WHITE MATTER MICROSTRUCTURAL AND EXTRACELLULAR FREE-WATER CHANGES ASSOCIATED WITH COGNITION IN AMNESTIC MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE

Alzheimer's Disease (AD) and amnestic Mild Cognitive Impairment (aMCI) are associated with white matter (WM) microstructure abnormalities revealed by diffusion tensor imaging (DTI) methods (Acosta-Cabronero et al., 2010). However, the current DTI model suffers from partial volume effects, therefore preventing accurate quantification of WM abnormalities and their roles in cognitive deficits in the prodromal and clinical stages of AD (Metzler-Baddeley et al., 2012). Free-water (FW) imaging method can resolve this problem by differentiating the water compartment in the extracellular space from tissue in a voxel-based manner (Pasternak et al., 2009). We hypothesized that aMCI would have widespread FW increase and temporal WM microstructural damage whereas AD would have further deterioration. Moreover, we sought to investigate the association of FW increases and WM microstructural changes with memory impairment. 39 healthy controls (HC), 41 aMCI, and 36 AD patients underwent MR imaging (Siemens Tim Trio, 3T). The FW method was applied to derive individual FW and tissue compartment fractional anisotropy (FAT) maps. To assess group differences, we carried out voxel-wise statistical analyses on the FW and FAT images using two-sample t-tests. To assess region-specific WM changes underlying cognitive decline across aMCI and AD subjects, we built voxel-wise general linear models (GLM) with the skeletonized FW/DTI indices as the dependent variable, visual/verbal memory performance z-scores as the independent variables. All analyses were controlled for age, gender, handedness, and ethnicity. aMCI had widespread FW increases compared to HC. FW was further increased in AD compared with aMCI (Fig. 1A & C). Moreover, aMCI only had focal FAT reductions in frontal, hippocampal-temporal regions. FAT was further reduced in frontal, parietal, and occipital regions in AD (Fig. 1B & D). More importantly, visual/verbal memory impairment in aMCI and AD patients were associated with FW increases in several WM regions, but not in the body of the fornix. In contrast, visual/verbal memory decline was associated with FAT reductions in the body of the fornix (Fig. 2). Our findings suggest that FW correction isolates vascular damage from WM microstructural alterations and characterize their differential contributions to cognitive impairment in AD. Increased free-water (FW) and reduced tissue compartment fractional anisotropy (FAT) alone AD progression. (A) aMCI had widespread FW increase than HC. The FW level further increased when they reached the AD stage. White matter skeleton is highlighted in green color. (B) FAT reduced in frontal, mid-temporal and parietal regions in aMCI. Then, it further reduced in frontal and occipital parts in AD stage. All results are reported at the threshold of p < 0.05, TFCE and FWE corrected. (C) Mean FW (derived from group difference mask) increase in AD progression (D) Mean FAT (derived from group difference mask) reduce in AD progression. ‘**’ indicates p<0.05. Free-water (FW) increase and tissue compartment fractional anisotropy (FAT) deterioration correlated with verbal memory deficits. (A) Whole-brain voxel-wise linear regression indicated that increased FW values in widespread brain regions were associated with worse verbal memory. (B) Region-specific FAT reduce was associated with verbal memory deficits only in the body of fornix. White matter skeleton is highlighted in green color. All results are reported at the threshold of p < 0.05, TFCE and FWE corrected.