Weihong Lu

Association Between BDNF Val66Met Polymorphism and Cognitive Performance in Antipsychotic-Naïve Patients with Schizophrenia

Cognitive impairment is one of the core symptoms in schizophrenia, which reflects the neurodevelopmental deficits in the etiology of this disease. Brain-derived neurotrophic factor (BDNF) plays an important role in various neurodevelopmental processes. Growing evidence has shown that BDNF may be involved in the etiology of schizophrenia. The aim of this study was to examine the association of the BDNF Val66Met polymorphism with cognition in patients with schizophrenia. Various neuropsychological tests including the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale-Revised, and the Wisconsin Card Sorting Test (WCST) were employed in a sample of 112 antipsychotic-naïve patients with schizophrenia and 63 healthy controls. We examined the Val66Met polymorphism in the 112 patients and 394 controls. Among the patients, cognition was compared between Met allele carriers and non-Met allele carriers. A wide range of cognitive deficits were demonstrated in the schizophrenic patients, compared with the controls (Ps < 0.01). No significant differences of genotype or allele distribution were identified between patients and controls. The patients with Met allele showed more percent WCST perseverative errors than those without Met allele (P = 0.007). After stratification based on gender, an association between the Met allele and a higher percentage of perseverative errors was found in male patients (P = 0.014), but not in females (P = 0.09). Cognitive performance is broadly impaired in schizophrenic patients. The BDNF Val66Met polymorphism may be involved in the impaired executive function. This effect may have gender-specific characteristics.

Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive–compulsive symptoms

RationaleClinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive–compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology.ObjectivesThis study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms.MethodsA total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y-BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped.ResultsTrends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene–gene interaction model (p = 0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score (F6, 137 = 7.650, p < 0.001), and individuals with AA/TT genotypes had a significantly higher mean Y-BOCS score than those with other genotypes, except AG/TT.ConclusionsThese results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine.

Brain-derived neurotrophic factor levels and bipolar disorder in patients in their first depressive episode: 3-Year prospective longitudinal study

BACKGROUND Early identification of patients with bipolar disorder during their first depressive episode is beneficial to the outcome of the disorder and treatment, but traditionally this has been a great challenge to clinicians. Recently, brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the pathophysiology of bipolar disorder and major depressive disorder (MDD), but it is not clear whether BDNF levels can be used to predict bipolar disorder among patients in their first major depressive episode. AIMS To explore whether BDNF levels can differentiate between MDD and bipolar disorder in the first depressive episode. METHOD A total of 203 patients with a first major depressive episode as well as 167 healthy controls were recruited. After 3 years of bi-annual follow-up, 164 patients with a major depressive episode completed the study, and of these, 21 were identified as having bipolar disorder and 143 patients were diagnosed as having MDD. BDNF gene expression and plasma levels at baseline were compared among the bipolar disorder, MDD and healthy control groups. Logistic regression and decision tree methods were applied to determine the best model for predicting bipolar disorder at the first depressive episode. RESULTS At baseline, patients in the bipolar disorder and MDD groups showed lower BDNF mRNA levels (P<0.001 and P = 0.02 respectively) and plasma levels (P = 0.002 and P = 0.01 respectively) compared with healthy controls. Similarly, BDNF levels in the bipolar disorder group were lower than those in the MDD group. These results showed that the best model for predicting bipolar disorder during a first depressive episode was a combination of BDNF mRNA levels with plasma BDNF levels (receiver operating characteristics (ROC) = 0.80, logistic regression; ROC = 0.84, decision tree). CONCLUSIONS Our findings suggest that BDNF levels may serve as a potential differential diagnostic biomarker for bipolar disorder in a patients first depressive episode.

