Integrating retrogenesis theory to Alzheimer's disease pathology: insight from DTI-TBSS investigation of the white matter microstructural integrity

Abstract

Microstructural abnormalities in white matter (WM) are often reported in Alzheimer's disease (AD) and may reflect primary or secondary circuitry degeneration (i.e., due to cortical atrophy). The interpretation of diffusion tensor imaging (DTI) eigenvectors, known as multiple indices, may provide new insights into the main pathological models supporting primary or secondary patterns of WM disruption in AD, the retrogenesis, and Wallerian degeneration models, respectively. The aim of this review is to analyze the current literature on the contribution of DTI multiple indices to the understanding of AD neuropathology, taking the retrogenesis model as a reference for discussion. A systematic review using MEDLINE, EMBASE, and PUBMED was performed. Evidence suggests that AD evolves through distinct patterns of WM disruption, in which retrogenesis or, alternatively, the Wallerian degeneration may prevail. Distinct patterns of WM atrophy may be influenced by complex interactions which comprise disease status and progression, fiber localization, concurrent risk factors (i.e., vascular disease, gender), and cognitive reserve. The use of DTI multiple indices in addition to other standard multimodal methods in dementia research may help to determine the contribution of retrogenesis hypothesis to the understanding of neuropathological hallmarks that lead to AD.

Figure 1

(a) Wallerian degeneration occurs as a secondary product of gray matter loss, while retrogenesis hypothesis outlines the degeneration of late-myelination fibers in neocortical areas. The Wallerian degeneration model postulates a posterior-anterior gradient of fibre degeneration (right side, arrows); the normal myelinisation occurs throughout the first life decades, beginning at dorsal brain and reaching neocortical areas at end stages (right side, arrows). According to the retrogenesis model, neocortical fibers are those more likely to suffer early degeneration by AD; (b) myelin breakdown and axonal damage are one of the key pathological mechanisms underlying white matter microscopic lesions (b). (c) A projection of the ellipse onto the three main axes (λ ₁, λ ₂, λ ₃) or eigenvectors. The main DTI indices of fractional anisotropy (FA) and axial (DA), radial (DR) and mean (MD) diffusivity are based on the eigenvector calculations (bottom).

Figure 2

DTI changes are evidenced in Alzheimer subjects when compared with healthy controls. Overlapping areas of FA decreased/DR increased are indicative of increased diffusion perpendicular to fibre orientation, possibly due to myelin breakdown (yellow-red). These areas can be observed in the corpus callosum (anterior and middle segments), anterior cingulum, and uncinate fasciculus (anterior portion) and remain when adjusting for group differences in gray matter atrophy (a) and white matter burden volume (c). Notes: FA: fractional anisotropy; DR: radial diffusivity.