A biomarker-based classification of corticobasal syndrome 

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Corticobasal syndrome (CBS) is a clinically defined syndrome with progressive movement disorders and cortical signs and symptoms, which can be caused by a spectrum of different neuropathologically defined disease entities. CBS is most frequently associated with 4-repeat tauopathies (4RTs), including progressive supranuclear palsy (PSP) and corticobasal degeneration, or the mixed 3-repeat / 4-repeat tauopathy Alzheimer’s disease (AD). However, Lewy-type α-synucleinopathies (LTS), TDP-43 proteinopathies, or mixed pathologies may also present as CBS. Yet the clinical relevance of the different pathologies underlying CBS remains poorly understood. Therefore, the current study aimed to molecularly classify CBS patients by leveraging biomarkers for amyloid (Aβ), Tau, and α-synuclein (αSyn), allowing for an in vivo subclassification. 

We conducted a prospective cohort study involving 50 CBS patients that were clinically monitored at LMU University Hospital Munich. Biomarker analyses included cerebrospinal fluid (CSF) measures of Aβ42 and Aβ42/40 ratios, [18F]Flutemetamol β-amyloid-PET, [18F]PI-2620 Tau-PET, and CSF αSyn seed amplification assays. Neurofilament light chain (NfL) in CSF served as a non-specific marker of neurodegeneration. Biomarker positivity or negativity allowed a stratification of CBS into six groups, identifying bona fide disease entities based on Aβ, Tau, and αSyn combinations.  

Our findings revealed a high prevalence of Tau positivity, with 90% of CBS patients being Tau-positive, while Aβ and αSyn positivity were observed in 28% and 24% of cases, respectively. Stratification by biomarker-defined disease entities showed that 52% of CBS cases were consistent with 4RT, 18% with AD, 10% with co-occurrence of AD and LTS, 10% with 4RT and LTS, and 4% with isolated LTS. 6% remained unclassified. αSyn-positivity was more common in CBS cases with presumed AD (36%), compared to those with presumed 4RT (16%). Clinically, Aβ-positivity was associated with stronger cognitive impairment in the Montreal Cognitive Assessment and the Dementia Apraxia Test. Tau positivity was associated with more severe motor symptoms but showed no significant effect on disease progression rates. In contrast, αSyn positive patients presented with milder motor symptoms, lower PSP rating scale scores, and a slower progression over time, accompanied by significantly lower baseline CSF NfL levels. 

Our study underscores the molecular heterogeneity of CBS, highlighting the potential of biomarker-based stratification to improve diagnostic accuracy and guide targeted treatments. 

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