Genetic modulation of working memory deficits by ankyrin 3 gene in schizophrenia

Neuropsychological endophenotype approach is an emerging strategy in schizophrenia research to understand and identify the functional importance of genetically transmitted, brain-based deficits present in this disorder. Accumulating evidence indicated that working memory deficit is a core neuropsychological dysfunction in schizophrenia and a primary endophenotype indexing the liability to develop schizophrenia. Genetic variation in ankyrin 3 gene (ANK3) is likely to have widespread cognitive effects. Our previous study has identified a significant association of ANK3 SNPs and schizophrenia. In this study, we aimed to examine whether the schizophrenia-risk SNPs within ANK3 may affect working memory deficits in schizophrenia patients. Herein, we assess the working memory performance in 163 patients with first-episode, antipsychotic-naïve schizophrenia and 42 sex, age-matched healthy subjects using N-back task. Two SNPs rs10761482 and rs10994336 were genotyped among the patients and 209 controls. Our results showed that schizophrenia patients showed significantly poorer performance than healthy controls on N-back task (ps<0.01). After adjusting for the scores of intelligence quotient, memory quotient and the demographic factors, there was a significant genotype effect of the rs10994336 on the accuracy rate and reaction time of 2-back item (p=0.048 and 0.024, respectively). Post-hoc analyses showed that patients with rs10994336T/T genotype had significantly lower accuracy rate and more reaction time at 2-back task than those with T/C and C/C genotypes. The association of SNP rs10994336 with schizophrenia was replicated in our sample (genotypic p=0.024 and allelic p=0.006). However, we did not find any significant association of rs10761482 with schizophrenia and parameters in N-back task. Our results indicated that genetic variation within ANK3 may exert gene-specific modulating effects on working memory deficits in schizophrenia.

Mitochondrial DNA haplogroup B5 confers genetic susceptibility to Alzheimer's disease in Han Chinese.

Mitochondrial dysfunction has been widely reported in psychiatric and neurodegenerative diseases. We aimed to investigate the association between matrilineal structures of Han Chinese populations and Alzheimers disease (AD) by a 2-stage case-control study: A total of 341 AD patients and 435 normal individuals from Southwest China were analyzed for mitochondrial DNA sequence variations and were classified into respective haplogroups. A total of 371 AD patients and 470 normal individuals from East China, as validation samples, were genotyped for the variants defining the risk haplogroup. Haplogroup B5 had a significantly higher frequency in AD patients (7.33%) than in control subjects (3.68%) from Southwest China, and we found a similar pattern of higher frequency of B5 in patients in the case-control sample from East China. In the combined population, association of haplogroup B5 with AD risk was strengthened (p = 0.02; odds ratio = 1.74; 95% confidence interval = 1.10-2.76). In lymphoblastoid cell lines belonging to haplogroup B5a, we observed significantly increased reactive oxygen species and decreased mitochondrial mass. Hela cells with stable expression of the MT-ATP6 gene with B5-defining variant m.8584G>A also showed a significantly decreased mitochondrial function. Taken together, our results indicated that haplogroup B5 conferred genetic susceptibility to AD in Han Chinese, and this effect was most likely mediated by ancient variant m.8584G>A. The predisposing effect of B5 to AD is consistent with the ancestral-susceptibility model of complex diseases.

No association of the LRRK2 genetic variants with Alzheimer's disease in Han Chinese individuals

The leucine-rich repeat kinase-2 (LRRK2) gene has been regarded as 1 of the most common genetic causes of Parkinsons disease (PD). We hypothesized that LRRK2-susceptible allele(s) for PD might pose a risk for Alzheimers disease (AD). In this study, we screened 12 LRRK2 gene variants in 2 independent cohorts from southwestern China (341 AD patients and 435 normal individuals) and eastern China (297 AD patients and 384 normal individuals), to discern the potential association between this gene and AD. No variant was identified to be associated with AD in either case-control sample. As both of the cohorts were of Han Chinese origin, we combined the LRRK2 variant data for the 2 sample sets together (a total of 638 AD patients and 819 normal individuals) and still found no association between the LRRK2 gene and AD, suggesting that LRRK2 gene variants may not affect the development of AD in Han Chinese individuals.

