Tau deposition patterns are associated with functional connectivity in primary tauopathies

Area of Science:

• Neuroscience
• Neuropathology
• Neuroimaging

Background:

• Tau pathology drives neuronal dysfunction in 4-repeat tauopathies like progressive supranuclear palsy.
• Mechanisms of tau propagation, especially in 4-repeat tauopathies involving multiple cell types, remain unclear.
• Tau is hypothesized to spread via prion-like mechanisms across neural connections.

Purpose of the Study:

• To investigate the association between brain connectivity and tau deposition patterns in 4-repeat tauopathies.
• To differentiate the role of connectivity in neuronal versus non-neuronal tau accumulation.
• To correlate in vivo tau imaging with post-mortem histopathological findings.

Main Methods:

• Combined resting-state functional MRI (fMRI) connectomics with 2nd generation 18F-PI-2620 tau-PET imaging in 46 patients.
• Analyzed cell-type-specific regional tau levels from two independent progressive supranuclear palsy post-mortem cohorts (n=97 and n=96).
• Assessed associations between inter-regional connectivity and tau deposition patterns across imaging and histology.

Main Results:

• Inter-regional connectivity correlated with tau deposition patterns observed via tau-PET and post-mortem tau levels.
• The association between connectivity and tau deposition was stronger for neuronal tau than for astroglial or oligodendroglial tau.
• Patient-specific tau patterns correlated with the connectivity of subcortical tau 'epicenters' identified by tau-PET.

Conclusions:

• Brain connectivity is significantly associated with tau deposition patterns in 4-repeat tauopathies.
• Connectivity primarily influences neuronal tau accumulation, supporting prion-like spread models.
• This study provides integrated in vivo and histopathological evidence linking brain networks to tau pathology progression.