Predictive value of serum matrix metalloproteinase 9 combined with tissue inhibitor of metalloproteinase 1 for post-stroke cognitive impairment.

BACKGROUND: Post-stroke cognitive impairment (PSCI) seriously affects the quality of life of patients. Identifying early predictors of PSCI to realize timely intervention of PSCI can provide effective information for patient rehabilitation and follow-up treatment, and has important clinical significance for delaying its progression to dementia. METHODS: Montreal Cognitive Assessment (MoCA) and National Institutes of Health Stroke Scale (NIHSS) were used to assess patients' cognitive and neurological function separately. ELISA was used to analyze serum tissue inhibitor of metalloproteinase 1 (TIMP 1) and matrix metalloproteinase 9 (MMP 9) levels of patients on admission. RESULTS: 180 patients with first-ever acute ischemic stroke (AIS) were included in the study. After three months of follow-up, 78 patients were diagnosed with PSCI, and 102 patients did not have PSCI. MMP 9 and TIMP 1 were elevated in PSCI patients on admission relative to non-PSCI groups, and they were positively correlated with patients' NIHSS scores on admission (p < 0.001). Serum levels of MMP 9 and TIMP 1 in PSCI patients were negatively correlated with MoCA scores at the end of the 3-month follow-up (p < 0.001). Serum MMP 9 (p < 0.001), TIMP 1 (p = 0.02) and combined detection (p < 0.001) of AIS patients at admission appear to have predictive value for the diagnosis of PSCI three months later. CONCLUSION: Serum MMP 9 and TIMP 1 levels in stroke patients were statistically predictive of PSCI.

Influence of genetic polymorphisms in homocysteine and lipid metabolism systems on antidepressant drug response.

BACKGROUND: Variation in genes implicated in homocysteine and lipid metabolism systems may influence antidepressant response for patients with major depressive disorder (MDD). This study aimed to investigate whether association of polymorphisms on the MTHFR, ApoE and ApoA4 genes with the treatment response in MDD subjects. METHODS: A total of 281 Han Chinese MDD patients received a single antidepressant drug (SSRI or SNRI) for at least 6 weeks, among whom 275 were followed up for 8 weeks. Their response to 6 weeks' treatment and remission to 8 weeks' treatment with antidepressant drugs was determined by changes in the 17-item Hamilton Depression Rating Scale (HARS-17) score. Single SNP and haplotype associations with treatment response were analyzed by UNPHASED 3.0.13. Logistic regression analysis was used to explore the interactions between genotypes and gender or drug type on treatment outcome, only those SNPs that had interactional association with gender or drug type were subjected to further stratified analysis. RESULTS: In total group, the haplotype (C-A) in MTHFR (rsl801133 and rs1801131) and the ApoE rs405509 AA genotype were significantly associated with better efficacy of antidepressants; In gender subgroups, only haplotype (C-A) in MTHFR (rsl801133 and rs1801131) was significantly associated with better efficacy of antidepressants in male subgroup; In drug type subgroup, the haplotype (C-A) in MTHFR (rsl801133 and rs1801131) and haplotype (G-C) in ApoE (rs7412 and rs405509) were associated with better efficacy of antidepressants in SNRI treated subgroup; The ApoA4 rs5092 G allele and GG genotype were associated with worse efficacy of antidepressants in SNRI treated subgroup. CONCLUSIONS: Genetic polymorphisms in homocysteine and lipid metabolism systems are associated with antidepressant response, particularly for the interactions of the certain genetic with gender or drug type.

The initial glycemic variability is associated with early neurological deterioration in diabetic patients with acute ischemic stroke.

