ABSTRACT
Stimulation of the serotonin (5-HT)1A receptor (HTR1A) has been shown to contribute to the mechanism of action of some atypical antipsychotic drugs (APDs), including clozapine and lurasidone. A meta-analysis of rs6295, a functional polymorphism located at the promoter region of HTR1A, showed association with clinical response in schizophrenic patients treated with atypical APD. We have now tested whether other SNPs related to rs6295 predict response to lurasidone. We first evaluated whether rs358532 and rs6449693, tag SNPs for rs6295, predicted response to lurasidone, using data from two clinical trials of acutely psychotic schizophrenia patients with European (EUR, n = 171) or African (AFR, n = 131) ancestry; we then determined if those findings could be replicated in a third trial of lurasidone of similar design. Weekly changes (up to 6 weeks) in the Positive and Negative Syndrome Scale (PANSS) Total score and its five subscales were used to assess response. In EUR, a significant association, or trends for association, were observed for PANSS Total (p = 0.035), positive (p = 0.039), negative (p = 0.004), and disorganization (p = 0.0087) subscales, at week 1-6. There was a trend for replication with PANNS Total (p = 0.036) in the third trial. No significant association was observed in AFR or the placebo group. Meta-analysis of five studies, including the three with lurasidone, showed that rs6295 was associated with improvement in positive (p = 0.023) and negative (p ≤ 0.0001) symptoms in EUR patients with schizophrenia. This is the first study to show a significant association between functional HTR1A polymorphisms and treatment response to lurasidone. The meta-analysis provides additional evidence that rs6295 could be a race-dependent biomarker for predicting treatment response to APDs in schizophrenic patients with European Ancestry.
Subject(s)
Antipsychotic Agents/therapeutic use , Lurasidone Hydrochloride/therapeutic use , Polymorphism, Single Nucleotide/genetics , Receptor, Serotonin, 5-HT1A/genetics , Schizophrenia/genetics , Black People/genetics , Humans , Multicenter Studies as Topic/methods , Predictive Value of Tests , Randomized Controlled Trials as Topic/methods , Schizophrenia/drug therapy , Treatment Outcome , White People/geneticsABSTRACT
AIM: Hypofunction of N-methyl-D-aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ. METHODS: First, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC, AMT, GCSH, and DLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation-dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n = 5) and controls (n = 5) by capillary electrophoresis time-of-flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined. RESULTS: Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC, a potential neural tube defect causative mutation; and R253X in AMT. Marked elevation of plasma 5-oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r = -0.942, P = 0.0166). CONCLUSION: These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.
Subject(s)
Amino Acid Oxidoreductases/genetics , Carrier Proteins/genetics , Metabolome/genetics , Multienzyme Complexes/genetics , Schizophrenia/genetics , Schizophrenia/metabolism , Schizophrenia/physiopathology , Transferases/genetics , Adult , Female , Humans , Male , Metabolomics , Middle AgedABSTRACT
AIM: Schizophrenia (SZ) and bipolar disorder (BD) have been known to share genetic and environmental risk factors, and complex gene-environmental interactions may contribute to their pathophysiology. In contrast to high genetic overlap between SZ and BD, as revealed by genome-wide association studies, the extent of epigenetic overlap remains largely unknown. In the present study, we explored whether SZ and BD share epigenetic risk factors in the same manner as they share genetic components. METHODS: We performed DNA methylation analyses of the CpG sites in the top five candidate regions (FAM63B, ARHGAP26, CTAGE11P, TBC1D22A, and intergenic region [IR] on chromosome 16) reported in a previous methylome-wide association study (MWAS) of SZ, using whole blood samples from subjects with BD and controls. RESULTS: Among the five candidate regions, the CpG sites in FAM63B and IR on chromosome 16 were significantly hypomethylated in the samples from subjects with BD as well as those from subjects with SZ. On the other hand, the CpG sites in TBC1D22A were hypermethylated in the samples from subjects with BD, in contrast to hypomethylation in the samples from subjects with SZ. CONCLUSION: Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations.
