Professor Colin Doherty

During the first two years of operation, research in WP3, 4 and 7 led to the identification of circulating microRNAs in plasma that are biomarkers of epilepsy and acute seizures 1, three tRNA fragments (or 'tsRNAs') that increase in advance of epileptic seizures 2, and the development of rapid-detection technology for these 3,4. FutureNeuro genomics work in WP1 has shown that 1-3% of sporadic epilepsy is caused by identifiable monogenic causes (unpublished/in preparation). We also have an increased understanding of the contribution of genetic burden to disease risk. For example, over the past 3 years the community has illustrated how focal and generalised epilepsies show an enrichment for both common and rare genetic burden 5,6. The predictive ability of genetic burden for disease state will increase steadily as ever larger collaborative studies emerge. The challenge now is to understand how these signatures correlated with treatment outcome. In addition, bioinformatics studies have shown mechanistic links between some of the targets of these circulating miRNAs and proteins present in plasma that can be measured that may correlate with neurophysiological phenotypes or responses to anti-miRNA therapies in epilepsy and Rett syndrome, a neurodevelopmental disorder accompanied by seizures (Henshall/Tropea, unpublished data). There are significant industry interests in these advances with negotiations underway with UCB Pharma to perform microRNA and genetic profiling to define the molecular landscape of drug-resistant epilepsy. Together, these discoveries have led to FutureNeuro having a leading position in the area of circulating diagnostic biomarkers that was recognised during the recent two-year Site Visit. We propose to capitalise on our leading position in this field and genomics during the remaining funding period. Broadly, we want to explore the value of these biomarkers at the earliest stage of the patient journey (i.e. upon first presentation of a seizure), test the benefits of different combinations of the biomarkers for epilepsy and rare diseases (Rett syndrome), extend evidence for pathophysiological links to disease, and begin the process of commercialisation toward a clinical/diagnostic test using either existing technology or techniques developed by the Centre. Background to proposal for years 3-6 Epilepsy affects 40,000 people in Ireland and the majority will present to the emergency room at some point in the course of their illness. However, more than half of the 7,000 or so admissions in Ireland every year are not people with epilepsy but those with symptomatic seizures related to intoxication with alcohol and other drugs; head injuries; brain infections and other serious illnesses. There are also a large number of mimic syndromes such as psychogenic non-epileptic seizures, recurrent fainting and collapses of unknown cause. Finding biomarkers that can distinguish between a. Epileptic seizures and non-epileptic attacks as well as other mimic disorders. b. Epileptic seizures and symptomatic seizures (such as alcohol withdrawal seizures). c. Epileptic seizures that will result in severe refractory disease as opposed to an isolated event. would be extremely scientifically interesting, clinically valuable, timesaving and economically beneficial for the health system.

Qualitative Study 'From the Outside-In': A qualitative study involving PWE, their carers and healthcare practitioners (HCP) This study will be an in-depth examination of the thoughts, opinions and behaviours of PWE, carers and HCP with regard to how they approach self-management of the condition, what supports they use and where they believe improvement is needed. This research will utilise 'co-production' to generate ideas for the future of epilepsy care provision in Ireland. Patients seldom are given a voice when it comes to such design of healthcare services - hence the study being provisionally titled 'From the Outside-In: Co-Designing Tools to Promote Independence and Wellbeing in Epilepsy Care'. Within the cohort recruited for qualitative research will be homeless PWE, keyworkers and clinicians working with Safetynet Homeless Service. I have become a member of the All Ireland Inclusion Health forum's Research Advisory Group (AIHF RAG) with a view to researching the challenges faced specifically by homeless PWE and clinicians working in the care of homeless patients. There are three work-streams planned for this study. Work-stream 1 involves obtaining ethical approval, creating consent forms, participant information leaflets and a data protection impact assessment. It also involves design of the ethnography, interviews and focus groups.

Rationale: The CoVID-19 virus is genetically similar to other zoonotic coronaviruses that can cause brain damage in animals. The ACE-2 receptor, thought to be the cellular invasion point, is widely expressed in the cerebral vasculature. Despite this, clinical observations in Ireland and elsewhere of the spectrum of neurological complications are large enough now to tell us, at least in this acute phase, that there is no unique neurological signature of CoVID-19 apart possibly from anosmia (loss of the sense of smell) that has been observed in 30-50% of cases. This indicates some protective processes in the human brain and the presence of anosmia points to one possible candidate, the Blood Brain Barrier (BBB) which is heterogeneous within the olfactory bulb with areas of less evolved barrier integrity. Aim: To determine the integrity of the BBB in acute and convalescent cases of CoVID-19 patients, with and without neurological symptoms in particular anosmia. Significance: A strong protective function for the BBB in supressing brain invasion may have significance for future therapies as well as policy and health service planning for any future pandemics. Objective neurological imaging combined with serological assessments may also hold enormous prognostic value in the short term.