Next-generation imaging biomarkers of cortical microstructure for measuring presymptomatic cortical degeneration in Alzheimer’s disease and associations with molecular pathology

In Alzheimer’s disease (AD) there is a drive towards earlier clinical trials, before symptoms manifest, prior to significant neuronal loss. However current approaches for identifying those at risk of imminent decline and tracking progression lack sensitivity. I previously identified a characteristic pattern of early cortical loss in AD.

In the current fellowship I will develop sensitive quantitive cortical imaging biomarkers, and improve understanding of early AD-related neurodegeneration and its link to molecular pathology.

First, I will undertake multi-compartmental modelling of multi-shell diffusion MRI to track presymptomatic microstructural breakdown of cortical neurons, across three separate cohorts, and compare with established imaging markers.

Secondly, I will acquire ultra high field (7T) MRI and undertake quantitive multiparameter mapping to characterize extra-neuronal cortical microstructure, including myeloarchitecture and iron deposition, at sub-millimetre resolution. Thirdly, I will assess associations between tau PET and microstructural imaging.

I will use my expertise in blood-based biomarkers and novel measures of cognitive decline to explore their relationship with cortical microstructure.

Goals: - Assess how microstructural change can be optimally assessed in-vivo. - Determine the nature, timing, and distribution of early cortical breakdown. - Use microstructural cortical imaging to estimate proximity to symptom onset. - Examine how neuronal breakdown is mediated by tau deposition.