Subject(s)
Antipsychotic Agents/pharmacology , Bipolar Disorder/genetics , DNA Methylation/drug effects , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Genome-Wide Association Study , Risperidone/pharmacology , Schizophrenia/genetics , Adult , Animals , Antipsychotic Agents/administration & dosage , Callithrix , Chromosomes, Human, Pair 16/genetics , DNA, Intergenic/genetics , Female , Humans , Japan , Male , Middle Aged , Risperidone/administration & dosage , Ubiquitin Thiolesterase/geneticsABSTRACT
Multichannel near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that enables easy-to-use and noninvasive measurement of changes in blood oxygenation levels. We developed a clinically-applicable method for estimating resting state functional connectivity (RSFC) with NIRS using a partial correlation analysis to reduce the influence of extraneural components. Using a multi-distance probe arrangement NIRS, we measured resting state brain activity for 8min in 17 healthy participants. Independent component analysis was used to extract shallow and deep signals from the original NIRS data. Pearson's correlation calculated from original signals was significantly higher than that calculated from deep signals, while partial correlation calculated from original signals was comparable to that calculated from deep (cerebral-tissue) signals alone. To further test the validity of our method, we also measured 8min of resting state brain activity using a whole-head NIRS arrangement consisting of 17 cortical regions in 80 healthy participants. Significant RSFC between neighboring, interhemispheric homologous, and some distant ipsilateral brain region pairs was revealed. Additionally, females exhibited higher RSFC between interhemispheric occipital region-pairs, in addition to higher connectivity between some ipsilateral pairs in the left hemisphere, when compared to males. The combined results of the two component experiments indicate that partial correlation analysis is effective in reducing the influence of extracerebral signals, and that NIRS is able to detect well-described resting state networks and sex-related differences in RSFC.
Subject(s)
Cerebral Cortex/physiology , Connectome/methods , Spectroscopy, Near-Infrared/methods , Adult , Cerebral Cortex/diagnostic imaging , Female , Humans , Male , Sex FactorsABSTRACT
RATIONALE: The benefits of COVID-19 mRNA vaccination are claimed to be substantial; however, vaccination-related myocarditis and pericarditis have also been observed globally, particularly among young men. In most cases, the symptoms are mild and resolve on their own; however, fatal cases have rarely been described. PATIENT CONCERNS: A healthy 40-year-old Japanese man suddenly experienced tachycardia and lost consciousness 2 days after vaccination. Continued resuscitation recovered the spontaneous heartbeat; however, the patient did not regain consciousness and died 9 days later. Electrocardiography after resuscitation showed marked ST-segment depression and incomplete right bundle branch block. Influenza antigen and polymerase chain reaction tests for SARS-CoV-2 were negative. DIAGNOSES: Fatal arrhythmia after a second COVID-19 mRNA vaccination. INTERVENTIONS: We performed an autopsy and studied the material morphologically and immunohistochemically. OUTCOMES: At autopsy, several small inflammatory foci with cardiomyocytic necrosis were scattered in the right and left ventricles, with a propensity for the right side. Some inflammatory foci were located near the atrioventricular nodes and His bundles. The infiltrating cells predominantly consisted of CD68-positive histiocytes, with a small number of CD8-positive and CD4-positive T cells. In this case, myocarditis was focal and mild, as is mostly observed following COVID-19 mRNA vaccination. However, the inflammatory foci were close to the conduction system and were considered the cause of fatal arrhythmia. LESSONS: Although the benefits of COVID-19 vaccination appear to outweigh the side effects, it should be noted that fatal arrhythmias may rarely occur, and caution should be taken if individuals, particularly young men, complain of any symptoms after vaccination.
