Epileptogenesis is a gradual and dynamic process leading to difficult-to-treat seizures. Several cellular, molecular, and pathophysiologic mechanisms, including the activation of inflammatory processes.  The use of human brain tissue represents a crucial strategy to advance our understanding of the underlying neuropathology and the molecular and cellular basis of epilepsy and related cognitive and behavioral comorbidities,  The mounting evidence obtained during the past decade has emphasized the critical role of inflammation  in the pathophysiological processes implicated in a large spectrum of genetic and acquired forms of  focal epilepsies. Dissecting the cellular and molecular mediators of  the pathological immune responses and their convergent and divergent mechanisms, is a major requisite for delineating their role in the establishment of epileptogenic networks. The role of small regulatory molecules involved in the regulation of  specific pro- and anti-inflammatory pathways  and the crosstalk between neuroinflammation and oxidative stress will be addressed.    The observations supporting the activation of both innate and adaptive immune responses in human focal epilepsy will be discussed and elaborated, highlighting specific inflammatory pathways as potential targets for antiepileptic, disease-modifying therapeutic strategies.

Caroline Williams-Gray is a Principal Research Associate in the Department of Clinical Neurosciences, University of Cambridge, and an honorary consultant neurologist specializing in Parkinson’s disease and movement disorders. She leads a translational research group investigating the clinical and biological heterogeneity of PD, with the ultimate goal of developing more targeted therapies for different Parkinson’s subtypes. Her recent work has focused on the theory that the immune system plays a significant role in mediating the heterogeneity of PD and its progression. Her lab is investigating this using blood and CSF -based immune markers, PET neuroimaging and neuropathology in stratified PD cohorts; and she is leading the first randomized controlled trial repurposing a peripheral immunosuppressive drug (azathioprine) to slow the progression of PD.

Recent studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material." https://doi.org/10.1016/j.cell.2022.09.030

Alterations in sleep are hallmarks of the ageing process and emerges as risk factors for Alzheimer’s disease (AD). While the fine-tuned coalescence of sleep microstructure elements may influence age-related cognitive trajectories, its association with AD-related processes is not fully established. We investigated whether sleep arousals and the coupling of spindles and slow waves, key elements of sleep microstructure, are associated with early amyloid-beta (Aβ) brain burden, hallmark of AD neuropathology, and cognitive change at 2 years in 100 late-midlife healthy individuals. We first found that arousals interrupting sleep continuity were positively linked to Aβ burden, while, by contrast, the more prevalent arousals upholding sleep continuity were associated with lower Aβ burden and better cognition. We further found that young-like co-occurrence of spindles and slow-depolarisation slow waves is associated to lower burden of Aβ over the medial prefrontal cortex and is predictive of memory decline at 2-year follow-up. We provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. We further show the altered coupling of sleep microstructure elements that are key to its mnesic functions may contribute to poorer brain and cognitive trajectories. The presentation will end with preliminary data show that activity of the locus coeruleus, essential to sleep and showing some of the earliest signs of AD-related pathological processes, is associated with sleep quality. These preliminary findings are the first of a project ailed at link sleep and AD through the locus coeruleus.

Over the past years, genetic studies have uncovered hundreds of genetic variants to be associated with complex brain disorders. While this really represents a big step forward in understanding the genetic etiology of brain disorders, the functional interpretation of these variants remains challenging. We aim to help with the functional characterization of variants through transcriptomic data analysis. For instance, we rely on brain transcriptome atlases, such as Allen Brain Atlases, to infer functional relations between genes. One example of this is the identification of signaling mechanisms of steroid receptors. Further, by integrating brain transcriptome atlases with neuropathology and neuroimaging data, we identify key genes and pathways associated with brain disorders (e.g. Parkinson's disease). With technological advances, we can now profile gene expression in single-cells at large scale. These developments have presented significant computational developments. Our lab focuses on developing scalable methods to identify cells in single-cell data through interactive visualization, scalable clustering, classification, and interpretable trajectory modelling. We also work on methods to integrate single-cell data across studies and technologies.

