Mild Cognitive Impairment In Type 2 Diabetes Mellitus Patients Research Articles

Association between plasma osteopontin level and mild cognitive impairment in patients with type 2 diabetes mellitus

Objective: To analyze the influencing factors of type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI), and to explore the association between plasma osteopontin (OPN) levels and MCI. Methods: A retrospective analysis was conducted on the clinical data of 254 patients with T2DM admitted to Zhongda Hospital Affiliated to Southeast University from October 2021 to May 2023. The patients were divided into MCI group (n=106) and normal cognitive function control group (n=148) according to whether they had MCI. Clinical data were collected, cognitive function was assessed using neurological scales and plasma OPN levels were measured by enzyme linked immunosorbent assay. A multivariate logistic regression model was applied to analyze the influencing factors of MCI in T2DM patients. Interaction terms between gender, age, body mass index (BMI), and OPN were established to verify their significance levels. Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive value of OPN for MCI in T2DM patients. The mediation model of OPN-FPG-montreal cognitive assessment(MoCA) was constructed with fasting plasma glucose (FPG) as the mediating variable to test the mediating effect, and the mediating effect percentage was calculated. Results: A total of 254 patients were included, including 162 males and 92 females, with an average age of (61.5±7.5) years old. Compared with the control group, the patients in MCI group were older[63.0(59.0, 69.0) years vs 60.0(54.2, 66.8) years], had a greater proportion of females [(43.4%(46/106) vs 31.1%(46/148)], shorter years of education[12(9, 12) years vs 12(9,15) years], longer duration of diabetes[15.0(8.0, 20.0) years vs 10.0(5.0, 15.0) years], and higher levels of FPG[7.78(6.07, 10.23) mmol/L vs 6.86(5.36, 8.59) mmol/L], insulin resistance index[2.93(2.47, 3.98) vs 2.79(2.27, 3.25)], glycated hemoglobin (HbA1c) [9.24%(7.89%, 10.96%) vs 7.97%(7.00%, 9.45%)], total cholesterol(TC)[(4.51±1.17) mmol/L vs (4.19±0.99) mmol/L], and OPN [11.30(8.68, 12.84) ng/ml vs 9.69(7.82, 11.74) ng/ml] (all P<0.05). The scores of various neuropsychological tests in MCI patients were lower than those in control group with normal cognitive function (all P<0.05). Spearman correlation analysis showed that age(r=-0.212), duration of diabetes mellitus(r=-0.156), duration of hypertension(r=-0.132), FPG(r=-0.207), insulin resistance index(r=-0.171), HbA1c(r=-0.271), OPN(r=-0.238), and total cholesterol (r=-0.125) were negatively correlated with MoCA scores, whereas years of education(r=0.285) were positively correlated with MoCA scores(all P<0.05). Multifactorial logistic regression analysis showed that age, years of education, duration of diabetes mellitus, HbA1c, TC and OPN levels were the influencing factors of T2DM patients with MCI, and the risk of MCI increased by 15% for every 1 ng/ml increase in OPN (OR=1.15, 95%CI: 1.021-1.295, P=0.021), and the relationship was not affected by age, gender and BMI(The interaction effects are all P>0.05). The area under the curve (AUC) of the working curve of subjects with OPN predicting combined MCI in patients with T2DM was 0.612 (95%CI: 0.541-0.682), and the AUC was 0.702 (95%CI: 0.638-0.767) after the combination of HbA1c and OPN. The results of the mediated effect model showed that FPG partially mediated the correlation between OPN and MoCA in T2DM patients, and the mediated effect accounted for 11.34% of the total effect. Conclusions: Plasma OPN level is associated with MCI in patients with T2DM,and the higher the OPN level, the higher the risk of T2DM patients developing MCI.

Interleukin-5: an indicator of mild cognitive impairment in patients with type 2 diabetes mellitus - a comprehensive investigation ranging from bioinformatics analysis to clinical research.

Neuroinflammation constitutes an underlying mechanism for cognitive impairment. Here, we endeavor to scrutinize the potential contribution of interleukin-5 (IL-5) towards mild cognitive impairment (MCI), and to assess its diagnostic value for MCI in patients with type 2 diabetes mellitus (T2DM). RNA-seq was used to explore the potential neuroinflammation factors in the hippocampus of diabetic mice with cognitive decline. Additionally, the promising risk factor was verified in animals. Finally, the association between IL-5 levels and cognitive function and its diagnostic value for MCI were assessed. In animals, up-regulated IL-5 mRNA and protein levels were detected by RNA-seq and (or) verified experiments in the hippocampus of diabetic db/db mice with cognitive decline, compared to those of db/m mice without diabetes. In human, compared to diabetic patients without MCI, those with MCI demonstrate elevated levels of IL-5. It is natively associated with Montreal Cognitive Assessment (MoCA) scores, reflecting global cognitive function, and positively correlated with Trail Making Test A (TMTA) scores, reflecting information processing speed. Furthermore, an elevated level of IL-5 is identified as a risk factor for MCI, and a factor that influences TMTA scores. Finally, it is recommended that the cut-off value for IL-5 in the diagnosis of MCI is 22.98 pg/mL, with a sensitivity of 68.6% and specificity of 72.9%. IL-5 is considered a risk factor for MCI in T2DM patients and is associated with their performance in information processing speed. Moreover, an elevated level of IL-5 is a plausible biomarker for MCI in T2DM patients.

