Advanced Diffusion MRI of White Matter in Aging and AD

Abstract

Changes in brain white matter occur in normal aging and prior to the onset of cognitive impairment. We have shown that advanced diffusion MRI and biophysical modeling yield sensitive and specific metrics that distinguish age‐related (e.g. myelin remodeling) from amyloid‐related pathological processes (e.g. myelin repair) in the preclinical stage. In this presentation we provide an update on our ongoing observational longitudinal study to determine the extent to which these metrics can serve as predictive biomarkers of incident cognitive impairment. Cognitively unimpaired older adults completed brain MRI (including Diffusional Kurtosis Imaging) and standard clinical procedures (NACC UDS v3) at baseline and ∼2 years later, with 91.2% retention and 13.1% incident MCI (CDR = 0.5) at follow‐up. We found that in participants with preclinical AD, late‐myelinating white matter tracts demonstrate signs of myelin repair/gliosis as evidenced by greater diffusion restriction. We also observed that greater diffusion restriction predicts incident MCI over and above age, a finding we did not observe with other AD neuroimaging biomarkers of amyloid pathology, neurodegeneration, and white matter lesions. In the next 5 years of funding, we will expand our cohort in size and representativeness, incorporate complementary MRI biomarkers of myelin/gliosis (i.e. myelin water imaging [ViSTa] and 1H‐MRS of myo‐inositol and NAA) to test our inferences, and further develop diffusion MRI‐based biophysical modeling techniques (i.e. Fiber Ball Imaging‐based white matter modeling). Expected outcomes from this work include clinically feasible MRI biomarkers with which to empirically test a proposed conceptual model of white matter‐related changes in aging and AD, thereby providing translational support for trials of myelin/glia‐focused therapies which are grossly underexplored for asymptomatic AD. Our goal is to have an impact on the evolving conceptualization of how aging leads to AD and, critically, to illuminate novel mechanisms by which AD can be prevented or treated.