Abstract
PurposeBrain iron accumulation has been suggested as a pathomechanism in patients with type 2 diabetes mellitus (T2DM) with cognitive impairment. This research aims to examine the total-brain pattern of iron accumulation in relation to executive function decline in patients with T2DM by voxel-based quantitative susceptibility mapping (QSM) analysis.Materials and MethodsA total of 32 patients with T2DM and 34 age- and sex-matched healthy controls (HCs) were enrolled in this study. All participants underwent brain magnetic resonance examination, and 48 individuals underwent cognitive function assessments. Imaging data were collected with three-dimensional fast low-angle shot sequences to achieve magnitude as well as phase images. Using voxel-based QSM analysis, we compared the voxel-wise susceptibility values of the whole brain among groups and explored whether the susceptibility values had correlations with cognitive data.ResultsAmong the 66 participants, cognitive function was estimated in 23 patients with T2DM (11 males and 12 females; average age, 64.65 ± 8.44 years) and 25 HCs (13 males and 12 females; average age, 61.20 ± 7.62 years). T2DM patients exhibited significantly (t = 4.288, P < 0.001) lower Montreal Cognitive Assessment (MoCA) scores [T2DM, 27 (27, 28); HCs, 29 (28, 29); normal standard ≥ 26)] and higher Trail-making Test (TMT)-A/TMT-B scores [71 (51, 100)/185 (149, 260)] than HCs [53 (36.5, 63.5)/150 (103, 172.5)] (Z = 2.612, P = 0.009; Z = 2.797, P = 0.005). Subjects with T2DM showed significantly higher susceptibility values than HCs in the caudate/putamen/pallidum, frontal inferior triangular gyrus, and precentral gyrus on the right hemisphere. In contrast (HC > T2DM), no region showed a significant difference in susceptibility values between the groups. The correlation analysis between susceptibility values and cognitive function scores was tested by voxel-based susceptibility value with sex and age as covariates. After multiple comparison correction, in T2DM patients, the left thalamus showed a significant relationship with TMT-A (R2 = 0.53, P = 0.001). The right thalamus and left thalamus showed a significant relationship with TMT-B (R2 = 0.35, P = 0.019; and R2 = 0.38, P = 0.017, respectively). In HCs, the cluster of right precentral/middle frontal gyrus/inferior frontal gyrus/inferior triangular gyrus showed a significant relationship with TMT-B (R2 = 0.59, P = 0.010). No relationship was found between the susceptibility values with MoCA in the brain region in both two groups.ConclusionPatients with T2DM presented declined cognitive assessments and elevated iron deposition in the striatum and frontal lobe, suggesting that executive function decline in T2DM might be associated with the cerebral iron burden and that changes in susceptibility values may represent a latent quantitative imaging marker for early assessment of cognitive decline in patients with T2DM.
Highlights
In type 2 diabetes mellitus (T2DM), peripheral insulin resistance together with compensatory insulin hypersecretion from pancreatic islets likely results in some complications, such as neuropathy, nephropathy, atherosclerosis, and retinopathy (Forbes and Cooper, 2013)
We found that in T2DM patients, the left thalamus showed a significant relationship with Trail-making Test (TMT)-A (R2 = 0.53, P = 0.001)
We found that T2DM patients exhibited lower Montreal Cognitive Assessment (MoCA) scores and higher TMT-A/TMT-B scores and that the susceptibility values of some brain regions showed significant correlation with TMT-A or TMT-B
Summary
In type 2 diabetes mellitus (T2DM), peripheral insulin resistance together with compensatory insulin hypersecretion from pancreatic islets likely results in some complications, such as neuropathy, nephropathy, atherosclerosis, and retinopathy (Forbes and Cooper, 2013). Insulin resistance in the brain will lead to subsequent sequelae, which might result in tau hyperphosphorylation and/or amyloid accretion. Insulin functions through the distribution of iron in neuronal tissue; an insulin-resistant state has a disruptive role in the process, resulting in detrimental iron overload (Medhi and Chakrabarty, 2013). Insulin resistance leads to high permeability of the blood–brain barrier (BBB), and increased permeability with leakage of material into the vessel wall and perivascular tissue will cause inflammation (Wardlaw et al, 2013; Takechi et al, 2017). The accumulation of iron in neurons will induce damage by apoptosis (Ward et al, 2014). We speculated that the iron excess caused by T2DM can generate damage within the central nervous system
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