UC San Diego

The retrogenesis model of Alzheimer's disease (AD) posits that changes in white matter (WM) follow an inverse pattern of myelogenesis. Diffusion tensor imaging (DTI) was used to test the retrogenesis model. Specifically, greater loss of WM microstructural integrity (e.g., lower values of fractional anisotropy; FA) was predicted in late -myelinating WM fiber pathways (e.g., association pathways) in AD patients relative to healthy older adults, whereas early-myelinating fiber pathways (e.g., projection pathways) were not expected to show group differences. Furthermore, it has been proposed that AD includes a disconnection syndrome. Thus, higher cognitive functions dependent upon the synchronization of distributed neural networks (e.g., executive functions) were predicted to correlate with WM integrity. This study included 16 AD patients (mean age = 77.4, 64% female) and 14 demographically-matched healthy older adults (mean age = 77.3, 50% female). Image processing via tract-based spatial statistics (TBSS) was used to perform voxelwise statistics across subjects on FA skeleton maps. Additionally, region of interest (ROI) group comparisons were performed on early-myelinating (posterior limb of internal capsule, cerebral peduncles), late-myelinating (inferior longitudinal fasciculus, superior longitudinal fasciculus), and commissural (genu, splenium) fiber pathways. Permutation-based voxelwise analysis corrected for multiple comparisons revealed significantly lower FA values in AD patients compared to healthy older adults in late-myelinating association fiber pathways (superior longitudinal fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus) and other fiber pathways that connect brain regions afflicted early by AD neuropathology (cingulum, fornix, splenium; p < .05). No significant differences were seen in early-myelinating pathways. These group differences remained significant after controlling for grey matter, WM, and white matter hyperintensity volumes. ROI analyses showed significantly lower FA in the inferior longitudinal fasciculus (p < .05). Pearson correlations revealed that dementia severity and neuropsychological composite scores in the domains of executive functions, processing speed, and memory were significantly related to WM integrity (p < .05). In conclusion, we found that patients with AD show demonstrable changes in vulnerable WM fiber pathways that likely reflect both retrogenesis and Wallerian degeneration (WM degeneration secondary to neuronal loss). WM integrity was associated with changes in higher-order cognition, supporting the view of AD as a disconnection syndrome. Knowledge of the pattern of WM microstructural changes in AD and its underlying mechanisms may contribute to earlier detection and intervention in at-risk groups