Subject(s)
COVID-19 , Myocarditis , Male , Humans , Adult , COVID-19 Vaccines/adverse effects , Myocarditis/etiology , COVID-19/prevention & control , SARS-CoV-2 , Arrhythmias, Cardiac , Vaccination , Autopsy , RNA, MessengerABSTRACT
Patients with bipolar disorder often report self-perceived treatment resistance. However, it is not known to what extent it is due to actual treatment resistance. The Juntendo University provides "Bipolar Disorder Treatment Rebuilding Program," in which patients with self-reported treatment resistant bipolar disorder are hospitalized for 2 weeks and undergo detailed examinations. In this study, we report our experience with the initial 43 patients hospitalized during the one and half years after the launch of the program. Among the patients who underwent full assessment, only one was regarded as having genuine treatment-resistant bipolar disorder without comorbidity. In other cases, ten were not diagnosed with bipolar disorder, 3 had organic brain diseases, 12 had comorbid mental disorders and its symptoms were regarded as treatment-resistant bipolar symptoms by the patients, and 18 did not receive adequate treatment because attendant physicians did not adhere to the treatment guidelines or patients did not adhere to the treatment because of lack of insight. The number of participants was not large, and selection bias hampered the generalization of the findings. Insight and adherence were assessed without the use of validated tools. We could not verify recovery after adequate treatment because of the limited hospitalization period. The findings suggest that most patients with self-perceived treatment-resistant bipolar disorder may not have genuine treatment-resistant bipolar disorder. These results shed light on the difficulties of public education of bipolar disorder and importance of providing appropriate services for diagnosis and treatment of bipolar disorder in the community.
Subject(s)
Bipolar Disorder , Brain Diseases , Humans , Bipolar Disorder/drug therapy , Brain , Allied Health Personnel , HospitalizationABSTRACT
Adenocarcinomas with enteroblastic differentiation are rare clear cell tumors that are positive for enteroblastic markers. Enteroblastic differentiation is particularly uncommon in colorectal adenocarcinomas. Herein, we report a case of clear cell adenocarcinoma with enteroblastic differentiation in the sigmoid colon of a 38-year-old Japanese woman that metastasized to the lower left ureter. After neoadjuvant chemotherapy, the patient underwent low anterior resection. The tumor consisted of tubular, cribriform, and focal micropapillary proliferation of clear cells immunopositive for spalt-like transcription factor 4 (SALL4), glypican 3, and alpha-fetoprotein. Six months after the colonic resection, a tumor was found in the left lower ureter, which was resected. The ureteral tumor revealed clear cell adenocarcinoma, which was identical to the colonic tumor proliferating in the ureteral mucosa. Metastatic ureteral tumors are rare. We performed a literature search and found only 50 reported cases of ureteral metastases from colorectal cancer. Of these, only 10 metastatic tumors were identified in the ureteral mucosa. No case of ureteral metastasis of clear cell colorectal adenocarcinoma or colorectal adenocarcinoma with enteroblastic differentiation has been reported. Hence, it can be challenging to distinguish them from clear cell adenocarcinoma of the urinary tract and/or clear cell urothelial carcinoma. This paper discussed the differential diagnosis of these tumors and reviewed the clinicopathological features of colorectal carcinomas metastasizing to the ureter.
