Type 2 Diabetes and Biomarkers of Brain Structure, Perfusion, Metabolism, and Function in Late Mid-Life: A Multimodal Discordant Twin Study

Background: Type 2 diabetes (T2D) is associated with an increased risk of dementia and early features may become evident even in mid-life. Characterizing these early features comprehensively requires multiple measurement modalities and careful selection of participants with and without T2D. Objective: We conducted a cross-sectional multimodal imaging study of T2D-discordant twins in late mid-life to provide insights into underlying mechanisms. Methods: Measurements included computerized cognitive battery, brain MRI (including arterial spin labelling, diffusion tensor, resting state functional), fluorodeoxyglucose (FDG)-PET, and retinal optical coherence tomography. Results: There were 23 pairs, mean age 63.7 (±6.1) years. In global analyses, T2D was associated with poorer attention (β= -0.45, p <0.001) and with reduced FDG uptake (β= -5.04, p = 0.02), but not with cortical thickness (p = 0.71), total brain volume (p = 0.51), fractional anisotropy (p = 0.15), mean diffusivity (p = 0.34), or resting state activity (p = 0.4). Higher FDG uptake was associated with better attention (β= 3.19, p = 0.01) but not with other cognitive domains. In regional analyses, T2D was associated with lower accumbens volume (β= -44, p = 0.0004) which was in turn associated with poorer attention. Conclusion: T2D-related brain dysfunction in mid-life manifests as attentional loss accompanied by evidence of subtle neurodegeneration and global reduction in cerebral metabolism, in the absence of overt cerebrovascular disease.