Medicine (RMH) - Theses
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ItemInvestigation of the synergy between Alzheimer’s Disease and epilepsy through data-driven molecular networks( 2023-03)Overview: In the recent years, a bi-directional association between Alzheimer’s Disease (AD) and epilepsy has been observed, with AD-like cognitive impairments often presenting in epilepsy patients, and high rates of epileptic seizures seen in a sub-set of AD patients. These seizure-prone AD patients reportedly show accelerated cognitive decline and more aggressive disease progression compared to those without seizures. The mechanism and primary mode of action of this association remains unknown, although a synergistic interaction has been proposed. The general aim of this doctoral research was to investigate the electrical and molecular properties of the above-mentioned pathophenotypes and elucidate the mechanisms underlying the potential synergy between AD-like amyloid pathology and epileptiform activity, and their role in accelerated cognitive decline. Introduction and literature review: The introductory sections of Chapter 1 provide an overview of the current literature on epilepsy and Alzheimer’s Disease, focusing on pathophysiological mechanisms commonly implicated in both syndromes. The subsequent sections discuss several benchmark studies that first reported on the increased co-occurrence of seizures among AD patients, followed by a critical review of the most prominent as well as recently emerged hypotheses that aim to provide mechanistic insight into the nature of the proposed bi-directional association between AD and acquired epilepsy. The concluding sections provide a gentle introduction into the emerging field of network medicine, systems- based analysis, interrogation methods of high-throughput biological data and the general framework of computational models and methodology that was implemented throughout this work. Experimental chapters: The first and second experimental chapters aim to characterize the molecular signature of a brain affected by amyloid pathology and seizures. Utilizing proteomic and metabolomic data from two collaborative studies as well as publicly available transcriptomic data, Chapter 2 describes the molecular signature of human AD and that of most widely used mouse models of AD, while Chapter 3 captures the molecular profile of well- established rat models of genetic (GAERS) and acquired (post SE) epilepsies. Informed by the insight gained from Chapters 2 and 3, the third experimental chapter (Chapter 4) aimed to capture the shared molecular signature associated with AD and temporal lobe epilepsy (TLE) – the most common type of epilepsy comorbid with AD. A hypothesis-free, systems-level approach was used to characterize the pathophysiological state of each disease on a molecular level by constructing data-driven gene coexpression networks representing the respective pathologies. The topology and architecture as well as the preservation of functional gene modules between the two networks were compared through network preservation analysis, identifying two clusters of synaptic reorganization and signalling-associated genes as highly preserved between AD and TLE. The fourth and final experimental chapter (Chapter 5) aims to investigate the mechanism and potential mediators of the bi-directional relationship between amyloid pathology and epilepsy by examining the effect of recurrent seizures on hallmark features of AD pathology such as amyloid plaque deposition and cognitive performance. RNA sequencing and bioinformatic analysis of mouse hippocampal tissue was conducted in order to investigate the molecular mechanisms of synergy between recurrent seizures and already- present AD pathology as well as identify key mediators of accelerated disease progression, which could serve as promising targets for intervention. Discussion and conclusions: Informed by computational analysis from chapters 2, 3 and 4, and reinforced by experimental evidence from chapter 5, the final chapter of this thesis (Chapter 6) provides a synthesis of the newly gained insights into the strong synergistic nature of the relationship between amyloid pathology and recurrent seizures. A subsequent extensive review of the most current molecular neuroscience research facilitated interpretation of our results, leading to the proposal of a “dual-pathology” disease model for epilepsy and AD. In this paradigm, the synergistic self-propagating interaction between epileptiform activity and amyloid pathology defines a distinct subpopulation of “dual-pathology” patients, characterized by faster disease progression and more severe cognitive decline. Furthermore, I describe specific cellular pathways mediating the synergy between amyloid pathology and recurrent seizure activity and introduce a mechanistic framework underlying the chain of events through which this synergy leads to accelerated cognitive deterioration. Each step in this framework or chain of events is reinforced by a benchmark proof-of-concept study published in leading peer- reviewed journals and which, with the exception of the most recent 2022-2023 studies, have been independently replicated by other research groups. The concluding sections of this chapter emphasize the utility of integrating phenotypic and electroencephalographic data from in vivo studies with high-throughput “omics” data into network-based computational models for a holistic examination of pathophysiological mechanisms underlying complex diseases and identification of novel therapeutic targets.