Predictive model for identifying mild cognitive impairment in patients with type 2 diabetes mellitus: A CHAID decision tree analysis.

As the population ages, mild cognitive impairment (MCI) and type 2 diabetes mellitus (T2DM) become common conditions that often coexist. Evidence has shown that MCI could lead to reduced treatment compliance, medication management, and self-care ability in T2DM patients. Therefore, early identification of those with increased risk of MCI is crucial from a preventive perspective. Given the growing utilization of decision trees in prediction of health-related outcomes, this study aimed to identify MCI in T2DM patients using the decision tree approach. This hospital-based case-control study was performed in the Endocrinology Department of Xiangya Hospital affiliated to Central South University between March 2021 and December 2022. MCI was defined based on the Petersen criteria. Demographic characteristics, lifestyle factors, and T2DM-related information were collected. The study sample was randomly divided into the training and validation sets in a 7:3 ratio. Univariate and multivariate analyses were performed, and a decision tree model was established using the chi-square automatic interaction detection (CHAID) algorithm to identify key predictor variables associated with MCI. The area under the curve (AUC) value was used to evaluate the performance of the established decision tree model, and the performance of multivariate regression model was also evaluated for comparison. A total of 1001 participants (705 in the training set and 296 in the validation set) were included in this study. The mean age of participants in the training and validation sets was 60.2 ± 10.3 and 60.4 ± 9.5 years, respectively. There were no significant differences in the characteristics between the training and validation sets (p>.05). The CHAID decision tree analysis identified six key predictor variables associated with MCI, including age, educational level, household income, regular physical activity, diabetic nephropathy, and diabetic retinopathy. The established decision tree model had 15 nodes composed of 4 layers, and age is the most significant predictor variable. It performed well (AUC=.75 [95% confidence interval (CI): .71-.78] and .67 [95% CI: .61-.74] in the training and validation sets, respectively), was internally validated, and had comparable predictive value compared to the multivariate logistic regression model (AUC=.76 [95% CI: .72-.80] and .69 [95% CI: .62-.75] in the training and validation sets, respectively). The established decision tree model based on age, educational level, household income, regular physical activity, diabetic nephropathy, and diabetic retinopathy performed well with comparable predictive value compared to the multivariate logistic regression model and was internally validated. Due to its superior classification accuracy and simple presentation as well as interpretation of collected data, the decision tree model is more recommended for the prediction of MCI in T2DM patients in clinical practice.

Risk factors and metabolomics of mild cognitive impairment in type 2 diabetes mellitus.

Objective: This study aimed to explore the risk factors, metabolic characteristics, and potential biomarkers of mild cognitive impairment in type 2 diabetes mellitus (T2DM-MCI) and to provide potential evidence for the diagnosis, prevention, and treatment of mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 103 patients with T2DM were recruited from the Endocrinology Department of The Second Affiliated Hospital of Dalian Medical University for inclusion in the study. The Montreal Cognitive Assessment (MoCA) was utilized to evaluate the cognitive functioning of all patients. Among them, 50 patients were categorized into the T2DM-MCI group (MoCA score < 26 points), while 53 subjects were classified into the T2DM without cognitive impairment (T2DM-NCI) group (MoCA score ≥ 26 points). Serum samples were collected from the subjects, and metabolomics profiling data were generated by Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS). These groups were analyzed to investigate the differences in expression of small molecule metabolites, metabolic pathways, and potential specific biomarkers. Results: Comparison between the T2DM-MCI group and T2DM-NCI group revealed significant differences in years of education, history of insulin application, insulin resistance index, insulin-like growth factor-binding protein-3 (IGFBP-3), and creatinine levels. Further binary logistic regression analysis of the variables indicated that low educational level and low serum IGFBP-3 were independent risk factor for T2DM-MCI. Metabolomics analysis revealed that differential expression of 10 metabolites between the T2DM-MCI group and T2DM-NCI group (p < 0.05 and FDR<0.05, VIP>1.5). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis revealed that fatty acid degradation was the most significant pathway. Receiver operating characteristic (ROC) analysis shows that lysophosphatidylcholine (LPC) 18:0 exhibited greater diagnostic efficiency. Conclusion: This study revealed that a shorter duration of education and lower serum IGFBP-3 levels are independent risk factors for T2DM-MCI. Serum metabolites were found to be altered in both T2DM-MCI and T2DM-NCI groups. T2DM patients with or without MCI can be distinguished by LPC 18:0. Abnormal lipid metabolism plays a significant role in the development of MCI in T2DM patients.

