Objective:

To determine whether cortical atrophy mediates the relationship between clinical severity and retinal neurodegeneration in SCA3, highlighting a potential cortical–retinal axis of disease progression.

Background:

Pathological changes in spinocerebellar ataxia type 3 (SCA3) extend beyond the cerebellum, with optical coherence tomography (OCT) revealing retinal thinning. However, the interplay among clinical severity, cortical atrophy, and retinal neurodegeneration remains unclear, limiting OCT’s value as a biomarker.

Design/Methods:

Ninety genetically confirmed SCA3 patients and 32 age- and sex-matched healthy controls (HCs) were recruited. Participants underwent OCT, structural MRI, and neurological assessments using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). OCT metrics were compared between groups. Within SCA3, correlations linked retinal thickness with disease duration, clinical scores, and cortical volumes. Mediation analysis tested whether atrophy in 20 cortical regions mediated associations between clinical severity and retinal thinning.

Results:

SCA3 patients showed significant retinal layer thinning compared with HCs (p < 0.05). Longer disease duration and higher SARA scores correlated with reduced perifoveal thickness. Mediation analysis identified six significant indirect pathways. Atrophy of the left calcarine cortex mediated the link between SARA scores and right-eye inferior perifoveal thickness (p = 0.04) and also mediated associations between disease duration and perifoveal thinning (p < 0.001). Atrophy in the right lingual and left precentral gyri further mediated effects of disease duration on parafoveal thickness (p < 0.001).

Conclusions:

Cortical atrophy within visual and motor cortices mediates the impact of clinical severity on retinal neurodegeneration in SCA3. These findings support a cortical–retinal axis and suggest OCT-derived retinal metrics as noninvasive biomarkers of cortical integrity and disease progression.