Cortical microstructural changes in autosomal dominant Alzheimer’s disease

Abstract

AbstractBackgroundAutosomal dominant Alzheimer's Disease (ADAD) is an important area of study to understand the pathogenesis of AD. Previous studies suggested that mutations in the genes coding for amyloid precursor protein cause early deposition of amyloid‐β peptide (Aβ), resulting in an amyloid‐induced inflammatory response and cortical microstructural changes during the cognitively asymptomatic phase, several years before clinical onset. The aim of this work was to investigate the cortical microstructural changes in an ADAD population, using novel diffusion tensor imaging (DTI) metrics that are correlated with specific neuropathology and disruption of cortical minicolumns.MethodA total of 270 individuals from families with known mutations in the PSEN1, PSEN2, and APP genes (168 mutation carriers and 102 non‐carriers) from the Dominantly Inherited Alzheimer’s Network (DIAN) were included in the study. 3DT1 and DTI scans at baseline were used to calculate the cortical grey matter fraction, cortical thickness, mean diffusivity (MD), and three novel cortical diffusivity measures, namely: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD), and the principal diffusion component parallel with the minicolumns (ParlPD). A multivariate General Linear model (GLM) was used to investigate cross‐sectional differences. Mutation carrier status was added as a fixed factor, and “sex” and “age” as covariates. Differences across the clinical spectrum are evaluated with box‐plots of metrics grouped by clinical dementia rating (CDR) Figure 1.ResultDifferences in cortical diffusivity measures were found between mutation carriers and non‐carriers. The GLM results revealed a significant main effect of mutation carrier status (p<0.05) as well as age (p<0.001) and sex (p<0.001). Between‐subjects effects revealed that PerpPD (p<0.0001), ParlPD (p<0.0001), and MD (p<0.0001) were significantly higher in the mutation carrier group. As expected, the cortical grey matter fraction (p<0.005) and cortical thickness (p<0.01) were significantly lower in the mutation carrier group.ConclusionIn autosomal dominant (inherited) Alzheimer’s disease, differences emerge in several novel cortical diffusivity measures, years before the expected diagnosis based on parental age of onset. These findings support using cortical diffusivity measures as a surrogate of cortical microstructure quality for identification of the early stages of AD.