White matter deficits in cocaine use disorder: convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomic analysis

Lucca Pizzato Tondo,Alexandre Rosa Franco,Joy M Schmitz,Consuelo Walss-Bass,Leonardo Mello Rothmann,Laura Stertz,Gabriel R Fries,Scott D Lane,Thomas Meyer,Bruno Kluwe-Schiavon,Ruifeng Hu,Pedro Ferreira,Rodrigo Grassi-Oliveira,Renata Cupertino,Zhongming Zhao,Thiago Wendt Viola

doi:10.1038/s41398-021-01367-x

Abstract

White matter (WM) abnormalities in patients with cocaine use disorder (CUD) have been studied; however, the reported effects on the human brain are heterogenous and most results have been obtained from male participants. In addition, biological data supporting the imaging findings and revealing possible mechanisms underlying the neurotoxic effects of chronic cocaine use (CU) on WM are largely restricted to animal studies. To evaluate the neurotoxic effects of CU in the WM, we performed an in vivo diffusion tensor imaging assessment of male and female cocaine users (n = 75) and healthy controls (HC) (n = 58). Moreover, we performed an ex vivo large-scale proteomic analysis using liquid chromatography-tandem mass spectrometry in postmortem brains of patients with CUD (n = 8) and HC (n = 12). Compared with the HC, the CUD group showed significant reductions in global fractional anisotropy (FA) (p < 0.001), and an increase in global mean (MD) and radial diffusion (RD) (both p < 0.001). The results revealed that FA, RD, and MD alterations in the CUD group were widespread along the major WM tracts, after analysis using the tract-based special statistics approach. Global FA was negatively associated with years of CU (p = 0.0421) and female sex (p < 0.001), but not with years of alcohol or nicotine use. Concerning the fibers connecting the left to the right prefrontal cortex, Brodmann area 9 (BA9), the CUD group presented lower FA (p = 0.006) and higher RD (p < 0.001) values compared with the HC group. A negative association between the duration of CU in life and FA values in this tract was also observed (p = 0.019). Proteomics analyses in BA9 found 11 proteins differentially expressed between cocaine users and controls. Among these, were proteins related to myelination and neuroinflammation. In summary, we demonstrate convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomics analysis of WM disruption in CUD.

Highlights

Cocaine use disorder (CUD) is a chronic disease characterized by compulsive drug use with negative most neuroimaging studies have examined the chronic cocaine use (CU) effects on specific gray matter brain regions, several recent investigations haveTondo et al Translational Psychiatry (2021)11:252 focused on revealing the white matter (WM) signature of CUD7
Given that the tract-based special statistics (TBSS) cluster analysis revealed a major effect of years of crack-cocaine consumption on fractional anisotropy (FA) in the genu of the corpus callosum, and that previous studies demonstrated a main effect of cocaine in this anterior region[17], we further explored this association by focusing on specific fibers of the frontal lobe
At least 1/3 of them could be classified as polysubstance users, as they met the criteria for cannabis, alcohol, or tobacco use disorders

Summary

Introduction

Cocaine use disorder (CUD) is a chronic disease characterized by compulsive drug use with negative most neuroimaging studies have examined the chronic cocaine use (CU) effects on specific gray matter brain regions, several recent investigations haveTondo et al Translational Psychiatry (2021)11:252 focused on revealing the white matter (WM) signature of CUD7. A recent meta-analysis of data obtained from DTI studies that included patients with stimulant use disorder revealed a small-to-moderate group-effect in reducing the FA values; a subanalysis focusing on patients with CUD showed greater heterogeneity of findings and effect sizes[16].

Results

Conclusion