Clinical Diagnosis of Progressive Supranuclear Palsy (PSP): A Clinicopathological Comparison of Patients with Confirmed PSP and Clinical Mimics.

Background: Several neurodegenerative diseases can mimic the clinical presentation of progressive supranuclear palsy (PSP), limiting accurate diagnosis during life. This has important implications for clinical practice, biomarker studies, and therapeutic trial design.

Objectives: To investigate whether the proportion of clinically diagnosed PSP patients with non-PSP pathology (termed 'mimics') has changed over the past 20 years since last examined in this cohort, and to identify clinical features that distinguish confirmed PSP from these mimics.

Methods: We reviewed the clinical records of pathologically confirmed PSP patients donated to the Queen Square Brain Bank from 2010 to 2022, and PSP mimics donated from 1989 to 2022. Demographic information, clinical features, and progression milestones were recorded.

Results: We included 236 pathologically confirmed PSP patients and 72 mimics. The main pathologies in PSP mimics were Lewy body disease (30.5%), corticobasal degeneration (23.6%), and multiple system atrophy (18.1%). A final clinical diagnosis of PSP between 2010 and 2022 had a positive predictive value of 86% for underlying PSP pathology and a false negative rate of 17%. Clinical features present in the first 3 years that favoured non-PSP pathology in this cohort include levodopa responsiveness, orthostatic hypotension, dysarthria, and a subcortical phenotype.

Conclusions: Clinical diagnosis of PSP has improved since last examined in this cohort 20 years ago. Although certain clinical features may point to non-PSP pathologies, a proportion of patients are difficult to distinguish on clinical grounds alone. This should be reflected in clinical trial design, and further studies will be required to determine the utility of emerging biomarkers in this setting. © 2025 International Parkinson and Movement Disorder Society.