Cerebral white matter integrity in Type-2 Diabetes Mellitus and integrated role of Interleukin-6: Findings in multiethnic middle-aged and older US-adults

Introduction: Peripheral neural injuries, known as polyneuropathy, are largely described in patients with Type-2 Diabetes Mellitus (T2DM). However, less is known about the T2DM-associated cerebral White Matter (WM) integrity. Previous studies highlighted mediating effects of inflammation in the T2DM-brain association. It is, however, still unclear whether Interleukin-6 (IL-6) mediates specifically T2DM-cerebral WM integrity. Methods: The multiethnic 50 years and older study population is a subset of the Health and Aging Brain Study: Health Disparities (HABS-HD) study. Diffusion-weighted scans were analyzed, and diffusion parameters were averaged in major WM tracts. Effect sizes (Cohen s d) were calculated after adjusting for relevant confounders. Mediation analysis was performed using 1000-fold non-parametric bootstrapping of 95% confidence intervals (CI). The results were adjusted for multiple testing using the False Discovery Rate method (FDR). Results: Several WM tracts showed significant impairment in T2DM participants after adjusting for confounders and multiple testing (posterior thalamic radiation (adj. Cohen s d=0.14[0.03-024]), anterior corona radiata (adj. Cohen s d=0.15[0.04-0.26]), cingulum (adj. Cohen s d=0.14[0.03-0.25]), inferior fronto-occipital fasciculus (adj. Cohen s d=0.16[0.06-0.27]), genu of the corpus callosum (adj. Cohen s d=0.13[0.03-0.24]), and body of the corpus callosum (adj. Cohen s d=0.28[0.17-0.38])). Within two years, the effect sizes showed an increasing trend. Even in cognitively unimpaired participants, T2DM was associated with locally reduced WM integrity. IL-6 statistically mediated up to 15% of these major associations. Conclusions: The study demonstrated T2DM-associated impairment of intracerebral WM integrity. In T2DM, microstructural WM changes might start before clinically objectified cognitive impairment. The role of systemic inflammation needs to be assessed in causal frameworks.