Alterations in metamemory capacity and neural correlates in a subtype of subjective cognitive decline.

BACKGROUNDS: Subjective cognitive decline (SCD), one of the important clinical indicators for preclinical Alzheimer's disease (AD), is primarily defined as self-perceived cognitive decline without objective evidence for cognitive impairment. However, the accuracy of their self-evaluation of cognition is unclear. This study sought to investigate the capacity for self-evaluation of own cognitive performance in SCD by applying an objective metamemory paradigm. METHODS: 147 individuals with SCD were classified into four subgroups by their subjective feeling of worse performance than peers or not (P+/-) and whether they have objectively slight cognitive impairment compared to normative data (S+/-). Metamemory scores, the amplitude of the low-frequency fluctuation (ALFF), fractional low-frequency fluctuation amplitude (fALFF), and cortical thickness were compared among four subgroups. Partial correlations between neuropsychological scores and neuroimaging measures were examined, controlling for age, sex, and education years. RESULTS: SCD S+P- showed the worst performance in short-term delayed recall and the worst metamemory performance, indicated by the highest value in the degree of confidence of short-term delayed recall (DOC-N4) and long-term cued recall (DOC-N6) and the worst value in relative accuracy of judgments of short-term delayed recall (ROJ-N4). ALFF values in the bilateral superior medial frontal and olfactory cortices and the left superior orbitofrontal gyrus cortex were significantly higher in SCD P- compared with SCD P+ groups (all P < 0.05, FWE-corrected, cluster-wise level). A significant S × P interaction effect in the left hippocampus and middle cingulate cortex was found for the fALFF signals (all P < 0.05, FWE-corrected, cluster-wise level). Significant interaction and main effects on cortical thickness were reported. The parahippocampal and posterior cingulate cortices were significantly decreased in SCD S+P- (all P < 0.05). CONCLUSION: SCD S+P- showed the worst episodic memory performance, altered metamemory capacity (overconfidence and less accuracy of judgment), and altered neuroimaging measures, though they had feelings of similar performance with peers. Our results indicate that metamemory capacity is affected in a subtype of SCD with reduced cortical thickness and intensity of regional spontaneous activity in key areas for metamemory processing.

Plasma Aß as a biomarker for predicting Aß-PET status in Alzheimer's disease：a systematic review with meta-analysis.

OBJECTIVE: Amyloid-ß positron emission tomography (Aß-PET) scan has been proposed to detect amyloid-ß (Aß) deposition in the brain. However, this approach is costly and not ideal for the early diagnosis of Alzheimer's disease. Blood-based Aß measurement offers a scalable alternative to the costly or invasive biomarkers. The aim of this study was to statistically validate whether plasma Aß could predict Aß-PET status via meta-analysis. METHODS: We systematically searched for eligible studies from PubMed, Embase and Cochrane Library, which reported plasma Aß levels of amyloid-ß positron emission tomography-positive (PET (+)) and amyloid-ß positron emission tomography-negative (PET (-)) subjects. We generated pooled estimates using random effects meta-analyses. For any study that has significant heterogeneity, metaregression and subgroup analysis were further conducted. Publication bias was appraised by funnel plots and Egger's test. RESULTS: 16 studies with 3047 participants were included in the meta-analysis. Among all the enrolled studies, 10 studies reported plasma Aß40 values, while 9 studies reported plasma Aß42 values and 13 studies reported Aß42/Aß40 ratio. The pooled standardised mean difference (SMD) was 0.76 (95% CI -0.61 to 2.14, p=0.28) in the plasma Aß40 values group. Plasma Aß42 values group has a pooled SMD of -0.60 (95% CI -0.80 to -0.41, p<0.0001). In the plasma Aß42/Aß40 ratio group, the pooled SMD was -1.44 (95% CI -2.17 to -0.72, p<0.0001). CONCLUSION: Plasma Aß40 values might not distinguish between PET (+) and PET (-) people. However, plasma Aß42 values and plasma Aß42/Aß40 ratio could be served as independent biomarkers for predicting Aß-PET status.

Circular RNA DLGAP4 is down-regulated and negatively correlates with severity, inflammatory cytokine expression and pro-inflammatory gene miR-143 expression in acute ischemic stroke patients.

