Prevalent versus incident progressive supranuclear palsy: An analysis of the frequencies of neuropathological and clinical features at U.S. Alzheimer's Disease Research Centers indicate a relatively common tauopathy of aging.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease diagnosed according to its histopathologic pattern of tau proteinopathy ("tauopathy"). It is increasingly appreciated that PSP is heterogeneous in both clinical and pathological presentations. However, the prevalence of PSP subtypes, in comparison to other tauopathies, remain incompletely characterized. Here we analyzed NACC Neuropathology Data Set data aggregated from 37 U.S. Alzheimer's Disease Research Centers (ADRCs). Clinical and gold-standard neuropathologic features of autopsied participants were compared, stratifying on cognitive status at recruitment into the study. The final sample comprised 6994 individuals who were followed approximately annually for 4.0 years on average before autopsy. Among those with dementia at recruitment (n=4309), 2.9% had autopsy-confirmed corticobasal degeneration (CBD), 2.6% Pick's disease, and 4.6% PSP. By contrast, among those recruited while cognitively normal (n=1452), 0.7% had CBD, 0.1% Pick's disease, and, remarkably, 3.3% were diagnosed with PSP pathology. The relatively high frequency of PSP pathology detected among individuals recruited while cognitively normal suggests there is a subtype of PSP that is unexpectedly common in the broader population. In comparing between incident (recruited normal) and prevalent (recruited with dementia) autopsy-confirmed PSP, those with incident PSP died older (89.6 years versus 76.2 years on average). Furthermore, incident PSP pathology cases were less likely to manifest stereotypical PSP clinical features, but more likely to have parkinsonism, compared to prevalent PSP pathology cases. In a convenience sample of autopsy-confirmed PSP from the University of Kentucky ADRC (n=23), digital pathology analyses using HALO software and AI-based analytic modules revealed that PSP tau pathology was more severe in prevalent PSP, but in the putamen, incident cases had a higher proportion of tufted astrocytes and lower proportion of NFTs. In summary, incident PSP pathology is a relatively common tauopathy in older ADRC participants, often differing clinically and pathologically from prevalent PSP.