Cognitive changes and brain structural abnormalities in female carriers of DMD pathogenic variants.

Background: Skeletal and cardiac muscle damage have been increasingly recognized in female carriers of DMD pathogenic variants (DMDc). Little is known about cognitive impairment in these women or whether they have structural brain damage.

Objective: To characterize the cognitive profile in a Brazilian cohort of DMDc and determine whether they have structural brain abnormalities using multimodal MRI.

Methods: Thirty-three DMDc and 33 age-matched healthy women were recruited. The Addenbrooke cognitive examination revised (ACE-R) and the Beck depression inventory (BDI) were used to assess cognition and depressive symptoms. 3T Brain MRI was acquired for both groups. Using volumetric T1 sequence, we computed cerebral cortical thickness (FreeSurfer), basal ganglia (T1 Multi-atlas) and cerebellar (Cerebnet) volumetry. Diffusion tensor imaging (DTI) assessed white-matter integrity (DTI Multi-atlas). Groups were compared using a generalized linear model with Bonferroni-corrected p values < 0.05.

Results: Mean age of DMDc was 38.2 ± 8.2 years, 48.5% of them had abnormal cognition, but only 15% showed meaningful depressive symptoms. Multiple cognitive domains were affected: Attention in 51.5%, Verbal Fluency in 36.4%, Visuospatial Ability in 36.4%, Language in 27.3%, and Memory in 21.2%. Multimodal MRI revealed bilateral, symmetric atrophy in parieto-occipital cortices in DMDc relative to controls, but no basal ganglia, white matter, or cerebellar changes. Parietal cortex thinning correlated with attention, memory, and verbal fluency scores.

Interpretation: DMDc should no longer be seen as 'asymptomatic'. They have cognitive abnormalities and cerebral structural changes compared to healthy women. These manifestations should be actively identified and managed in clinical practice.