In this webinar, Dr Ye Tian and A/Prof Andrew Zalesky will present new research on mapping the functional architecture of the human subcortex. They used 3T and 7T functional MRI from more than 1000 people to map one of the most detailed functional atlases of the human subcortex to date. Comprising four hierarchical scales, the new atlas reveals the complex topographic organisation of the subcortex, which dynamically adapts to changing cognitive demands. The atlas enables whole-brain mapping of connectomes and has been used to optimise targeting of deep brain stimulation. This joint work with Professors Michael Breakspear and Daniel Margulies was recently published in Nature Neuroscience. In the second part of the webinar, Dr Ye Tian will present her current research on the biological ageing of different body systems, including the human brain, in health and degenerative conditions. Conducted in more than 30,000 individuals, this research reveals associations between the biological ageing of different body systems. She will show the impact of lifestyle factors on ageing and how advanced ageing can predict the risk of mortality. Associate Professor Andrew Zalesky is a Principal Researcher with a joint appointment between the Faculties of Engineering and Medicine at The University of Melbourne. He currently holds a NHMRC Senior Research Fellowship and serves as Associate Editor for Brain Topography, Neuroimage Clinical and Network Neuroscience. Dr Zalesky is recognised for the novel tools that he has developed to analyse brain networks and their application to the study of neuropsychiatric disorders. Dr Ye Tian is a postdoctoral researcher at the Department of Psychiatry, University of Melbourne. She received her PhD from the University of Melbourne in 2020, during which she established the Melbourne Subcortex Atlas. Dr Tian is interested in understanding brain organisation and using brain imaging techniques to unveil neuropathology underpinning neuropsychiatric disorders.

This seminar is part of our “Emergent Scientists” series, an initiative that provides a platform for scientists at the critical PhD/postdoc transition period to share their work with a broad audience and network. Summary: These talks cover Alzheimer’s disease (AD) research in both mice and humans. Christiana will discuss in particular the translational aspects of applying mouse work to humans and the importance of timing in disease pathology and intervention (e.g. timing between AD biomarkers vs. symptom onset, timing of therapy, etc.). Siddharth will discuss a rare variant of Alzheimer’s disease called “Logopenic Progressive Aphasia”, which presents with temporo-parietal atrophy yet relative sparing of hippocampal circuitry. Siddharth will discuss how, despite the unusual anatomical basis underlying this AD variant, degeneration of the angular gyrus in the left inferior parietal lobule contributes to memory deficits similar to those of typical amnesic Alzheimer’s disease. Christiana’s abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that causes severe deterioration of memory, cognition, behavior, and the ability to perform daily activities. The disease is characterized by the accumulation of two proteins in fibrillar form; Amyloid-β forms fibrils that accumulate as extracellular plaques while tau fibrils form intracellular tangles. Here we aim to translate findings from a commonly used AD mouse model to AD patients. Here we initiate and chronically inhibit neuropathology in lateral entorhinal cortex (LEC) layer two neurons in an AD mouse model. This is achieved by over-expressing P301L tau virally and chronically activating hM4Di DREADDs intracranially using the ligand dechloroclozapine. Biomarkers in cerebrospinal fluid (CSF) is measured longitudinally in the model using microdialysis, and we use this same system to intracranially administer drugs aimed at halting AD-related neuropathology. The models are additionally tested in a novel contextual memory task. Preliminary findings indicate that viral injections of P301L tau into LEC layer two reveal direct projections between this region and the outer molecular layer of dentate gyrus and the rest of hippocampus. Additionally, phosphorylated tau co-localize with ‘starter cells’ and appear to spread from the injection site. Preliminary microdialysis results suggest that the concentrations of CSF amyloid-β and tau proteins mirror changes observed along the disease cascade in patients. The disease-modifying drugs appear to halt neuropathological development in this preclincial model. These findings will lead to a novel platform for translational AD research, linking the extensive research done in rodents to clinical applications. Siddharth’s abstract: A distributed brain network supports our ability to remember past events. The parietal cortex is a critical member of this network, yet, its exact contributions to episodic remembering remain unclear. Neurodegenerative syndromes affecting the posterior neocortex offer a unique opportunity to understand the importance and role of parietal regions to episodic memory. In this talk, I introduce and explore the rare neurodegenerative syndrome of Logopenic Progressive Aphasia (LPA), an aphasic variant of Alzheimer’s disease presenting with early, left-lateralized temporo-parietal atrophy, amidst relatively spared hippocampal integrity. I then discuss two key studies from my recent Ph.D. work showcasing pervasive episodic and autobiographical memory dysfunction in LPA, to a level comparable to typical, amnesic Alzheimer’s disease. Using multimodal neuroimaging, I demonstrate how degeneration of the angular gyrus in the left inferior parietal lobule, and its structural connections to the hippocampus, contribute to amnesic profiles in this syndrome. I finally evaluate these findings in the context of memory profiles in other posterior cortical neurodegenerative syndromes as well as recent theoretical models underscoring the importance of the parietal cortex in the integration and representation of episodic contextual information.