A Biomarker‐Based Classification of Corticobasal Syndrome
Carla Palleis, Alexander Bernhardt, Endy Weidinger, Urban M. Fietzek, Alexander Jäck, Sabrina Katzdobler, Johannes Gnörich, Theresa Bauer, Nicolai Franzmeier, Robert Perneczky, German Imaging Initiative for Tauopathies (GII4T), Matthias Brendel, Johannes Levin, Günter U. Höglinger
Abstract
BACKGROUND: Corticobasal 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. OBJECTIVES: To subclassify CBS patients in vivo using biomarkers for amyloid-β (Aβ), Tau, and α-synuclein (αSyn), and assess the clinical relevance of this stratification. METHODS: F]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. RESULTS: Tau 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. CONCLUSIONS: CBS 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.