Background: Progressive supranuclear palsy (PSP) is clinically heterogeneous. Clinical diagnostic criteria were revised in 2017, to increase sensitivity and operationalize the diagnosis of PSP Richardson's syndrome (PSP-RS) and 'variant' syndromes (vPSP). Objectives: To determine the (1) sensitivity and specificity of the 1996 NINDS-SPSP and 2017 MDS-PSP criteria; (2) false positive rates in frontotemporal dementia with frontotemporal lobar degeneration (FTLD); and (3) clinical evolution of variant PSP syndromes (vPSP). Methods: Retrospective multicenter review of 108 neuropathologically-confirmed PSP patients and 81 patients with other forms of FTLD: 38 behavioral variant frontotemporal dementia (bvFTD), 14 non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), and 29 corticobasal degeneration (CBD). Sensitivity and specificity of the MDS-PSP criteria were compared to the NINDS-SPSP criteria at baseline. In a subset of cases, the timing and frequency of clinical features were compared across groups over six years. Results: Sensitivity for recognition of probable and possible PSP pathology was higher by MDS-PSP criteria (72.2-100%) than NINDS-SPSP criteria (48.1-61.1%). Specificity was higher by NINDS-SPSP criteria (97.5-100%) than MDS-PSP criteria (53.1-95.1%). False positives by MDS-PSP criteria were few for bvFTD (10.5-18.4%) but common for CBD and nfvPPA (fulfilling 'suggestive of' PSP). Most vPSP cases developed PSP-RS-like features within six years, including falls and supranuclear gaze palsy, distinguishing frontal presentations of PSP from bvFTD, and speech/language presentations of PSP from nfvPPA. Conclusions: The 2017 MDS-PSP criteria successfully identify PSP, including variant phenotypes. This independent validation of the revised clinical diagnostic criteria strengthens the case for novel therapeutic strategies against PSP to include variant presentations.

Neuropathological validation of the MDS-PSP criteria with PSP and other frontotemporal lobar degeneration