Exosomal miR-let-7c-5p is involved in the cognitive function of type 2 diabetes mellitus patients by interleukin 10: A cross-sectional study.

Interleukin (IL)-10 plays a notable role in the inflammatory-associated mild cognitive impairment (MCI). We aimed to investigate whether IL-10 and its upstream factors exert an impact on MCI in type 2 diabetes mellitus (T2DM) patients. A total of 117 T2DM patients were recruited and divided into Control group and MCI group based on the presence or absence of MCI. Clinical parameters were collected. The Montreal Cognitive Assessment (MoCA) was conducted for global cognitive function. Digit Span Test (DST), Verbal Fluency Test (VFT), and Trail Making Test-B (TMTB) were used to evaluate the executive functions of the diabetic patients. Trail Making Test-A (TMTA) was performed to examine the information processing speed function. Patients' scene memory was examined by Logical Memory Test (LMT). After the baseline data were compared, correlation and regression analyses were performed to explore the relationship amongIL-10, miR-let-7c-5p and cognitive function. Compared to 80 patients in the control group, 37 patients in the MCI group exhibited lower IL-10 in plasma and higher miR-let-7c-5p levels in exosomes from plasma. The IL-10 level was negatively associated with MoCA. Likewise, miR-let-7c-5p levels were negatively correlated with IL-10 levels and MoCA. Elevated miR-let-7c-5p levels and decreased IL-10 levels are risk factors for MCI in T2DM patients. Increased miR-let-7c-5p and downregulated IL-10 may influence VFT and TMTB, respectively, associated with executive function. We demonstrated that IL-10 is correlated to the executive function of T2DM patients. Decreased IL-10 may result from the regulation of miR-let-7c-5p in exosomes.

The use of nomogram for detecting mild cognitive impairment in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is highly prevalent worldwide and may lead to a higher rate of cognitive dysfunction. This study aimed to develop and validate a nomogram-based model to detect mild cognitive impairment (MCI) in T2DM patients. Inpatients with T2DM in the endocrinology department of Xiangya Hospital were consecutively enrolled between March and December 2021. Well-qualified investigators conducted face-to-face interviews with participants to retrospectively collect sociodemographic characteristics, lifestyle factors, T2DM-related information, and history of depression and anxiety. Cognitive function was assessed using the Mini-Mental State Examination scale. A nomogram was developed to detect MCI based on the results of the multivariable logistic regression analysis. Calibration, discrimination, and clinical utility of the nomogram were subsequently evaluated by calibration plot, receiver operating characteristic curve, and decision curve analysis, respectively. A total of 496 patients were included in this study. The prevalence of MCI in T2DM patients was 34.1% (95% confidence interval [CI]: 29.9%-38.3%). Age, marital status, household income, diabetes duration, diabetic retinopathy, anxiety, and depression were independently associated with MCI. Nomogram based on these factors had an area under the curve of 0.849 (95% CI: 0.815-0.883), and the threshold probability ranged from 35.0% to 85.0%. Almost one in three T2DM patients suffered from MCI. The nomogram, based on age, marital status, household income, duration of diabetes, diabetic retinopathy, anxiety, and depression, achieved an optimal diagnosis of MCI. Therefore, it could provide a clinical basis for detecting MCI in T2DM patients.

Detection of mild cognitive impairment in type 2 diabetes mellitus based on machine learning using privileged information

Type 2 diabetes mellitus (T2DM) patients may develop into mild cognitive impairment (MCI) or even dementia. However, there is lack of reliable machine learning model for detection MCI in T2DM patients based on machine learning method. In addition, the brain network changes associated with MCI have not been studied. The aim of this study is to develop a machine learning based algorithm to help detect MCI in T2DM. There are 164 participants were included in this study. They were divided into T2DM-MCI (n = 56), T2DM-nonMCI (n = 49), and normal controls (n = 59) according to the neuropsychological evaluation. Functional connectivity of each participant was constructed based on resting-state magnetic resonance imaging (rs-fMRI). Feature selection was used to reduce the feature dimension. Then the selected features were set into the cascaded multi-column random vector functional link network (RVFL) classifier model using privileged information. Finally, the optimal model was trained and the classification performance was obtained using the testing data. The results show that the proposed algorithm has outstanding performance compared with classic methods. The classification accuracy of 73.18 % (T2DM-MCI vs NC) and 79.42 % (T2DM-MCI vs T2DM-nonMCI) were achieved. The functional connectivity related to T2DM-MCI mainly distribute in the frontal lobe, temporal lobe, and central region (motor cortex), which could be used as neuroimaging biomarkers to recognize MCI in T2DM patients. This study provides a machine learning model for diagnosis of MCI in T2DM patients and has potential clinical significance for timely intervention and treatment to delay the development of MCI.

