Shahid, Syed Salman; Wen, Qiuting; Risacher, Shannon L; Farlow, Martin R; Unverzagt, Frederick W; Apostolova, Liana G; Foroud, Tatiana M; ... Wu, Yu-Chien; + view all Shahid, Syed Salman; Wen, Qiuting; Risacher, Shannon L; Farlow, Martin R; Unverzagt, Frederick W; Apostolova, Liana G; Foroud, Tatiana M; Zetterberg, Henrik; Blennow, Kaj; Saykina, Andrew J; Wu, Yu-Chien; - view fewer (2022) Hippocampal-subfield microstructures and their relation to plasma biomarkers in Alzheimer's disease. Brain , 145 (6) pp. 2149-2160. 10.1093/brain/awac138.

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Abstract

Hippocampal subfields exhibit differential vulnerabilities to Alzheimer's disease (AD)-associated pathology including abnormal accumulation of beta-amyloid deposition and neurofibrillary tangles. These pathological processes extensively impact on the structural and functional interconnectivities of the subfields and may explain the association between hippocampal dysfunction and cognitive deficits. In the present study, we investigated the degree of alterations in the microstructure of hippocampal subfields across the clinical continuum of AD. We applied a gray matter (GM) specific multi-compartment diffusion model (Cortical-NODDI) to understand the differential effects of AD pathology on the hippocampal subfield microstructure. A total of 119 participants were included in this cross-sectional study. Participants were stratified into three categories, cognitively normal (CN; N = 47), mild cognitive impairment (MCI; N = 52), and AD (N = 19). Diffusion MRI, plasma biomarkers, and neuropsychological test scores were used to determine the association between the microstructural integrity and AD associated molecular indicators and cognition. For AD-related plasma biomarkers, we studied amyloid beta (Aβ), total tau (T-tau), and neurofilament light (NfL); for AD-related neuropsychological tests, we included the Trail Making Test (TMT), Rey Auditory Verbal Learning Test (RAVLT), Digit Span, and Montreal Cognitive Assessment (MoCA). Comparisons between CN and MCI showed significant microstructural alterations in the hippocampal cornu ammonis (CA) 4 and dentate gyrus (DG) region, whereas CA1-3 was the most sensitive region for the later stages in the AD clinical continuum. Among imaging metrics for microstructures, the volume fraction of isotropic diffusion for interstitial free water demonstrated the largest effect size in between-group comparisons. Regarding the plasma biomarkers, NfL appeared to be the most sensitive biomarker for associations with microstructural imaging findings in CA4-DG. CA1-3 was the subfield which had stronger correlations between cognitive performance and microstructural metrics. Particularly, poor performance in RAVLT and MoCA was associated with decreased intracellular volume fraction. Overall, our findings support the value of tissue-specific microstructural imaging for providing pathologically relevant information manifesting in the plasma biomarkers and neuropsychological outcomes across various stages of AD.

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