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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.
Synaptic loss determines functional deficits in primary tauopathies
I address the challenging problem of why neurodegeneration impairs behaviour. Previous research focusses on atrophy, the reduction in brain volume from massive cell loss. But, cell death occurs late in dementia pathogenesis, and neurocognitive systems fail before atrophy is evident. Animal models of Alzheimer’s disease indicate synaptic regression and loss of plasticity without cell death, in response to oligomeric tau. Similarly, post-mortem PSP data indicate severe reductions in synapse density, with normal prefrontal neuronal numbers.
I test the hypothesis that synaptic loss contributes to cognitive change in humans. I focus on the primary tauopathy progressive supranuclear palsy (PSP), where network physiology and cognition are impaired in the absence of significant cortical atrophy. I also study the related tau-opathy of corticobasal degeneration (CBD), which combines dementia and parkinsonism. I exploit clinical heterogeneity to determine causal relationships between pathology, functional anatomy, and syndromic variability.
Recent advances in PET radiochemistry will quantify synapse ‘density’, using the UCBJ-ligand for presynaptic vesicle protein-2a. I examine (i) the relationship of synaptic density to clinical severity, in cognitive and motor function and (ii) relationships between regional variation in synaptic loss and phenotype, linking pathology to phenotype via network connectivity, and atrophy of the network nodes.
The primary aim is to identify mechanisms of human neurodegenerative disease, in vivo. The methods may also provide quantitative biomarkers for future early stage interventional studies. A better understanding of in vivo pathophysiology would provide a rationale for novel approaches to designing disease modifying therapies against PSP and CBD, and other dementias.
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.
Biomarker discovery for neurological Wilson’s disease in preparation for novel therapies
Wilson's disease (WD) is an inherited movement disorder that causes abnormal copper accumulation in the brain and/or liver. Current treatment involves copper-binding medication to remove excess copper from the body and is required lifelong. Some patients respond well to this treatment but others deteriorate despite treatment or develop debilitating side effects. New treatment approaches aiming to fix the underlying gene defect are in the early stages of development however our inability to monitor disease activity in the brain will limit our ability to test these therapies in a clinical trial. An exact role for magnetic resonance imaging (MRI), cerebrospinal fluid tests or other measures of brain damage, commonly used in other neurological disorders, is unclear.
In this study we aim to identify new approaches to monitoring neurological involvement in WD in order to prepare for clinical trials of new treatments. We will perform clinical assessments in combination with novel MRI techniques, blood tests and urine tests in 30 WD patients with neurological disease and 10 WD patients with liver disease (and without neurological involvement). We will then repeat this for each patient after 12-18 months to assess for any improvement or deterioration. We will perform lumbar punctures to sample the cerebrospinal fluid in a subset of patients.
Through identifying which novel MRI techniques, blood tests and cerebrospinal fluid tests measure disease activity in the brain we aim to enable trials for novel WD therapies within ten years and refine current management within the next five years.
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.
Hearing impairment in dementia: defining deficits and predicting impact
Scope. Hearing impairment has been linked to clinical deterioration in dementia, with immense implications for public health and potentially opportunities for treatment. However, important questions remain: are hearing changes in dementia due primarily to deafness or altered brain processing of sounds? How does this relate to symptoms and daily life impact in different diseases? How does hearing impairment affect disease course and brain damage? My Fellowship aims to: i) assess and compare different aspects of hearing in patients with Alzheimer’s disease and primary progressive aphasia, a major dementia of middle life that profoundly affects processing of speech and other sounds; ii) establish how hearing changes relate to clinical symptoms, disability and care burden; iii) assess whether hearing impairment drives disease course, clinically and in the brain Methods. I will use a new, comprehensive test protocol to assess hearing and auditory brain functions systematically and over time in patients versus healthy older people. Associated brain changes will be assessed using MRI scanning. New hearing measures will be compared with standard hearing tests and measures of dementia diagnosis and impact.
Outcomes and timeframe. Within the lifetime of my Fellowship, this work will generate new tools and markers that define and predict the clinical and brain impact of hearing impairment in major dementias, and how this affects the daily lives of patients and caregivers. Over the next five to ten years, my findings will inform future clinical trials and interventions for improving communication and auditory environments in people with dementia.
