Toward implementable biomarkers for corticobasal syndrome: A narrative review

Corticobasal syndrome has heterogeneous underlying pathology, complicating etiologic diagnosis and enrollment in pathology-targeted trials. We performed a targeted narrative review of autopsy cohorts and blood, cerebrospinal fluid, positron emission tomography, and tau seed amplification assays relevant to corticobasal syndrome. Across autopsy series, corticobasal degeneration and progressive supranuclear palsy were the most common diagnoses, while Alzheimer’s disease accounted for a substantial minority of cases. Their relative frequencies varied across cohorts because of differences in referral setting and case selection. Plasma phosphorylated tau at threonine 217 has the strongest corticobasal syndrome-specific blood evidence and is best used as a first-line triage marker for Alzheimer’s disease biology. The cerebrospinal fluid amyloid-β 42/40 ratio or amyloid positron emission tomography can establish amyloid-β status, whereas Alzheimer’s disease-type tau positron emission tomography, which preferentially detects paired helical filament tau, can provide additional evidence that Alzheimer’s disease is the primary underlying disease. Amyloid-β positivity alone does not establish Alzheimer’s disease as the principal cause because co-pathology is common. Evidence for primary four-repeat tauopathy is less mature: four-repeat-oriented tau positron emission tomography remains tracer-dependent and mainly group-level; low cerebrospinal fluid microtubule-binding region-tau275/total tau or microtubule-binding region-tau282/total tau may enrich for corticobasal degeneration after Alzheimer’s disease co-pathology has been assessed; cerebrospinal fluid tau seeding remains at the proof-of-concept stage; and skin assays are better supported for progressive supranuclear palsy than for corticobasal degeneration. We propose a staged framework that evaluates Alzheimer’s disease biology before investigational four-repeat-directed tests are considered when Alzheimer’s disease is absent or insufficient to explain the phenotype. The complete pathway is unvalidated and requires prospective multicenter studies with harmonized assays and autopsy follow-up.