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ItemDietary Therapies For Adults With Epilepsy( 2022)Epilepsy is a chronic neurological condition, characterised by recurrent, spontaneous seizures. For the majority of people with epilepsy, their seizures will be controlled by anti-seizure medications. However, one-third of people with epilepsy will not have their seizures controlled, and in these patients with drug-resistant epilepsy, alternatives to medications should be considered. Ketogenic diet therapy is well-established in paediatric epilepsy care, however it has not been widely translated into adult practice. This thesis focuses on the feasibility, safety and efficacy of novel diets and dietary supplements as potential treatments for adults living with epilepsy in Australia, and emerging evidence for this approach as an adjunct treatment for super-refractory status epilepticus. The first aim of this thesis was to determine the feasibility and efficacy of novel dietary therapies for adults with drug-resistant epilepsy. To address this aim, we first conducted a 12-week randomised-controlled trial and 12-month open label extension study of oral triheptanoin oil as an add-on treatment for adults with drug-resistant epilepsy. Next, we investigated the feasibility and efficacy of the modified Atkins diet for epilepsy in adults in a 12-week randomised-controlled trial. Finally, we conducted a prospective audit of a newly established dietary therapy for epilepsy service embedded in a quaternary teaching hospital. The findings of these trials highlight challenges of conducting clinical trials of dietary therapy for epilepsy in adults, such as adherence and high attrition rate. We observed some adults with drug-resistant epilepsy may benefit from dietary therapy, with few serious adverse effects associated with its use. The second aim of this thesis was to investigate the emerging role of dietary therapy as treatment for super-refractory status epilepticus in adults. A review of the literature found a small number of retrospective, observational studies reporting use of the classical 4:1 ratio ketogenic therapy in this setting. We then conducted a retrospective cohort study at two quaternary teaching hospitals of patients treated with a 2:1 ratio ketogenic therapy for super-refractory status epilepticus. This lower ratio ketogenic therapy may be associated with fewer complications and better align with current critical care nutrition guidelines. The development and implementation of non-drug treatment options for epilepsy is crucial in the context of a multifaceted approach to improving seizure control and reducing disease burden. The research in this thesis demonstrated the safety, acceptability, practicality, and efficacy of dietary approaches as adjunct therapies for patients with drug-resistant epilepsy as an outpatient, and for critical care inpatients with super-refractory status epilepticus. There remains a significant need for ongoing research focusing on optimal dietary regimens and strategies to increase patient retention of dietary therapy long term for adults with epilepsy.
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ItemGlutamate as a biomarker of post-stroke epilepsy( 2021)Stroke is one of the most important causes of acquired epilepsy in adults. Patients with seizures after stroke have higher mortality and disability than those without seizures. There is a building body of evidence to suggest that post-stroke epilepsy may be mediated by dysregulation of glutamate homeostasis, given the central role of glutamate in the pathogenesis of both stroke and seizures. There is currently no evidence to support the use of antiseizure medications as primary prevention of epilepsy in stroke patients. Ideally, anti-epileptogenic treatment would be targeted at those stroke patients at highest risk of epilepsy according to established biomarkers – studying glutamate as one such biomarker has been limited by a reliance on invasive procedures including lumbar puncture to quantify concentrations of glutamate in the brain. This thesis focuses on the role of 7T MRI as a method of brain glutamate quantification in the setting of stroke. The research has been conducted in the Department of Neurology, Royal Melbourne Hospital, the Department of Medicine (The Royal Melbourne Hospital), University of Melbourne, and the Melbourne Node of the National Imaging Facility, Department of Radiology, University of Melbourne. 22 patients with acute ischaemic or haemorrhagic stroke were recruited from the inpatient stroke unit at Royal Melbourne Hospital, with 7T MRI scans performed at the Melbourne Brain Centre Imaging Unit, University of Melbourne. In addition, peripheral blood samples were collected and underwent metabolomics analysis for plasma glutamate quantification at the Monash Institute of Pharmaceutical Sciences, Parkville. Across the patient cohort, glutamate concentration was lower in the region of infarction than in the corresponding hemisphere, when measured by Magnetic Resonance Spectroscopy. When measured by glutamate weighted chemical exchange saturation transfer imaging (GluCEST), the results were more heterogeneous, ranging from decreased to increased, ipsilateral to infarction. One patient in the cohort developed post-stroke epilepsy, with a GluCEST profile similar to the population overall. A single