The association between glycemic variability and early neurological deterioration (END) in acute ischemic stroke remains unclear. This study attempted to explore whether initial glycemic variability increases END in diabetic patients with acute ischemic stroke. We enrolled type 2 diabetic patients undergoing acute ischemic stroke from November 2015 to November 2016. A total of 336 patients within 72 h from stroke onset were included. The serum glucose levels were checked four times per day during the initial 3 hospital days. The standard deviation of blood glucose (SDBG) values and the mean amplitude of glycemic excursions (MAGE) were calculated for glycemic variability. END was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) ≥ 2 points between hospital days 0 and 5. The frequencies of END and HbA1c were significantly different in subjects grouped according to tertiles of MAGE (9.09, 12.07 and 50.00%, p < 0.001 for END; 7.36 ± 1.91, 7.83 ± 1.93 and 8.56 ± 1.79, p < 0.001 for HbA1c). Compared to patients without END, patients with END had significantly higher HbA1c levels (8.30 ± 1.92 vs 7.80 ± 1.93, p = 0.043), increased SDBG (3.42 ± 1.14 vs 2.60 ± 0.96, p < 0.001), and increased MAGE (6.46 ± 2.09 vs 4.59 ± 1.91, p < 0.001). In a multivariable logistic regression, stroke etiology (OR 0.675; 95% CI 0.485-0.940, p = 0.020), baseline NIHSS (OR 1.086; 95% CI 1.004-1.175, p = 0.040), and MAGE (OR 1.479; 95% CI 1.162-1.882, p = 0.001) were significantly associated with END. Initial glycemic variability is associated with END in diabetic patients with acute ischemic stroke.

Modulation of GSK-3ß/ß-Catenin Signaling Contributes to Learning and Memory Impairment in a Rat Model of Depression.

Background: It is widely accepted that cognitive processes, such as learning and memory, are affected in depression, but the molecular mechanisms underlying the interactions of these 2 disorders are not clearly understood. Recently, glycogen synthase kinase-3 beta (GSK-3ß)/ß-catenin signaling was shown to play an important role in the regulation of learning and memory. Methods: The present study used a rat model of depression, chronic unpredictable stress, to determine whether hippocampal GSK-3ß/ß-catenin signaling was involved in learning and memory alterations. Results: Our results demonstrated that chronic unpredictable stress had a dramatic influence on spatial cognitive performance in the Morris water maze task and reduced the phosphorylation of Ser9 of GSK-3ß as well as the total and nuclear levels of ß-catenin in the hippocampus. Inhibition of GSK3ß by SB216763 significantly ameliorated the cognitive deficits induced by chronic unpredictable stress, while overexpression of GSK3ß by AAV-mediated gene transfer significantly decreased cognitive performance in adult rats. In addition, chronic unpredictable stress exposure increased the expression of the canonical Wnt antagonist Dkk-1. Furthermore, chronic administration of corticosterone significantly increased Dkk-1 expression, decreased the phosphorylation of Ser9 of GSK-3ß, and resulted in the impairment of hippocampal learning and memory. Conclusions: Our results indicate that impairment of learning and memory in response to chronic unpredictable stress may be attributed to the dysfunction of GSK-3ß/ß-catenin signaling mediated by increased glucocorticoid signaling via Dkk-1.

TPH-2 Polymorphisms Interact with Early Life Stress to Influence Response to Treatment with Antidepressant Drugs.

BACKGROUND: Variation in genes implicated in monoamine neurotransmission may interact with environmental factors to influence antidepressant response. We aimed to determine how a range of single nucleotide polymorphisms in monoaminergic genes influence this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. An initial study of monoaminergic coding region single nucleotide polymorphisms identified significant associations of TPH2 and HTR1B single nucleotide polymorphisms with treatment response that showed interactions with childhood and recent life stress, respectively (Xu et al., 2012). METHODS: A total of 47 further single nucleotide polymorphisms in 17 candidate monoaminergic genes were genotyped in 281 Chinese Han patients with major depressive disorder. Response to 6 weeks' antidepressant treatment was determined by change in the 17-item Hamilton Depression Rating Scale score, and previous stressful events were evaluated by the Life Events Scale and Childhood Trauma Questionnaire-Short Form. RESULTS: Three TPH2 single nucleotide polymorphisms (rs11178998, rs7963717, and rs2171363) were significantly associated with antidepressant response in this Chinese sample, as was a haplotype in TPH2 (rs2171363 and rs1487278). One of these, rs2171363, showed a significant interaction with childhood adversity in its association with antidepressant response. CONCLUSIONS: These findings provide further evidence that variation in TPH2 is associated with antidepressant response and may also interact with childhood trauma to influence outcome of antidepressant treatment.