Biomarkers and Modulation of Cortical Hyperexcitability in ALS
Amyotrophic lateral sclerosis (ALS) is a fatal condition involving degeneration of the motor system of the brain and spinal cord. At least 5000 people in the UK live with ALS, and many more bear the physical and emotional burden of their care. The average time from first symptoms to death is 3 years. Around 10% of all cases of ALS are caused by a specific genetic mutation. New medications, including revolutionary genetic treatments for ALS, are being actively developed. To show that they are effective, sensitive markers of disease activity (biomarkers) are urgently needed.
The motor output of the brain is over-active in ALS, referred to as cortical hyperexcitability. I will use advanced MRI scanning techniques as a source of biomarkers for cortical hyperexcitability. I will also attempt to reduce the brain’s motor excitability in ALS patients using a technique called non-invasive brain stimulation.
I will study a group of affected people carrying the abnormal genetic code, and a group with the same gene who have not yet developed the disease. By comparing these groups, I hope to identify the earliest disease changes. Future treatments might then target the disease before a person is aware of weakness. Sensitive biomarkers for those already affected by ALS will help to make clinical trials faster and cheaper, accelerating the prospects for better treatments.
Investigating the pathological mechanisms underlying the neuropathy in POEMS syndrome
POEMS syndrome is a severely debilitating cause of peripheral nerve damage, driven by the presence of a blood derived cancer similar to multiple myeloma. My research project is to identify the cause of neuropathy in such patients, which we believe is driven by inflammation molecules in the blood.
To date, we have collated data on the largest European cohort of POEMS patients to understand more about the natural history of disease, treatments and outcomes. We have in addition set up a biobank and collected over 1500 samples of patient serum, plasma and CSF for analysis.
We are currently analysing patient sera for 30 inflammatory cytokines which we believe to be implicated in POEMS syndrome, whilst providing a more in depth full proteomic analysis using mass spectrometry. We are also developing biomarker assays to quantify peripheral nerve damage in POEMS syndrome and a range of other inflammatory neuropathies.
Lastly, through collaboration with The Nuffield Department of Clinical Neurosciences, Oxford University, we are growing human sensory nerves from stem cells, and assessing mechanisms of nerve damage when exposed to POEMS patient sera and that of similar neurological conditions.
Utility of second-line investigations in TIA and non-disabling ischaemic stroke at older ages: clinical and health economic considerations
I have been actively involved in ongoing collection of data in the Oxford Vascular Study, which will contribute to the datasets on which my research is based. I have also started a number of projects which will form my thesis. These are:
Defining clinical and genetic biomarkers in Multiple System Atrophy
The UK MSA clinical and sample bio-bank was created and to date includes 42 longitudinal cases, 54 cross-sectional cases, serum, plasma, CSF, DNA and RNA.
Results achieved and future research:
Disease-modifiers in Huntington’s disease
Huntington’s Disease (HD) is a life-shortening autosomal dominant neurodegenerative disease characterised by chorea, psychiatric disturbance, and dementia. It is caused by a CAG repeat expansion in the HTT gene. Previous work has implicated DNA repair processes in triggering CAG repeat expansion in striatal neurons, thereby accelerating onset of HD.
We have used exome sequencing in 500 HD patients with particularly early or late onset disease to show that there are variations in the CAG repeat sequence associated with early or late onset disease. In addition, there are multiple other trans-acting variants that are linked to altered disease onset. Many of these are in DNA repair pathways.
In addition, we have been developing a cell model of HD with 109 CAG repeats. We have shown that this repeat is unstable in cell culture and it therefore provides a good platform for testing our variants of interest. We have engineered an isogenic control line (with 20 CAG repeats) and are introducing our DNA repair variants using CRISPR/Cas9 techniques. Cells will be assayed for repeat instability and various downstream phenotypes including DNA damage and repair, mitochondrial and lysosomal function, and synapse formation.
Attention and functional movement disorders: its role in symptom generation and sense of agency
Functional (psychogenic) movement disorders are involuntary, abnormal movements, such as tremor or paralysis, that are illogical in terms of classical neurology. Intriguingly, they typically manifest when patients pay attention to them and disappear with distraction. We hypothesise that misdirected attention brings about these abnormal, involuntary movements. Instead of focusing on the goal, on the desired outcome, patients direct their attention onto the movement itself, onto “how” to perform it, thereby hampering its automatic execution. The results so far show that functional tremor improves when patients are distracted, when they move quickly, and when they perform a movement that appears to be of no importance. The next step is an fMRI study which will evaluate the effects of different attentional foci on brain activation. The idea is to show that commonly found abnormal activation patterns might in fact be caused by abnormal attentional foci. If misdirected attention is implicated in functional movement disorders, changing its focus would offer a simple and effective treatment strategy.
