APOE-e4-related differences in left thalamic microstructure in cognitively healthy adults

APOE-ε4 is a main genetic risk factor for developing late onset Alzheimer’s disease (LOAD) and is thought to interact adversely with other risk factors on the brain. However, evidence regarding the impact of APOE-ε4 on grey matter structure in asymptomatic individuals remains mixed. Much attention has been devoted to characterising APOE-ε4-related changes in the hippocampus, but LOAD pathology is known to spread through the whole of the Papez circuit including the limbic thalamus. Here, we tested the impact of APOE-ε4 and two other risk factors, a family history of dementia and obesity, on grey matter macro- and microstructure across the whole brain in 165 asymptomatic individuals (38–71 years). Microstructural properties of apparent neurite density and dispersion, free water, myelin and cell metabolism were assessed with Neurite Orientation Density and Dispersion (NODDI) and quantitative magnetization transfer (qMT) imaging. APOE-ε4 carriers relative to non-carriers had a lower macromolecular proton fraction (MPF) in the left thalamus. No risk effects were present for cortical thickness, subcortical volume, or NODDI indices. Reduced thalamic MPF may reflect inflammation-related tissue swelling and/or myelin loss in APOE-ε4. Future prospective studies should investigate the sensitivity and specificity of qMT-based MPF as a non-invasive biomarker for LOAD risk

Moving beyond the tensor: Advanced characterisation of white matter microstructure in Huntington’s Disease using translational neuroimaging

Huntington’s disease (HD) is a genetic neurodegenerative disorder leading to devastating cognitive, psychiatric and motor symptoms. Currently, this disease cannot be cured, and a research priority is to increase the understanding of its pathogenesis and to provide biomarkers for evaluating the efficacy of targeted therapies. Subtle and progressive white matter (WM) alterations have been observed early in HD progression, before clinical onset of the disease. However the aetiology of WM degeneration and its role in disease pathogenesis remain unclear. The assessment of early WM microstructural changes in the HD brain is therefore of fundamental importance, as this might prove useful for the identification of disease-related biomarkers and for measuring responsiveness to pharmaceutical and other therapeutic approaches. The primary aim of this work was to exploit both ultra-strong gradients (300 mT/m) and ultra-high field (7 Tesla, 9.4 Tesla) to assess WM microstructure in HD, using a variety of MRI techniques in premanifest and manifest patients, as well as in a mouse model of the disease. Specifically, this Thesis moved beyond the diffusion tensor framework, with the application of advanced WM microstructural imaging. Using these advanced MR techniques I was able to provide a comprehensive and detailed characterisation of WM microstructural alterations in the HD brain, and to better tease apart changes in apparent myelin from alterations in axon microstructure. Assessing both human patients and a mouse model of HD allowed for direct cross-species comparisons and bi-directional translation of results. Additionally, I was able to exploit the improved compartmental specificity obtained by complementing standard DTI metrics with advanced MRI measurements, to study the effects of two months of a novel drumming training on WM plasticity in patients with manifest HD