Genetics pathway-based imaging approaches in Chinese Han population with Alzheimer's disease risk.

The tau hypothesis has been raised with regard to the pathophysiology of Alzheimer's disease (AD). Mild cognitive impairment (MCI) is associated with a high risk for developing AD. However, no study has directly examined the brain topological alterations based on combined effects of tau protein pathway genes in MCI population. Forty-three patients with MCI and 30 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) in Chinese Han, and a tau protein pathway-based imaging approaches (7 candidate genes: 17 SNPs) were used to investigate changes in the topological organisation of brain activation associated with MCI. Impaired regional activation is related to tau protein pathway genes (5/7 candidate genes) in patients with MCI and likely in topologically convergent and divergent functional alterations patterns associated with genes, and combined effects of tau protein pathway genes disrupt the topological architecture of cortico-cerebellar loops. The associations between the loops and behaviours further suggest that tau protein pathway genes do play a significant role in non-episodic memory impairment. Tau pathway-based imaging approaches might strengthen the credibility in imaging genetic associations and generate pathway frameworks that might provide powerful new insights into the neural mechanisms that underlie MCI.

[Influence of interleukin-1 beta gene polymorphism and childhood maltreatment on antidepressant treatment].

OBJECTIVE: To explore the influence of interleukin-1 beta (IL1B) gene polymorphism and childhood maltreatment on antidepressant treatment. METHODS: Two hundred and four patients with major depressive disorder (MDD) have received treatment with single antidepressant drugs and were followed up for 8 weeks. Hamilton depression scale-17 (HAMD-17) was used to evaluate the severity of depressive symptoms and therapeutic effect. Childhood maltreatment was assessed using Childhood Trauma Questionnaire, a 28-item Short Form (CTQ-SF). Single nucleotide polymorphism (SNP) of the IL1B gene was determined using a SNaPshot method. Correlation of rs16944 gene polymorphism with response to treatment was analyzed using Unphased 3.0.13 software. The main and interactive effects of SNP and childhood maltreatment on the antidepressant treatment were analyzed using Logistic regression analysis. RESULTS: No significant difference of gender, age, year of education, family history, episode time, and antidepressant agents was detected between the remitters and non-remitters. Association analysis has found that the SNP rs16944 in the IL1B AA genotype carriers antidepressant response was poorer (χ2=3.931, P=0.047). No significant difference was detected in the CTQ scores between the two groups. Genetic and environmental interaction analysis has demonstrated a significant correlation between rs16944 AA genotype and childhood maltreatment and poorer response to antidepressant treatment. CONCLUSION: The SNP rs16944 in the IL1B gene and its interaction with childhood maltreatment may influence the effect of antidepressant treatment for patients with MDD.

Influence of genetic polymorphisms involved in the hypothalamic-pituitary-adrenal axis and their interactions with environmental factors on antidepressant response.

AIMS: To investigate the role of genetic polymorphisms in candidate genes associated with the HPA axis and their interactions with environmental stressors in antidepressant response. METHODS: The remission of depressive symptoms after 8 weeks of antidepressant treatment was tested against 21 single nucleotide polymorphisms (SNPs) in five candidate genes associated with the HPA axis in a Chinese Han sample suffering from unipolar depression (n = 273). Any history of childhood trauma and recent negative life events were measured using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) (n = 206) and the Life Event Scale (48 item, LES) (n = 207), respectively. Reporter gene assays were used to evaluate the possible effects of the most significant SNP on gene expression. RESULTS: A functional polymorphism at 3'UTR of the corticotropin-releasing hormone receptor 1 (CRHR1) gene (rs28364032) and three haplotypes containing it showed significant relationships with antidepressant remission. Further laboratory-based genomic studies showed that the G-to-A change of rs28364032 resulted in a 10-12% decrease in the intensity of luciferase activity. However, we failed to find association of environments and their interaction with HPA system-related genes with antidepressant remission. CONCLUSIONS: Our results support a definite role for CRHR1 in the pharmacogenetics of antidepressant drugs. This may contribute to interpatient differences in their responses to antidepressant drugs.

