The clinical syndromes of
frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as
neuroinflammation may be common across the disease spectrum. We investigated how
neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of
neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in
tauopathies and TDP-43-related disease, and which is used as a
surrogate marker of non-
amyloid-β
protein aggregation. We assessed 31 patients with
frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-
PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two
ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in
ligand affinity for TDP-43 and different tau
isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant
primary progressive aphasia compared to controls in the temporal regions, and both semantic variant
primary progressive aphasia and behavioural variant
frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in
FTLD-TDP (A),
FTLD-TDP (C), and
FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of
neuroinflammation were associated with different
frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between
neuroinflammation and
protein aggregation in
frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of
frontotemporal dementia.