Title: Functional Brain Connectivity in Neurodegenerative Tauopathy
Funder: Medical Research Council

Abstract: We will develop network-based imaging analysis of tau-associated neurodegenerative disease, bridging the gap between cellular and clinical phenotypic analysis and enabling networking approaches to characterise disease patterns. Our hypothesis is that specific patterns of progression of tau protein aggregation and cell death are associated with characteristic functional brain connectivity disturbances. Selective vulnerability of neural networks and mode of network disruption underlie specific clinical features. We predict graph theory metrics of magnetic resonance images and magnetoencephalography will reveal reduced network efficiency. Importantly, different candidate mechanisms of disease progression predict contrasting graph metrics results. For example, selective vulnerability of neuronal subpopulations to oxidative stress suggests highly connected hub areas would be most affected. In contrast, prion-like spread predicts contiguous reduction in measures of network efficiency and clustering. Although the tauopathy progressive supranuclear palsy is relatively uncommon, it has advantages of high clinicopathological correlation and relatively discrete molecular pathology. Insights gained from this prototypical tauopathy will translate to a range of neurodegenerative diseases including Alzheimer‘s, Pick‘s and Parkinson‘s disease. Our objectives are to: 1. analyse resting state functional magnetic resonance imaging data of patients with progressive supranuclear palsy using graph theory metrics. 2. analyse resting state magnetoencephalography data of patients with progressive supranuclear palsy in the same way; compare results with fMRI data; contrast pathological changes in network function at different frequency ranges. 3. apply these techniques to other neurodegenerative disorders with tau-based pathology, including corticobasal degeneration. An existing patient cohort will be supplemented by new cases, scanned using 3-Tesla EPI-fMRI at rest for 10 minutes. Optimised structural MPRAGE and DWI images will be acquired concurrently but this project focuses on analysis of functional networks. A subset of cases will undergo magnetoencephalography (Elekta Neuromag 406). Analysis will focus on metrics of functional connectivity using techniques developed in part by my second supervisor (Bullmore). The study will lead to a new model of tau-mediated neurodegeneration described by dynamic interactions among distributed brain networks. This approach helps understand clinical features such as dementia, apathy and imbalance which are difficult to ascribe to focal neurodegeneration. New features this method are: (a) joint applicability to fMRI and MEG, capturing frequency dependent and independent signals, (b) detecting effects of disease in hub regions, local clusters and their interconnections and relating these to models of disease progression (c) Like covariance-based analyses of functional connectivity, we expect high disease sensitivity, important for any potential surrogate marker of disease modification.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL