Relationship Between Dp140 Genotype and Cortical Similarity Network Phenotype in Duchenne Muscular Dystrophy: Preliminary T1 Weighted Study.

BACKGROUND

Dp140-related mutations associate with neurodevelopmental impairments in Duchenne muscular dystrophy (DMD), their effects on cortical similarity network organization remain unclear.

PURPOSE: To characterize alterations in morphometric similarity networks (MSN) in DMD with different Dp140 genotypes, assess their associations with clinical phenotypes and gene expression.

STUDY TYPE: Prospective.

POPULATION: One hundred and fifteen boys with DMD (75 Dp140-: 9.63 ± 2.25 years; 40 Dp140+: 10.99 ± 2.25 years) and 69 healthy controls (all male, 10.65 ± 2.43 years).

FIELD STRENGTH/SEQUENCE: Gradient echo at 3 T.

ASSESSMENT: MRI were processed using FreeSurfer and GRETNA. Behavior data were based on Wechsler Intelligence Scale for children-Fourth edition while transcriptional profiles were from the Allen Human Brain Atlas.

STATISTICAL TESTS: Independent T-tests, chi-square tests, general linear models, permutation testing, multivariable linear regression, mediation analyses, partial least squares regression, spatial permutation tests (Spin test), Gene Ontology enrichment analysis and cell-type analysis. FDR-corrected p < 0.05 and p spin  < 0.05 were considered significant.

RESULTS

Dp140- subgroup had lower working memory index (WMI) than Dp140+ DMD (81.63 ± 15.48 vs. 90.78 ± 15.31; p = 0.01, Cohen's d = 0.179). Dp140- DMD showed reduced cortical similarity in bilateral lateral prefrontal cortex and parietal cortex regions, increased modular segregation (Hedge's g = -0.298, 95% CI [-0.408, -0.187]), and more hubs loss within frontal parietal network (FPN). The indirect effect of Dp140 genotype on WMI through mean FPN cortical similarity was significant (β = -0.121, p = 0.03, 95% CI [-0.282, -0.001]). The Dp140-specific MSN changes were spatially associated with transcriptional profile, which are enriched in neuronal projection development pathways of excitatory neurons (p spin  < 0.05).

DATA

CONCLUSION

By linking genotype, neuroimaging, and transcriptional data, these findings offer further insight into mechanisms possibly involved in working memory deficits among Dp140- DMD.

EVIDENCE LEVEL: 2.

TECHNICAL EFFICACY: Stage 2.