Kinase gene haplotypes and gene-gene interactions in the Ras-Raf-MAPK signaling pathway: association with antidepressant remission.

Signal transduction has been reported to be involved in antidepressant treatment outcomes; however, its mechanisms remain unclear. The aims of this study were to explore the associations between antidepressant remission and single nucleotide polymorphisms (SNPs), haplotypes, and gene-gene interactions in the Ras-Raf-MAPK intracellular signaling pathway. A total of 302 inpatients with major depressive disorder (DSM-IV Axis I) were assessed using the 17-item Hamilton Depression Rating Scale before and after 8 weeks of antidepressant treatment to determine the remission rate in the samples. Twenty-four SNPs at five kinase genes (Ras-Raf-MEK-ERK-RSK), which are a part of the Ras-Raf-MAPK signaling pathway, were identified to investigate a genetic association with antidepressant drug outcome. Correlations between 24 SNPs at the five kinase genes in the Ras-Raf-MAPK signaling pathway and antidepressant drug outcome were not found. The percentage of the CCAGA haplotype that RSK(2/3/4)-RSKL(1/2) gene loci SNPs constructed was markedly lower in the remitter group when compared with the nonremitter group in female depressed patients (P=0.04), whereas the proportion of AAAGGG haplotype that RSK(2/3/4)-RSKL(1/2) gene loci SNPs constructed in the remitter group was significantly greater than that in the nonremitter group in male patients (P=0.02). In addition, MEK1 (rs28730804) and RSK3 (rs2229712) in the Ras-Raf-MAPK signaling pathway showed a gene-gene interaction that affected antidepressant drug outcome in female depressed patients (P=0.041). Although this study did not find that SNPs at the five kinase genes in the Ras-Raf-MAPK signaling pathway are important markers for antidepressant outcome, certain haplotypes that SNPs at the RSK(2/3/4)-RSKL(1/2) gene constructed may be important markers for antidepressant drug efficacy. We observed a gene-gene interaction in this signaling pathway that influenced antidepressant efficacy in female depressed patients. Therefore, it is likely that in female depressed patients, different haplotypes and gene-gene interaction in the Ras-Raf-MAPK signaling pathway are involved in mediating the pharmacological action of an antidepressant, and eventually influence antidepressant efficacy.

[Influence of methylenetetrahydrofolate reductase gene polymorphisms on antidepressant response].

OBJECTIVE: To assess the influence of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene on response to antidepressant treatment. METHODS: Two hundred and eight one Chinese Han patients have received single antidepressant drugs for at least 6 weeks, among whom 275 were followed up for 8 weeks. Hamilton depression scale 17 (HAMD-17) was used to evaluate the severity of depressive symptoms and therapeutic effects. Single nucleotide polymorphisms (SNPs) of the MTHFR gene were determined using gene chips. Associations of single loci and haplotypes with response to treatment were analyzed using an Unphased 3.0.13 software. RESULTS: No significant differences in gender, age, year of education, family history, episode times, and antidepressant agents were found between responders and non-responders (all P U+003E 0.05), while the baseline scores of HAMD-17 was significantly different(t=2.891, P=0.004). There was also no significant difference between age, years of education, family history, baseline scores of HAMD-17 and antidepressant agents between remitters and non-remitters (both P U+003E 0.05), while proportion of male patients was significantly higher in non-remission group than remission group (t=2.381, P=0.018), and episode times in non-remission group was significantly higher (t=-1.983, P=0.049). Single locus association analysis has found no significant association between SNPs rs1801131 and rs1801133 in the MTHFR gene with antidepressant response (P U+003E 0.05). On the other hand, haplotype A-C of MTHFR gene (rs1801131 and rs1801133) was significantly associated with antidepressant response in total group (U+03C7 2=11.39, P=0.0007), male subgroup (U+03C7 2=8.767, P=0.003) and serotonin noradrenaline reuptake inhibitors (SNRIs) subgroup (U+03C7 2=10.51, P=0.001). CONCLUSION: Particular haplotype of MTHFR gene may be related with antidepressant effect, in which the haplotype (rs1801131, rs1801133) A-C type may be associated with better antidepressant efficacy, particularly in males and patients receiving SNRIs drugs.