This study aimed to investigate the expression of circular RNA DLGAP4 (circ-DLGAP4) and its correlation with severity, inflammation, inflammatory cytokine levels as well as microRNA-143 (miR-143) expression in acute ischemic stroke (AIS) patients. One hundred and seventy AIS patients and 170 non-AIS controls were enrolled in this study. PBMC and serum from all participants were collected. Circ-DLGAP4 and miR-143 expression in PBMC were detected by qPCR, and TNF-α, IL-1ß, IL-6, IL-8, IL-17 as well as IL-22 expressions in serum were detected by ELISA. The information of CRP, ESR, and National Institutes of Health Stroke Scale (NIHSS) score of AIS patients was collected. PBMC circ-DLGAP4 was down-regulated in AIS patients compared with controls, and ROC curve analysis disclosed that PBMC circ-DLGAP expression had good value in predicting lower AIS risk with area under curve 0.816. Spearman's rank correlation test showed that PBMC circ-DLGAP4 expression negatively correlated with NIHSS score and CRP level in AIS patients. In addition, PBMC circ-DLGAP4 level also was negatively associated with serum expressions of TNF-α, IL-6, IL-8 as well as IL-22. Moreover, PBMC circ-DLGAP4 expression was negatively correlated with PBMC miR-143, and PBMC miR-143 was positively associated with NIHSS score, CRP, ESR, TNF-α, IL-1ß, IL-6, IL-8, IL-17, as well as IL-22 levels. Circulating circ-DLGAP4 could serve as a novel biomarker for diagnosis and disease surveillance of AIS and is negatively correlated with inflammation and miR-143 expression in AIS patients.

Autophagy of macrophages is regulated by PI3k/Akt/mTOR signalling in the development of diabetic encephalopathy.

The development of diabetic encephalopathy (DE) is enhanced by inflammatory macrophages, and is suppressed by macrophage autophagy. However, the molecular signaling that controls macrophage autophagy in DE remains ill-defined. Here, DE is induced in rats that received intraperitoneal injection of streptozotocin (STZ). In macrophages isolated from the brain of the rats, we detected downregulated autophagy activity and enhanced PI3k/Akt/mTOR/S6K1 signaling. In order to examine the role of autophagy and PI3k/Akt/mTOR signaling in DE development, an mTOR inhibitor, rapamycin, or an autophagy inhibitor, chloroquine (CQ), were administered to the rats that that received STZ. We found that rapamycin significantly enhanced DE development through mTOR suppression-induced augmentation of macrophage autophagy, while CQ significantly decreased DE development through suppression of macrophage autophagy. Together, our data suggest that PI3k/Akt/mTOR signaling may promote the development of DE through suppression of macrophage autophagy.

Mecobalamin and early functional outcomes of ischemic stroke patients with H-type hypertension.

OBJECTIVE: To analyze the effect of mecobalamin on the early-functional outcomes of patients with ischemic stroke and H-type hypertension. METHODS: From October of 2014 to October of 2016, 224 cases of ischemic stroke and H-type hypertension were selected. The patients were randomly divided into treatment control groups, with 112 patients in each group. The control group was treated with the conventional therapy. The observation group was treated with 500 µg of mecobalamin three times a day in addition to the conventional therapy. We compared serum homocysteine (Hcy), hs-CRP levels, carotid plaques, and NIHSS scores between the two groups on the 2nd day and at 4 weeks, 8 weeks, 3 months, and 6 months. RESULTS: After 4 weeks, 8 weeks, 3 months and 6 months, the difference of serum Hcy level between the two groups was statistically significant (t = 4.049, 3.896, 6.052, 6.159, respectively. All P <0.05). After the treatment, at 4 weeks, 8 weeks, 3 months and 6 months, the levels of hs-CRP in the treatment group were significantly lower than those in the control group (t = 37.249, 28.376, 26.454, 20.522, respectively. All P <0.01). After 3 months and 6 months, the carotid artery plaques were significantly reduced in the treatment group compared to those in the control group (t = 2.309 and 2.434. All P <0.05). After 3 months and 6 months, the NIHSS score was significantly higher in the treatment group compared to those in the control group (t = 2.455 and 2.193. All P <0.05). CONCLUSION: Mecobalamin can reduce the level of plasma homocysteine, then lead to reductions of levels of plasma inflammatory factors and volume of carotid artery plaques, resulting in more significant functional recovery.

