Open Access

Roderick P.P.W.M. Maas, Hector Garcia-Moreno, Jennifer Faber, Carlos Gonzalez, Ludger Schöls, Jeroen J. de Vries, Khalaf Bushara, Kathrin Reetz, Chiadi U. Onyike, Heike Jacobi, Friedrich Erdlenbruch, Jon Infante, Magda M. Santana, Jeannette Hübener-Schmid, Luís Pereira de Almeida, Manuela Lima, Paola Giunti, Thomas Klockgether, Bart P.C. van de Warrenburg, Dagmar Timmann, Andreas Thieme, Gülin Öz, Michal Povazan

• Background Cognitive deficits are common in spinocerebellar ataxia type 3 (SCA3), but their neurobiological correlates remain largely unknown. Objectives To investigate cognitive performance in a large international cohort of SCA3 mutation carriers covering the entire disease course and to explore associations with posterior cerebellar volumes, basal ganglia and thalamus volumes, and plasma neurofilament light chain (NfL) concentration. Methods The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive impairment in this prospective, observational cohort study involving 13 ataxia referral centers. Standardized motor assessments, brain MR imaging, and peripheral blood biosampling were also performed. Results MoCA data were collected from 61 pre-ataxic SCA3 mutation carriers, 231 ataxic SCA3 patients, and 111 healthy controls. After adjustments for educational level and age, there were significant differences in MoCA total score, as well as visuospatial/executive, attention, language, and abstraction subscores, between healthy controls and ataxic, but not pre-ataxic individuals. MoCA scores declined with ataxia severity, especially in patients with a lower educational level. Patients with a MoCA score < 26 had lower pallidal volumes and higher plasma NfL concentrations than those with a score ≥ 26. However, only the interaction term between ataxia severity and educational level was independently associated with cognitive performance in multivariable regression analyses containing demographic, clinical, volumetric, and biochemical parameters. Conclusion Cognitive deficits in SCA3 generally appear after clinical ataxia onset and progress in parallel with ataxia severity, especially in patients with a lower cognitive reserve. Other measured biochemical and imaging parameters did not have a significant additional contribution.