From clinical phenotypes to molecular precision: multimodal biomarkers for progressive supranuclear palsy.

Progressive Supranuclear Palsy (PSP) is the most prevalent primary 4R-tauopathy, characterized by the pathogenic accumulation of misfolded tau protein within neurons and glial cells. Historically, clinical diagnosis relied upon the identification of Richardson's Syndrome, however, the recognition of diverse clinical phenotypes that overlap with Parkinson's disease, corticobasal syndrome, and frontotemporal dementia has complicated the diagnostic landscape and hindered the success of developing therapeutic interventions. As the field transitions toward a precision medicine paradigm, there is a growing need for validated biomarkers that can provide molecular specificity, facilitate early diagnosis, and accurately track disease progression. This paper reviews the recent advancements in neuroimaging and fluid-based biomarkers, assessing their potential to delineate PSP from similar neurodegenerative conditions and unlock the 4R-tau therapeutic pipeline. In the domain of neuroimaging, while structural magnetic resonance imaging (MRI) and the Magnetic Resonance Parkinsonism Index (MRPI) continue to provide measures of subcortical atrophy, the emergence of second-generation tau-selective positron emission tomography (PET) radioligands represents a transformative shift. New tau PET tracers offer the ability to visualize tau pathology