Diffusion MRI tracks cortical microstructural changes during the early stages of Alzheimer's disease

Abstract

There is increased interest in developing markers reflecting microstructural changes that could serve as outcome measures in clinical trials. This is especially important after unexpected results in trials evaluating disease-modifying therapies targeting amyloid-β (Aβ), where morphological metrics from MRI showed increased volume loss despite promising clinical treatment effects. In this study, changes over time in cortical mean diffusivity, derived using diffusion tensor imaging, were investigated in a large cohort (n = 424) of non-demented participants from the Swedish BioFINDER study. Participants were stratified following the Aβ/tau (AT) framework. The results revealed a widespread increase in mean diffusivity over time, including both temporal and parietal cortical regions, in Aβ-positive but still tau-negative individuals. These increases were steeper in Aβ-positive and tau-positive individuals and robust to the inclusion of cortical thickness in the model. A steeper increase in mean diffusivity was also associated with both changes over time in fluid markers reflecting astrocytic activity (i.e. plasma level of glial fibrillary acidic protein and CSF levels of YKL-40) and worsening of cognitive performance (all P < 0.01). By tracking cortical microstructural changes over time and possibly reflecting variations related to the astrocytic response, cortical mean diffusivity emerges as a promising marker for tracking treatments-induced microstructural changes in clinical trials.

Keywords: Alzheimer’s disease; amyloid-β; astrocytes; clinical trials; cortical mean diffusivity.

Figure 1

Changes over time in cortical mean diffusivity across groups. (A and B) The colour scale represents standardized-β values from the multiple regression model comparing mean diffusivity (MD) across groups. For visualization purposes, the standardized-β values of each region of interest have been plotted on a standard cortical surface. Only results corrected for multiple comparisons are displayed (false discovery rate, P < 0.05). Changes over time are defined by individualized slopes from the linear mixed-effect (LME) model. [A(i)] Difference in in cortical MD between amyloid-β (Aβ)-negative/tau-negative and Aβ-positive/tau-negative participants. [A(ii)] Difference in changes over time in cortical MD between Aβ-negative/tau-negative and Aβ-positive/tau-negative participants including baseline cortical thickness from the same region as a covariate in the model. [B(i)] Difference in changes over time in cortical MD between Aβ-positive/tau-negative and Aβ-positive/tau-positive participants. [B(ii)] Difference in changes over time in cortical MD between Aβ-positive/tau-negative and Aβ-positive/tau-positive participants including baseline cortical thickness from the same region as a covariate in the model. (C and D) Difference in changes over time in cortical MD focusing on two a priori defined meta-ROIs: one encompassing regions accumulating Aβ early in the disease process (C), one encompassing neocortical temporal regions (D). The spaghetti plots represent the individual trajectories while the regression lines report the results of the LME models described in the text. The shadowed areas around the regression line represent the 95% confidence interval. Both the data-points and the regression lines are colour-coded accordingly to the biomarker-defined groups (A−T− = Aβ-negative/tau-negative; A+T− = Aβ-positive/tau-negative; A+T+ = Aβ-positive/tau-positive).

Figure 2

Association between changes over time in mean diffusivity and changes over time in fluid markers of astrocytic activity and neurodegeneration. The colour scale represents standardized-β values from the multiple regression. Only results corrected for multiple comparisons are displayed (false discovery rate, P < 0.05). Changes over time are quantified as individualized slopes from linear mixed-effect modelling. [A(i)] Association between changes over time in cortical mean diffusivity (MD) and changes over time in plasma levels of GFAP. [A(ii)] Association between changes over time in cortical MD and changes over time in plasma levels of GFAP including baseline cortical thickness from the same region as a covariate in the model. [A(iii)] Association between changes over time in cortical MD in the temporal region of interest (ROI) and changes over time in plasma levels of GFAP. [B(i)] Association between changes over time in cortical MD and changes over time in CSF levels of YKL-40. [B(ii)] Association between changes over time in cortical MD and changes over time in in CSF levels of YKL-40 including baseline cortical thickness from the same region as a covariate in the model. [B(iii)] Association between changes over time in cortical MD in the temporal ROI and changes over time in CSF levels of YKL-40. [C(i)] Association between changes over time in cortical MD and changes over time in plasma levels of NfL. [C(ii)] Association between changes over time in cortical MD and changes over time in in plasma levels of NfL including baseline cortical thickness from the same region as a covariate in the model. [C(iii)] Association between changes over time in cortical MD in the temporal ROI and changes over time in plasma levels of NfL. The standardized-β and P-value reported are derived from the multiple linear regression model described in the text. The shadowed areas around the regression line represent the 95% confidence interval.