Subject(s)
Adenocarcinoma, Clear Cell , Carcinoma, Transitional Cell , Colonic Neoplasms , Colorectal Neoplasms , Stomach Neoplasms , Urinary Bladder Neoplasms , Urinary Tract , Female , Humans , Adult , Adenocarcinoma, Clear Cell/diagnosis , Biomarkers, Tumor , Stomach Neoplasms/pathology , Colonic Neoplasms/diagnosis , Urinary Tract/pathology , Cell DifferentiationABSTRACT
Aim: To investigate the real-world effectiveness and safety of lemborexan for treating comorbid insomnia associated with other psychiatric disorders, and whether lemborexant helps reduce the dose of benzodiazepines (BZs). Methods: This retrospective observational study was conducted on outpatients and inpatients treated by physicians of Juntendo University Hospital Mental Clinic between April 2020 and December 2021. Results: Data of 649 patients who were treated with lemborexant were eventually enrolled. About 64.5% of patients were classified as the responder group. Response rates of ≥60% were recorded for most psychiatric disorders. Upon administration of lemborexant, diazepam-equivalent dose of BZs had been significantly reduced in participants (3.7 ± 8.2 vs. 2.9 ± 7.9, p < 0.001). The results of logistic regression analysis showed that outpatient (odds ratios: 2.310; 95% confidence interval [CI]: 1.32-4.05), shorter duration of BZ use (<1 year) (odds ratios: 1.512; 95% CI: 1.02-2.25), no adverse events (odds ratios: 10.369; 95% CI: 6.13-17.54), larger reduction of diazepam-equivalent dose of BZs upon introducing lemborexant prescription (odds ratios: 1.150; 95% CI: 1.04-1.27), and suvorexant was the replacement drug (odds ratios: 2.983; 95% CI: 1.44-6.19), which were significant predictors of good response. Conclusion: Although this is a retrospective and observational study with many limitations, our study results suggest that lemborexant is effective and safe.
ABSTRACT
Psychotic-like experiences (PLEs) occur occasionally in adolescence and mostly disappear with increasing age. Their presence, if persistent, is considered a robust risk factor for subsequent psychiatric disorders. To date, only a few biological markers have been investigated for persistent PLE prediction. This study identified urinary exosomal microRNAs that can serve as predictive biomarkers for persistent PLEs. This study was part of a population-based biomarker subsample study of the Tokyo Teen Cohort Study. A total of 345 participants aged 13 (baseline) and 14 (follow-up) years underwent PLE assessments by experienced psychiatrists using semi-structured interviews. We defined remitted and persistent PLEs based on longitudinal profiles. We obtained urine at baseline and the expression levels of urinary exosomal miRNAs were compared between 15 individuals with persistent PLEs and 15 age- and sex-matched individuals with remitted PLEs. We constructed a logistic regression model to examine whether miRNA expression levels could predict persistent PLEs. We identified six significant differentially expressed microRNAs, namely hsa-miR-486-5p, hsa-miR-199a-3p, hsa-miR-144-5p, hsa-miR-451a, hsa-miR-143-3p, and hsa-miR-142-3p. The predictive model showed an area under the curve of 0.860 (95% confidence interval: 0.713-0.993) for five-fold cross-validation. We found a subset of urinary exosomal microRNAs that were differentially expressed in persistent PLEs and presented the likelihood that a microRNA-based statistical model could predict them with high accuracy. Therefore, urine exosomal miRNAs may serve as novel biomarkers for the risk of psychiatric disorders.
ABSTRACT
We examined whether common variants from the extended major histocompatibility complex (xMHC) region contribute to the response to antipsychotic drugs (APDs) in patients with schizophrenia with persistent psychosis. Subjects participated in a prospective longitudinal study of the effect of APDs on psychopathology were temporally split into discovery (n = 88) and replication (n = 42) cohorts. The primary endpoint was a change in Brief Psychiatric Rating Scale at 6-week or 6-month after treatment. rs204991 (ß = 3.917, p = 3.72 × 10-6), the strongest signal associated with response at 6-week was located near C4A/C4B after a linear regression adjusted for covariates. xMHC SNP imputation disclosed much stronger signals (rs9268469, ß = 5.140, p = 1.57 × 10-7) and other weaker signals (p < 1 × 10-5) spanning the entire xMHC region. All the variants were previously identified schizophrenia risk loci. Conditional fine-mapping revealed three subgroups of SNPs which were the eQTLs (p < 1 × 10-7) for C4A, HLA-C, and BTN3A2 in disease-relevant tissue. Epistasis between HLA-C and C4A was observed (p = 0.019). Minor allele (G) carriers of rs204991, eQTL for C4A, having decreased risk for schizophrenia and lower imputed expression of C4A, had a better response to APDs. Some imputed HLA alleles associated with a decreased risk for schizophrenia had a positive association with improvement in psychotic symptoms. An independent cohort validated the association of change in psychosis with C4A. We provide evidence that genetic risk factors for schizophrenia from the xMHC region are associated with response to APDs and those variants significantly alter the imputed expression of C4A, HLA-C, and BTN3A2. The minor alleles predicting higher C4A level are associated with diminished improvement in psychotic symptoms after APD treatment.
