Diffusion MRI track cortical microstructural changes over time during the early stages of the Alzheimer’s disease continuum

Abstract

AbstractBackgroundMarkers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Previous cross‐sectional investigations suggested that diffusion MRI (dMRI) can provide metrics sensitive to cortical microstructural alteration linked to multiple aspects of the AD pathological cascade including Aβ‐accumulation and astrocytic activity. However, currently little evidence is available regarding the ability of dMRI in tracking changes over time.MethodsMean diffusivity (MD) was computed from dMRI data acquired from 363 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐1 study. Each participant underwent multiple dMRI scan (range 2‐4 scans) and was classified as Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on CSF levels of Aβ42/40 and ptau‐181. Rates of changes in MD, cortical thickness and plasma level of GFAP were computed in a linear mixed effect framework. Cortical regional values of MD were compared across biomarkers‐defined groups as well as to rates of change of GFAP.ResultsAnalyses of MD revealed widespread differences in rates of change already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation (fig.1). Further, analyses focusing on two composite ROIs, one encompassing regions that accumulate Aβ early in the disease process and a temporal meta‐ROI, confirmed that rates of change in MD significantly differed between groups even when cortical thickness was included in the model (Ps<0.05,fig.2). Regional MD rates of change in both neocortical temporal areas and key regions for Aβ‐accumulation, were also positively correlated with rates of change in GFAP (fig.3). Such result was supported by the analysis based on the two meta‐ROIs which confirmed the positive association between rates of change GFAP and MD.ConclusionMean diffusivity from dMRI is able to track cortical microstructural changes over time and to differentiate trajectories even during the early stages of the AD pathological cascade. The association between rates of change of MD and rates of change of GFAP suggested dMRI might reflect microstructural changes related to the astrocytic response to AD pathology. dMRI might help monitoring the effects of disease‐modifying therapies (e.g. Ab immunotherapies) in clinical trials.