Mecobalamin and early functional outcomes of ischemic stroke patients with H-type hypertension

SUMMARY OBJECTIVE To analyze the effect of mecobalamin on the early-functional outcomes of patients with ischemic stroke and H-type hypertension. METHODS From October of 2014 to October of 2016, 224 cases of ischemic stroke and H-type hypertension were selected. The patients were randomly divided into treatment control groups, with 112 patients in each group. The control group was treated with the conventional therapy. The observation group was treated with 500 µg of mecobalamin three times a day in addition to the conventional therapy. We compared serum homocysteine (Hcy), hs-CRP levels, carotid plaques, and NIHSS scores between the two groups on the 2nd day and at 4 weeks, 8 weeks, 3 months, and 6 months. RESULTS After 4 weeks, 8 weeks, 3 months and 6 months, the difference of serum Hcy level between the two groups was statistically significant (t = 4.049, 3.896, 6.052, 6.159, respectively. All P <0.05). After the treatment, at 4 weeks, 8 weeks, 3 months and 6 months, the levels of hs-CRP in the treatment group were significantly lower than those in the control group (t = 37.249, 28.376, 26.454, 20.522, respectively. All P <0.01). After 3 months and 6 months, the carotid artery plaques were significantly reduced in the treatment group compared to those in the control group (t = 2.309 and 2.434. All P <0.05). After 3 months and 6 months, the NIHSS score was significantly higher in the treatment group compared to those in the control group (t = 2.455 and 2.193. All P <0.05). CONCLUSION Mecobalamin can reduce the level of plasma homocysteine, then lead to reductions of levels of plasma inflammatory factors and volume of carotid artery plaques, resulting in more significant functional recovery.

RESUMO OBJETIVO Analisar o efeito de mecobalamin sobre os primeiros resultados funcionais de pacientes com AVC isquêmico e hipertensão H-type. MÉTODOS De outubro de 2014 a outubro de 2016, 224 casos de AVC isquêmico e hipertensão H-type foram selecionadas. Os pacientes foram divididos aleatoriamente em grupo de tratamento e grupo controle, com 112 doentes em cada grupo. O grupo controle foi tratado com a terapia de rotina. O grupo de observação foi tratado com 500 µg de mecobalamin três vezes por dia, além da rotina de tratamento. No segundo dia, 4 semanas, 8 semanas, 3 meses e 6 meses, comparamos níveis séricos da homocisteína (Hcy) e de hs-CRP, placas da carótida e pontuações NIHSS entre os dois grupos. RESULTADOS Após 4 semanas, 8 semanas, 3 meses e 6 meses, a diferença dos níveis séricos de Hcy entre os dois grupos foi estatisticamente significativa (t= 4,049, 3,896, 6,052, 6,159, respectivamente. Todos os P<0,05). Após o tratamento de 4 semanas, 8 semanas, 3 meses e 6 meses, os níveis de hs-CRP no grupo de tratamento foram significativamente inferiores aos do grupo controle (t=37,249, 28,376, 26,454, 20,522, respectivamente. Todos os P<0,01). Depois de 3 meses e 6 meses, as placas da artéria carótida foram significativamente reduzidas no tratamento, em comparação com os do grupo controle (t=2,309 e 2,434. Todos os P<0,05). Depois de 3 meses e 6 meses, as pontuações NIHSS foram significativamente mais elevadas no tratamento em comparação com as do grupo controle (t=2,455 e 2,193. Todos os P<0,05). CONCLUSÃO Mecobalamin pode reduzir o nível de homocisteína plasmática, o que conduz à redução dos níveis de plasma inflamatórios e do volume das placas na artéria carótida, resultando em maior recuperação funcional.

Control of macrophage autophagy by miR-384-5p in the development of diabetic encephalopathy.

