The Role of N-Methyl-D-Aspartate Receptor Neurotransmission and Precision Medicine in Behavioral and Psychological Symptoms of Dementia

While the world’s population is aging, the prevalence of dementia and the associated behavioral and psychological symptoms of dementia (BPSD) rises rapidly. BPSD are associated with worsening of cognitive function and poorer prognosis. No pharmacological treatment has been approved to be beneficial for BPSD to date. Dysfunction of the N-methyl-D-aspartate receptor (NMDAR)-related neurotransmission leads to cognitive impairment and behavioral changes, both of which are core symptoms of BPSD. Memantine, an NMDAR partial antagonist, is used to treat moderate to severe Alzheimer’s disease (AD). On the other hand, a D-amino acid oxidase inhibitor improved early-phase AD. Whether to enhance or to attenuate the NMDAR may depend on the phases of dementia. It will be valuable to develop biomarkers indicating the activity of NMDAR, particularly in BPSD. In addition, recent reports suggest that gender difference exists in the treatment of dementia. Selecting subpopulations of patients with BPSD who are prone to improvement with treatment would be important. We reviewed literatures regarding the treatment of BPSD, focusing on the NMDAR-related modulation and precision medicine. Future studies examining the NMDAR modulators with the aid of potential biomarkers to tailor the treatment for individualized patients with BPSD are warranted

Early Identification and Intervention of Schizophrenia: Insight From Hypotheses of Glutamate Dysfunction and Oxidative Stress

Schizophrenia is a severe mental disorder which leads to functional deterioration. Early detection and intervention are vital for better prognosis. However, the diagnosis of schizophrenia still depends on clinical observation to date. Without reliable biomarkers, schizophrenia is difficult to detect in its early phase. Further, there is no approved medication for prodromal schizophrenia because current antipsychotics fail to show satisfactory efficacy and safety. Therefore, to develop an effective early diagnostic and therapeutic approach for schizophrenia, especially in its prodromal phase, is crucial. Glutamate signaling dysfunction and dysregulation of oxidative stress have been considered to play important roles in schizophrenic prodrome. The N-methyl-D-aspartate receptor (NMDAR) is one of three types of ionotropic glutamate receptors. In this article, we reviewed literature regarding NMDAR hypofunction, oxidative stress, and the linkage between both in prodromal schizophrenia. The efficacy of NMDAR enhancers such as D-amino acid oxidase inhibitor was addressed. Finally, we highlighted potential biomarkers related to NMDAR and oxidative stress regulation, and therefore suggested the strategies of early detection and intervention of prodromal schizophrenia. Future larger-scale studies combining biomarkers and novel drug development for early psychosis are warranted

Benzoate, a D-Amino Acid Oxidase Inhibitor, for the Treatment of Early-Phase Alzheimer's Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

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Combination of G72 Genetic Variation and G72 Protein Level to Detect Schizophrenia: Machine Learning Approaches

The D-amino acid oxidase activator (DAOA, also known as G72) gene is a strong schizophrenia susceptibility gene. Higher G72 protein levels have been implicated in patients with schizophrenia. The current study aimed to differentiate patients with schizophrenia from healthy individuals using G72 single nucleotide polymorphisms (SNPs) and G72 protein levels by leveraging computational artificial intelligence and machine learning tools. A total of 149 subjects with 89 patients with schizophrenia and 60 healthy controls were recruited. Two G72 genotypes (including rs1421292 and rs2391191) and G72 protein levels were measured with the peripheral blood. We utilized three machine learning algorithms (including logistic regression, naive Bayes, and C4.5 decision tree) to build the optimal predictive model for distinguishing schizophrenia patients from healthy controls. The naive Bayes model using two factors, including G72 rs1421292 and G72 protein, appeared to be the best model for disease susceptibility (sensitivity = 0.7969, specificity = 0.9372, area under the receiver operating characteristic curve (AUC) = 0.9356). However, a model integrating G72 rs1421292 only slightly increased the discriminative power than a model with G72 protein alone (sensitivity = 0.7941, specificity = 0.9503, AUC = 0.9324). Among the three models with G72 protein alone, the naive Bayes with G72 protein alone had the best specificity (0.9503), while logistic regression with G72 protein alone was the most sensitive (0.8765). The findings remained similar after adjusting for age and gender. This study suggests that G72 protein alone, without incorporating the two G72 SNPs, may have been suitable enough to identify schizophrenia patients. We also recommend applying both naive Bayes and logistic regression models for the best specificity and sensitivity, respectively. Larger-scale studies are warranted to confirm the findings

