who are undergoing combined PET/MRI imaging. I will measure inflammatory markers and the CSF/serum albumin ratio which is the gold standard of quantifying in vivo BBB permeability and examine its relationship with radiological markers of SVD.

This will be complemented by analysis of longitudinal data to determine whether regions of BBB permeability and neuroinflammation progress to tissue damage, as assessed by diffusion tensor imaging (DTI) parameters which are the most sensitive markers of white matter structural damage. These results will build on existing knowledge of the pathophysiology of SVD and potentially inform future options for therapeutic intervention.

Investigating T-Lymphocyte Function across Neuronal Surface Antibody associated Diseases

An increasingly common group of autoimmune diseases of the brain and nervous system are now recognised to be caused by antibodies. Antibodies are produced by a population of white blood cells called B-cells and, normally, play an important role in the body’s ability to fight infection. However sometimes the immune system becomes confused and attacks our own body in a process termed ‘autoimmunity’.

My research aims to explore and understand why the immune system attacks our own body in neurological diseases caused by antibodies. I will be focusing on a group of white blood cells called T-cells, which regulate the production of the B-cells producing self-attacking antibodies. If we can identify the reasons why these immune safety nets fail, we can then explore ways in which to manipulate them to stop the disease process. Taking samples from patients with varying degrees of disease severity, I will systematically isolate subgroups of T-cells and directly assess whether they alter autoantibody production by B-cells. This will provide valuable information into how T-cells fail to stop disease-causing B-cells. It will also identify cell subsets that could be targeted to ameliorate these diseases. This is a viable therapeutic aim, as drugs already exist to target these cell types and could be translated to this cohort within 3 years. By working in a group with a very active clinical programme, I will also learn to assess and treat patients with these illnesses.

Blood pressure and cerebral artery pulsatility in small vessel disease-related TIA and ischaemic stroke

Stroke is the second leading cause of death worldwide, and high blood pressure (BP) is the most important treatable factor that increases a person’s risk of suffering a stroke. Stiffness of the blood vessels supplying the brain, possibly due to long-standing raised BP, is also likely to be a factor that increases stroke risk. Such increased stiffness results in the blood flow through these vessels being more pulsatile than usual, and this pulsatility can be assessed by an ultrasound scan. This research is focused on assessing the relationship between this pulsatility and the risk of stroke in patients who have already had a stroke or “mini-stroke” in the past, and in particular to see if this relationship can be explained by raised BP alone. The Oxford Vascular Study (OXVASC) recruits all patients with stroke or “mini-stroke” from a single population, and shortly after such an event, participants undergo multiple investigations including an ultrasound assessment of pulsatility. They are provided with a home monitor that sends results wirelessly to our unit and facilitates detailed measurement of BP, and are followed up at regular intervals to assess for possible recurrent events. The OXVASC study represents an ideal opportunity to investigate the risk of stroke associated with BP and arterial stiffness, and this will allow us to better assess patients’ risk and identify possible new treatments for reducing arterial stiffness and stroke risk.