The molecular development of diabetic encephalopathy remains ill-defined. Recently, we reported that elimination of inflammatory macrophages alleviated the progress and severity of diabetic encephalopathy. Here, we studied the underlying mechanism. Inflammatory macrophages were isolated from the brain of the mice that received i.p. injection of streptozotocin (STZ) to develop diabetes 6 weeks before, and showed enhanced autophagy activity, seemingly through augmentation of Beclin-1 levels. However, the increases in Beclin-1 levels did not result from enhanced gene transcription, but appeared to result from suppression of a Beclin-1-inhibitory microRNA, miR-384-5p. Overexpression of miR-384-5p in the inflammatory macrophages through an adeno-associated virus mediated gene transfer system significantly reduced inflammatory macrophages in the diabetic brain, resulting in attenuation of the STZ-induced decreases in brain malondialdehyde, catalase and superoxidase anion-positive cells, and the STZ-induced increases in brain nitric oxide. Thus, these data suggest that downregulation of miR-384-5p in the inflammatory macrophages may enhance macrophage autophagy and contribute to the development of diabetic encephalopathy, which may be suppressed by re-expression of miR-384-5p in macrophages.

Myricetin ameliorates scopolamine-induced memory impairment in mice via inhibiting acetylcholinesterase and down-regulating brain iron.

The aim of our study was to investigate to investigate the effect of myricetin on Alzheimer's disease (AD) and its underlying mechanisms. In our study, Myricetin effectively attenuated Fe2+-induced cell death in SH-SY5Y cells in vitro. In a mouse model of AD, myricetin treatment significantly reversed scopolamine-induced cognitive deficits deriving from a novel action of inhibiting acetylcholinesterase (AChE) and down-regulating brain iron. Furthermore, Myricetin treatment reduced oxidative damage and increased antioxidant enzymes activity in mice. Interestingly, the effect of myricetin was largely abolished by high iron diet. Therefore we suggested that treatment with myricetin attenuated cognitive deficits in mice via inhibiting AChE and brain iron regulation. In addition, myricetin reduce iron contents may via inhibiting transferrin receptor 1 (TrR1) expression. In conclusion, accumulated data demonstrates that myricetin is a potential multifunctional drug for AD.

Macrophage autophagy regulated by miR-384-5p-mediated control of Beclin-1 plays a role in the development of atherosclerosis.

Macrophages play an essential and complicated role in the pathogenesis of atherosclerosis. However, the regulation of macrophage autophagy as well as it role in the development of atherosclerosis is unclear. MicroRNA-384-5p (miR-384-5p) is a new miRNA that attracted attention very recently, while its effects on Beclin-1 and cell autophagy has not been reported. Here, we studied macrophage autophagy in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of Beclin-1 and the levels of miR-384-5p in the purified F4/80+ macrophages from mouse aorta. Prediction of the binding between miR-384-5p and 3'-UTR of Beclin-1 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. We found that HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as NOR mice) did not. Compared to NOR mice, HFD mice had significantly lower levels of macrophage autophagy, and significantly higher levels of macrophage death, resulting from decreases in Beclin-1. The decreases in Beclin-1 in macrophages were due to HFD-induced increases in miR-384-5p, which suppressed the translation of Bectlin-1 mRNA via 3'-UTR binding. Together, our study suggests that upregulation of miR-384-5p by HFD may impair the Beclin-1-mediated protection of macrophages through autophagy to accelerate the development of atherosclerosis.

Stereoselective metabolism of donepezil and steady-state plasma concentrations of S-donepezil based on CYP2D6 polymorphisms in the therapeutic responses of Han Chinese patients with Alzheimer's disease.

The therapeutic response rates of patients to donepezil vary from 20% to 60%, one of the reasons is their genetic differences in donepezil-metabolizing enzymes, which directly influence liver metabolism. However, the mechanism of donepezil metabolism and that of its enantiomers is unknown. This study evaluated CYP2D6 polymorphisms to elucidate the stereoselective metabolism of donepezil and to confirm the association between the steady-state plasma concentrations of the pharmaco-effective S-donepezil and the therapeutic responses of Han Chinese patients with Alzheimer's disease. The in vitro study of the stereoselective metabolism demonstrated that CYP2D6 is the predominant P450 enzyme that metabolizes donepezil and that different CYP2D6 alleles differentially affect donepezil enantiomers metabolism. A total of 77 Han Chinese patients with Alzheimer's disease were recruited to confirm these results, by measuring their steady-state plasma concentrations of S-donepezil. The related CYP2D6 genes were genotyped. Plasma concentrations of S-donepezil (based on CYP2D6 polymorphisms) were significantly associated with therapeutic responses. This finding suggests that plasma concentrations of S-donepezil influence therapeutic outcomes following treatment with donepezil in Han Chinese patients with Alzheimer's disease. Therefore, determining a patient's steady-state plasma concentration of S-donepezil in combination with their CYP2D6 genotype might be useful for clinically monitoring the therapeutic efficacy of donepezil.

