Cognitive impairment in SCA3: A multi-center cohort study with demographic, imaging, and biomarker correlates

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Spinocerebellar ataxia type 3 (SCA3) (n=403). Intervention: Ataxic spinocerebellar ataxia type 3 (SCA3) mutation status and ataxia severity vs. Healthy controls and pre-ataxic SCA3 mutation carriers. Primary outcome: Montreal Cognitive Assessment (MoCA) total score (partial eta-squared 0.07 (r = -0.44 with SARA score), p=<0.001).

Q: What question did this study set out to answer?

To examine cognitive performance across pre-ataxic and ataxic stages of spinocerebellar ataxia type 3 (SCA3) and identify its demographic, imaging, and biochemical correlates.

Roderick P.P.W.M. Maas; Hector Garcia-Moreno; Jennifer Faber; Carlos Eduardo Fortes Gonzalez; Ludger Schöls; Jeroen J. de Vries; S. H. Subramony; Reetz Kathrin; Chiadi U. Onyike; Heike Jacobi; Friedrich Erdlenbruch; Jon Infante; Magda Magnolia Santana; Sandro Romanzetti; Luís Pereira de Almeida; M. João Lima; Paola Giunti; Thomas Klockgether; Bart P.C. van de Warrenburg; Andreas Thieme; Dagmar Timmann; Gülin Öz; Michal Považan

doi:10.1016/j.nbd.2026.107301

Key result

Ataxic SCA3 patients had significantly lower MoCA scores than healthy controls (25.31 vs 27.57, p<0.001), with cognitive decline correlating with ataxia severity (r=-0.44, p<0.001).

Key Points

To examine cognitive performance across pre-ataxic and ataxic stages of spinocerebellar ataxia type 3 (SCA3) and identify its demographic, imaging, and biochemical correlates.
Multicenter cohort study analyzing 61 pre-ataxic SCA3 mutation carriers, 231 ataxic SCA3 patients, and 111 healthy controls from the ESMI cohort.
MoCA total scores differed across groups (F(2, 383) = 13.8, p < 0.001, partial η2 = 0.07), with lower scores in ataxic patients (25.31 ± 4.14) than healthy controls (27.57 ± 2.23; p < 0.001) and pre-ataxic carriers (27.66 ± 1.79; p < 0.001), while pre-ataxic carriers did not differ from controls (p = 0.99).
MoCA scores inversely correlated with SARA scores in ataxic patients (r = -0.44, p < 0.001), with a stronger correlation in individuals with 12 years of education or less (r = -0.52, p < 0.001) than in those with more than 12 years (r = -0.26, p < 0.001; interaction p < 0.001).
Multivariable linear regression identified only the interaction between SARA score and educational level as an independent predictor of MoCA score (p < 0.001, explaining 40% of variance), whereas MRI volumes and plasma NfL concentrations were not retained.

Study Design

Type

Cohort (n=403)

Multicenter

Yes

PICO

P

Population

403 participants (61 pre-ataxic SCA3 mutation carriers, 231 ataxic SCA3 patients, and 111 healthy controls; mean age ~47.9 years, 51.6% female) evaluated at baseline across 13 international ataxia referral centers.

E

Exposure / Comparator

Ataxic spinocerebellar ataxia type 3 (SCA3) mutation status and ataxia severity vs Healthy controls and pre-ataxic SCA3 mutation carriers

O

Primary Outcome

Montreal Cognitive Assessment (MoCA) total score — partial eta-squared 0.07 (r = -0.44 with SARA score), p=<0.001

Main Result

Effect estimate: partial eta-squared 0.07 (r = -0.44 with SARA score)

Absolute Event Rate: 25.31% vs 27.57%

p-value: p=<0.001

Limitations

Used the MoCA screening tool rather than extensive neuropsychological examinations or the Cerebellar Cognitive Affective Syndrome Scale (CCAS-S).
Structural brain MRI and plasma NfL measurements were only performed at a subset of study sites and participants.
Cross-sectional baseline analysis lacking longitudinal follow-up to capture progression of cognitive changes over time.
Neurofilament light chain (NfL) was measured in plasma rather than cerebrospinal fluid (CSF).

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Implication

Cohort study reveals cognitive deficits correlated with ataxia severity in SCA3, suggesting important implications.

Abstract

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.

Discussion

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Cite This Study

Maas et al. (2026) conducted a cohort in Spinocerebellar ataxia type 3 (SCA3) (n=403). Ataxic spinocerebellar ataxia type 3 (SCA3) mutation status and ataxia severity vs. Healthy controls and pre-ataxic SCA3 mutation carriers was evaluated on Montreal Cognitive Assessment (MoCA) total score (partial eta-squared 0.07 (r = -0.44 with SARA score), p=<0.001). Ataxic SCA3 patients had significantly lower MoCA scores than healthy controls (25.31 vs 27.57, p<0.001), with cognitive decline correlating with ataxia severity (r=-0.44, p<0.001).

synapsesocial.com/papers/698acaad7c832249c30b9f75 https://doi.org/10.1016/j.nbd.2026.107301

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Cognitive impairment in SCA3: A multi-center cohort study with demographic, imaging, and biomarker correlates

Key Points

Study Design

PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Cognitive impairment in SCA3: A multi-center cohort study with demographic, imaging, and biomarker correlates

Key Points

Study Design

PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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