Neuroinflammation and protein aggregation co-localize across the spectrum of frontotemporal dementia

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but each major phenotype has been associated with both aggregation of misfolded protein and neuroinflammation. We used positron emission tomography, with [11C]PK-11195 to measure activated microglia, and [18F]AV-1451 to quantify the burden of Tau or TDP-43, in 31 patients with frontotemporal dementia (10 behavioural variant, 11 semantic variant and 10 non-fluent variant) and 15 matched controls, to test the hypothesis that neuroinflamma- tion co-localises with pathological protein aggregation.Analyses included: (1) region-of-interest binding potentials; (2) pairwise correlation across regions between ligands; (3) principal component analysis of each ligand distribution and (4) multivariate classification of binding distributions.The analyses converged in showing (a) significant differences in [11C]PK-11195 binding between each patient group and controls in frontotemporal regions; (b) a strong positive correlation between [11C] PK-11195 and [18F]AV-1451 binding in all disease groups, across widespread cortical regions. Thesein vivoresults were confirmed bypost mortemimmunohistochemistry in 12 brains. In addition, we found (c) distinct distributional patterns of [11C]PK-11195 binding associated with different frontotemporal dementia syndromes, that supported more accurate classification of participants than [18F]AV-1451.Neuroinflammation may be important in shaping the clinical and neuropathological patterns of fronto- temporal dementia, and be a target for disease-modification.richard.bevanjones@doctors.org.uk