White Matter Microstructural Alteration in Type 2 Diabetes: A Combined UK Biobank Study of Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging

Background Type 2 diabetes mellitus impacts the brain microstructural environment. Diffusion tensor imaging (DTI) has been widely used to characterize white matter microstructural abnormalities in type 2 diabetes but fails to fully characterise disease effects on complex white matter tracts. Neurite orientation dispersion and density imaging (NODDI) has been proposed as an alternative to DTI with higher specificity to characterize white matter microstructures. Although NODDI has not been widely applied in diabetes, this biophysical model has the potential to investigate microstructural changes in white matter pathology. Aims and objectives (1) To investigate brain white matter alterations in people with type 2 diabetes using DTI and NODDI; (2) To assess the association between white matter changes in type 2 diabetes with disease duration and diabetes control as reflected by glycated haemoglobin (HbA1c) levels. Methods We examined white matter microstructure in 48 white matter tracts using data from the UK Biobank in 3,338 participants with type 2 diabetes (36% women, mean age 66 years) and 30,329 participants without type 2 diabetes (53% women, mean age 64 years). The participants had undergone 3.0T multiparametric brain imaging, including T1 weighted imaging and diffusion imaging for DTI and NODDI. Region of interest analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), orientation dispersion index (ODI), intracellular volume fraction (ICVF), and isotropic water fraction (IsoVF) were conducted to assess white matter abnormalities. A general linear model was applied to evaluate intergroup white matter differences and their association with the metabolic profile. Result Reduced FA and ICVF and increased MD, AD, RD, ODI, and IsoVF values were observed in participants with type 2 diabetes compared to non-type 2 diabetes participants ( P <0.05). Reduced FA and ICVF in most white matter tracts were associated with longer disease duration and higher levels of HbA1c (0< r ≤0.2, P <0.05). Increased MD, AD, RD, ODI and IsoVF also correlated with longer disease duration and higher HbA1c (0< r ≤0.2, P <0.05). Discussion NODDI detected microstructural changes in brain white matter in participants with type 2 diabetes. The revealed abnormalities are proxies for lower neurite density and loss of fibre orientation coherence, which correlated with longer disease duration and an index of poorly controlled blood sugar. NODDI contributed to DTI in capturing white matter differences in participants with type 2 diabetes, suggesting the feasibility of NODDI in detecting white matter alterations in type 2 diabetes. Conclusion Type 2 diabetes can cause white matter microstructural abnormalities that have associations with glucose control. The NODDI diffusion model allows the characterisation of white matter neuroaxonal pathology in type 2 diabetes, giving biophysical information for understanding the impact of type 2 diabetes on brain microstructure. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants provided informed consent forms. Ethical approval was obtained from the Northwest Multi-centre Research Ethics Committee. The current study was approved under the UK Biobank application ID 43822. Details of the UK Biobank cohort and consent are available on the UK Biobank website. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.