| Section 1:Connection between vascular injury and neurodegenerative cytokines associated with diabetic cognitive impairmentBackgroundRecent studies showed that type 2 diabetes mellitus(T2-DM)may increase the risk of cognitive impairment,but there are few biomarkers to diagnostically discriminate T2-DM with cognitive impairment and cognitive impairment alone.In this study,we assessed certain cytokines involved in neurodegeneration,inflammation and vascular diseases and identified special panel of cytokines that could differentiate between T2-DM with cognitive impairment and cognitive impairment alone.ObjectivesTo investigate associations and differences between T2-DM with cognitive impairment and cognitive impairment by cytokines analysis.MethodsThis study was conducted in the department of Geriatrics and endocrinology,Anhui Provincial Hospital,School of Medicine,Shandong University,and community healthcare center.A total of 264 participants were recruited,their blood samples were collected,and plasma and serum were separated and stored at-80? until the assessment of amyloid-?(A?42),A?40 and 8 kinds of cytokines:chitinase-3-like 1(CHI3L1/YKL-40);Neuron Specific Enolase(NSE);Interleukin-6(IL-6);Osteopontin(OPN);Progranulin(PRGN);S100B;Intercellular adhesion molecule 1(ICAM-1);Vascular endothelial growth factor(VEGF)by Luminex multiplex assays.ResultsPlasma A?40 is higher whereas A?42/40 ratio is lower in cognitive impairment and T2-DM with cognitive impairment compared to other groups.As compared to the health control,YKL-40 level was upregulated in cognitive impairment,PRGN was downregulated in T2-DM with cognitive impairment,OPN was substantially decreased in T2-DM,and IL-6 was elevated in cognitive impairment and T2-DM with cognitive impairment.Interestingly,VEGF and S100B were induced in T2-DM when compared with cognitive impairment,and NSE level in T2-DM with cognitive impairment is significantly lower than in T2-DM or cognitive impairment.ConclusionA?42,A?40,and A?42/40 ratio cannot distinguish T2-DM with cognitive impairment from cognitive impairment.Some vascular injury and neurodegenerative cytokines(YKL-40,NSE,and VEGF)have good performance in distinguishing T2-DM with cognitive impairment from simple cognitive impairment.Taken together,this may improve the accuracy of the diagnosis and establishment of individualized therapy.Section 2:Connection between serum inflammatory cytokines and diabetic cognitive impairmentBackgroundThe prevalence of cognitive decline is closely linked to diabetes and its progression.However,the cognitive impairment(CI)induced by diabetes is often underestimated and kept undiagnosed,leading to thousands of diabetic people suffering from the worsening memory.Thus,targeting diabetes-related brain dysfunction and to explore valuable biomarkers for cognitive decline at early stage are critical problems to be solved urgently.Alzheimer's Disease(AD)is the most typical form of dementia.Patients with AD have complex chronic inflammatory responses in their brains.Immune-related cells including astrocytes and microglia cluster around a? plaques.These cells are thought to release inflammatory cytokines,which further activate neuroinflammation as well as further cytokine production.Moreover,in our present study,we find that a panel of neurovascular cytokines can discriminate T2DM and cognitive impairment,but inflammatory associated cytokines are similar in these patients.This suggests that inflammation may be a link between diabetes and cognitive impairment.But there are few studies show the relationship between chronic inflammation and cognition,consider that multiple markers are able to have better performance in diagnosis and prognostic assessment,and provide targets for treatment.Therefore,in this study,we selected some serum inflammatory factors that may be related to cognitive impairment to evaluate their relationship with the onset and progression of cognitive impairment.ObjectivesTo investigate the changes of serum inflammatory markers in patients with type 2 diabetes mellitus(T2-DM)with cognitive impairment.MethodsThis study was conducted in the Department of geriatrics and endocrinology,Anhui Provincial Hospital,School of Medicine,Shandong University and community healthcare center.We recruited 120 elderly patients,and all participants signed informed consent.Blood samples were collected from 40 T2-DM patients without cognitive impairment,40 T2-DM patients with cognitive impairment,and 40 healthy control subjects.Serum levels of different inflammatory markers-interleukin-6(IL-6),interleukin-8(IL-8),interleukin-12(interleukin-12),interleukin-1(IL-1),interleukin-10(IL-10),and tumor necrosis factor-?