Subject(s)
Antipsychotic Agents , Psychotic Disorders , Schizophrenia , Alleles , Antipsychotic Agents/therapeutic use , Humans , Longitudinal Studies , Prospective Studies , Psychotic Disorders/complications , Psychotic Disorders/drug therapy , Psychotic Disorders/genetics , Schizophrenia/complications , Schizophrenia/drug therapy , Schizophrenia/geneticsABSTRACT
Intrahepatic cholangiocarcinoma with rhabdoid morphology is rare, and only three case reports have been published to date, none of which discuss the genetic changes in the rhabdoid component. We present a case of intrahepatic cholangiocarcinoma with focal rhabdoid features and SMARCA4-deficiency detected using immunohistochemistry. A Japanese man in his 60s without viral hepatitis was diagnosed with an avascular tumor in the liver, measuring 4.4â cm in the greatest dimension. The tumor was mostly composed of moderately differentiated adenocarcinoma, focal poorly differentiated adenocarcinoma, and an undifferentiated rhabdoid component. Immunohistochemical analysis showed an inclusion-like staining pattern for keratin AE1/AE3 and vimentin in the rhabdoid component. BRG1/SMARCA4 was detected in the differentiated component but not in the poorly- and undifferentiated components. Our novel findings reflecting the morphological and genetic heterogeneity of intrahepatic cholangiocarcinoma and will aid the research on drugs targeting the aberrant SWItch/Sucrose NonFermentable complex.
Subject(s)
Adenocarcinoma , Bile Duct Neoplasms , Cholangiocarcinoma , Rhabdoid Tumor , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/genetics , Bile Ducts, Intrahepatic/pathology , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/genetics , DNA Helicases/genetics , Humans , Immunohistochemistry , Male , Nuclear Proteins/genetics , Rhabdoid Tumor/diagnosis , Rhabdoid Tumor/genetics , Rhabdoid Tumor/pathology , Transcription Factors/geneticsABSTRACT
We previously identified a subtype of schizophrenia (SCZ) characterized by increased plasma pentosidine, a marker of glycation and oxidative stress (PEN-SCZ). However, the genetic factors associated with PEN-SCZ have not been fully clarified. We performed a genome-wide copy number variation (CNV) analysis to identify CNVs associated with PEN-SCZ to provide an insight into the novel therapeutic targets for PEN-SCZ. Plasma pentosidine was measured by high-performance liquid chromatography in 185 patients with SCZ harboring rare CNVs detected by array comparative genomic hybridization. In three patients with PEN-SCZ showing additional autistic features, we detected a novel deletion at 7q31.1 within exons 2 and 3 of IMMP2L, which encodes the inner mitochondrial membrane peptidase subunit 2. The deletion was neither observed in non-PEN-SCZ nor in public database of control subjects. IMMP2L is one of the SCZ risk loci genes identified in a previous SCZ genome-wide association study, and its trans-populational association was recently described. Interestingly, deletions in IMMP2L have been previously linked with autism spectrum disorder. Disrupted IMMP2L function has been shown to cause glycation/oxidative stress in neuronal cells in an age-dependent manner. To our knowledge, this is the first genome-wide CNV study to suggest the involvement of IMMP2L exons 2 and 3 in the etiology of PEN-SCZ. The combination of genomic information with plasma pentosidine levels may contribute to the classification of biological SCZ subtypes that show additional autistic features. Modifying IMMP2L functions may be useful for treating PEN-SCZ if the underlying biological mechanism can be clarified in further studies.
