Clinical value of dyslipidemia and glycemic variability for progression to dementia in type 2 diabetes mellitus-associated mild cognitive impairment.

Object: The purpose of our study was to investigate the microstructural changes of the medial temporal cortex in mild cognitive impairment (MCI) patients with cerebral small vascular disease (cSVD) using diffusion kurtosis imaging (DKI) and to examine whether DKI parameters are correlated with MCI.Method: A total of 82 cSVD patients admitted to the Department of Neurology Beijing Chaoyang Hospital, Capital Medical University, were retrospectively enrolled in this study. The Montreal cognitive assessment scale (MoCA) score was used to assess overall cognitive function. According to the presence or absence of MCI, these patients were divided into an MCI group (n = 48) and a non-MCI group (n = 34). The general clinical data of the two groups were collected and analyzed. The regions of interest (ROIs) in the medial temporal cortex were selected for investigation. The averaged values of DKI parameters were measured in each ROI and compared between the two groups, and the correlations between DKI parameters and MoCA score and between diffusion and kurtosis parameters were examined.Results: Compared to the non-MCI group, MCI patients showed significantly increased mean diffusion (MD) and radial diffusion (RD) and significantly decreased mean kurtosis (MK) in the left hippocampus (P = 0.005, 0.006, 0.002, respectively). In the left hippocampus, fractional anisotropy (FA), MK, radial kurtosis (RK), and kurtosis fractional anisotropy (KFA) showed significantly positive correlations with MoCA score (r = 0.374, 0.37, 0.392, 0.242, respectively, all P < 0.05), while MK and RD were negatively correlated with MoCA score (r = −0.227, −0.255, respectively, both P < 0.05). In the left parahippocampal region, axial kurtosis (AK) and KFA were positively correlated with MoCA score (r = 0.228, 0.282, respectively, both P < 0.05), while RK was positively correlated with MoCA score in the right parahippocampal region (r = 0.231, P < 0.05). Significant correlations of MD with MK, RD with RK, and FA with KFA were observed in the medial temporal cortex (r = −0.254, −0.395, 0.807, respectively, all P < 0.05) but not of axial diffusion (AD) with AK.Conclusion: The DKI technique can be used to observe microstructural changes of the medial temporal cortex in MCI patients with cSVD. The DKI-derived parameters might be a feasible means of evaluating patients with MCI.

ObjectivePatients with type 2 diabetes mellitus (T2DM) have high risk of frailty. The clinical frailty scale (CFS) has been used to evaluate clinical frailty. To evaluate the association between CFS and visit-to-visit glycated hemoglobin (HbA1C) variability in T2DM patients.MethodsPatients who were hospitalized with T2DM and received at least three HbA1C tests after discharging from endocrinology department and general practice department during 12-month follow-up were retrospectively enrolled. The patients were divided into the low-HbA1C variability group and the high-HbA1C variability group according to the results of the HbA1C variability score (HVS). The baseline clinical information, including CFS during hospitalization, was collected and compared between the two groups. We performed a propensity score match (PSM) to eliminate the influences of other confounding factors.ResultsA total of 370 patients were included in this study. Most baseline demographic, clinical parameters and metabolic parameters were comparable between the two groups except age, baseline HbA1C, albumin, and comorbidities including hypertension and dyslipidemia between the two groups before PSM. All of the relative parameters were comparable after a 1:1 PSM. Uni-variable and multi-variable logistic analysis revealed that higher CFS was associated with higher HbA1C variability and receiver operating characteristic curve showed that CFS had good predictive value in HVS.ConclusionHigher CFS was associated with higher visit-to-visit HbA1C variability.

ObjectiveOur study aimed to investigate the correlations between microstructural changes of cingulum and patients with mild cognitive impairment (MCI) by diffusion kurtosis imaging (DKI) technique.MethodA total of 104 patients with cerebral small vessel diseases (cSVD) were retrospectively enrolled in this study. According to Montreal Cognitive Assessment Scale (MoCA) scores, these patients were divided into MCI group (n = 59) and non-MCI group (n = 45). The general clinical data was collected and analyzed. The regions of interests (ROIs) were selected for investigation in cingulum. The values of DKI parameters were measured in each ROI and compared between the two groups, the correlations between DKI parameters and MoCA scores were examined.ResultsCompared to non-MCI group, MCI patients had more severe white matter hyperintensities (WMHs) (P = 0.038) and lower MoCA scores (P < 0.01). MCI patients showed significantly decreased fractional anisotropy (FA), axial kurtosis (AK), mean kurtosis (MK), radial kurtosis (RK), and kurtosis fractional anisotropy (KFA) in the left cingulum in the cingulated cortex (CgC) region (all P < 0.0125). In the left CgC region, FA, AK, MK, RK, and KFA were positively correlated with MoCA scores (r = 0.348, 0.409, 0.310, 0.441, 0.422, all P < 0.001). Meanwhile, FA, AK, MK, RK, and KFA were also positively correlated with MoCA scores (r = 0.338, 0.352, 0.289, 0.380, 0.370, all P < 0.001) in the right CgC region.ConclusionDKI technique could be used to explore the microstructural changes of cingulum in MCI patients and DKI-derived parameters might be feasible to evaluate MCI patients.

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.

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.

Although studies have shown that glycemic variability is positively associated with an increased risk of cardiovascular disease, few studies have compared hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) variability with adverse cardiovascular events in patients with type 2 diabetes mellitus (T2DM). This was a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Cox proportional hazards models were used to explore the relationship between HbA1c or FPG variability and the incidence of major adverse cardiovascular events (MACEs). In total, 9,547 patients with T2DM were enrolled in this study. During the median 4.6 ± 1.5 years follow-up period, 907 patients developed MACEs. The risk of MACEs increased in the HbA1c variability group in each higher quartile of HbA1c variability (P < 0.01). Compared with those in the first quartile of HbA1c variability, patients in the fourth quartile had a hazard ratio of 1.37 (Model 2, 95% confidence interval: 1.13-1.67) for MACEs. Higher FPG variability was not associated with a higher risk of MACEs in patients with T2DM (P for trend=0.28). A U-shaped relationship was observed between HbA1c and FPG variability, and MACEs. Glucose control therapy modified the relationship between HbA1c and MACEs; participants with higher HbA1c variability receiving intensive glucose control were more likely to develop MACEs (P for interaction <0.01). In adults with T2DM, the relationship between glycemic variability evaluated using HbA1c and FPG was U-shaped, and an increase in HbA1c variability rather than FPG variability was significantly associated with MACEs. The relationship between HbA1c variability and MACEs was affected by the glucose control strategy, and a higher HbA1c variability was more strongly associated with MACEs in patients receiving an intensive glucose control strategy.

High Activities of BACE1 in Brains with Mild Cognitive Impairment

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.

A high risk of developing mild cognitive impairment (MCI) is faced by elderly patients with type 2 diabetes mellitus (T2DM). In this study, independent risk factors for MCI in elderly patients with T2DM were investigated, and an individualized nomogram model was developed. In this study, clinical data of elderly patients with T2DM admitted to the endocrine ward of the hospital from November 2021 to March 2023 were collected to evaluate cognitive function using the Montreal Cognitive Assessment scale. To screen the independent risk factors for MCI in elderly patients with T2DM, a logistic multifactorial regression model was employed. In addition, a nomogram to detect MCI was developed based on the findings of logistic multifactorial regression analysis. Furthermore, the accuracy of the prediction model was evaluated using calibration and receiver operating characteristic curves. Finally, decision curve analysis was used to evaluate the clinical utility of the nomogram. In this study, 306 patients were included. Among them, 186 patients were identified as having MCI. The results of multivariate logistic regression analysis demonstrated that educational level, duration of diabetes, depression, glycated hemoglobin, walking speed, and sedentary duration were independently correlated with MCI, and correlation analyses showed which influencing factors were significantly correlated with cognitive function (p <0.05). The nomogram based on these factors had an area under the curve of 0.893 (95%CI:0.856-0.930)(p <0.05), and the sensitivity and specificity were 0.785 and 0.850, respectively. An adequate fit of the nomogram in the predictive value was demonstrated by the calibration plot. The nomogram developed in this study exhibits high accuracy in predicting the occurrence of cognitive dysfunction in elderly patients with T2DM, thereby offering a clinical basis for detecting MCI in patients with T2DM.

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.

