High rates of diagnostic discordance and co-pathology: Insights into PSP from the NACC dataset

Alzheimers Dement. 2025 May;21(5):e70248. doi: 10.1002/alz.70248.

ABSTRACT

INTRODUCTION: Clinical features associated with accurate clinico-pathologic correlation within cognitive-predominant progressive supranuclear palsy (PSP) presentations have not been extensively studied. We identified features affecting PSP diagnosis within the National Alzheimer’s Coordinating Center (NACC) dataset, a cognitive/behavioral research database.

METHODS: Autopsied NACC participants with clinical or neuropathologic PSP diagnoses were categorized by diagnostic modality (Clinical-only, Neuropathology-only, both). Group differences in clinical, demographic, neuropsychologic, and neuropathologic features were assessed.

RESULTS: Only 38.8% of neuropathologically identified PSP had clinical PSP diagnosis while 63.5% of clinically identified PSP had PSP pathology. Neuropathology-only cases had fewer motor symptoms and better processing speed/executive functioning than the Clinical-Neuropathology group. Nearly 70% demonstrated co-neuropathologies including Alzheimer-type, Lewy body, and corticobasal degeneration pathologies.

DISCUSSION: Within NACC, discordant clinical and neuropathologic PSP diagnoses highlight the heterogeneity of PSP presentation, possibly driven by reliance on “classic” ante mortem symptoms. Further studies should assess the impact of co-pathology on clinical neurodegenerative disease presentations.

HIGHLIGHTS: A high rate of clinico-pathologic PSP diagnostic discordance is seen within NACC. Cases without clinical PSP diagnosis had fewer classic motor and cognitive symptoms. Isolated PSP neuropathology is uncommon, with nearly 70% showing co-neuropathology.

PMID:40346726 | DOI:10.1002/alz.70248