Subject(s)
Schizophrenia , Autism Spectrum Disorder , Comparative Genomic Hybridization , DNA Copy Number Variations , Endopeptidases , Exons , Genome-Wide Association Study , Humans , Oxidative Stress , Schizophrenia/genetics , Schizophrenia/pathologyABSTRACT
Muscular strength, assessed by handgrip, is a risk indicator for psychiatric disorders, including psychosis. However, the biological mechanisms underlying this association remain unclear. Since advanced glycation end products (AGEs) play a key role in skeletal muscle underdevelopment and psychosis, we examined the role of AGEs in the longitudinal association between muscular strength and psychotic symptoms among adolescents. We first evaluated the direction of the relationship between handgrip strength and urine levels of pentosidine, a representative AGEs in a population-based birth cohort of 1,542 adolescents at ages 12 and 14. Then, we examined the role of AGEs in the longitudinal association between handgrip strength and thought problems (TP), as a psychotic symptom indicator, in a subsample of 256 adolescents at ages 13 and 14. An autoregressive cross-lagged model revealed that handgrip strength at age 12 negatively predicted pentosidine levels at age 14 (ß = -0.20, p < 0.001), whereas pentosidine levels at age 12 did not predict handgrip strength at age 14 (ß = 0.04, p = 0.062). Moreover, pentosidine levels had a significant indirect effect on the relationship between handgrip strength and TP (standard indirect effect = -0.051, p = 0.012), which remained significant after adjusting for gender and preceded TP and pentosidine levels. Thus, adolescents with low muscular strength are at a high risk of developing psychotic symptoms, which could be mediated by AGEs. Future studies need to investigate whether interventions focused on muscular strength prevent the accumulation of AGEs and thereby prevent the development of psychosis.
ABSTRACT
We have reported that a subpopulation of patients with schizophrenia have lower levels of vitamin B6 (VB6) in peripheral blood than do healthy controls. In a previous study, we found that VB6 level was inversely proportional to the patient's positive and negative symptom scale (PANSS) score for measuring symptom severity, suggesting that the loss of VB6 might contribute to the development of schizophrenia symptoms. In the present study, to clarify the relationship between VB6 deficiency and schizophrenia, we generated VB6-deficient (VB6(-)) mice through feeding with a VB6-lacking diet as a mouse model for the subpopulation of schizophrenia patients with VB6 deficiency. After feeding for 4 weeks, plasma VB6 level in VB6(-) mice decreased to 3% of that in control mice. The VB6(-) mice showed social deficits and cognitive impairment. Furthermore, the VB6(-) mice showed a marked increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brain, suggesting enhanced noradrenaline (NA) metabolism in VB6(-) mice. We confirmed the increased NA release in the prefrontal cortex (PFC) and the striatum (STR) of VB6(-) mice through in vivo microdialysis. Moreover, inhibiting the excessive NA release by treatment with VB6 supplementation into the brain and α2A adrenoreceptor agonist guanfacine (GFC) suppressed the increased NA metabolism and ameliorated the behavioral deficits. These findings suggest that the behavioral deficits shown in VB6(-) mice are caused by enhancement of the noradrenergic (NAergic) system.
