Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies
Anika Finze, Gloria Biechele, Boris‐Stephan Rauchmann, Nicolai Franzmeier, Carla Palleis, Sabrina Katzdobler, Endy Weidinger, Selim Guersel, Sebastian Schuster, Stefanie Harris, Julia Schmitt, Leonie Beyer, Johannes Gnörich, Simon Lindner, Nathalie L. Albert, Christian H. Wetzel, Rainer Rupprecht, Axel Rominger, Adrian Danek, Lena Burow, Carolin Kurz, Maia Tatò, Julia Utecht, Boris Papazov, Mirlind Zaganjori, Lena‐Katharina Trappmann, Oliver Goldhardt, Timo Grimmer, Jan Haeckert, Daniel Janowitz, Katharina Büerger, Daniel Keeser, Sophia Stoecklein, Olaf Dietrich, Estrella Morenas‐Rodríguez, Henryk Barthel, Osama Sabri, Peter Bartenstein, Mikael Simons, Christian Haass, Günter U. Höglinger, Johannes Levin, Robert Perneczky, Matthias Brendel
Abstract
Abstract β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z -score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: β T = 0.412 ± 0.196 vs. β A = 0.142 ± 0.123, p < 0.001; AD-CBS: β T = 0.385 ± 0.176 vs. β A = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (β T = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.