Cortical Microstructure Mediates CSF Amyloid and Tau Associations with Episodic Memory Performance

Abstract

AbstractBackgroundEpisodic memory impairment is common in early stages of Alzheimer’s disease (AD) and has been linked to atrophy in cortical regions that are vulnerable to AD neuropathological processes (e.g., amyloid and tau accumulation). Volumetric measures are relatively insensitive to microstructural brain changes that can occur in earlier disease stages. Microstructural properties of brain tissue can be non‐invasively assessed using advanced diffusion MRI (dMRI) models such as neurite orientation dispersion and density imaging (NODDI). While a number of studies have related white matter microstructure to AD pathology and memory, few have evaluated advanced dMRI indices in cortical gray matter where the earliest histopathological changes are thought to occur.MethodWe evaluated 66 ADNI participants (age 71.8±6.2 years; 25 Males; 46 CN/18 MCI/2 AD) with available MRI (T1‐weighted and multi‐shell diffusion) and CSF Aβ1–42, pTau181, and pTau181/Aβ1–42 data (Fig1A). Episodic memory was assessed using WMS‐R delayed logical memory scores (Del‐Mem). We estimated average NODDI ICVF, ECVF, ISOVF, and ODI (Fig1B) in an AD‐metaROI of cortical gray matter regions that are sensitive to early AD (Fig1C,D). We tested whether the effect of CSF biomarkers on Del‐Mem were mediated by metaROI measures (Fig2A), adjusting for age, sex, education, and MRI site as a grouping variable. For comparison, we re‐ran analyses with AD‐metaROI cortical thickness as the mediator.ResultLower CSF Aβ1–42 and higher pTau181/Aβ1–42 were significantly associated with lower Del‐Mem performance (FDR; q=0.05); pTau181 was not associated (Fig2B).Lower cortical ICVF, ODI, and thickness and higher ISOVF were associated both with lower Aβ1–42 and higher pTau181/Aβ1–42 (Fig2C).The effect of Aβ1–42 on Del‐Mem was fully mediated by ICVF. The effect of pTau181/Aβ1–42 on Del‐Mem was partially mediated by ISOVF. Del‐Mem was not mediated by ODI or thickness (Table1). Sensitivity analyses in the 64 non‐demented individuals revealed comparable results.ConclusionLower cortical ICVF and higher ISOVF with greater Aβ and pTau/Aβ burden, respectively, may indicate neuronal loss or edema. While both ICVF and ISOVF findings can be driven by reduced diffusion restriction, larger pTau/Aβ effects on episodic memory mediated through ISOVF may indicate that tau hyperphosphorylation and aggregation induces a greater degree of inflammation, neuronal dysfunction and death.