A Pilot Study of iPad-Assisted Cognitive Training for Schizophrenia

In this pilot study, we aimed to examine whether iPad-assisted cognitive training could be beneficial in ameliorating some of the cognitive impairment that accompany schizophrenia. Totally, 20 first-episode schizophrenia patients were randomly assigned to an experiment group (with cognitive training) or to a control group (without cognitive training). The N-back task was assessed at baseline and after intervention, to see what effects iPad-assisted training might have (week 4). The experimental group exhibited significant improvement in the accuracy rate at 2-back, and reaction time at 0, 1 and 2-back tasks. These findings suggest that iPad- or other technically-assisted cognitive training may potentially be a valid strategy for pursuing cognitive rehabilitation among those with schizophrenia.

T102C polymorphism of serotonin 2A type receptor gene confers susceptibility to (early onset) schizophrenia in Han Chinese: An association study and meta‐analysis

Several lines of evidence have indicated that serotonin 2A receptor (HTR2A) may be involved in the pathophysiology of schizophrenia. One functional polymorphism in HTR2A (T102C) has been widely investigated; however, the results have been inconsistent. The purpose of this study was to evaluate the association between HTR2A T02C polymorphism and schizophrenia in a Chinese Han population.

Crosstalk between 5-HT2cR and PTEN signaling pathway in atypical antipsychotic-induced metabolic syndrome and cognitive dysfunction

Accumulating evidence indicates that chronic treatment with atypical antipsychotics (AAPs) leads to metabolic syndrome (MetS) and cognitive dysfunction. It has been found that patients receiving antipsychotic treatment with MetS have significantly worse cognitive function when compared to those without the MetS, suggesting an intrinsic relationship between MetS and cognitive dysfunction. Thus, investigating the reasons for the side effects induced by AAPs is an important step in the effort to understand the patholophysiology of this condition. The 5-HT2c receptor (5-HT2cR) antagonist properties of AAPs are likely to contribute to AAP-induced MetS. There is crosstalk between phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and 5-HT2cR. PTEN negatively regulates the activity of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which plays an important role in obesity-induced insulin resistance in peripheral tissue. In the central nervous system, PI3K/AKT signaling modulates synaptic plasticity, a mechanism underlying learning and memory processes. This suggests that PI3K/AKT signaling contributes to both metabolic and cognitive activities. Since PTEN negatively regulates PI3K/AKT signaling and has crosstalk with 5-HT2cR, we hypothesized that the 5-HT2cR antagonism of AAPs may disrupt its crosstalk with PTEN and then trigger the PI3K/AKT signaling, and AAP-induced MetS and cognitive impairments may occur via this analogous signaling pathway.

A Preliminary Genetic Analysis of Complement 3 Gene and Schizophrenia

Complement pathway activation was found to occur frequently in schizophrenia, and complement 3 (C3) plays a major role in this process. Previous studies have provided evidence for the possible role of C3 in the development of schizophrenia. In this study, we hypothesized that the gene encoding C3 (C3) may confer susceptibility to schizophrenia in Han Chinese. We analyzed 7 common single nucleotide polymorphisms (SNPs) of C3 in 647 schizophrenia patients and 687 healthy controls. Peripheral C3 mRNA expression level was measured in 23 drug-naïve patients with schizophrenia and 24 controls. Two SNPs (rs1047286 and rs2250656) that deviated from Hardy-Weinberg equilibrium were excluded for further analysis. Among the remaining 5 SNPs, there was no significant difference in allele and genotype frequencies between the patient and control groups. Logistic regression analysis showed no significant SNP-gender interaction in either dominant model or recessive model. There was no significant difference in the level of peripheral C3 expression between the drug-naïve schizophrenia patients and healthy controls. In conclusion, the results of this study do not support C3 as a major genetic susceptibility factor in schizophrenia. Other factors in AP may have critical roles in schizophrenia and be worthy of further investigation.