Chain Mediating Role of Illness Perception and Fear of Hypoglycemia in Impaired Hypoglycemic Awareness 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.

Background and aimsPrevious study found that interleukin 1β (IL-1β) is associated with diabetic cognitive dysfunction. Heat shock protein 27 (HSP27) is one of the factors related to IL-1β associated inflammation. Here, we aim to investigate the role of HSP27 in mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM).Materials and methodsIn this study, individuals with T2DM with and without MCI were recruited and categorized into Control and MCI groups. Plasma HSP27 levels were assessed and compared between the Control and MCI groups. Furthermore, the relationship between HSP27 and diabetic dysfunction was elucidated through association and regression analyses. Finally, diagnostic values were determined using ROC curves.ResultsIn humans, individuals with T2DM and MCI exhibit decreased levels of HSP27 compared to those without MCI. Notably, the levels of HSP27 are associated with neuropsychological test scores that reflect cognitive preferences. Additionally, decreased HSP27 levels serve as one of the risk factors for MCI in T2DM patients (OR = 0.355, P = 0.002). Moreover, there is a defined cut-off point for HSP27 in diagnosing MCI, set at 3.51 pg/ml, with a sensitivity of 47.2%, a specificity of 94.4%, and an area under the curve (AUC) of 0.695.ConclusionsGenerally speaking, HSP27 is linked to cognitive decline in individuals with T2DM. Decreased levels of HSP27 in plasma are identified as both a risk factor for MCI and a potential diagnostic biomarker for MCI in patients with T2DM. The diagnostic value of HSP27 in MCI is primarily reflected in its demonstrated true negative rate.

PurposeNeuroinflammation 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).MethodsRNA-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.ResultsIn 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%.ConclusionsIL-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.

Type 2 diabetes mellitus (T2DM) is a significant risk factor for cognitive impairment. Zinc deficiency contributes to T2DM development, while copper may exacerbate diabetes through prooxidant mechanisms. Higher zinc levels may protect against copper toxicity. This study investigates the association of plasma zinc and copper levels with mild cognitive impairment (MCI) in T2DM patients. T2DM patients admitted to Tongji Hospital from 2012 to 2018 were classified into MCI (n = 136) and control (n = 136) groups, matched by age (± 3 years) and gender. Conditional logistic regression was used to assess the associations between plasma zinc, copper levels and MCI. A generalized additive model (GAM) evaluated the dose-response relationship between plasma zinc, copper levels and Mini-Mental State Examination (MMSE) scores. The median of plasma metal levels in MCI and control groups were 831.31 μg/L and 936.29 μg/L for zinc, 932.07 μg/L and 860.47 μg/L for copper, and 0.91 and 1.11 for the zinc-to-copper (Zn/Cu) ratio. Compared to participants in the lowest tertile, the multivariable-adjusted odds ratios with 95% confidence intervals (CI) for MCI in the highest tertile were 0.33 (0.13, 0.79) for zinc, 3.56 (1.42, 8.94) for copper, and 0.37 (0.15, 0.93) for the Zn/Cu ratio. Plasma Aβ40 levels were significantly lower (p = 0.009) and plasma Aβ42/40 levels were significantly higher (p = 0.008) in MCI group compared with those in control group. Zinc concentration was positively associated with Aβ42. For per SD (327.71 μg/L) increase in plasma zinc levels, the percent change (95% CI) of Aβ42 were 2.90 (0.85, 4.99). Higher plasma zinc levels and higher Zn/Cu ratio were associated with lower odds of MCI in T2DM patients, while higher copper levels increased the risk of MCI. This study provides insights on plasma zinc, copper, and Zn/Cu ratio and Aβ of MCI, further studies are needed to clarify the underlying mechanisms for novel therapies that could prevent or cure multiple T2DM-related cognitive impairments.

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.

