Abstract
Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer’s disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11C-Pittsburgh compound-B-PET, 18F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.
Highlights
Alzheimer’s disease (AD) is characterized by the misfolding and deposition of amyloid-β (Aβ) and hyperphosphorylated tau in the brain [1, 2], a process that begins years before clinical onset [3]
The association of Entorhinal FTP (entFTP) with vertexwise cortical mean diffusivity (cMD) was localized to clusters in the entorhinal and inferiormiddle-temporal gyrus on the right hemisphere (Fig. 1A), while inferior-temporal FTP (i-tFTP) was associated with more widespread increases in cMD in bilateral clusters of entorhinal, isthmus cingulate, fusiform gyrus, inferior-middle-temporal gyrus, and parts of lateral occipital, lateral orbitofrontal cortex and precuneus (Fig. 1C)
Increased cMD at baseline predicted faster cognitive decline, which remained significant after correction for global Aβ, regional cortical thickness (CTh), and entorhinal tau
Summary
Alzheimer’s disease (AD) is characterized by the misfolding and deposition of amyloid-β (Aβ) and hyperphosphorylated tau in the brain [1, 2], a process that begins years before clinical onset [3]. Accumulating evidence from preclinical and clinical studies supports the notion that Aβ and tau pathologies interact synergistically in the preclinical stages of AD, contributing to faster neurodegeneration and cognitive decline [4,5,6,7]. In vivo imaging biomarkers of AD proteinopathy, neuronal injury and neurodegeneration are of interest to elucidate the dynamic interplay among biological mechanisms underlying disease progression. Complementary noninvasive imaging biomarkers of subtle neuronal injury—whether alone or in combination with Aβ– may help select participants at the earliest stages with an enhanced risk of impending cognitive decline or clinical progression. Biomarkers for identification of at-risk individuals prior to widespread neurodegeneration are of great interest for optimization of secondary prevention trials [13,14,15], and as outcome measures of therapeutic efficacy
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