Influence of genetic polymorphisms in the glutamatergic and GABAergic systems and their interactions with environmental stressors on antidepressant response.

AIM: To investigate the role of genetic polymorphisms in glutamatergic and GABAergic genes and their interactions with environmental stressors in antidepressant response. METHODS: A set of 114 SNPs of 34 glutamatergic and GABAergic genes, mainly in promoter and coding regions, were genotyped in 281 Chinese Han major depressive disorder patients. The 17-item Hamilton Depression Rating Scale was used to evaluate the symptom severity and therapeutic efficacy. Childhood Trauma Questionnaire and Life Events Scale were used for assessing early-onset and recent stressful life events, respectively. RESULTS: The single SNPs rs1954787 (GRIK4), rs1992647 (GABRA6), rs10036156 (GABRP) and rs3810651 (GABRQ) were significantly associated with antidepressant response, as were haplotypes in GRIK4 and GABRP genes. A genetic interaction between rs11542313 (GAD1), rs13303344 (GABRD) and rs2256882 (GABRE) was identified as impacting therapeutic response. SNPs in GRIA3 demonstrated interactions with early-onset adverse events and recent negative life stress that influence treatment outcome. CONCLUSION: Genetic polymorphisms in the glutamatergic and GABAergic systems and certain genetic interactions, as well as gene-environment interactions, are associated with antidepressant response.

Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

To investigate the relationship between amnestic mild cognitive impairment (aMCI) and candidate gene polymorphisms in a Chinese population, 116 aMCI patients and 93 normal controls were recruited. Multi-dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects. MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms (SNPs) and analyse allelic, genotypic or haplotypic distributions. The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls. The distributions of SNPs relating to the amyloid cascade hypothesis (TOMM40 rs157581 G and TOMM40 rs2075650 G), to the cholesterol metabolism hypothesis (ApoE rs429358 C, LDLR rs11668477 G and CH25H rs7091822 T and PLAU rs2227564 CT) and to the tau hypothesis (MAPT/STH rs242562 GG) in aMCI were significantly different than those in normal controls. Interactions were also found in aMCI amongst SNPs in LDLR rs11668477, PLAU rs2227564, and TOMM40 rs157581, between SNPs in TOMM40 rs157580 and BACE2 rs9975138. The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD--those of the amyloid cascade, tau and cholesterol metabolism pathways. Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways.

Influence and interaction of genetic polymorphisms in the serotonin system and life stress on antidepressant drug response.

Variation in genes implicated in serotonin neurotransmission may interact with environmental factors to influence antidepressant response. We aimed to determine how a range of polymorphisms in serotonergic genes determine this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. In total, 14 single nucleotide polymorphisms (SNPs) in coding regions of 10 serotonergic genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR3A, HTR3C, HTR3D, HTR3E, HTR5A and TPH2) were genotyped in 308 Chinese Han patients with major depressive disorder. Response to 6 weeks' antidepressant treatment was determined by change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score, and previous stressful events were evaluated by the Life Events Scale (LES) and Childhood Trauma Questionnaire-Short Form (CTQ-SF). Two 5-HT1B receptor SNPs (rs6296 and rs6298) and one tryptophan hydroxylase2 (rs7305115) SNP were significantly associated with antidepressant response in this Chinese sample, as was a haplotype in TPH2 (rs7305115 and rs4290270). A gene-gene interaction on antidepressant response was found between SNPs in HTR1B, HTR3A and HTR5A in female subjects. The HTR1B SNPs demonstrated interaction with recent stress, while that for TPH2 interacted with childhood trauma to influence antidepressant response.

Genetic variation in the calcium/calmodulin-dependent protein kinase (CaMK) pathway is associated with antidepressant response in females.