Chronic inflammation associated oxidative stress is a key factor in complications of type 2 diabetes mellitus (T2DM), including mild cognitive impairment (MCI), partly associated with cerebrovascular lesions including both macrovascular and microvascular changes, and diabetic nephropathy (DN), a kind of diabetic microvascular complication. Heat shock protein 90α (Hsp90α) is known to play a significant role in inflammation associated oxidative stress and DN. This study aims to explore the role of Hsp90α in MCI and its potential as a diagnostic marker for MCI in T2DM patients. We included 119 T2DM patients and analyzed their clinical data, Hsp90α levels, and cognitive scores. The relationships among Hsp90α, cognitive function, and urinary albumin-to-creatinine ratio (UACR) were also examined. Binary logistic regression was used to identify MCI risk factors, and ROC curves assessed Hsp90α's diagnostic value for MCI in patients, with or without DN. Patients with MCI exhibit worse cognitive function, higher UACR, and elevated Hsp90α levels compared to those without MCI. Increased Hsp90α was linked to lower cognitive scores and was identified as a risk factor for MCI. Patients with DN had a higher rate of MCI and cognitive decline than those without DN, and Hsp90α levels correlated with UACR, a DN marker. In patients without DN, higher Hsp90α was a risk factor for MCI; however, this was not observed in those with DN. An Hsp90α cut-off point of 69.105 ng/mL had a sensitivity of 60.0% and specificity of 91.4% for predicting MCI in patients without DN. Elevated Hsp90α level is a risk factor for cognitive impairment and may serve as a biomarker for MCI in T2DM patients without DN.

Unravelling Neuroinflammation-Mediated Mitochondrial Dysfunction in Mild Cognitive Impairment: Insights from Targeted Metabolomics

ObjectiveTo investigate the association between retinal microcirculation changes, assessed using optical coherence tomography angiography (OCTA), and mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM), and to determine whether retinal microcirculation changes can serve as a potential biomarker for MCI in these patients.MethodsA total of 100 patients with T2DM who visited Hefei Aier Eye Hospital between April 2023 and December 2024 were selected. Retinal microcirculation indicators, including the perfusion density of the superficial capillary plexus (SCP), the perfusion density of the deep capillary plexus (DCP), the central foveal thickness (CMT) and the area of the foveal avascular zone (FAZ), were evaluated using OCTA. The cognitive function of the patients was assessed using the Montreal Cognitive Assessment. The association between retinal microcirculation indicators and MCI was explored using multivariate logistic regression analysis.ResultsThe perfusion density of SCP and DCP in all patients was lower than the normal value. Patients with CMT outside the normal range accounted for 73%, and those with FAZ outside the normal range accounted for 23%. No significant correlation was found between individual retinal microcirculation indicators and MCI. However, a significant association was observed when the four indicators were combined (p < 0.001), indicating that retinal microcirculation changes based on OCTA are significantly correlated with MCI in patients with T2DM.ConclusionRetinal microcirculation changes based on OCTA are significantly associated with MCI in patients with T2DM, suggesting that retinal microcirculation indicators may serve as potential biomarkers for MCI in these patients.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is reported to be associated with cognitive dysfunction, an important comorbidity factor in patients with type 2 diabetes mellitus (T2DM), especially in elderly populations, however, the underlying pathophysiological mechanisms are unclear. This study was performed to investigate the association between BDNF Val66Met polymorphism and mild cognitive impairment (MCI) in elderly patients with T2DM. In total, 105 MCI and 105 normal cognition controls of T2DM patients were enrolled; all of the patients underwent neuropsychological assessments. BDNF Val66Met polymorphism was genotyped via TaqMan SNP genotyping assay. Data from clinical and laboratory-based examinations were collected. The frequency of the BDNF Met allele was significantly higher in the MCI group than in the controls. Multiple regression analysis indicated an association of the Met allele with MCI in patients with T2DM (OR = 2.54; 95% CI 1.33-4.84; p = 0.005). Stratified by educational level, the BDNF Met allele was significantly associated with MCI in elderly T2DM patients (OR = 3.29; 95% CI 1.26-8.57; p = 0.015) among the group of low educational levels (< 12years); however, the association was insignificant among those with higher educational levels. BDNF Met allele carriers showed a higher frequency of MCI than Val/Val homozygotes in elderly T2DM patients. However, this association was only significant in patients with low education levels. BDNF Val66Met polymorphism may have a potential role in MCI in elderly T2DM patients, especially those with low educational levels.

Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment, and reduced heart rate variability (HRV) has been correlated with cognitive impairment in elderly individuals. This study investigated risk factors and validated a predictive model for mild cognitive impairment (MCI) in patients with T2DM using an autonomic function test. Patients with T2DM, 50-85years of age, who attended the diabetes clinic at Gyeongsang National University Hospital between March 2018 and December 2019, were included. A total of 201 patients had been screened; we enrolled 124 patients according to the inclusion and exclusion criteria in this study. Cognitive function was assessed using the Montreal Cognitive Assessment-Korean version (MOCA-K); MCI was defined as a total MOCA-K score ≤ 23. Risk factors for MCI in patients with T2DM, including demographic- and diabetes-related factors, and autonomic function test results, were analyzed. Based on multivariate logistic regression, a nomogram was developed as a prediction model for MCI. Thirty-nine of 124 patients were diagnosed with MCI. Age, education, and decreased cardiovagal function were associated with a high risk for MCI, with cardiovagal function exerting the greatest influence. However, diabetes-related factors, such as glycemic control, duration of diabetes, or medications, were not associated with the risk for MCI. The nomogram demonstrated excellent discrimination (area under the curve, 0.832) and was well calibrated. Approximately one-third of patients had MCI; as such, carefully evaluating cognitive function in elderly T2DM patients with reduced HRV is important to prevent progression to dementia.

Brainstem auditory evoked potential in cognitive impairment in patients with type 2 diabetes mellitus.

AimUric acid to high density lipoprotein cholesterol ratio (UA/HDL-c) related to nutrient metabolism disorder is associated with the onset of diabetic complications including mild cognitive impairment (MCI). However, the relationship between UA/HDL-c and MCI in type 2 diabetes mellitus (T2DM) patients with different gender remains unclear. Therefore, this study aims to explore the association between UA/HDL-c and MCI in female and male patients with T2DM.MethodsA total of 223 patients were stratified into either the control or the MCI group based on the presence or absence of MCI. Comparative analyses of clinical parameters were conducted, and the associations between UA/HDL-c and cognitive function were assessed across all patients as well as within female and male subgroups. Binary logistic regression was employed to identify independent risk factors for MCI in female and male patients with T2DM.ResultsCompared to the 137 participants without MCI, the 86 individuals with MCI exhibited significantly higher levels of UA/HDL-c. Higher UA/HDL-c levels were associated with lower scores on the Montreal Cognitive Assessment, which reflects global cognitive function, as well as with poorer performance on the Verbal Fluency Test and the Clock Drawing Test, which reflect executive and visuospatial functions in female patients, respectively. These associations were not observed in male patients. Furthermore, binary logistic regression analysis indicated that elevated UA/HDL-c levels were a risk factor for MCI in women, regardless of adjustments for age, duration of diabetes mellitus, and duration of hypertension.ConclusionElevated UA/HDL-c levels are not only associated with overall cognitive function in female patients with T2DM, but also specifically linked to impairments in executive function and visuospatial abilities. However, this association is not observed in male patients. Among women with T2DM, elevated UA/HDL-c levels serve as an independent risk factor for the development of MCI. These findings suggest a sex-specific relationship between UA/HDL-c levels and cognitive dysfunction.

