Quantitative Neuroimaging Assessment of White Matter Integrity in the Context of Aging and AD

PROJECT SUMMARY
Although the most significant risk factor for developing Alzheimer’s disease (AD) is advanced age, the changes
in tissue microstructure that signal the shift from normal aging to AD are not well understood. Thus, in response
to PAR-22-093, NOT-AG-21-039: Understanding AD in the Context of the Aging Brain, we seek to elucidate the
changes in white matter microstructure in preclinical AD using advanced diffusion MRI methods developed by
our group. During the 1st funding period of this grant, we established a longitudinal cohort of 165 cognitively
unimpaired participants ages 45-85 who completed extensive clinical procedures (i.e. MRI, amyloid PET,
neuropsychological testing, questionnaires), with an exceptional 92% retention rate at 2-year follow-up, including
14% of participants who have developed incident mild cognitive impairment (MCI) thus far. We showed 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 in the hippocampus
significantly 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. These results have significant
implications for disease monitoring and treatment development for the very earliest stages of AD, but further
work is needed to refine these methods and determine how they indicate both aging and disease progression
over time. Thus, during the 2nd funding period, we seek to continue studying this cohort longitudinally every 2
years, to enhance the cohort’s inclusivity and sample size, and to add new, complementary MRI biomarkers of
myelin/gliosis to test our inferences. Our overall objective is to delineate the natural history of white matter
changes from normal aging to preclinical AD and to MCI/dementia, illuminating what aspects of myelin/gliosis
drive changes in diffusivity, where these preferentially occur, and when in the course of disease these take place.
We will continue leveraging our interdisciplinary group’s expertise in diffusion MRI (Diffusional Kurtosis Imaging,
Fiber Ball Imaging) and biophysical modeling, adding new experts on T1-based myelin water imaging and 1H-
Magnetic Resonance Spectroscopy to assay myelin dynamics/gliosis. We hypothesize that advanced diffusion
MRI methods can indicate myelin repair/gliosis in the preclinical stage prior to myelin breakdown and axonal loss
in the symptomatic stage, a trajectory that is distinct from normal, homeostatic processes such as myelin
remodeling/maintenance. Thus, we aim to: Characterize longitudinal changes in white matter microstructure in
aging and AD (Aim 1); Quantify microscopic axonal fiber organization in aging and AD (Aim 2); Determine the
associations between diffusion MRI-derived microstructural parameters and complementary measures of
myelin/gliosis in aging and AD (Aim 3). This work will have the greatest overall impact in providing the critical
translational support for trials that target mechanisms such as innate immunity/inflammation and glial
senescence, which are very promising yet grossly underexplored in AD especially for the asymptomatic stage.

Grant Number: 5R01AG054159-09
NIH Institute/Center: NIH
Principal Investigator: Andreana Benitez