Free Triiodothyronine Levels are Related to Executive Function and Scene Memory in Type 2 Diabetes Mellitus Patients Without Diagnosed Thyroid Diseases.

PurposeWe aim to determine the role of free triiodothyronine (FT3), the main active ingredient of thyroid hormones (THs), in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI).Patients and MethodsA total of 255 T2DM patients without diagnosed thyroid diseases were recruited and divided into MCI group and healthy cognition group. Neuropsychological functions were observed by multidimensional cognitive function scales in including MoCA, Digit Span Test (DST), Verbal Fluency Test (VFT), Clock drawing test (CDT), Trail Making Test (TMT) A and B, Instantaneously Recalled Auditory Verbal Learning Test (AVLT-IR), Delayed Recalled Auditory Verbal Learning Test (AVLT-DR) and Logical Memory Test (LMT). Correlation and logistic regression analyses were performed to explore the association between FT3 and diabetic cognitive dysfunction.ResultsCompared with 147 normal cognition patients, 108 MCI patients exhibited lower FT3 and higher HOMA-IR. FT3 level was not only positively correlated with MoCA scores, but DST, VFT and LMT, while negatively associated with TMTB. Furthermore, there is a negative association between FT3 and HOMA-IR. Logistic regression showed that decreased FT3 is a risk factor of MCI in T2DM patients. Although FT3 is not the risk factor of MCI after homeostasis model assessment of insulin resistance (HOMA-IR) was entered as an independent variable, lower FT3 is associated with VFT and LMT adjusted by age, education, BMI, DM duration, HBP duration, smoking, HbA1c and HOMA-IR.ConclusionLower FT3 levels may involve in MCI, especially for executive function and scene memory in T2DM patients without diagnosed thyroid diseases.

Age Related Prevalence of Mild Cognitive Impairment in Type 2 Diabetes Mellitus Patients in the Indian Population and Association of Serum Lipids With Cognitive Dysfunction.

The magnitude of type 2 diabetes mellitus (T2DM) is ever-increasing in India, and at present, ~77 million people live with diabetes. Studies have established that T2DM increases the risk of neurodegenerative disorders. This study aimed to determine the age-related prevalence of mild cognitive impairment (MCI) in T2DM patients in the Indian population and to identify link between cognitive dysfunction in T2DM patients and serum lipid composition through untargeted and targeted lipidomic studies. Using a cross-sectional study, we evaluated 1278 T2DM patients with Montreal cognitive assessment test (MoCA) and digit symbol substitution test (DSST) for cognitive functions. As per MoCA, the prevalences of MCI in T2DM patients in age groups below 40, 41-50, 51-60, 61-70, 71-80 and 81-90 years were 13.7, 20.5, 33.5, 43.7, 57.1 and 75% with DSST scores of 45.8, 41.7, 34.4, 30.5, 24.2 and 18.8% respectively. Binomial logistic regression analysis revealed serum HbA1c ≥ 7.51, duration of T2DM over 20 years, age above 41 years, and females were independent contributors for cognitive dysfunction in T2DM patients. Preliminary studies with untargeted lipidomics of the serum from 20 T2DM patients, including MCI and normal cognition (NC) group, identified a total of 646 lipids. Among the identified lipids, 33 lipids were significantly different between MCI and NC group, which comprised of triglycerides (TGs, 14), sphingolipids (SL, 11), and phosphatidylcholines (PC, 5). Importantly, 10 TGs and 3 PCs containing long-chain polyunsaturated fatty acids (PUFA) were lower, while 8 sphingolipids were increased in the MCI group. Since brain-derived sphingolipids are known to get enriched in the serum, we further quantified sphingolipids from the same 20 serum samples through targeted lipidomic analysis, which identified a total of 173 lipids. Quantitation revealed elevation of 3 species of ceramides, namely Cer (d18:1_24:1), Hex1Cer (d16:0_22:6), and Hex2Cer (d28:1) in the MCI group compared to the NC group of T2DM patients. Overall, this study demonstrated an age-related prevalence of MCI in T2DM patients and highlighted reduced levels of several species of PUFA containing TGs and PCs and increased levels of specific ceramides in T2DM patients exhibiting MCI. Large-scale lipidomic studies in future could help understand the cognitive dysfunction domain in T2DM patients, while studies with preclinical models are required to understand the functional significance of the identified lipids.

Periphery Biomarkers for Objective Diagnosis of Cognitive Decline in Type 2 Diabetes Patients.

