Objective: This study aimed to identify early clinical phenotypes of corticobasal degeneration (CBD) using unsupervised analysis of a large clinicopathologic dataset.

Background: Early diagnosis of neurodegenerative diseases is increasingly important in the era of disease modifying therapies. However, CBD presents with diverse clinical features, and early phenotypes remain uncharacterized owing to the rarity of the disease and limited clinicopathologic cohorts.

Method: An automated pipeline abstracted 195 neurological symptoms and signs, along with the onset of each feature, from 10,645 brain bank donors. Among 360 patients with CBD, 252 with clinical evaluations within three years of disease onset were included.

Results:

Unsupervised clustering based on oculomotor dysfunction (OM), postural instability (PI), bradykinesia, rigidity, tremor, frontal presentation, aphasia, and cortical signs identified four early phenotypes. These, named after the predominant clinical syndrome, comprised corticobasal syndrome–Richardson syndrome spectrum (CBD-CBS/RS; n = 109), parkinsonism (CBD-P; n = 49), cortical syndrome including frontal presentation, apraxia, and cortical sensory deficit (CBD-CS; n = 55), and primary progressive aphasia (CBD-PPA; n = 39). CBD-CBS/RS was characterized by early manifestations of both CBS and RS features, including cortical signs (81.2% among evaluated patients), parkinsonism (96.8%), OM (88.3%), and PI (94.2%), and showed the shortest median disease duration (5 years). CBD-P was characterized by early parkinsonism (86.4%) preceding other features and had the longest median disease duration (7 years). CBD-CS demonstrated early frontal presentation (84.6%) and cortical signs (100%) without aphasia (0%). CBD-PPA was characterized by aphasia (100%), frontal presentation (90.0%), and cortical signs (81.2%). CBD-PPA showed a distinctive neuropathologic signature, including more frequent coiled bodies in the frontal cortex (P = 0.01), increased tau threads in the temporal cortex (P = 0.02), and a higher frequency of concomitant Alzheimer’s disease (AD; 15.4% vs 1.8–8.2%; P = 0.01).

Conclusion: This study identified distinct early phenotypes of CBD, highlighting an overlap of CBS and RS (CBD-CBS/RS), a relatively pure parkinsonian form (CBD-P) and cortical involvement (CBD-CS) at early stages, and a speech variant associated with concomitant AD pathology (CBD-PPA).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-overlap-of-corticobasal-syndrome-and-richardson-syndrome-in-corticobasal-degeneration-evidence-from-252-autopsy-confirmed-cases/