Abstract
Aims/hypothesis
Brain structure abnormality in patients with type 2 diabetes mellitus (T2DM)-related cognitive dysfunction (T2DM-CD) has been reported for decades in magnetic resonance imaging (MRI) studies. However, the reliable results were still unclear. This study aimed to make a systemic review and meta-analysis to find the significant and consistent gray matter (GM) and white matter (WM) alterations in patients with T2DM-CD by comparing with the healthy controls (HCs).
Methods
Published studies were systemically searched from PubMed, MEDLINE, Cochrane Library and Web of Science databases updated to November 14, 2021. Studies reporting abnormal GM or WM between patients with T2DM-CD and HCs were selected, and their significant peak coordinates (x, y, z) and effect sizes (z-score or t-value) were extracted to perform a voxel-based meta-analysis by anisotropic effect size-signed differential mapping (AES-SDM) 5.15 software.
Results
Total 15 studies and 16 datasets (1550 participants) from 7531 results were involved in this study. Compared to HCs, patients with T2DM-CD showed significant and consistent decreased GM in right superior frontal gyrus, medial orbital (PFCventmed. R, BA 11), left superior temporal gyrus (STG. L, BA 48), and right calcarine fissure / surrounding cortex (CAL. R, BA 17), as well as decreased fractional anisotropy (FA) in right inferior network, inferior fronto-occipital fasciculus (IFOF. R), right inferior network, longitudinal fasciculus (ILF. R), and undefined area (32, −60, −42) of cerebellum. Meta-regression showed the positive relationship between decreased GM in PFCventmed.R and MoCA score, the positive relationship between decreased GM in STG.L and BMI, as well as the positive relationship between the decreased FA in IFOF.R and age or BMI.
Conclusions/interpretation
T2DM impairs the cognitive function by affecting the specific brain structures. GM atrophy in PFCventmed. R (BA 11), STG. L (BA 48), and CAL. R (BA 17), as well as WM injury in IFOF. R, ILF. R, and undefined area (32, −60, −42) of cerebellum. And those brain regions may be valuable targets for future researches. Age, BMI, and MoCA score have a potential influence on the altered GM or WM in T2DM-CD.
Gray and white matter abnormality in patients with T2DM-related cognitive dysfunction: a systemic review and meta-analysis
Discussion
In our systemic review and meta-analysis, GM and WM abnormalities in patients with T2DM-CD were the first to be explored. The GMV, GMD, and cortical thickness changes between T2DM-CD and HCs were combined to explore the specific brain regions with GM alterations in T2DM-CD. The FA changes between T2DM-CD and HCs were pooled to explore the specific brain regions with WM abnormalities. Main analysis showed that patients with T2DM-CD had the significant decreased GM in PFCventmed.R (BA 11), STG.L (BA 48), and CAL.R (BA 17), as well, as they had decreased FA in IFOF.R, ILF.R, and undefined area of cerebellum area (32, −60, −42). Meta-regression showed that the BMI might be positively related with both decreased GM in STG.L and decreased FA in IFOF.R, the MoCA score might be positively related with the decreased GM in PFCventmed.R, and the age of patients might be positively related with the decreased FA in IFOF.R.
According to our main results, GM abnormalities in specific brain regions in patients with T2DM-CD were also consistent with the findings of previous systemic review and meta-analysis studies on brain structural alterations caused by T2DM. For example, previous meta-analysis of VBM studies reported that patients with T2DM had the significant GM reductions in bilateral STG, middle temporal gyrus (MTG), medial superior frontal gyrus (SFGmedial), insula (INS), median cingulate cortex, precuneus cortex, and the left lentiform nucleus [47]. Meanwhile, another meta-analysis study reported that the patients with T2DM showed a lower GMV in STG.L, MTG.R, right rolandic operculum (ROL.R), and left fusiform gyrus (FFG.L) than HCs [48]. In addition, the recent systemic review and meta-analysis also showed that the patients with T2DM had the significant decreased GMV in bilateral STG/ROL, MTG.L, ITG.L, and left supramarginal gyrus (SMG.L) [49]. Similarly, our study found that the patients with T2DM-CD had the significant decreased GM in STG.L compared to HCs. Taken together, the GM reduction in STG.L was robust in both T2DM and T2DM-CD. It was reported that the STG played a crucial role in extracting meaningful information from speech input [50]. Previous evidences also demonstrated that the functional deficit of STG was the common mechanism of CD caused by various diseases including T2DM, schizophrenia, and multiple sclerosis [37, 51, 52]. Therefore, the GM reduction in STG.L may be a specific biomarker for T2DM to T2DM-CD by impairing the function of speech information encoding.
Furthermore, our study also found that patients with T2DM-CD had the significant decreased FA in IFOF.R compared to HCs, which was consistent with the findings of previous systemic review and meta-analysis studies. For example, previous meta-analysis study reported that the patients with T2DM showed the significant decreased FA in IFOF.R, corpus callosum (CC), and left olfactory cortex compared to HCs [17]. Another same study found that patients with T2DM had the significant decreased FA in CC (genu and body), bilateral anterior and superior corona radiata (CR), bilateral cingulum, and bilateral superior fronto-occipital fasciculus (SFOF) [53]. Taken together, the decreased FA in FOF was robust in both T2DM and T2DM-CD. It was reported that the damaged WM integrity of IFOF.R was related with the episodic memory and attention function impairment in patients with T2DM [19]. And the previous studies have demonstrated that the FOF fiber tract was significantly involved in the linguistic, spatial, and visual functions [54,55,56]. Therefore, the decreased FA in FOF might be another specific biomarker for T2DM to T2DM-CD by impairing the memory and attention functions.
In addition to the robust results in both T2DM and T2DM-CD, our study also found that the patients with T2DM-CD had the significant GM reduction in PFCventmed.R (BA 11) and CAL.R (BA 17), as well as decreased FA in ILF.R and undefined area of cerebellum (32, −60, −42). Although previous studies have shown that the first three structural abnormalities were involved in the T2DM or CD [57,58,59], the further exploration in T2DM-CD was suggested. Furthermore, the decreased FA in undefined area of cerebellum (32, −60, −42) that was adjacent to the cerebellar dentate nucleus (CDN) was newly found in T2DM-CD. Previous studies reported that the abnormal functional connectivity between CDN and cerebral cortex was significantly correlated with the CD in Alzheimer’s disease (AD) or first-episode schizophrenia [60, 61]. Therefore, impaired information transmission resulting from decreased FA in the CDN-adjacent WM region might also be associated with T2DM-CD. Meta-regression showed that the risk factors of BMI, age of patients, and MoCA score might play an effect on the GM or WM alterations in T2DM-CD, but the results need to be verified due to the limited datasets. The other factors including MMSE score, percentage of female patients, HbA1c, and disease duration were suggested to be further explored in the future.
Some limitations in this study were declared as follows: Firstly, only published studies from 4 databases were searched; secondly, only peak coordinates and effect sizes of studies included were extracted and analyzed; thirdly, subgroup analysis was not performed because of limited datasets; fourthly, GMV, GMD, and cortical thickness were pooled into this meta-analysis, which might increase the heterogeneity; fifthly, the results of meta-regression should be accepted with caution because of the limited datasets.
In conclusion, GM and WM abnormalities caused by T2DM in specific brain regions (STG.L and FOF) were significantly correlated with the visual and linguistic dysfunctions, which might play a crucial role in the process of T2DM-CD. Our findings also showed that T2DM damages the GM and its functionally related WM (e.g., IFOF. R and PFCventmed.R), but not the adjacent WM. Those results might be a reference for researchers in the future studies.
Source: Nature
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