OBJECTIVE: Antidepressant effects on monoamine neurotransmission may be influenced by genetic variation in intracellular signal transduction pathways, such as the cyclic adenosine monophosphate (cAMP)--protein kinase A (PKA) pathway, Ras-mitogen activated protein kinase (MAPK) pathway and calcium/calmodulin-dependent protein kinase (CaMK) pathway. The aims of this study were to examine the association of polymorphisms in candidate genes of these three signal transduction pathways with response to antidepressant treatment, and to determine the effects of, and interactions with, environment factors. METHODS: We recruited 412 patients who met diagnosis criteria for major depressive disorder (MDD) (DSM-IV Axis I). 284 patients completed 8 weeks treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenergic reuptake inhibitors (SNRIs). Severity of depression was measured with the Hamilton Depression Rating Scale (HDRS) before and after 8 weeks antidepressant treatment. 209 patients completed the Childhood Trauma Questionnaire, 28 item Short Form (CTQ-SF) which was used to evaluate childhood adverse events. 218 patients completed the Life Events Scale (LES) which were used to evaluate life stress before onset. 155 SNPs in 66 candidate genes were genotyping by Illumina GoldenGate, including 28 SNPs in 15 genes of cAMP-PKA pathway, 37 SNPs in 17 genes of Ras-MAPK pathway and 90 SNPs in 34 genes of CaMK pathway. The remission criterion was HDRS score equal to or less than 7. Single SNP and haplotype associations were analyzed by UNPHASED 3.3.13. Gene-environment interactions were analyzed by binary logistic regression with SPSS 11.0 software. RESULTS: The rs2230372 SNP in ITPR2, rs2280272 in PRKCZ, rs17109671, and rs17109674 in PLCE1 were significant associated with remission, as were haplotypes in PRKCZ and PLCE1. All these positive associations were found in genes of the CaMK pathway, but not the cAMP-PKA or Ras-MAPK pathways. There were no significant differences in CTQ scores and LES scores between remitters and non-remitters. No significantly interactions between candidate genes and environment effects were observed. CONCLUSION: The CaMK pathway may be important in determining antidepressant response. But recent adverse life events, childhood adversity, and interactions between candidate genes and environment factors appear not to influence short term antidepressant outcome.

Influence and interaction of genetic polymorphisms in catecholamine neurotransmitter systems and early life stress on antidepressant drug response.

BACKGROUND: Catecholamine neurotransmission plays an important role in major depression. Variation in genes implicated in the synthesis and signal transduction of catecholamines (norepinephrine and dopamine) may interact with environmental factors to affect the outcome of antidepressant treatment. We aimed to determine how a range of polymorphisms in noradrenergic and dopaminergic genes influence this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. METHODS: In a sample of 308 Chinese Han patients with major depressive disorder, 13 single nucleotide polymorphisms (SNPs) in coding regions of six genes (MAOA, SLC6A2, TH, COMT, DRD2, DRD3) with minor allele frequencies >5% were successfully genotyped from an initial series of 35 SNPs in 11 candidate genes associated with catecholamine neurotransmission. The responses to 6 weeks' treatment with antidepressant drugs was determined by changes in the 17-item Hamilton Depression Rating Scale (HAMD-17) score, and previous stressful events were evaluated by the Life Events Scale (LES) and Childhood Trauma Questionnaire-Short Form (CTQ-SF). Single SNP and haplotype associations with treatment response were analysed by UNPHASED 3.0.13, gene-gene interactions were analysed by generalized multifactor dimensionality reduction (GMDR) and gene-environment interactions by logistic regression. RESULTS: A haplotype in MAOA (rs1137070 and rs6323) was significantly associated with antidepressant response in the total group, the nonSSRI subgroup and the female subgroup. Two haplotypes in COMT (involving rs4633, rs4818 and rs769224) were significantly associated with antidepressant response in the nonSSRI subgroup. The SLC6A2 SNPs interacted with childhood trauma to influence antidepressant response. CONCLUSIONS: A haplotype in MAOA and two haplotypes in COMT are found to be associated with antidepressant treatment response in this sample. Stressors in early life may interact with polymorphisms in SLC6A2 to influence response to antidepressant treatment.