Objective: To determine the pathological and molecular determinants of phenotypic diversity in PSP.

Background: PSP exhibits broad variability in clinical phenotype and progression, however the pathomechanisms responsible for this clinical heterogeneity are largely unknown.

Method: Consecutive pathologically confirmed PSP cases donated to the Queen Square Brain Bank between 2010-2022 were selected. Longitudinal clinical information was recorded, and cases were phenotyped according to the Movement Disorder Society criteria. Tissue sections immunostained for hyperphosphorylated tau were digitised and tau pathology was quantified using an automated, machine learning-based digital image analysis approach. Tau pathology progression was modelled using subtype and stage inference (SuStaIn). To assess cell-specific gene expression, spatial transcriptomics was performed on frontal grey and subcortical white matter tissue from PSP-RS, PSP-CBS, and PSP-P cases using Nanostring GeoMx.

Results: We identified 236 PSP cases. SuStaIn indicated the presence of 3 data-driven subtypes with distinct tau pathology progression patterns. Significant differences in tau pathology burden were observed between clinical phenotypes in anatomically relevant grey and white matter structures, including higher tau pathology burden in distinct cortical grey matter, and subcortical white matter regions of PSP-CBS and PSP-SL cases. Survival was correlated with tau pathology burden in specific grey and white matter regions. Differential gene expression analysis identified significant region- and cell-specific dysregulation of genes involved in tau uptake and spread, glycolysis and neuroinflammation in PSP-CBS cases (n=4) compared to both PSP-RS (n=5) and PSP-P (n=3) cases.

Conclusion: We have identified distinct data-driven patterns of regional tau pathology progression and phenotype-specific signatures of tau pathology burden in grey and white matter and elucidated the relationship between regional tau pathology burden and survival. We have also identified a spatially resolved, cell-specific gene expression signature in clinically and pathologically well-defined PSP-CBS cases suggesting that differences in cell-specific gene expression influence selective regional vulnerability to tau pathology, phenotypic diversity and survival. Further research is warranted to validate these findings.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/quantitative-regional-tau-pathology-and-spatial-transcriptomics-identify-signatures-of-phenotypic-diversity-in-progressive-supranuclear-palsy/