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|Faculty of Fellows|
Faculty of Fellows
The phenotype, spectrum and immunological mechanisms of neuronal surface antibody mediated diseases.
The initial aim of my DPhil was to look at the role of the immune system in neurodegenerative disorders, a strand of enquiry that was conducted in my first year and led to important negative findings. This did, however, necessitate a shift in the focus for the remainder my studies. During this time, I also contributed to Professor Irani’s clinic, gaining exposure to patients with antibody-mediated neurological conditions. I became fascinated by these patients and pivoted towards working with them. This began with learning the literature, leading to two first author reviews and a clinical study, phenotyping the movement disorder in NMDAR-antibody patients, recently published in JNNP.
My second year comprised a combined clinico-immunological study of CASPR2-antibody patients. I collected a substantial cohort, with detailed clinical phenotyping and biological samples for further study. I developed a cell culture system to ask a wide variety of pertinent biological questions, a key result of which was underlining the importance of T cell help in the production of CASPR2 antibodies. The human leukocyte antigen (HLA), presents peptide-antigen to T cells, leading to their expansion and propagation of the immune response. Concomitantly we discovered a novel HLA association in patients with CASPR2 antibodies and this was recently published in Brain. The discovery of this HLA association, in combination with my previous work on in vitro lymphocyte culture models has meant I am uniquely placed to advance this work significantly and quickly, knowing the patients clinically and from a research perspective. To this end I am using the last few months of my fellowship to explore the T cell biology of these patients, with exciting results so far.
Investigating the premonitory stage of triggered migraine attacks using functional magnetic resonance imaging (fMRI)
This study aimed to investigate areas of brain activation during the premonitory phase of nitroglycerin (NTG) triggered attacks compared to baseline. The study has now closed to recruitment and I have obtained NTG-triggered premonitory and headache phenotypic data for 53 subjects. I have imaging data for the baseline-premonitory and baseline-headache comparisons for 25 subjects and have analysed most of the acquired data, which has now been written up for my PhD thesis and is also being prepared for publication of papers.
We have produced exciting results confirming increased regional cerebral blood flow in areas of interest in the premonitory stage of migraine, including the hypothalamus, midbrain and limbic areas. We have also provided supportive findings for the role of the thalamus, midbrain and pons during migraine headache. This study involves the largest cohort of subjects to date in the literature to be exposed to nitroglycerin on serial visits, with a view to phenotyping premonitory symptoms and headache and looking at the reproducibility of these phenotypes across serial exposures to nitroglycerin. We have evidence for moderate agreement in symptom reporting and headache laterality of triggered attacks in comparison to spontaneous attacks, as well as agreement for many symptoms across different episodes of nitroglycerin triggering. In addition, we have been able to provide some quantitative evidence for alterations in alertness and fatigue that patients commonly report in the lead up to a migraine compared to baseline using validated questionnaires.
As a result of the findings of this study, going forwards, I hope to be able to look at the effects of intravenous aspirin and subcutaneous sumatriptan as effective migraine abortive agents on the areas of brain activation seen during pain, as well as any other changes that these agents may induce, to attempt to assess how these painkillers work in migraine and to attempt to correlate the brain findings after headache resolution with clinical symptoms that can persist once pain has resolved.
The Physiology of Dementia: network reorganisation in progressive non-fluent aphasia as a model of neurodegeneration
My PhD fellowship, funded by the ABN and Patrick Berthoud Charitable Trust, has been very successful, and its outputs have allowed me to obtain an NIHR clinical lectureship to continue my work. I have been involved in a large number of projects, which have yielded a large number of publications, but my main personal focus has been on three studies. Firstly, I conducted a magnetoencephalography study in non-fluent variant Primary Progressive Aphasia, which led to new insights into the way in which the brain makes predictions, especially for language. This work was published in Nature Communications. I have also conducted some follow-up work, rescanning the same patients after a two-year interval. This work is in preparation. Secondly, I combined data from positron emission tomography with a ‘tau’ tracer and resting-state functional MRI in Alzheimer’s Disease and Progressive Supranuclear Palsy to examine the causes and consequences of tau accumulation in these diseases. This work was published in Brain, where widespread media coverage led to it being the most read-online paper ever published in that journal (273,832 HTML paper reads, 3,806 PDF downloads at time of writing). My oral presentation of this work at the ABN conference 2018 was awarded the Charles Symonds prize. Thirdly, in the final months of my fellowship I am conducting a 7-tesla fMRI study of language processing in non-fluent variant Primary Progressive Aphasia.
What are the neurobiological mechanisms that underlie the disruption of temporal lobe function in NMDA receptor encephalitis?
Two years into my neurology training I stepped out of programme to study for a PhD. My research project investigates the effect of anti-NMDA receptor antibodies from patients with NMDA receptor encephalitis, on EEG rhythms known to be relevant to learning and memory. Patients develop severe memory impairment during this auto-immune illness. I use an animal model oscillatory network to examine the effects of the antibodies on network properties in medial temporal lobe structures as well as on individual nerve cells in the network. I thereby hope to gain a better understanding of the role played by these antibodies in NMDA receptor encephalitis, as well as their mechanism of action.
The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models
Motor neurone disease is currently untreatable and in most cases progresses rapidly, with death from respiratory failure within a couple of years of onset. In order to find effective treatments it is critical to produce good laboratory models. I am studying the pathogenesis of motor neurone disease by investigating the effects of disease-causing mutations in the FUS gene, which is known to be the cause of MND in a minority of patients. Observing the effects of mutant FUS protein on cultured cells, including motor neurones, can help us to gain insight into the events in the cell which lead to degeneration in human disease.
The role of the cerebellum in the pathophysiology of dystonia
I was offered a Clinical Research Training Fellowship in 2010 at the mid point of my clinical registrar training. I am exploring the role of the cerebellum in the pathophysiology of dystonia using a variety of research techniques including non invasive brain stimulation, robotics and brain imaging under the supervision of Dr Mark Edwards and Prof John Rothwell. In particular we are critically examining the potential of the cerebellum as a new neuroanatomical target in the treatment of dystonia. In addition to my research I greatly value the excellent clinical apprenticeship in movement disorders I receive due to the close collaboration with the clinical team at Queen Square. I am extremely grateful to the Guarantors of Brain, my grant providers, and the ABN for mediating the award. The fellowship provided the perfect springboard into what will hopefully be a fruitful career in academic neurology.
The chronobiology and sleep physiology of cluster headache
I was awarded a clinical research fellowship by the Patrick Berthoud Charitable Trust, which allowed me to take 3 years out of programme, formulating my own research proposal investigating sleep and headache disorders. It has enabled me to gain the research skills required to dynamically measure and record human sleep and biological rhythms. In parallel, I have been able to develop my clinical training in sleep medicine. The fellowship has enabled me to participate in wider educational activities, such as a visiting scholarship programme to ETH Zurich, funded by the European Sleep Research Society.