Association of cortical microstructure with amyloid-β and tau: impact on cognitive decline, neurodegeneration, and clinical progression in older adults

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.

Inter- and intra-individual variation in brain structural-cognition relationships in aging

“…This suggests that including both structural and diffusion MRI measures increased our sensitivity to complementary underlying structural alterations. While the complexities of DWI underpinnings in grey matter remain as discussed above, our findings support a growing body of literature which demonstrates the utility of cortical DWI measurements to capture age- and cognitive-related variance ( Callow et al, 2021 ; Grydeland et al, 2013 ; Philippi et al, 2016 ; Radhakrishnan et al, 2022 ; Raz & Rodrigue, 2006 ; Reas et al, 2018 ; Rodriguez-Vieitez et al, 2021 ; Schneider et al, 2019 ). We also note that across all components identified as contributing to brain-cognition relationships, DWI metrics displayed a complementary nature.…”

Association of cortical and subcortical microstructure with disease severity: impact on cognitive decline, and language impairments in frontotemporal lobar degeneration

“…Higher cMD is thought to predict macroscopic cortical alterations by re ecting microstructural disarray and rupture of cellular membranes [18]. It has been proposed that microstructural changes in cortical structure precede macrostructural changes in cortical structure [9,25,40]. Our research expands on these ndings by using a large sample of individuals with three unique FTLD subgroups.…”

“…Both clinical measures of cognitive function and disease severity showed better correlations with cMD than with cortical thickness [38]. Recent studies reported increased cMD as a crucial and noninvasive biomarker for cortical surveillance of neurodegeneration-related microstructural alterations in possible and probable bvFTD [9], ALS-FTD continuum [25], Alzheimer's disease continuum [26], autosomal dominant Alzheimer's disease [39], and even normal aging adults [40]. Higher cMD is thought to predict macroscopic cortical alterations by re ecting microstructural disarray and rupture of cellular membranes [18].…”

Association of cortical and subcortical microstructure with disease severity: impact on cognitive decline and language impairments in frontotemporal lobar degeneration

“…Both clinical measures of cognitive function and disease severity showed better correlations with cMD than with cortical thickness. Recent studies reported increased cMD as a crucial and noninvasive biomarker for cortical surveillance of neurodegeneration-related microstructural alterations in possible and probable bvFTD [ 9 ], ALS-FTD continuum [ 22 ], Alzheimer’s disease (AD) continuum [ 20 ], autosomal dominant Alzheimer’s disease [ 37 ], and even normal aging adults [ 38 ]. Higher cMD is thought to predict macroscopic cortical alterations by reflecting microstructural disarray and rupture of cellular membranes [ 21 ].…”

“…Higher cMD is thought to predict macroscopic cortical alterations by reflecting microstructural disarray and rupture of cellular membranes [ 21 ]. It has been proposed that microstructural changes in cortical structure precede macrostructural changes in cortical structure [ 9 , 22 , 38 – 40 ]. Our research expands on these findings by using a large sample of individuals with three unique FTLD subgroups.…”