Suming Zhang, Xiaoyu Niu, Qing Hu, Xun Wang, Ke Xu, Hang Fu, Xinyuan Zhang, Ziqi Zhou, Yu Song, Yukun Ren, Yuehua Chen, Ruzhi Zhang, Yuchen Liu, Jiaojian Wang, Xiaotang Cai, Xu Huayan, Qing Wu, Yingkun Guo
ABSTRACT 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.