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Tau deposition patterns are associated with functional connectivity in primary tauopathies.

ABSTRACT: Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2^nd generation ¹⁸F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

SUBMITTER: Franzmeier N

PROVIDER: S-EPMC8924216 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Tau deposition patterns are associated with functional connectivity in primary tauopathies.

Franzmeier Nicolai N Brendel Matthias M Beyer Leonie L Slemann Luna L Kovacs Gabor G GG Arzberger Thomas T Kurz Carolin C Respondek Gesine G Lukic Milica J MJ Biel Davina D Rubinski Anna A Frontzkowski Lukas L Hummel Selina S Müller Andre A Finze Anika A Palleis Carla C Joseph Emanuel E Weidinger Endy E Katzdobler Sabrina S Song Mengmeng M Biechele Gloria G Kern Maike M Scheifele Maximilian M Rauchmann Boris-Stephan BS Perneczky Robert R Rullman Michael M Patt Marianne M Schildan Andreas A Barthel Henryk H Sabri Osama O Rumpf Jost J JJ Schroeter Matthias L ML Classen Joseph J Villemagne Victor V Seibyl John J Stephens Andrew W AW Lee Edward B EB Coughlin David G DG Giese Armin A Grossman Murray M McMillan Corey T CT Gelpi Ellen E Molina-Porcel Laura L Compta Yaroslau Y van Swieten John C JC Laat Laura Donker LD Troakes Claire C Al-Sarraj Safa S Robinson John L JL Xie Sharon X SX Irwin David J DJ Roeber Sigrun S Herms Jochen J Simons Mikael M Bartenstein Peter P Lee Virginia M VM Trojanowski John Q JQ Levin Johannes J Höglinger Günter G Ewers Michael M

Nature communications 20220315 1

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting ...[more]

PMID: 35292638

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Project description:Background: Integrity of functional brain networks is closely associated with maintained cognitive performance at old age. Consistently, both carrier status of Apolipoprotein E ε4 allele (APOE4), and age-related aggregation of Alzheimer's disease (AD) pathology result in altered brain network connectivity. The posterior cingulate and precuneus (PCP) is a node of particular interest due to its role in crucial memory processes. Moreover, the PCP is subject to the early aggregation of AD pathology. The current study aimed at characterizing brain network properties associated with unimpaired cognition in old aged adults. To determine the effects of age-related brain change and genetic risk for AD, pathological proteins β-amyloid and tau were measured by Positron-emission tomography (PET), PCP connectivity as a proxy of cognitive network integrity, and genetic risk by APOE4 carrier status. Methods: Fifty-seven cognitively unimpaired old-aged adults (MMSE = 29.20 ± 1.11; 73 ± 8.32 years) were administered 11C Pittsburgh Compound B and 18F Flutemetamol PET for assessing β-amyloid, and 18F AV-1451 PET for tau. Individual functional connectivity seed maps of the PCP were obtained by resting-state multiband BOLD functional MRI at 3-Tesla for increased temporal resolution. Voxelwise correlations between functional connectivity, β-amyloid- and tau-PET were explored by Biological Parametric Mapping (BPM). Results: Local β-amyloid was associated with increased connectivity in frontal and parietal regions of the brain. Tau was linked to increased connectivity in more spatially distributed clusters in frontal, parietal, occipital, temporal, and cerebellar regions. A positive interaction was observable for APOE4 carrier status and functional connectivity with brain regions characterized by increased local β-amyloid and tau tracer retention. Conclusions: Our data suggest an association between spatially differing connectivity systems and local β-amyloid, and tau aggregates in cognitively normal, old-aged adults, which is moderated by APOE4. Additional longitudinal studies may determine protective connectivity patterns associated with healthy aging trajectories of AD-pathology aggregation.

Dataset Information

Tau deposition patterns are associated with functional connectivity in primary tauopathies.

Publications

Tau deposition patterns are associated with functional connectivity in primary tauopathies.

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