Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
Published version
Peer-reviewed
Repository URI
Repository DOI
Type
Change log
Authors
Abstract
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 localisation of Tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used positron emission tomography in vivo with (a) [11C]PK-11195, a marker of activated microglia and a proxy index of neuroinflammation, and (b) [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-β-amyloid 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 controls (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 control 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 svPPA compared to controls in the temporal regions, and both svPPA and bvFTD 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-Picks. 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.
Description
Keywords
Journal Title
Conference Name
Journal ISSN
1460-2156
Volume Title
Publisher
Publisher DOI
Sponsorship
Wellcome Trust (103838/Z/14/Z)
Medical Research Council (MR/P01271X/1)
Medical Research Council (MR/M024873/1)
Medical Research Council (MR/M009041/1)