Connectomic-genetic signatures in the cerebral small vessel disease

Small vessel disease (SVD) is a disorder that causes vascular lesions in the entire parenchyma of the human brain. At present, it is not well understood how primary and secondary damage interact to give rise to the complex scenario of white matter (WM) and grey matter (GM) lesions. Using novel cross-sectional and longitudinal connectomic approaches, we unveil the bidirectional nature of GM and WM changes, that is, primary cortical neurodegeneration that leads to secondary alterations in vascular border zones, and WM lesions that lead to secondary neurodegeneration in cortical projecting areas. We found this GM-WM interaction to be essential for executive cognitive performance. Moreover, we also observed that the interlocked degeneration of GM and WM over time associates with prototypical expression levels of genes potentially linked to SVD. Among these connectomic-genetic intersections, we found that the Androgen Receptor (AR) gene, is a particularly central candidate gene that might confer key vulnerability for brain lesion development in SVD. In conclusion, this study advances in the understanding of the bidirectional relationships between GM and WM lesions, primary and secondary vascular neurodegeneration, and sheds light on the genetic signatures of SVD. •We described the bidirectional nature of neurodegeneration (ND) and vascular damage (VD) in the small vessel disease (SVD).•ND-VD bidirectional connectomics are key to understand the associated cognitive changes.•ND-VD connectomics relates to cortical expression levels of candidate genes linked to SVD.•Androgen Receptor gene confers central vulnerability for brain lesion development in SVD.•This study describes the intersection of primary and secondary ND and VD, and their potential genetic signatures in SVD.