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

Abstract

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 in vivo, providing a more direct assessment of the underlying proteinopathy than traditional volumetric measures. These advancements are complemented by significant progress in fluid biomarkers. Plasma phosphorylated tau at residue 217 (p-tau217) has gained prominence as a robust marker for Alzheimer’s disease, and its primary utility in PSP research currently serves as a critical negative signature to exclude amyloid-associated co-pathology. In contrast, novel assays targeting microtubule-binding region tau fragments show burgeoning potential for the specific identification of 4R-tau isoforms. Furthermore, neurofilament light chain (NfL) has been firmly established as a sensitive, albeit non-specific, indicator of neuroaxonal injury and clinical severity. Additional advancements with digital health approaches and electrophysiological assessments add to the opportunities for improved objective measures. This review concludes that the shift from clinical-only diagnostic criteria to a biomarker-enabled molecular framework is the necessary catalyst for developing effective disease-modifying therapies for PSP and related 4R-tauopathies. The synthesis of these multimodal biomarkers into a unified framework will be essential to improve participant stratification, enable the use of adaptive trial models, and provide supportive evidence of target engagement for future clinical trials.