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

Andrew J Larner,Franklin I Aigbirhio,James B Rowe,John T O’Brien,Jonathan P Coles,Karalyn Patterson,Kieren Allinson,Luca Passamonti,Oliver Green,P Simon Jones,Robert Arnold,Sanne S Kaalund,Thomas E Cope,Tim D Fryer,W Richard Bevan-Jones,Young T Hong

doi:10.1093/brain/awaa033

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 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.

Highlights

Frontotemporal dementia (FTD) encompasses a clinically and pathologically heterogeneous group of neurodegenerative conditions, including the behavioural variant (Rascovsky et al, 2011), non-fluent variant primary progressive aphasia and semantic variant primary progressive aphasia (Gorno-Tempini et al, 2011)
Neuroinflammation is regionally co-localized with protein aggregation within the individual syndromes, including most strongly in semantic variant primary progressive aphasia (svPPA), where the predominant aggregated protein inclusions are TAR DNA-binding protein 43 (TDP-43) rather than tau (Fig. 2)
The distribution of protein aggregation appears to be less focal than neuroinflammation in non-fluent variant primary progressive aphasia (nfvPPA)

Summary

Introduction

Frontotemporal dementia (FTD) encompasses a clinically and pathologically heterogeneous group of neurodegenerative conditions, including the behavioural variant (bvFTD) (Rascovsky et al, 2011), non-fluent variant primary progressive aphasia (nfvPPA) and semantic variant primary progressive aphasia (svPPA) (Gorno-Tempini et al, 2011). There is converging evidence for the role of neuroinflammation in neurodegenerative dementias, including FTD, from genetic associations (Guerreiro et al, 2013; Rayaprolu et al, 2013; Broce et al, 2018), CSF (Sjogren et al, 2004; Woollacott et al, 2018), epidemiology (Miller et al, 2013, 2016), post-mortem tissue (Venneti et al, 2008; Lant et al, 2014) and animal models (Yoshiyama et al, 2007; Bhaskar et al, 2010; Yin et al, 2010) Both the intensity of neuroinflammation and its distribution across the brain may be relevant determinants of the clinical syndrome. We aim to build on recent in vivo studies of Alzheimer’s disease, which demonstrate that neuroinflammation correlates spatially with tau aggregation (Dani et al, 2018), by assessing whether this association extends to FTD, which is associated with many different conformations of pathological tau, or other protein aggregates such as TDP-43

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