); fax 886-4-2236-1230; hylane@gmail

The WCST, a widely used measure of prefrontal cognitive functions (including executive function, abstraction and working memory), is sensitive to a person's ability to generate hypotheses, establish response sets and fluently shift sets. 9,10 A recent meta-analysis 11 suggests that there is a small but significant relation between Val158Met genotype and WCST performance in healthy people but not in those with schizophrenia. Because the COMT Val158Met polymorphism accounts for a small portion of the variability in prefrontal cognition, it is warranted to explore whether other genetic mutations have potential effects. Of dopamine receptors, D 1 and D 3 may deserve foremost attention. D 1 receptors play a critical role in the activation of prefrontal cognition such as working memory. 3 In addition, D 1 activation modulates rodents' social cognition, 13 which depends substantially on prefrontal function. 14 Among genetic variants of D 1 receptors, the A-48G polymorphism is associated with glucose metabolic rates in human brain regions, including the prefrontal cortex. 15 The D 3 receptor, although structurally highly homologous to other D 2 -like dopamine receptors, differs from them in regulating neuropsychological performance. 6 D 2 may also regulate spatial working memory, but the latter is principally attributed to D 1 receptor-mediated mechanisms. 22 By interacting with the dopaminergic system, serotonergic transmission also plays a significant role in prefrontal cognitive function. 23 Its action is mediated via specific receptors, possibly serotonin 5-HT 2A and 5-HT 6 , located in crucial brain structures, primarily the nucleus basalis magnocellularisfrontal cortex. In rats, 5-HT 2A receptors regulate prefrontal cortex-related execution of primed responses. 3 In healthy volunteers, 5-HT 2A agonists impair the continuous performance task, 24 which is mainly determined by prefrontal function. 25 Among 5-HT 2A receptor polymorphisms, T102C has received considerable attention. For instance, this genetic variance affects treatment response to antipsychotics. The 5-HT 6 receptor is responsible for endogenous 5-HT-mediated facilitation of dopamine release in the rat prefrontal cortex 30 and regulates brain cholinergic neurotransmission. 31,32 It has been indicated that, among 5-HT 6 receptor polymorphisms, 33 T267C is associated with Alzheimer disease. 35 The current study aims to explore the effects of the aforementioned genetic variances of D 1 , D 3 , 5-HT 2A and 5-HT 6 on WCST performance, which reflects prefrontal executive function, in a healthy population. Methods Participants This study was approved by the institutional review board of China Medical University Hospital and carried out in accordance with the Declaration of Helsinki (www.wma.net /e/policy/b3.htm). The participants were 216 unrelated healthy volunteers (81 men and 135 women) with a mean age of 48.6 (standard deviation [SD] 9.4) years (range 20-65 y) and a mean education level of 10.9 (SD 3.7) years (range 0-20 y). All were Han Chinese living in Taiwan. The subjects in this study gave their consent to participate after procedures were explained to them. All subjects were free of any axis I or II psychiatric disorders, as determined by a research psychiatrist using the Structured Clinical Interview for DSM-IV. WCST assessments An experienced psychologist (Y-LC) administered the WCST. Genotyping Genomic DNA was extracted from the subjects' white blood cells. The 4 polymorphisms were genotyped according to the polymerase chain reaction-restriction fragment length polymorphism technique. Forward and reverse primers and restriction enzymes for each polymorphism were as follows: 5′-ACT GAC CCC TAT TCC CTG CT-3′, 5′-AGC ACA GAC CAG CGT GTT C-3′, DdeI for A-48G polymorphisms in the promoter region of the dopamine D 1 receptor gene; 38 5′-GCT CTA TCT CCA ACT CTC ACA-3′, 5′-AAG TCT ACT CAC CTC CAG GTA-3′, MscΙ for the D 3 Ser9Gly polymorphism; 39,40 5′-TCT GCT ACA AGT TCT GGC TT-3′, 5′-CTG CAG CTT TTT CTC TAG GG-3′, MspI for 5-HT 2A T102C; 41,42 and 5′-AAC TTC TTC CTG GTG TCG CTC TTC-3′, 5′-ATG AGC AGG TAG CGG TCC AGG-3′, RsaI for T267C polymorphisms in the 5-HT 6 receptor gene. Data analyses We used a 2-tailed Mann-Whitney U test for WCST performance comparisons between male and female subjects. Kruskal-Wallis tests were carried out with each genetic polymorphism as the independent variable and percentage of perseverative errors and number of categories as the dependent measures. These nonparametric statistical methods were used because the distributions of perseverative errors and categories numbers were skewed to the right (data not shown). We also compared the subjects' demographic characteristics among genotypes of each genetic polymorphism, using Kruskal-Wallis tests for continuous variables and χ 2 tests for categorical variables. Statistical significance was defined as p < 0.05 or corrected for multiple comparisons as needed (p < 0.0125 = 0.05/4 [genetic polymorphisms]). To control for the effects of other confounding factors, we used multiple linear regression in a single analysis to evaluate impacts of sex, age, sex × age interaction, education level and the 4 genetic polymorphisms simultaneously on WCST performance. Because all these comparisons were performed in a single multiple regression analysis, no correction for multiple comparisons was required. However, the distributions of the WCST data were skewed to the right and unsuitable for regression analyses. To convert the skewed distribution to a normal one, we measured each perseverative error value in its natural logarithmic scale before the regression analysis. 44,45 Results In all 216 subjects, the mean percentage of WCST perseverative errors was 20.1% (SD 13.1%) and the mean number of WCST categories completed was 4.18 (SD 3.08). Men and women had comparable mean perseverative errors at 18.7 (SD 12.0) and 20.9 (SD 13.8) (p = 0.46), respectively, and comparable mean numbers of categories completed at 4.4 (SD 3.2) and 4.1 (SD 3.0) (p = 0.55). Allele frequencies of the genetic polymorphisms in our Han Chinese sample are similar to those in other Han Chinese populations but may be different from those in white populations WCST perseverative errors and genotype

