Diagnostic utility of biomarkers in progressive supranuclear palsy: toward a biotyping framework

Progressive supranuclear palsy (PSP) is a rare and debilitating four-repeat (4R) tauopathy, characterized by motor dysfunction, cognitive decline, and oculomotor abnormalities, yet it lacks reliable biomarkers for early diagnosis, disease stratification, and prognosis. This review critically examines recent advancements in human biomarker research for PSP across multiple domains, including fluid specimen assays, i.e., blood and cerebrospinal fluid (CSF) assays, molecular profiling, and neuroimaging, with the aim of identifying markers that facilitate differential diagnosis, monitor disease progression, and support subtype classification. By synthesizing the findings of studies published, this article highlights the established biomarkers and emerging biomarkers from novel analytical methods and in vivo technologies and their potential utility for clinical trials. Emerging potential biomarkers considered include exosomal α-synuclein and tau aggregates, circulating molecular biomarkers, and relevant biomarkers from magnetic resonance spectroscopy (MRS), diffusion tensor imaging, neuromelanin MRI (NM-MRI), and functional MRI (fMRI) methods. Furthermore, the heterogeneous clinical presentations clearly reflect variable anatomical and molecular pathology in PSP and indicate that relying solely on clinical classification risks misdiagnosis, delayed treatment, and inappropriate management. A biologically grounded biotyping framework, which includes multimodal data integration and artificial intelligence, can resolve this heterogeneity by aligning observable phenotypes with underlying pathophysiology. To move beyond purely clinical classifications, this review proposes a conceptual biotyping framework to categorize PSP based on underlying biological processes, such as neurodegeneration, tau pathology, and neuroinflammation. This framework aims to guide future biomarker validation efforts, facilitate patient stratification in clinical trials, and accelerate the transition toward precision medicine approaches in PSP.