(TNF-?)were detected,and the correlation between the above inflammatory markers and the expression of Beta-Site APP Cleaving Enzyme 1(BACE1)and Mini-mental State Examination(MMSE).Results1.serum levels of different inflammatory markers:serum IL-6,IL-8,IL-12,IL-1? and TNF-a levels were increased in patients with type 2 diabetes mellitus(T2-DM)with cognitive impairment compared with T2-DM without cognitive impairment(P<0.05).Overall,serum levels of pro-inflammatory markers IL-6,IL-8,IL-12,IL-1?,and TNF-? were higher in patients with T2-DM and T2-DM with cognitive impairment compared with healthy subjects(P<0.05).In addition,serum IL-10 levels were lower in the T2-DM group and the T2-DM with cognitive impairment group compared with the healthy group(p<0.05).2.Correlation between the expression of inflammatory markers and BACE1 and the MMSE:serum levels of inflammatory markers such as IL-6,IL-8,IL-12,IL-1? and TNF-? were higher in T2-DM patients with cognitive impairment than in T2-DM patients without cognitive impairment.There were significant negative correlations between MMSE scores and various inflammatory markers in serum in different groups,such as IL-1?(r=-0.45,P?0.01),IL-12(r=-0.30,P?0.01),TNF-?(r=-0.39,P?0.01),IL-6(r=-0.39,P?0.01),IL-8(r=-0.37,P?0.01),except for IL-10(r=0.35,P?0.01).There were significant positive correlations between BACE1 expression and different inflammatory markers in different groups,such as IL-1?(r=0.24,P?0.05),IL-12(r=0.19,P?0.05),TNF-?(r=0.21,P?0.05),and IL-6(r=0.24,P?0.05).There was no significant difference between the expression of BACE1 and IL-8(r=0.12,P>0.05)in different groups.It was negatively correlated with IL-10(r=-0.29,P?0.01).ConclusionSerum inflammatory response and BACE1 level was elevated in patients with T2-DM with cognitive impairment compared with T2-DM without cognitive impairment and the healthy groups.The association of increased peripheral BACE1 level with both CI patients and 2-DM valid.Again,there was elevated enzymatic level of the antibody-captured BACE1 in plasma of 2-DM patients with CI compared with health subjects.BACE1 activities were associated with disease progression as measured by MMSE.Moreover,there was also a negative correlation detected between MMSE and level of BACE1 in health subjects and 2-DM versus 2-DM with CI patients.Based on the results of this study,changes in serum inflammatory response may induce abnormal BACE1 expression,these factors are risk factors for cognitive decline in patients with T2-DM.Section 3:Association between plasma BACE1 expression and cognitive impairment in type 2 diabetes mellitusBackgroundCognitive impairment is a common complication of type 2 diabetes mellitus(T2-DM),and evidences revealed that patients with T2-DM have twice at the rate of cognitive decline than people without T2-DM.In view of the lack of effective treatment of cognitive impairment,especially severe cognitive impairment,early diagnosis and intervention of cognitive impairment are particularly important.Current studies have found that ?-secretase(Beta-Site APP Cleaving Enzyme 1,BACE1)is an important risk factor for Alzheimer's disease(AD)dementia,and plasma BACE 1 could accurately reflect pathologies and cognitive function in brain.In our present study,inflammation levels are elevated in T2-DM patients,and is positively correlated with BACE1 levels,so whether BACE1 is also elevated in diabetic patients and promotes the occurrence of diabetes-related cognitive impairment?This is still poorly understood.ObjectivesTo investigate the expression of plasma BACE1 and potential role in cognitive impairment in patients with type 2 diabetes mellitus(T2-DM).MethodsThis study was conducted in the department of Geriatrics and endocrinology,Anhui Provincial Hospital,School of Medicine,Shandong University,and community healthcare center.We recruited 264 elderly subjects who all signed informed consent.Blood samples were collected including 56 T2-DM patients,82 T2-DM patients with cognitive impairment,69 cognitive impairment and 57 healthy subjects.We detected plasma BACE1 levels and BACE1 enzymatic activity for APPsw.At the same time,subjects were evaluated by Mini-mental State Examination(MMSE).Results1.Plasma BACE1 levels in patients with T2DM and T2DM with cognitive impairment:Plasma BACE1 levels were detected by ELISA as well as Immunofluorescence and immunoblotting.We found the increased BACE 1 levels in patients with T2DM only and T2DM with cognitive impairment as patients with cognitive impairment only when compared with age-match healthy controls2.Inplasma BACE1 enzymatic activity in patients with T2DM and T2DM with cognitive impairment:Consistently,the increased BACE1 enzymatic activity were also observed by fluorescence energy transfer assay in patients with T2DM only,T2DM with cognitive impairment and cognitive impairment only(p<0.05).In addition,we compared BACE1 levels and BACE1 enzymatic activity with cognitive function,we found both BACE1 levels and BACE1 activity for APPsw were negatively correlated with MMSE scores.ConclusionThe increased BACE1 levels and BACE1 enzymatic activity for APPsw were found in patients with T2DM with cognitive impairment and these two indices were positively correlated with cognitive impairment,suggesting that the abnormally elevated BACE1 may be a potential mechanism that promote high occurrence of cognitive impairment in T2DM.Thus,the increased BACE1 should also be considered as a biomarker that predict cognitive impairment in T2DM. |
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