Developing a validated biomarker of cortical neurodegeneration in Alzheimer's disease using high-gradient diffusion MRI

SUMMARY The pathological changes of Alzheimer’s disease (AD) develop long before the onset of symptoms, with the gradual accumulation of amyloid and tau in the brain followed by neuronal loss. While macroscopic brain changes such as hippocampal atrophy and cortical thinning are well-established as markers of symptomatic AD, the predictive value of such structural imaging measures is limited prior to the onset of dementia. High-gradient diffusion MRI has emerged as a sensitive tool for probing microstructural alterations throughout the whole brain and holds great promise for capturing the earliest microscopic gray matter abnormalities present in AD, before their overt manifestation on conventional MRI. With the recent introduction of commercially available high- performance gradient systems for clinical research, further elucidation of these imaging findings across the AD spectrum and systematic comparison against histopathology is timely and critical for gaining a better understanding of neuronal degeneration and the pathogenic factors influencing disease progression. The goal of this project is to leverage the sensitivity of high-gradient diffusion MRI to map alterations in gray matter microstructure in patients with mild cognitive impairment (MCI)/AD and individuals at risk of developing AD. This work will build on the hardware and acquisition advances that our group has worked on for over a decade as part of the Human Connectome Project and BRAIN Initiative to push the limits of diffusion MRI for mapping brain tissue microstructure in the living human brain. We propose to acquire advanced diffusion MRI measures on the next-generation Connectome scanner to map cortical and white matter microstructure in MCI/AD patients from the Massachusetts General Hospital Alzheimer’s Disease Research Center (MADRC) and individuals from the Human Connectome Project-Lifespan/Aging (HCP-Aging) cohort. Aim 1 will assess the relationship between cortical microstructural metrics obtained from high-gradient diffusion MRI and amyloid and tau PET uptake in MCI/AD and cognitively healthy older adults. Aim 2 will validate diffusion MRI measures of cellular morphology against histopathology performed in vulnerable regions of postmortem brain specimens obtained from patients with pathology-proven AD. At the end of this project, we anticipate the development of a validated, multi-scale advanced diffusion MRI protocol targeted for evaluating alterations in cortical microstructure in older adults of differing AD pathology status, with clear measures that can be translated to large-scale AD studies. Such information will inform the interpretation of diffusion imaging metrics acquired using commercially available MRI scanner hardware and provide key information regarding the underlying disease evolution to aid in the development of future neuroprotective therapies for AD.