Objective: To evaluate distribution pattern of tau pathology in different PSP clinical subtypes and develop a staging system.

Background: Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes and oligodendroglia associated with various clinical phenotypes. It is not yet fully clear whether clinical subtypes are distinguishable based on tau pathology distribution patterns.

Method: We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. We included 84 PSP-Richardson-syndrome, 25 PSP-frontal variant, 20-PSP-Parkinsonism, 20 PSP-postural instability, 10 PSP-speech-language variant, and 9 PSP-corticobasal syndrome.

Results: Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axisin different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n=81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. Based on these, for practical neuropathological diagnostic purposes, we propose to distinguish four stages by examining the degree of different tau cytopathologies in the globus pallidus, subthalamic nucleus, and striatum (stages 1 and 2), frontal cortex and/or dentate nucleus/cerebellar white matter (stage 3), and occipital cortex (stage 4).

Conclusion: Our study supports the notion that the initiating site of neuronal degeneration and tau pathology seems to be similar in clinical subtypes, but the dynamics and propagation patterns distinguish them.Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation,and informs tau-neuroimaging on distribution patterns.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/can-we-stage-tau-pathology-in-psp/