Objective To study the macro and microstructural MRI correlates of brain astrocytosis, measured with 11C-deuterium-L-deprenyl (11C-DED)-PET, in familial autosomal-dominant Alzheimer's disease (ADAD). Methods The total sample (n=31) comprised ADAD mutation carriers (n=10 presymptomatic, 39.2 ± 10.6 years old; n=3 symptomatic, 55.5 ± 2.0 years old) and non-carriers (n=18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers, and 11 non-carriers) also underwent 11C-DED-PET. Results Vertex-wise interaction analyses revealed a differential relationship between carriers and non-carriers in the association between 11C-DED binding and estimated years to onset (EYO), and between cortical mean diffusivity (MD) and EYO. These differences were due to higher 11C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to non-carriers; and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to non-carriers. Using a vertex-wise local correlation approach, 11C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness (CTh). Conclusions Our proof-of-concept study is the first to show that micro- and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer's disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.
|Date made available||15 Apr 2021|