Introduction: Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer’s disease (AD), and populations with mild cognitive impairment (MCI) have high incidence to suffer from AD. Therefore, discerning who may be more vulnerable to MCI, among the increasing T2DM populations, is important for early intervention and eventually decreasing the prevalence rate of AD. This study was to explore whether the change of plasma β-amyloid (Aβ) could be a biomarker to distinguish MCI (T2DM-MCI) from non-MCI (T2DM-nMCI) in T2DM patients.Methods: Eight hundred fifty-two T2DM patients collected from five medical centers were assigned randomly to training and validation cohorts. Plasma Aβ, platelet glycogen synthase kinase-3β (GSK-3β), apolipoprotein E (ApoE) genotypes, and olfactory and cognitive functions were measured by ELISA, dot blot, RT-PCR, Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test based on the diluted butanol, and Minimum Mental State Examination (MMSE) test, respectively, and multivariate logistic regression analyses were applied.Results: Elevation of plasma Aβ1-42/Aβ1-40 is an independent risk factor of MCI in T2DM patients. Although using Aβ1-42/Aβ1-40 alone only reached an AUC of 0.631 for MCI diagnosis, addition of the elevated Aβ1-42/Aβ1-40 to our previous model (i.e., activated platelet GSK-3β, ApoE ε4 genotype, olfactory decline, and aging) significantly increased the discriminating efficiency of T2DM-MCI from T2DM-nMCI, with an AUC of 0.846 (95% CI: 0.794–0.897) to 0.869 (95% CI: 0.822–0.916) in the training cohort and an AUC of 0.848 (95% CI: 0.815–0.882) to 0.867 (95% CI: 0.835–0.899) in the validation cohort, respectively.Conclusion: A combination of the elevated plasma Aβ1-42/Aβ1-40 with activated platelet GSK-3β, ApoE ε4 genotype, olfactory decline, and aging could efficiently diagnose MCI in T2DM patients. Further longitudinal studies may consummate the model for early prediction of AD.

Elevated Plasma Free Fatty Acid Susceptible to Early Cognitive Impairment in Type 2 Diabetes Mellitus.

Elevated free fatty acid (FFA) induces lipotoxicity, attributed to diabetes and cognitive decline. Sterol regulatory element-binding protein-1c (SREBP-1c) regulates lipid metabolism. We investigated the roles of FFA in mild cognitive impairment (MCI) of type 2 diabetes mellitus (T2DM) patients and determine its association with rs11868035 polymorphism. We recruited 191 Chinese T2DM patients into two groups through Montreal Cognitive Assessment. Demographic and clinical data were collected, multiple domain cognitive functions were tested, plasma FFA levels were measured through ELISA, and SREBP-1c rs11868035 genotype was detected using the Seqnome method. In comparison with the healthy-cognition group (n = 128), the MCI group (n = 63) displayed lower glucose control (p = 0.012) and higher plasma FFA level (p = 0.021), which were independent risk factors of MCI in T2DM patients in multivariate regression analysis (OR = 1.270, p = 0.003; OR = 1.005, p = 0.036). Additionally, the plasma FFA levels of MCI patients were positively correlated with Stroop color word test-C time scores (r = 0.303, p = 0.021) and negatively related to apolipoprotein A1 levels (r = -0.311, p = 0.017), which are associated positively with verbal fluency test scores (r = 0.281, p = 0.033). Both scores reflected attention ability and executive function. Moreover, the G allele carriers of rs11868035 showed higher digit span test scores than non-carriers in T2DM patients (p = 0.019) but without correlation with plasma FFA levels. In T2DM, elevated plasma level of FFA, when combined with lower apolipoprotein A1 level portends abnormal cholesterol transport, were susceptible to early cognitive impairment, especially for attention and execution deficits. The G allele of SREBP-1c rs11868035 may be a protective factor for memory.

White Matter Atrophy in Type 2 Diabetes Mellitus Patients With Mild Cognitive Impairment.

Type 2 diabetes mellitus (T2DM) patients are highly susceptible to developing dementia, especially for those with mild cognitive impairment (MCI), but its underlying cause is still unclear. In this study, we performed a battery of neuropsychological tests and high-resolution sagittal T1-weighted structural imaging to explore how T2DM affects white matter volume (WMV) and cognition in 30 T2DM-MCI patients, 30 T2DM with normal cognition (T2DM-NC) patients, and 30 age-, sex-, and education-matched healthy control (HC) individuals. The WMV of the whole brain was obtained with automated segmentation methods. Correlations between the WMV of each brain region and neuropsychological tests were analyzed in the T2DM patients. The T2DM-NC patients and HC individuals did not reveal any significant differences in WMV. Compared with the T2DM-NC group, the T2DM-MCI group showed statistically significant reduction in the WMV of seven brain regions, mainly located in the frontotemporal lobe and limbic system, five of which significantly correlated with Montreal Cognitive Assessment (MoCA) scores. Subsequently, we evaluated the discriminative ability of these five regions for MCI in T2DM patients. The WMV of four regions, including left posterior cingulate, precuneus, insula, and right rostral middle frontal gyrus had high diagnostic value for MCI detection in T2DM patients (AUC > 0.7). Among these four regions, left precuneus WMV presented the best diagnostic value (AUC: 0.736; sensitivity: 70.00%; specificity: 73.33%; Youden index: 0.4333), but with no significant difference relative to the minimum AUC. In conclusion, T2DM could give rise to the white matter atrophy of several brain regions. Each WMV of left posterior cingulate, precuneus, insula, and right rostral middle frontal gyrus could be an independent imaging biomarker to detect cognitive impairment at the early stage in T2DM patients and play an important role in its pathophysiological mechanism.

