Neural Correlates of Intellectual Dysfunction in Episodic Ataxia Type 2

Episodic ataxia type 2 (EA2) is characterized by episodes of vertigo and ataxia due to mutations in CACNA1A that encodes the α1A subunit of the P/Q-type voltage-gated calcium channel. This study aimed to identify neural correlates of cognitive dysfunction in EA2 by investigating brain atrophy in these patients and determining the relationships between regional brain volumes and intellectual dysfunction.

We recruited 12 patients with EA2 (including 6 males; age=30.5±14.3 years, mean±standard deviation) in 3 university hospitals of South Korea from 2019 to 2023. Regional brain volumes were quantified using voxel-based morphometry and the brainstem-structures feature of FreeSurfer. The results were compared with those for healthy controls. The relationships between regional gray-matter volumes (GMVs) and cognitive function were assessed using voxel-wise multiple regression analyses within the general linear model framework.

Brain volumetry revealed a significant decrease in cerebellar volumes, particularly in the vermis (lobules IV, V, and VIII), bilateral flocculi (lobule X), and brainstem. The Full-Scale Intelligence Quotient was positively correlated with the GMVs in the left parahippocampal gyrus, right caudate nucleus, and right cerebellar crus II; the Verbal Comprehension Index was correlated with the GMVs in the bilateral cerebellar crura I and II; and the Processing Speed Index was correlated with the GMV in the right parahippocampal gyrus.

Volumetric analyses revealed brain atrophy in patients with EA2 that was correlated with the clinical features observed in this disorder. These findings may further expand the imaging spectrum of disorders associated with CACNA1A mutations, although the identified correlations need to be interpreted with caution.