Inflammatory Macrophages Promotes Development of Diabetic Encephalopathy.

BACKGROUND/AIMS: Diabetes and Alzheimer's disease are often associated with each other, whereas the relationship between two diseases is ill-defined. Although hyperglycemia during diabetes is a major cause of encephalopathy, diabetes may also cause chronic inflammatory complications including peripheral neuropathy. Hence the role and the characteristics of inflammatory macrophages in the development of diabetic encephalopathy need to be clarified. METHODS: Diabetes were induced in mice by i.p. injection of streptozotocin (STZ). Two weeks after STZ injection and confirmation of development of diabetes, inflammatory macrophages were eliminated by i.p. injection of 20µg saporin-conjugated antibody against a macrophage surface marker CD11b (saporin-CD11b) twice per week, while a STZ-treated group received injection of rat IgG of same frequency as a control. The effects of macrophage depletion on brain degradation markers, brain malondialdehyde (MDA), catalase, superoxidase anion-positive cells and nitric oxide (NO) were measured. RESULTS: Saporin-CD11b significantly reduced inflammatory macrophages in brain, without affecting mouse blood glucose, serum insulin, glucose responses and beta cell mass. However, reduced brain macrophages significantly inhibited the STZ-induced decreases in brain MDA, catalase and superoxidase anion-positive cells, and the STZ-induced decreases in brain NO. CONCLUSION: Inflammatory macrophages may promote development of diabetic encephalopathy.

Epigenetic suppression of hippocampal BDNF mediates the memory deficiency induced by amyloid fibrils.

Accumulating evidences demonstrated that epigenetic modification of the expression of specific genes contributed to the pathogenesis of neurological disorders with dementia, including Alzheimer's disease (AD). Emerging reports also found the reduction of hippocampal brain-derived neurotrophic factor (BDNF) in the patients and rodent models of AD, while the mechanism and functional significance remain debated. The present study aims to study the epigenetic mechanism underlying the BDNF reduction and its functional significance in the rats with hippocampal infusion of amyloid fibrils. In the rats injected with amyloid fibrils, significant decreases of BDNF expression and the mRNA of Bdnf exon VI were found in the hippocampal CA1 area. Significantly increased hippocampal HDAC2 expression and its occupancy in the promoter region of Bdnf exon VI were also observed, thus contributing to the histone H3 deacetylation and BDNF suppression in the hippocampal CA1 in the rats injected with amyloid fibrils. Inhibition of HDAC2 activity by trichostatin A substantially recovered the histone H3 acetylation in the promoter region of Bdnf exon VI and BDNF expression, thus mitigating the synaptic dysfunction and memory deficiency induced by amyloid fibrils. These results elucidate the epigenetic mechanism underlying the BDNF reduction induced by amyloid fibrils, and provided novel insights into the pathogenic mechanism of Alzheimer's disease.

Platelet glycoprotein IIIa gene polymorphism (Leu33Pro) and aspirin resistance in a very elderly Chinese population.

OBJECTIVES: To study the relationship between platelet glycoprotein IIIa gene (GP IIIa) polymorphism (Leu33Pro) and aspirin resistance in a very elderly Chinese population. METHODS: Four hundred fifty very elderly Chinese people receiving aspirin therapy were enrolled in the study. Patients who underwent arachnoid acid-induced platelet aggregation were then divided into two groups based on their resistance to aspirin: aspirin-resistant (AR) group (n=236) and aspirin-sensitive (AS) group (n=214). The Leu33Pro polymorphism of the GP IIIa gene was scanned by polymerase chain reaction-restriction fragment-length polymorphism. RESULTS: In the AR group, 224 participants had the A1/A1 genotype and 12 had the A1/A2 genotype. All patients in the AS group had the A1/A1 genotype. Thus, there was significant difference between these two groups in the genotype distribution (p<0.05). CONCLUSION: The genetic polymorphism of the GP IIIa gene was associated with AR in a very elderly Chinese population.

