Cerebral white matter integrity in Type-2 Diabetes Mellitus and integrated role of Interleukin-6: Findings in multiethnic middle-aged and older US-adults
- 1Charite Universitatsmedizin Berlin
Abstract
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.
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BibTeX
@misc{hallab2026cerebral,
title = {{Cerebral white matter integrity in Type-2 Diabetes Mellitus and integrated role of Interleukin-6: Findings in multiethnic middle-aged and older US-adults}},
author = {A. Hallab and The Health and Aging Brain Study (HABS-HD) Study Team},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.02.26367084},
url = {https://www.medrxiv.org/content/10.64898/2026.11.02.26367084v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Cerebral white matter integrity in Type-2 Diabetes Mellitus and integrated role of Interleukin-6: Findings in multiethnic middle-aged and older US-adults
AU - A. Hallab
AU - The Health and Aging Brain Study (HABS-HD) Study Team
PY - 2026
DA - 2026/11/02
PB - medRxiv
DO - 10.64898/2026.11.02.26367084
UR - https://www.medrxiv.org/content/10.64898/2026.11.02.26367084v1
AB - 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.
ER -