The prevalence of mild cognitive impairment in type 2 diabetes mellitus patients: a systematic review and meta-analysis.

Mild Cognitive impairment (MCI) is common in type 2 diabetes mellitus (T2DM) patients. The impaired cognitive function had harmful effect on patients' diabetic conditions. This study aimed to estimate the prevalence of MCI in T2DM (T2DM-MCI) patients by conducting a systematic review and meta-analysis of observational studies. We carried out a literature search until June 1, 2020, for all observational studies in the following databases: Medline (PubMed), Web of Science, and Embase. Two independent reviewers initially screened the eligible articles. Then, a meta-analysis (random effects model) was conducted to estimate the prevalence of MCI in people with T2DM with STATA 16. A total of 1808 articles were first considered after reading title and abstract, 12 of which remained after reviewing the full text. The combined prevalence of MCI in T2DM patients was estimated to be 45.0% (95% CI=36.0, 54.0). There was no significant heterogeneity through meta-regression and sensitivity analysis. Overall, Europe (n=2, r=36.6%, 95% CI=26.3, 46.9, I2=82.3%) had a lower prevalence than Asia (n=10, r=46.4%, 95% CI=36.2, 56.6, I2=98%). The overall prevalence in female patients (n=14, r=46.9%, 95% CI=34, 59.8, I2=98.3%) was higher than that in male patients (n=14, r=38.8%, 95% CI=27, 50.7, I2=98%). Subgroup analysis based on age demonstrated a lower prevalence in patients older than 60years (n=9, r=44.3%, 95% CI=33.1, 55.6, I2=98.3%) than patients younger than 60years (n=3, r=46.4%, 95% CI=33.3, 59.5, I2=91.2%). Our results demonstrate that the pooled estimated prevalence of mild cognitive impairment in type 2 diabetes mellitus patients is high worldwide, especially in China Asia. Primary care clinicians should pay more attention to the cognitive function of T2DM patients, as mild cognitive impairment is one of the risk factors for Alzheimer's disease.

Associations of Plasma BACE1 Level and BACE1 C786G Gene Polymorphism with Cognitive Functions in Patients with Type 2 Diabetes: A Cross- Sectional Study.

β-Site APP-cleaving enzyme 1 (BACE1) is a key enzyme involved in the pathophysiology of Type 2 Diabetes Mellitus (T2DM) and Mild Cognitive Impairment (MCI). We aimed to investigate the potential associations of plasma BACE1 levels and BACE1 gene polymorphism with different cognitive performances in T2DM patients with MCI. The recruited 186 T2DM subjects were divided into 92 MCI group and 94 healthy-cognition controls, according to the Montreal Cognitive Assessment (MoCA) scores. Sociodemographic characteristics, clinical parameters and neuropsychological tests were assessed. BACE1 C786G gene polymorphism and plasma BACE1 level were determined. Compared to controls, MCI patients exhibited higher plasma BACE1 levels. Plasma BACE1 levels were negatively associated with MoCA, Clock Drawing Test and Logical Memory Test scores, whereas positively associated with Trail Making Test-B time in the MCI group (all p<0.05), after adjusting fasting blood glucose, glycosylated hemoglobin, and homeostasis model assessment of insulin resistance by C-peptide. Multivariable logistic regression analysis showed a significant trend towards increased MCI risk with high plasma BACE1 level in T2DM patients (OR = 1.492, p = 0.027). The plasma BACE1 levels of GG and GC genotypes were obviously higher than that of CC genotype in T2DM-MCI patients (p = 0.035; p = 0.026, respectively). Increased plasma BACE1 levels were associated with poor overall cognition functions, especially visuospatial abilities, visual/logical memory and executive functions in T2DM-MCI patients. Additionally, elevated plasma BACE1 level was a risk factor for MCI in T2DM patients, and might be influenced by BACE1 C786G gene mutations.

Insulin Resistance Is a Risk Factor for Mild Cognitive Impairment in Elderly Adults with T2DM.