haemorrhagic stroke patient suffered a seizure prior to scan acquisition, with a pattern of increased cortical GluCEST contrast consistent with a post-seizure effect. The second part of the thesis focuses on a study protocol examining the anti-epileptogenic potential of the glutamate receptor antagonist and antiseizure medication perampanel in a population at high risk of post-stroke epilepsy. This involves a collaboration of clinicians at four Melbourne Hospitals (Alfred Hospital, Royal Melbourne Hospital, Monash Medical Centre, Austin Hospital), led by the candidate. Finally, there is evidence that patients with epilepsy have an increased risk of developing cerebrovascular or cardiovascular disease, although it is unclear whether this is due primarily to the epilepsy itself, or non-epilepsy factors such as antiseizure medications. The third part of the thesis comprises a data linkage study in the Department of Neurology, Royal Melbourne Hospital, based on medical records from a database of admitted video EEG monitoring patients from 1995 to 2015. It was found that the incidence of new-onset cerebrovascular disease was higher in epilepsy patients compared with the general Victorian population, although there was no difference in the composite incidence of cerebrovascular disease, cardiovascular disease and peripheral vascular between epilepsy and non-epilepsy patients in the cohort. Furthermore, patients taking treatment with valproic acid were at lower risk than both those taking enzyme-inducing antiseizure medications and those taking neither valproic acid nor enzyme-inducing antiseizure medications. Collectively, these results emphasise the role of non-epilepsy factors such as social determinants of health, medical comorbidity, and epilepsy treatment, in influencing vascular risk.
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ItemMultimodal Ultra-High-Field MRI Biomarkers of Epilepsy( 2020)The Default Mode Network (DMN), whose major hub is the PCC/precuneus, is one of the key resting-state networks in the brain. Many research groups have investigated its role in a range of neurological and psychiatric conditions. In particular, resting-state fMRI has demonstrated DMN alterations in various forms of epilepsy. However, most of these studies recruited patients with either focal or generalised epilepsy, and few comparisons were made between the fMRI characteristics of these conditions. Magnetic resonance spectroscopy (MRS) was employed in several studies of patients with epilepsy. The concentrations of metabolites such as glutamate and gamma-amino butyric acid (GABA), the major excitatory and inhibitory neurotransmitters in the CNS, and glutathione, the major free radical scavenging compound in the brain, could not be accurately determined in magnetic fields up to 4T due to overlapping resonances from other molecules using conventional vendor supplied sequences. The advent of 7T MRI may help improve quantification of these metabolites. In this study we developed a multimodal protocol consisting of resting-state fMRI and MRS of a cubic 8 mL voxel located in the PCC/precuneus using the stimulated echo acquisition mode (STEAM) sequence with ultrashort TE at 7T. Resting-state fMRI was acquired from 12 right-handed healthy volunteers, and reproducibility of quantitative MRS of glutamate, glutathione and GABA was assessed in 10 of these volunteers. We later recruited 35 right-handed patients with epilepsy (19 with temporal lobe epilepsy and 16 with idiopathic generalised epilepsy) who underwent 7T MRI scans using a protocol comprising resting-state fMRI and a single MRS sequence identical to the ones used in the healthy controls. We discovered a linear correlation between the ratio of glutamate to GABA concentration in the PCC/precuneus of healthy controls and a similar linear correlation with age of the functional connectivity of the PCC/precuneus to other major DMN hubs. However, no independent correlation was seen between PCC/precuneus functional connectivity and glutamate, GABA, or the ratio of their concentrations, thus lending further support to the use of both MRS and fMRI as complementary methods in a multimodal pipeline exploring the effects of epilepsy in the patient groups. Analysis of MRS results demonstrated an overall increased concentration of glutathione in patients with idiopathic generalised epilepsy as compared to healthy controls. Analysis of fMRI data led to the identification of several cortical clusters, whose functional connectivity, and in some cases also pattern of activation, is different between patients with idiopathic generalised epilepsy and temporal lobe epilepsy. Subgroup analysis related to seizure focus laterality and short-term seizure-freedom was also performed. No significant correlation was found between the glutamate/GABA ratio or the mean functional connectivity of the PCC/precuneus with age or duration of epilepsy in the patient groups. In conclusion, multimodal MRI sequences have demonstrated distinct patterns of resting-state connectivity and metabolic profiles that are different between patients and controls and between patient subgroups. If corroborated in larger cohorts, such findings may be useful in the diagnosis and management of patients with epilepsy, and especially in expediting the diagnosis of the important subgroup of patients with drug-resistant epilepsy.