Meta-analysis of plasma homocysteine content and cognitive function in elderly patients with Alzheimer's disease and vascular dementia.

OBJECTIVE: To evaluate the relationship between homocysteine and cognitive function of Alzheimer's disease (AD) patients and vascular dementia (VD) patients. METHODS: By Cochrane system evaluation we retrieved relevant publications from MEDLINE, Embase, OVID, controlled clinical trial database of the Cochrane library and others. Two evaluators jointly assessed the research quality of the retrieved publications and carried out meta-analysis on the homogeneous study. RESULTS: MMSE score in the AD group was lower than that in normal control group (MD = -11.98, 95% CI (-13.30, -10.65)), and the homocysteine content was higher than that in the normal control group (MD = 2.72, 95% CI (1.79, 3.64)), with a statistical difference between the two groups (P < 0.05). The homocysteine content in the AD group was higher than that in the VD group (MD = -4.76, 95% CI (-7.59, -1.93), P < 0.05). CONCLUSIONS: MSE score and homocysteine content can be used as useful indicators to distinguish AD and normal subjects; homocysteine content can be used as an indicator to differentiate AD from VD. Clinically, more randomized controlled trials are needed to test and verify the relationship in cognitive function between homocysteine and AD and VD.

Alprostadil plays a protective role in contrast-induced nephropathy in the elderly.

PURPOSE: To evaluate the protective effects of alprostadil on contrast-induced nephropathy (CIN) in elderly patients. METHODS: We randomized 370 patients into the control or alprostadil group. The patients in the control group were injected with 100 ml sterile saline and the patients in the alprostadil group with alprostadil (0.4 µg/kg/day) in 100 ml sterile saline before and after iohexol-enhanced (100 ml) computed tomography (CT). Serum creatinine (Scr), blood urea nitrogen (BUN), cystatin C (CysC), and creatinine clearance (Ccr) were analyzed or calculated. ΔScr and ΔCysC were determined by the changes between baseline and highest Scr and CysC levels. The standard for CIN was a postdose Scr increase >44.2 µmol/l or >25 % over baseline. RESULTS: In the control group, peak Scr (P < 0.05) and ΔScr (P < 0.01) were higher than those in the alprostadil group. The postdose CysC at 24 h (P < 0.05), 48 h (P < 0.05), and 72 h (P < 0.05), peak CysC (P < 0.01), and ΔCysC (P < 0.05) in the control group were higher than those in the alprostadil group. The incidence of CIN in the control group was 22.2 %, which was higher than in the alprostadil group (9.1 %, P < 0.01). Subgroup analyses in patients with advanced age (≥ 80 years), concomitant hypertension or diabetes, and abnormal baseline renal function (Ccr ≤ 60 ml/min) showed that the alprostadil group had lower ΔScr and ΔCysC than the control group after contrast-enhanced CT examination in all four subgroups (P < 0.05 or P < 0.01). CONCLUSIONS: In this cohort of older patients undergoing contrast CT, the use of alprostadil reduced the incidence of CIN.

Effect of CYP2D6*10 and APOE polymorphisms on the efficacy of donepezil in patients with Alzheimer's disease.

