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

Article type: Research Article

Authors: Karayiannis, Christopher C.^{a; b} | Srikanth, Velandai^{b; c; k; *} | Beare, Richard^{b; c; d} | Mehta, Hemal^{f; g} | Gillies, Mark^g | Phan, Thanh G.^e | Xu, Zheng Yang^{f; h} | Chen, Christine^{i; j} | Moran, Chris^{b; c; k; l; m}

Affiliations: [a] Department of Medicine, Peninsula Health, Melbourne, Australia | [b] Peninsula Clinical School, Central Clinical School, Monash University, Melbourne, Australia | [c] National Centre for Healthy Ageing, Melbourne, Australia | [d] Developmental Imaging, Murdoch Children’s Research Institute, Melbourne, Australia | [e] Stroke and Ageing Research Centre, School of Clinical Sciences, Monash University, Melbourne, Australia | [f] Royal Free London NHS Foundation Trust, London, UK | [g] Macular Research Group, University of Sydney, Sydney, Australia | [h] UCL Medical School, London, UK | [i] Ophthalmology Department, Monash Health, Melbourne, Australia | [j] Department of Surgery, School of Clinical Sciences, Monash University, Melbourne, Australia | [k] Department of Geriatric Medicine, Peninsula Health, Melbourne, Australia | [l] Department of Aged Care, Alfred Health, Melbourne, Australia | [m] School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia

Correspondence: [*] Correspondence to: Professor Velandai Srikanth, Professor of Medicine, Peninsula Health, Academic Unit, Monash University, 2 Hastings Rd, Frankston 3199, Victoria, Australia. Tel.: +61 3 97881723; E-mail: [email protected].

Abstract: 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.

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, multimodal imaging, twins, type 2 diabetes mellitus

DOI: 10.3233/JAD-230640

Journal: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1223-1233, 2024