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BackgroundCorticobasal syndrome (CBS) is a clinically defined syndrome with progressive movement and cortical dysfunction, caused by various underlying pathologies, most commonly tau-predominant pathologies such as progressive supranuclear palsy and corticobasal degeneration, or Alzheimer's disease (AD). Lewy-type α-synucleinopathies (LTS), TDP-43 proteinopathies, and mixed pathologies may also underlie CBS. The clinical impact of these pathologies remains poorly understood.ObjectivesTo subclassify CBS patients in vivo using biomarkers for amyloid-β (Aβ), Tau, and α-synuclein (αSyn), and assess the clinical relevance of this stratification.MethodsWe conducted a prospective cohort study of 50 CBS patients at LMU University Hospital Munich. Biomarker analysis included cerebrospinal fluid (CSF) Aβ42 and Aβ42/40, [18F]flutemetamol Aβ-PET, [18F]PI-2620 tau-PET, and αSyn seed amplification assays in CSF. CSF neurofilament light chain (NfL) served as a marker of neurodegeneration. Patients were stratified into six groups based on biomarker positivity.ResultsTau positivity was found in 90% of CBS cases, Aβ in 28%, and αSyn in 24%. Stratification identified: 52% consistent with tau-predominant pathology, 18% with AD, 10% with AD+LTS, 10% with tau-predominant+LTS, 4% with isolated LTS, and 6% unclassified. αSyn positivity was more frequent in AD-CBS (36%) than in tau-predominant-CBS (16%). Aβ-positive cases showed greater cognitive impairment; Tau positivity correlated with worse motor symptoms; αSyn-positive patients had milder motor symptoms, slower progression, and lower NfL levels.ConclusionsCBS is molecularly heterogeneous. Biomarker-based classification may enhance diagnostic precision and support personalized therapeutic strategies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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