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 2nd 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.

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

“…The relevance of regression models at the individual patient level was pinpointed by the observation of distinct heterogeneity of regional ATN biomarker alterations in patients with 4RTs and AD. In line, four distinct trajectories of tau deposition were recently identified in typical AD, which implies that pathology originates and spreads through distinct networks in the different subtypes (58, 65). Distinct regional patterns of neurodegeneration were similarly reported for 4RTs (68).…”

“…Patients with typical and atypical AD showed a significant influence of regional Aβ on microglial activation but this association was not found in 4RTs. This is of particularly interest since subthreshold levels of Aβ occur in 4RTs (65) but do not have a major impact on neuroinflammation according to our data.…”

“…A strength of this study is given by the use of the novel tau-PET tracer [ 18 F]PI-2620 which proved absent off-target binding to monoamine oxidases (75), high affinity to 3/4R-tau in AD (76) and also high affinity to recombinant 4R tau fibrils and PSP brain homogenate (75). Colocalization of [ 18 F]PI-2620 binding with 4R tau in micro-autoradiography (75) and quantitative agreement of autoradiography and immunohistochemistry (65, 77) as well as in vivo discrimination of PSP (21) and CBS (4) from controls highlight the potential of this radioligand. Furthermore, early-phase [ 18 F]PI-2620 PET indicated feasibility for perfusion surrogate imaging in patients with AD and 4RTs (34, 78), which was applied a “N” biomarker in the current study.…”

Multiclass prediction of different dementia syndromes based on multi-centric volumetric MRI imaging

“…Remarkably, patients with lvPPA had high probabilities for AD, suggesting a resemblance of atrophy patterns. Moreover, the clinical syndrome CBS might be related histopathologically to AD beside corticobasal degeneration, PSP and other diseases, which might have diminished accuracy in identification of CBS in our study ( Franzmeier et al, 2022 , Koga et al, 2022 ). NfvPPA in turn has been associated mainly with tau pathology that is also relevant for bvFTD ( Bonner et al, 2010 ), which is reflected in the probability distribution of patients with the diagnosis nfvPPA.…”

Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays?

“…Since 2009 [ 20 , 21 ], there has been increasing evidence pointing to the belief that tau can spread between cells in a “prion-like” manner. The “prion-like” hypothesis states that seeded aggregation and cell-to-cell spread of pathological tau are two fundamental pathological aspects of human tauopathies (see [ 22 ] as a recent example).…”