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.
Highlights
Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy
Linear mixed models were controlled for age, sex, study site, mean Euclidean distance to the tau epicenter as well as random intercept. When extending this analysis to the cortex, we found a similar result pattern, with highest 18F-PI-2620 PET binding in those cortical regions that were most closely connected to subcortical tau epicenters (i.e., Q1) vs. lowest 18F-PI-2620 PET binding in those cortical regions that were most weakly connected to subcortical tau epicenters (i.e., Q4) in Progressive supranuclear palsy (PSP)-RS (Fig. 6C, b/SE = 0.036/0.008, p < 0.001) and cortico-basal syndrome (CBS) (Fig. 6E, b/SE = 0.032/0.005, p < 0.001)
We combined template-based resting-state fMRI connectomics with (i) in vivo tau-PET in 46 PSP-RS and CBS patients and (ii) regional postmortem tau assessments in two independent samples with histopathologically confirmed 4 R tau PSP pathology (n = 97/n = 96)
Summary
Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Postmortem studies have reported a strong clinico-pathological correlation between 4R-tau deposition patterns and clinical phenotype: PSP most commonly presents as Richardson’s syndrome (PSP-RS, i.e., a combination of postural instability and ocular motor deficits), associated with brainstem and subcortical tau followed by progressive tau accumulation in parietal and motor cortices at later disease stages[7, 8]. Further variant predominance types include, among others, PSP with speech/language disorder with left inferior frontal tau aggregation or PSP with cognitive/behavioral presentation with fronto-temporal tau pathology, suggesting that clinical variability is driven by spatially heterogeneous tau patterns[8–10] In accord with this concept, CBD patients often present with mixed cortical/movement disorders termed cortico-basal syndrome (CBS), associated with tau accumulation in the motor cortex, brainstem, subthalamic nucleus, and striatum, yet clinical variants present as progressive aphasia, frontal-behavioral syndrome or Richardson’s syndrome[11, 12]. This spreading mechanism needs to be questioned in 4 R tauopathies since tau is exclusively present in neurons and in astroglia and oligodendroglia[8]
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