1. Tau spreading is driven by neuronal connectivity in primary tauopathies - evidence from tau-PET and histopathology
- Author
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Sabrina Katzdobler, Carolin Kurz, Robert Perneczky, Joseph Classen, Matthias Brendel, Anna Rubinski, Mikael Simons, Edward B. Lee, Ellen Gelpi, Nicolai Franzmeier, Michael Rullman, Milica Ječmenica Lukić, Günter U. Höglinger, Leonie Beyer, Anika Finze, Claire Troakes, Peter Bartenstein, Corey T. McMillan, John Q. Trojanowski, Maximilian Scheifele, Sigrun Roeber, Osama Sabri, Carla Palleis, Matthias L. Schroeter, John Seybl, David J. Irwin, Sharon X. Xie, Yaroslau Compta, Thomas Arzberger, Mengmeng Song, Emanuel Joseph, Lukas Frontzkowski, Jochen Herms, Michael Ewers, Davina Biel, Endy Weidinger, Laura Donker Laat, Virginia M.-Y. Lee, Laura Molina-Porcel, Victor L. Villemagne, Maike Kern, John L. Robinson, Gloria Biechele, Murray Grossman, Henryk Barthel, Armin Giese, Gabor G. Kovacs, Gesine Respondek, Jost J. Rumpf, Johannes Levin, Andreas Schildan, Boris-Stephan Rauchmann, David G. Coughlin, John C. van Swieten, Marianne Patt, Andrew Stephens, and Safa Al-Sarraj
- Subjects
Connectomics ,medicine.medical_specialty ,Tau pathology ,mental disorders ,medicine ,Histopathology ,Biology ,medicine.disease ,Neuroscience ,Progressive supranuclear palsy - Abstract
Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2nd generation 18F- PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type- specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau- PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with trans-neuronal tau spread. Using tau-PET we found that patient-level tau patterns can be predicted by the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence for brain connectivity as a key mediator of trans-neuronal tau spreading in 4RTs.
- Published
- 2021
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