Gene expression regulation in Multiple Sclerosis susceptibility and severity
The aims of my PhD are:
Aim 1: I have completed sample collection from over 100 patients. I have sorted CSF and peripheral blood cells by FACS (to isolate CD4* and CD8+ T T-cells) and extracted RNA and DNA. I have commenced cDNA library preparation and sequencing. Bioinformatic pipelines have been optimised for differential gene expression and QTL analysis and I have gained substantial training in bioinformatics skills and statistics. I am currently optimising my skills to perform TWAS (transcriptome-wide association study). Which will allow me to correlate gene expression with genotype.
Aim 2: I have completed a GWAS of time to EDSS 6 in a pilot cohort of 509 patients with MS. Through building a collaboration with Prof George Davey-Smith’s and Prof Yoav Ben-Shlomo’s groups at Bristol University, I have been able to genotype a further 1149 patients and am currently repeating the GWAS on the larger cohort and meta-analysis.
Improving the diagnosis of encephalitis through examining whole proteome and host gene expression patterns.
Encephalitis is often associated with an acute infection or an autoimmune process, but in up to two thirds of cases the cause is unknown. In my fellowship, supervised by Prof. Tom Solomon, I am exploring whether the diagnosis of encephalitis can be improved by using novel approaches to examine the host response.
Through the multicentre Brain Infections UK network, we have recruited patients with infectious and autoimmune encephalitis, and with encephalitis of unknown cause. Following diagnostic testing, I have used mass spectrometry and NMR spectroscopy in 90 patients to examine whole proteome and metabolite profiles in the cerebrospinal fluid (CSF) of patients with infectious and autoimmune encephalitis, along with disease controls. In parallel, I have used human gene microarray to explore host gene expression patterns in RNA-stabilised blood samples.
Currently, I am working with the Computational Biology Facility at the University of Liverpool to analyse and integrate these data. This will allow the determination of the best markers to distinguish infectious from autoimmune encephalitis, which can be applied to our cohort of samples from encephalitis of unknown cause. Through pathway analysis we will also gain new insights into encephalitis pathogenesis.
Adrenergic Signalling at the Neuromuscular Junction and Congenital Myasthenic Syndromes
My current research focuses on disorders of the neuromuscular junction, particularly congenital myasthenic syndromes (CMS).
My laboratory based research focuses on exploring the effect of treatments for these conditions in animal models, supervised by Prof Hanns Lochmüller. Using zebrafish models of myasthenic syndromes, we showed that adrenergic agonists have a direct effect on neuromuscular junction development and do so via a cyclic AMP and mediated pathway (McMacken et al Hum Mol Genet 2018). I am currently carrying out follow-up studies investigating the effect of these drugs in CMS mouse models.
My clinical research is aimed at characterising the involvement of the neuromuscular junction in inherited motor neuropathies, supervised by Prof Rita Horvath and Dr Roger Whittaker. Using detailed clinical and neurophysiological assessment, 14 patients with motor neuropathies with NMJ defects have been identified, including those due to defects in mitochondrial fusion-fission, synaptic vesicle transport, calcium channels and tRNA synthetises. The involvement of the NMJ may represent a novel therapeutic target in these conditions, and currently we are exploring the effect of therapies such as pyridostigmine and salbutamol in these cases.
In addition, I am involved in new CMS gene discovery and further clinical characterization of CMS subtypes. In collaboration with researchers at Inserm, Paris, we showed that mutations in SLC5A7, encoding the presynaptic choline transporter, cause a novel CMS with episodic apnoea (CMS-EA). In addition, we characterized a relatively large cohort of CMS-EA patients who were referred to our laboratory from around the world, providing new insights into the long-term outcomes of these patients (McMacken et al J Neurol 2017).
The Clinical Features and Prognosis of Scan-negative Uro-Neurological Disorder
With two neurosurgical colleagues we have commenced a prospective UK wide study of cauda equina syndrome in conjunction with the British Neurosurgical Trainee Research Collaborative (https://www.bntrc.org.uk/current-projects). To date 89 patients have been recruited and 40 centres have expressed an interest in taking part. We aim for 500 patients which will be the largest prospective study of cauda equina syndrome in the world.
ABN - Association of British Neurologists. PBCT - Patrick Berthold Charitable Trust. MSAT - Multiple System Atrophy Trust. GB - Guarantors of Brain. DMT - Dunhill Medical Trust. SA - Stroke Association. SF - Sobell Foundation.