ObjectiveThe aim of this study was to investigate the clinical effects of insulin resistance (IR) in the development of mild cognitive impairment (MCI) in elderly adults with Type 2 diabetes mellitus (T2DM).MethodsSeventy-eight patients with T2DM were recruited and divided into MCI group (<26, n=48) and normal group (≥26, n=30) according to the Montreal Cognitive Assessment (MoCA) score. The fasting plasma glucose (FPG), HbA1c, and fasting plasma C-peptide (FPC) were examined and compared between the two groups. The Pancreatic islets function (HOMA-islet) and Insulin Resistance Index (HOMA-IR) were also calculated for the two groups. Using the HOMA-IR and HOMA-islet as the reference, the predicted values for MCI in T2DM patients were calculated by sensitivity, specificity and area under the receiver operating characteristic (ROC) curve.ResultsThe MoCA scores were statistically different between the MCI and control groups (23.79±1.15 vs 28.50±1.01, p<0.05). The serum FPG and FPC were 10.38±2.36 mmol/L and 0.79±0.34 ng/mL in the MCI group which were significant different from those of the control group (8.96±2.55 mmol/L and 1.04±0.38 ng/mL; p<0.05). The HOMA-IR and HOMA-islet were 10.08±2.64 and 94.67±29.12 for the MCI group and 8.16±2.46 and 130.30±38.43 for the control group; both were statistically different (p<0.05). The serum HbA1c was 11.02±2.59% and 9.37±2.00% for the MCI and control groups (significantly different with p<0.5). A significant positive correlation was found between MoCA score and HOMA-islet (rpearson=0.44; p<0.001). A significant negative correlation existed between MoCA score and serum HbA1c (r=-0.25; p=0.03). The areas under the ROC curve were 0.70 (0.57~0.82), 0.69 (0.57~0.81), 0.69 (0.57~0.80), 0.72 (0.60~0.84), 0.72 (0.60~0.84) and 0.76 (0.65~0.88) respectively for FPG, FPC, HbA1c, HOMA-IR and HOMA-islet.ConclusionInsulin resistance is a risk factor for mild cognitive impairment and can be a biomarker for prediction of MCI in patients with T2DM.

Increased plasma Interleukin-1β level is associated with memory deficits in type 2 diabetic patients with mild cognitive impairment

Type 2 diabetes mellitus (T2DM) and mild cognitive impairment (MCI) are both chronic inflammatory diseases. We aimed to investigate the association of plasma Interleukin-1β (IL-1β) levels with the risk of MCI in T2DM patients. We divided recruited T2DM patients into two groups, MCI group and healthy-cognition controls, according to Montreal Cognitive Assessment (MoCA) scores. Demographic characteristics, clinical parameters and neuropsychological tests were examined. We recruited 202 T2DM patients in this study, including 94 MCI and 108 healthy-cognition controls. T2DM patients with MCI exhibited increased plasma IL-1β and decreased amyloid-β 42 (Aβ42) levels compared to the controls (all p < 0.05). After adjusting fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR) and Aβ42, plasma IL-1β levels were negatively correlated with MoCA and AVLT delayed recall scores, which represented memory function. Multivariable logistic regression model showed that high plasma IL-1β level and low plasma Aβ42 level were correlated with increased risk for MCI in T2DM patients. Increased plasma IL-1β level was significantly associated with MCI in T2DM patients, especially memory deficits. Our findings will provide additional insights into the inflammation pathogenesis of cognitive impairments in T2DM.

Association between Plasma Levels of PAI-1, tPA/PAI-1 Molar Ratio, and Mild Cognitive Impairment in Chinese Patients with Type 2 Diabetes Mellitus.

Plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) are involved in the complications of type 2 diabetes mellitus (T2DM) and early pathology of Alzheimer's disease. This study aimed to investigate the association between plasma PAI-1, tPA/PAI-1 molar ratio, and mild cognitive impairment (MCI) in Chinese T2DM patients. A total of 162 Chinese T2DM patients were recruited and divided into two groups according to the Montreal Cognitive Assessment score. Demographic data were collected, plasma PAI-1 and tPA levels were measured through enzyme-linked immunosorbent assay, tPA/PAI-1 molar ratio was calculated, and neuropsychological test results were examined. The association between PAI-1, tPA/PAI-1 molar ratio, and cognition was analyzed. There were 66 diabetic MCI patients and 96 healthy cognition participants (controls). T2DM patients with MCI displayed significantly increased plasma PAI-1 levels (p = 0.016) and decreased tPA/PAI-1 molar ratio (p = 0.021) compared with the controls. High PAI-1 levels and low tPA/PAI-1 molar ratio were associated with MCI in T2DM patients, e.g., plasma level of PAI-1 were negatively correlated (r = -0.343, p = 0.007) with logic memory in T2DM patients with MCI. Linear regression analysis further revealed that PAI-1 concentration was an independent factor of diabetic MCI (p = 0.001). High PAI-1 levels and low tPA/PAI-1 molar ratio were significantly correlated with T2DM-associated cognitive impairment, especially memory function, in Chinese patients.

Alterations of White Matter Integrity and Hippocampal Functional Connectivity in Type 2 Diabetes Without Mild Cognitive Impairment.

