Transcriptional specialization shapes abnormal cortical morphological similarity gradients in Wilson's disease

Neuroimaging studies have revealed structural abnormalities in the brains of individuals with Wilson's disease (WD), particularly within the basal ganglia, and the associated molecular mechanisms have been elucidated. However, the structural damage in the cerebral cortex, along with its underlying biological and molecular processes, remains elusive. Here, we investigated the abnormalities in cortical morphological similarity gradients associated with WD and further unraveled their underlying transcriptional specialization.

First, we analyzed cortical morphological features from structural magnetic resonance imaging scans from 102 WD patients and 90 healthy controls (HCs) and then computed the cortical morphological similarity (MS) connections. Subsequently, the diffusion map embedding approach was employed to investigate the cortical MS gradients. Finally, the differences in MS gradients between WD and HC were analyzed and their underlying clinical relevance and transcriptional specialization were revealed using clinical symptoms and gene expression data, respectively.

Compared with HC, WD patients exhibited regional differences across extensive brain networks in both the first and second MS gradients. Alterations in MS gradient alterations correlated with age, neurological symptoms, liver function symptoms, and motor-related processing. Partial least squares (PLS) regression analysis results indicated a significant association between MS gradients and gene expression profiles (PLS components). Gene enrichment analysis showed that the transcriptional specialization of PLS components was enriched in biological processes such as cell projection organization, regulation of protein organization, and GPTase-mediated signal transduction, all of which are relevant to WD. The transcriptional specializations influencing the MS gradient of WD were also enriched in WD's pathological genes associated with WD and other neuropsychiatric risks, such as dystonia and Parkinsonism.

Overall, this research offers new perspectives on the neurobiological foundations that govern the emergence of complex neural architectures and associated mental manifestations in WD.