Metabolic disorders, including insulin resistance, obesity, and hyperlipidemia occur frequently prior to hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and cause mild cognitive impairment (MCI). We investigated the involvement of resistin in these metabolic abnormalities contributes to MCI in patients with T2DM. A total of 138 hospitalized patients with T2DM were enrolled and categorized into MCI and non-MCI groups according to the Montreal Cognitive Assessment (MoCA) score. Metabolic indicators and cognitive state were assessed, and plasma resistin levels were determined by ELISA. The resistin levels and homeostasis model assessment of insulin resistance (HOMA-IR) scores of MCI and gender-stratified subgroups were significantly higher than those of controls without MCI (all p < 0.01). Correlation analysis showed that the resistin level was negatively associated with majority of cognitive domains, e.g., MoCA (r = -0.693, p < 0.001) and Mini-Mental State Examination (r = -0.571, p < 0.001), and was related to HOMA-IR (r = 0.667, p < 0.001) but not to obesity and lipid indices. Multivariable regression analysis indicated that resistin (β= -0.675, p < 0.001) and educational level (β= 0.177, p = 0.003) were independent risk factors of MoCA in patients with T2DM. High plasma resistin levels portend the insulin resistance-related susceptibility to early cognitive decline in Chinese patients with T2DM. The involvement of this adipokine in other metabolic disorders leading to diabetic MCI and its clinical value for early disease screening must be further studied.

BackgroundStudies show that diabetes mellitus is the greatest lifestyle risk factor for dementia. Appropriate management and treatment of type 2 diabetes mellitus could prevent the onset and progression of mild cognitive impairment to dementia.AimDetection of mild cognitive impairment in patients with type 2 diabetes mellitus.MethodsMild cognitive impairment was assessed using the Japanese version of the Montreal Cognitive Assessment. The study population was 33 non‐demented inpatients with type 2 diabetes mellitus receiving diabetes management training. The Japanese version of the Montreal Cognitive Assessment, the animal naming test and the digit‐symbol coding subtest of the Wechsler Adult Intelligence Scale were administrated in one‐to‐one interviews.ResultsThe prevalence of mild cognitive impairment in diabetic patients was 72%. The background characteristics of mild cognitive impairment in diabetic patients included fewer schooling years and higher glycated hemoglobin levels in comparison to subjects without mild cognitive impairment. Neuropsychological testing showed that diabetic patients with mild cognitive impairment scored lower on the Japanese version of the Montreal Cognitive Assessment (total score, P &lt; 0.0001), frontal lobe function (P &lt; 0.001) and delayed recall (P &lt; 0.05). The number of correct answers on the digit‐symbol coding subtest was also significantly lower in diabetic patients with mild cognitive impairment (P &lt; 0.05).ConclusionMild cognitive impairment with type 2 diabetes mellitus has a high prevalence. Our study suggests that mild cognitive impairment in diabetic patients can be classified into three groups: predominantly frontal lobe dysfunction, predominantly delayed recall impairment and a mixed‐type group.

BackgroundThe precise physiopathological association between the courses of neurodegeneration and cognitive decline in type 2 diabetes mellitus (T2DM) remains unclear. This study sought to comprehensively investigate the distribution characteristics of gray matter atrophy in middle-aged T2DM patients with newly diagnosed mild cognitive impairment (MCI).MethodsFour groups, including 28 patients with early-onset MCI, 28 patients with T2DM, 28 T2DM patients with early-onset MCI (T2DM-MCI), and 28 age-, sex-, and education-matched healthy controls underwent three-dimensional high-resolution structural magnetic resonance imaging. Cortical and subcortical gray matter volumes were calculated, and a structural covariance method was used to evaluate the morphological relationships within the default mode network (DMN).ResultsOverlapped and unique cortical/subcortical gray matter atrophy was found in patients with MCI, T2DM and T2DM-MCI in our study, and patients with T2DM-MCI showed lower volumes in several areas than patients with MCI or T2DM. Volume loss in subcortical areas (including the thalamus, putamen, and hippocampus), but not in cortical areas, was related to cognitive impairment in patients with MCI and T2DM-MCI. No associations between biochemical measurements and volumetric reductions were found. Furthermore, patients with MCI and those with T2DM-MCI showed disrupted structural connectivity within the DMN.ConclusionThese findings provide further evidence that T2DM may exacerbate atrophy of specific gray matter regions, which may be primarily associated with MCI. Impairments in gray matter volume related to T2DM or MCI are independent of cardiovascular risk factors, and subcortical atrophy may play a more pivotal role in cognitive impairment than cortical alterations in patients with MCI and T2DM-MCI. The enhanced structural connectivity within the DMN in patients with T2DM-MCI may suggest a compensatory mechanism for the chronic neurodegeneration.