Aims: To investigate the white matter (WM) integrity and hippocampal functional connectivity (FC) in type 2 diabetes mellitus (T2DM) patients without mild cognitive impairment (MCI) by using diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI), respectively.Methods: Twelve T2DM patients without MCI and 24 age, sex and education matched healthy controls (HC) were recruited. DTI and rs-fMRI data were subsequently acquired on a 3.0T MR scanner. Tract-based spatial statistics (TBSS) combining region of interests (ROIs) analysis was used to investigate the alterations of DTI metrics (fractional anisotropy (FA), mean diffusivity (MD), λ1 and λ23) and FC measurement was performed to calculate hippocampal FC with other brain regions. Cognitive function was evaluated by using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Brain volumes were also evaluated among these participants.Results: There were no difference of MMSE and MoCA scores between two groups. Neither whole brain nor regional brain volume decrease was revealed in T2DM patients without MCI. DTI analysis revealed extensive WM disruptions, especially in the body of corpus callosum (CC). Significant decreases of hippocampal FC with certain brain structures were revealed, especially with the bilateral frontal cortex. Furthermore, the decreased FA in left posterior thalamic radiation (PTR) and increased MD in the splenium of CC were closely related with the decreased hippocampal FC to caudate nucleus and frontal cortex.Conclusions: T2DM patients without MCI showed extensive WM disruptions and abnormal hippocampal FC. Moreover, the WM disruptions and abnormal hippocampal FC were closely associated.Highlights -T2DM patients without MCI demonstrated no obvious brain volume decrease.-Extensive white matter disruptions, especially within the body of corpus callosum, were revealed with DTI analysis among the T2DM patients.-Despite no MCI in T2DM patients, decreased functional connectivity between hippocampal region and some critical brain regions were detected.-The alterations in hippocampal functional connectivity were closely associated with those of the white matter structures in T2DM patients.This trial was registered to ClinicalTrials.gov (NCT02420470, https://www.clinicaltrials.gov/).

Increased Plasma Homocysteine Level isAssociated with Executive Dysfunction inType 2 Diabetic Patients with Mild Cognitive Impairment.

Homocysteine (Hcy) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. We aimed to investigate the role of Hcy in T2DM patients with mild cognitive impairment (MCI), and to determine whether methylene tetrahydrofolate reductase (MTHFR) C677T or cystathionine beta-synthase (CBS) 844ins68 polymorphism is related to T2DM-associated MCI. We recruited 285 T2DM patients and divided them into two groups, 140 patients with MCI, and 145 healthy-cognition controls, on the basis of Montreal Cognitive Assessment (MoCA) scores. Demographic characteristics, clinical parameters, and neuropsychological tests were assessed. MTHFR C677T and CBS 844ins68 polymorphisms were analyzed. The MCI group exhibited significantly higher plasma total Hcy (tHcy) levels than control group (p < 0.001). Plasma tHcy level was negatively correlated with MoCA scores (p = 0.002), but positively associated with Trail Making Test A and B scores (p = 0.044; p = 0.005, respectively). Multivariable logistic regression model showed that high tHcy level was an independent factor for MCI in T2DM patients. No significant difference was observed in the genotype or allele distributions of MTHFR and CBS between MCI and control groups. We did not find significant MCI risks in MTHFR T allele compared with C allele, and in CBS I allele compared with D allele (OR = 1.361, p = 0.067; OR = 1.048, p = 0.909, respectively). Increased plasma tHcy level was significantly related to T2DM-associated MCI, especially executive dysfunction. Further investigation with a large population size should be conducted to confirm these findings.

Gray matter volume abnormalities in type 2 diabetes mellitus with and without mild cognitive impairment

This study sought to evaluate the potential brain gray matter (GM) volume changes that occur with the transition from normal cognition to mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM) using voxel-based morphometry (VBM). VBM analyses of brain GM based on magnetic resonance imaging (MRI) data were performed on 28 T2DM patients with MCI, 25 T2DM patients without MCI, 28 MCI patients and 29 healthy controls (HC). Compared with the HC, the T2DM patients both with and without MCI showed significantly decreased total GM volume. Furthermore, the VBM results indicated that the T2DM patients without MCI exhibited extensively decreased GM volume compared with the HC in certain brain regions, including the superior and middle temporal gyrus (MTG), the superior and medial frontal gyrus and the middle occipital gyrus. In addition to more extensive GM atrophy in the aforementioned brain regions, the medial temporal lobe also exhibited GM loss in the T2DM patients with MCI. Furthermore, relative to the patients without MCI, only the left MTG exhibited a lower GM volume in the T2DM patients with MCI, which was positively correlated with the total MoCA score (r=0.699, P<0.01). Finally, relative to MCI, the left MTG atrophy was also found in the T2DM patients with MCI. Our findings suggest that MTG atrophy was associated with an increased risk for MCI in T2DM patients. The brain structural changes in many brain regions may underlie the transition from normal cognition to MCI in T2DM patients.