Identification of SNP barcode biomarkers for genes associated with facial emotion perception using particle swarm optimization algorithm

BACKGROUND: Facial emotion perception (FEP) can affect social function. We previously reported that parts of five tested single-nucleotide polymorphisms (SNPs) in the MET and AKT1 genes may individually affect FEP performance. However, the effects of SNP-SNP interactions on FEP performance remain unclear. METHODS: This study compared patients with high and low FEP performances (n = 89 and 93, respectively). A particle swarm optimization (PSO) algorithm was used to identify the best SNP barcodes (i.e., the SNP combinations and genotypes that revealed the largest differences between the high and low FEP groups). RESULTS: The analyses of individual SNPs showed no significant differences between the high and low FEP groups. However, comparisons of multiple SNP-SNP interactions involving different combinations of two to five SNPs showed that the best PSO-generated SNP barcodes were significantly associated with high FEP score. The analyses of the joint effects of the best SNP barcodes for two to five interacting SNPs also showed that the best SNP barcodes had significantly higher odds ratios (2.119 to 3.138; P < 0.05) compared to other SNP barcodes. In conclusion, the proposed PSO algorithm effectively identifies the best SNP barcodes that have the strongest associations with FEP performance. CONCLUSIONS: This study also proposes a computational methodology for analyzing complex SNP-SNP interactions in social cognition domains such as recognition of facial emotion

MET and AKT Genetic Influence on Facial Emotion Perception

Background: Facial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/ AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception. Methods: One hundred and eighty two unrelated healthy volunteers (82 men and 100 women) were recruited. Four single nucleotide polymorphisms (SNP) of MET (rs2237717, rs41735, rs42336, and rs1858830) and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Thorough neurocognitive functions were also assessed. Results: Regarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration), and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5%) performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM). In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM), even when neurocognitive functions were controlled (p = 0.046 by GLM)