Measurement of cortical mean diffusivity detects early microstructural breakdown of the cerebral cortex in presymptomatic familial Alzheimer’s disease

Diffusion-weighted MRI is sensitive to microstructural changes; with studies to date largely focusing on white matter. However, in AD cortical grey matter is affected early. Assessment of cortical diffusivity changes may therefore allow detection of early neurodegeneration. We aimed to assess this in individuals at risk of familial AD (FAD). Seventy-seven participants were recruited: 38 with pathological mutations (in PS1 or APP) and 39 controls (Table). Of the mutation carriers, 16 had developed progressive cognitive symptoms and 22 were presymptomatic. Presymptomatic inidivduals were divided, depending on time to predicted symptom onset (median time to onset=8.1 years), in to early presymptomatic and late presymptomatic. T1-weighted and diffusion-weighted images were acquired. T1 images underwent cortical parcellation using Freesurfer (v5.3.0), prior to being registered to the diffusion images. Mean diffusivity (MD), which rises with increasing microstructural breakdown, was calculated for each cortical region. A region of interest approach was taken, using a 6-region “cortical signature”, containing regions identified previously as undergoing most cortical thinning in symptomatic FAD (entorhinal cortex, inferior parietal cortex, precuneus, superior frontal gyrus, superior parietal lobule, supramarginal gyrus). Across all mutation carriers, correcting for age and gender, a significant positive correlation was found between cortical MD and disease progression (time to/from onset) in 5 of the 6 signature regions, and in a mean signature summary measure (p<0.0001). In late presymptomatic individuals, compared to controls, cortical MD was higher in all 6 regions, reaching statistical significance in the left inferior parietal cortex (p=0.04), and trend significance in the right inferior parietal cortex (p=0.06). A support vector machine approach found cortical MD of the 6 regions to have a sensitivity and specificity of 80% in separating late presymptomatic individuals from controls. In early presymptomatic individuals, contrary to what one may expect, 5 of the 6 regions had reduced MD compared to controls; possibly indicating an early inflammatory response to amyloid. Measurement of cortical MD has potential as a method for detecting microstructural cortical change in AD, and correlates with disease progression. Presymptomatic microstructural breakdown is detectable, providing reasonable sensitivity and specificity for differentiating early AD from normal inidividuals.