Insights into White Matter Damage in Alzheimer's Disease: From Postmortem to in vivo Diffusion Tensor MRI Studies

Abstract

Background: Alzheimer's disease (AD) has traditionally been considered a disease of the gray matter (GM). However, several pathological and neuroimaging studies provided evidence of white matter (WM) abnormalities in this disease. The advent of diffusion tensor (DT) MRI allowed researchers to study in vivo cerebral WM abnormalities in AD, including the earliest stage of the disease and its atypical variants. Objective: To provide a concise overview of the main neuropathological and DT MRI studies that explored WM damage in AD providing new insights into the underlying pathophysiological mechanisms. Results: Neuropathological studies revealed that GM and WM changes did not concur regionally in many areas, where well-preserved GM often lay over severely changed WM also in nondemented subjects with an underlying AD pathology. DT MRI studies confirmed in vivo a severe WM involvement in classical and atypical AD variants and in the prodromal stage of the disease. Microstructural WM damage was severer and more distributed than expected on the basis of cortical atrophy in all clinical AD phenotypes. Conclusions: AD is characterized by a relevant involvement of the WM as demonstrated by postmortem and in vivo evidence. WM microstructural damage in AD is not always secondary to neuronal loss, suggesting a role of other pathological mechanisms such as prion-like propagation of altered proteins or neuroinflammation. DT MRI offers new insight into AD pathophysiology and, more importantly, new possible targets for future experimental therapies.

Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia

“…In addition, several DTI studies have indicated that patients with typical AD or PPA display reductions in white matter structural integrity that precede or are independent of grey matter cortical atrophy and clinical symptoms . Discordant degeneration between white and grey matter has also been shown in a study of typical amnestic AD patients where grey and white matter changes did not always overlap anatomically . It remains to be determined if factors such as neuroinflammation or prion‐like propagation contribute to these patterns of degeneration.…”

White Matter Microstructural Damage as an Early Sign of Subjective Cognitive Decline

“…Although less studied, white matter (WM) degeneration has also been demonstrated as an important feature in the spectrum of AD, as identified by histological examination and neuroimaging studies (Caso et al, 2016). A meta-analysis of diffusion tensor imaging (DTI) research revealed that WM microstructural alterations in aMCI and AD were widespread throughout the brain (Sexton et al, 2011), particularly in direct connections from the ventromedial frontal cortex to the medial temporal lobe (MTL) and from the precuneus to the MTL by the way of retrosplenial cortex (Salat et al, 2010).…”

CSF β-amyloid and white matter damage: a new perspective on Alzheimer’s disease

“…Moreover, the presence of WMHs seems to increase the risk for conversion from mild cognitive impairment (MCI) to AD and to predict the progression of cognitive symptoms 10 11 19 20. Diffusion-weighted imaging (DWI) studies have demonstrated the presence of WM microstructural changes in AD brains at preclinical stages 3. In our study, we chose to use apparent diffusion coefficient (ADC) maps, obtained from DWI scans, as metrics to evaluate the integrity of WM at microscopic level.…”