Tracking reactive astrogliosis in autosomal dominant and sporadic Alzheimer's disease with multi-modal PET and plasma GFAP.

Background: Plasma assays for the detection of Alzheimer's disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-β burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer C-Deuterium-L-Deprenyl (C-DED) in a multi-modal PET design in participants with sporadic and Autosomal Dominant Alzheimer's disease.

Methods: Twenty-four individuals from families with known Autosomal Dominant Alzheimer's Disease mutations (mutation carriers = 10; non-carriers = 14) and fifteen patients with sporadic Alzheimer's disease were included. The individuals underwent PET imaging with C-DED, C-PIB and F-FDG, as markers of reactive astrogliosis, amyloid-β deposition, and glucose metabolism, respectively, and plasma sampling for measuring GFAP concentrations. Twenty-one participants from the Autosomal Dominant Alzheimer's Disease group underwent follow-up plasma sampling and ten of these participants underwent follow-up PET imaging.

Results: In mutation carriers, plasma GFAP levels and C-PIB binding increased, while C-DED binding and F-FDG uptake significantly decreased across the estimated years to symptom onset. Cross-sectionally, plasma GFAP demonstrated a negative correlation with C-DED binding in both mutation carriers and patients with sporadic disease. Plasma GFAP indicated cross-sectionally a significant positive correlation with C-PIB binding and a significant negative correlation with F-FDG in the whole sample. The longitudinal levels of C-DED binding showed a significant negative correlation with longitudinal plasma GFAP concentrations over the follow-up interval.

Conclusions: Plasma GFAP concentration and astrocyte C-DED brain binding levels followed divergent trajectories and may reflect different underlying processes. The strong negative association between plasma GFAP and C-DED binding in Autosomal Dominant and sporadic Alzheimer's disease brains may indicate that if both are markers of reactive astrogliosis, they may detect different states or subtypes of astrogliosis. Increased C-DED brain binding seems to be an earlier phenomenon in Alzheimer's disease progression than increased plasma GFAP concentration.