BACKGROUND: The aim of this study was to evaluate the effect of CYP2D6*10 and APOE polymorphisms on both steady-state plasma concentrations (Cp) and clinical response of donepezil in patients with mild-to-moderate Alzheimer's disease (AD). METHODS: A total of 110 Chinese AD patients participated in this study. Patients were treated with 5 to 10 mg of donepezil daily for 6 months. The genotypes of CYP2D6*10 and APOE were analyzed by polymerase chain reaction-restriction fragment length polymorphism. The steady-state Cp of donepezil was measured by high-performance liquid chromatography-tandem mass spectrometric assay method. The cognition of patients was evaluated at baseline and at 6-month follow-up by Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subscale. RESULTS: At 6-month follow-up, 56 of 96 patients (58.3%) were evaluated as responders and 40 patients (41.7%) as nonresponders to donepezil treatment. A significantly higher frequency of patients with genotypes CYP2D6*1/*10 and *10/*10 were found in responders than in nonresponders (P < 0.05). Besides, patients with CYP2D6*1/*10 and *10/*10 genotypes had higher Cp of donepezil and improved cognition scores than those with CYP2D6*1/*1 genotype (P < 0.05). However, the frequency of APOE [Latin Small Letter Open E]4 carriers and noncarriers showed no difference between the 2 groups (P > 0.05). CONCLUSIONS: AD patients with mutant allele (*10) in CYP2D6 gene may respond better to donepezil than those with wild allele (*1). We did not find the relationship between APOE [Latin Small Letter Open E]4 status and the efficacy of donepezil in our study.

Inhibition of NF-kappaB activation by Pyrrolidine dithiocarbamate partially attenuates hippocampal MMP-9 activation and improves cognitive deficits in streptozotocin-induced diabetic rats.

Matrix metalloproteinase-9 (MMP-9) has been found at significantly increased activity and also contributes to blood-brain barrier degradation in diabetes. Activation of NF-κB pathway is associated with diabetes-induced cognitive impairment, and MMP-9 gene promoter contains a highly conserved motif that matches the NF-κB p65 binding element. No data have been yet provided to show that diabetes-induced cognitive decline is actually associated with increased activity of MMP-9, however, so we sought to understand the potential role of NF-κB-MMP-9 pathway in diabetic rats' brain. Streptozocin (STZ) was used to induce diabetes in Wistar rats. Pyrrolidine dithiocarbamate (PDTC), an effective NF-κB inhibitor, was administrated to diabetic rats for 6 weeks from the end of diabetes induction. Six weeks later, separate cohorts of rats were tested for cognitive function with Morris water maze task, or euthanized to assess MMP-9 and NF-κB levels in hippocampus. The diabetic rats developed cognitive deficit which was associated with enhanced hippocampal MMP-9 and NF-κB expression. PDTC treatment returned the levels of NF-κB toward their control values and significantly improved diabetes-induced behavioral dysfunction. However, the hippocampal MMP-9 expression triggered by diabetes was only slightly (though significantly) attenuated because MMP-9 protein level in PDTC treated diabetic rats was still higher than that in control rats. Moreover, chronic PDTC treatment did not affect the body weight and plasma glucose levels as compared to the diabetic group, which suggested that PDTC could not ameliorate the diabetic metabolic disorder. In conclusion, these data reveal that diabetes-associated cognitive deficit stems partially from up-regulation of hippocampal MMP-9 via activation of NF-κB signaling pathway.

Effects of telmisartan on insulin resistance and visceral fat distribution in Chinese hypertensive patients with obesity.

OBJECTIVE: To investigate the effects of telmisartan on body fat distribution and insulin sensitivity in patients with hypertension and obesity. METHODS: In this prospective, randomized study, outpatients from the Sixth People's Hospital affiliated to Shanghai Jiaotong University, Shanghai, China were treated with telmisartan (n=23), or losartan (n=22) for 16 weeks between December 2009 to January 2011. Parameters such as waist and hip circumference, body mass index, fasting blood glucose, insulin, lipids, serum adiponectin, and tumor necrosis factor-alpha (TNF-alpha) were measured before and after treatment. The abdominal visceral fat area (VFA) and subcutaneous fat area (SFA) were determined by magnetic resonance imaging. Insulin sensitivity was estimated by homeostasis model assessment (HOMA-IR). RESULTS: Compared with baseline, the systolic and diastolic blood pressure decreased significantly in both groups. However, the levels of HOMA-IR, serum adiponectin, and TNF-alpha only improved in the telmisartan group. Similarly, the VFA was reduced in the telmisartan group, while the SFA did not change in either group. CONCLUSION: Telmisartan improves both hemodynamic and metabolic abnormalities found in hypertensive patients with obesity. The additional benefits may be partly due to visceral fat remodeling.