An integration of neuroimaging and serum proteomics analysis suggests immune and inflammation are associated with white matter microstructure changes in cerebral small vessel disease with depressive symptoms

Introduction: Depressive symptoms are a common concomitant of cerebral small vessel disease (CSVD), of which pathogenesis requires more study. White matter microstructural abnormalities and proteomic alternation have been widely reported regarding depression in the elderly with CSVD. Exploring the relationship between cerebral white matter microstructural alterations and serum proteins may complete the explanation of molecular mechanisms for the findings from neuroimaging research of CSVD combined with depressive symptoms. Methods: An untargeted proteomics approach based on mass spectrometry was used to obtain serum proteomic profiles, which were clustered into co-expression protein modules. White matter microstructural integrity was measured using the FMRIB Software Library (FSL) and MATLAB to analyze diffusion tensor imaging (DTI) data and calculate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for 50 regions of interest (ROI). Integrating the proteome with the DTI results, weighted gene co-expression analysis (WGCNA) was used to identify protein modules related to white matter micro- structural alterations, and the proteins of the corresponding modules were analyzed for functional enrichment through bioinformatics techniques. Results: DTI measurements were analCerebral small vessel disease (CSVD); Depression; Diffusion tensor imaging (DTI); Proteomics; Inflammationyzed between individuals with CSVD and depressive symptoms (CSVD+D) (n = 24) and those without depressive symptoms (CSVD-D) (n = 35). Results showed an overall increase in MD, AD, and RD within the left hemisphere of the CSVD+D group, suggesting widespread loss of white matter integrity and axonal demyelination, including left superior longitudinal fasciculus (SLF), left posterior corona radiata (PCR) and right external capsule (EC). We identified two protein modules associated with DTI diffusivity, and functional enrichment analyses revealed that complement and coagulation cascades and immune responses participate in the alternation of white matter microstructure in the CSVD+D group. Conclusion: The results suggested immune- and inflammation-related mechanism was associated with white matter microstructure changes in CSVD with depressive symptoms