BackgroundThe relationship between long-term glycemic variability (GV) represented by visit-to-visit HbA1c variability and baroreflex sensitivity (BRS) in type 2 diabetes mellitus (T2DM) has not been clarified by previous literature. The present study is the first to examine the relationships between visit-to-visit HbA1c variability and BRS.MethodsThis retrospective study initially analyzed data on 94 patients with T2DM. Visit-to-visit HbA1c variability was evaluated using the intrapersonal coefficient of variation (CV), standard deviation (SD), and adjusted SD of 8 or more serial measurements of HbA1c during a 2-year period. The BRS was analyzed using the sequence method. Short-term GV was assessed by measuring the glucose CV during 24-h continuous glucose monitoring (CGM). The primary objective was to determine if there was a relationship between visit-to-visit HbA1c variability (HbA1c CV) and BRS. Secondary objectives were to examine the relationship between other variables and BRS and the respective and combined effects of long-term GV (HbA1c CV) and short-term GV (CGM CV) on BRS.ResultsA total of 57 patients (mean age 67.2 ± 7.7 years, mean HbA1c 7.3 ± 1.0%) who met this study’s inclusion criteria were finally analyzed. In the univariate analysis, HbA1c CV (r = − 0.354, p = 0.007), HbA1c SD (r = − 0.384, p = 0.003), and adjusted HbA1c SD (r = − 0.391, p = 0.003) were significantly related to low levels of BRS. Multiple regression analysis showed that HbA1c CV, HbA1c SD, and adjusted HbA1c SD were inversely related to BRS. Furthermore, although the increase in either long-term GV (HbA1c CV) or short-term GV (CGM CV) as determined by 24-h CGM was inversely correlated with BRS, additional reductions in BRS were not shown in participants with both HbA1c CV and CGM CV values above the median.ConclusionsVisit-to-visit HbA1c variability was inversely related to BRS independently of the mean HbA1c in patients with T2DM. Therefore, visit-to-visit HbA1c variability might be a marker of reduced BRS in T2DM.

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

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.

Diabetes complications were shown to be associated with glycaemic control and variability. This study aims to identify the factors associated with HbA1c variability in type 2 diabetes mellitus (T2DM) patients. A retrospective cohort of T2DM patients who visited the clinics between January 2017 and October 2022 were included. HbA1c variability were measured using coefficient of variation and standard deviation, and stratified using medians of 9.16 and 0.75, respectively. Logistic regressions was performed and subgroup analyses based on HbA1c control were included. We included 2,532 T2DM patients with a mean age of 61.7 years, predominantly female (55.8%) and of Chinese ethnicity (39%). Mean diabetes duration was 5.9 years and 45.8% were obese. Prevalence of HbA1c < 7.0% was about one-third. Predominant prescription choices were biguanides and sulphonylureas. Malays, insulin usage, and elevated triglyceride levels were associated with high HbA1c variability across both HbA1c variability models. This study highlights that by recognizing the factors linking to HbA1c variability, clinicians can have more insights during patient monitoring and management. HbA1c variability can be a valuable measure as it does not require additional cost and can provide extra insight about patient's condition. Further investigation is needed to explore the impact of ethnicity on HbA1c variability.

BackgroundThe prognostic impact of long-term glycemic variability on clinical outcomes in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) remains unclear. We determined and compared hemoglobin A1c (HbA1c) variability and clinical outcomes for patients with HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF) and HF with reduced ejection fraction (HFrEF) in a prospective longitudinal study.MethodsPatients with HF and T2DM, undergone 3 or more HbA1c determinations during the first 18 months, were then followed for 42 months. The primary outcome was death from any cause. Secondary outcome was composite endpoints with death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF and HFrEF.ResultsOf 902 patients enrolled, 32.2% had HFpEF, 14.5% HFmrEF, and 53.3% HFrEF. During 42 months of follow-up, 270 (29.9%) patients died and 545 (60.4%) patients experienced composite endpoints of death and HF readmission. The risk of all-cause death or composite endpoints was lower for HFpEF than HFrEF. Moreover, higher HbA1c variability was associated with higher all-cause mortality or composite endpoints and HbA1c variability was an independent predictor of all-cause mortality or composite endpoints, regardless of EF.ConclusionsThis prospective longitudinal study showed that the all-cause death and composite events was lower for HFpEF than HFrEF. HbA1c variability was independently and similarly predictive of death or combined endpoints in the three HF phenotypes.