Subject(s)
Cognitive Dysfunction , Vitamin B 6 Deficiency , Animals , Diet , Humans , Mice , Norepinephrine , Vitamin B 6ABSTRACT
Previously, we identified a subpopulation of schizophrenia (SCZ) showing increased levels of plasma pentosidine, a marker of glycation and oxidative stress. However, its causative genetic factors remain largely unknown. Recently, it has been suggested that dysregulated posttranslational modification by copy number variable microRNAs (CNV-miRNAs) may contribute to the etiology of SCZ. Here, an integrative genome-wide CNV-miRNA analysis was performed to investigate the etiology of SCZ with accumulated plasma pentosidine (PEN-SCZ). The number of CNV-miRNAs and the gene ontology (GO) in the context of miRNAs within CNVs were compared between PEN-SCZ and non-PEN-SCZ groups. Gene set enrichment analysis of miRNA target genes was further performed to evaluate the pathways affected in PEN-SCZ. We show that miRNAs were significantly enriched within CNVs in the PEN-SCZ versus non-PEN-SCZ groups (p = 0.032). Of note, as per GO analysis, the dysregulated neurodevelopmental events in the two groups may have different origins. Additionally, gene set enrichment analysis of miRNA target genes revealed that miRNAs involved in glycation/oxidative stress and synaptic neurotransmission, especially glutamate/GABA receptor signaling, were possibly affected in PEN-SCZ. To the best of our knowledge, this is the first genome-wide CNV-miRNA study suggesting the role of CNV-miRNAs in the etiology of PEN-SCZ, through effects on genes related to glycation/oxidative stress and synaptic function. Our findings provide supportive evidence that glycation/oxidative stress possibly caused by genetic defects related to the posttranscriptional modification may lead to synaptic dysfunction. Therefore, targeting miRNAs may be one of the promising approaches for the treatment of PEN-SCZ.
Subject(s)
MicroRNAs , Schizophrenia , DNA Copy Number Variations , Humans , MicroRNAs/genetics , Schizophrenia/geneticsABSTRACT
Plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) concentration increases with progression of myxomatous mitral valve disease (MMVD) in dogs. This multicentre, prospective study compared plasma NT-proANP, N-terminal pro-brain natriuretic peptide (NT-proBNP), ANP, and cardiac troponin I (cTnI) concentrations in dogs with MMVD for their characteristics and discriminatory ability to detect cardiac dilatation and congestive heart failure (CHF). Thirty-six healthy dogs and 69 dogs with MMVD were included. Clinical variables were obtained via physical examination, thoracic radiography, and echocardiography. The discriminatory ability of each cardiac biomarker (CB) to determine the presence or absence of cardiac dilatation (event 1) and CHF (event 2) was evaluated using the receiver operating characteristic curves. Plasma NT-proANP, NT-proBNP, and ANP concentrations showed a significant association with the left atrium/aorta ratio (P<0.01). The area under the curve of plasma NT-proANP and NT-proBNP concentrations were 0.72 and 0.75, respectively in event1 and 0.72 and 0.76, respectively in event2. Plasma NT-proANP and NT-proBNP concentrations showed sensitivity 80.0 and 80.0%; specificity 67.6 and 64.7% in event1 (cutoff value; 8,497.81 pg/ml and 1,453.00 pmol/l, respectively) and sensitivity 85.7 and 81.0%; specificity 60.4 and 64.6% in event2 (cutoff value; 8,684.33 pg/ml and 1,772.00 pmol/l, respectively). In dogs with MMVD, plasma NT-proANP, NT-proBNP, and ANP concentrations increase with left atrial enlargement. Particularly, plasma NT-proANP and NT-proBNP concentrations appeared to be equally useful in the discriminatory ability to detect cardiac dilatation and CHF.
Subject(s)
Atrial Natriuretic Factor , Dog Diseases , Animals , Biomarkers , Dog Diseases/diagnosis , Dogs , Mitral Valve , Natriuretic Peptide, Brain , Peptide Fragments , Prospective StudiesABSTRACT
Advanced glycation end products play a key role in the pathophysiology of schizophrenia. Cognitive impairment is one of the central features of schizophrenia; however, the association between advanced glycation end products and cognitive impairment remains unknown. This study investigated whether advanced glycation end products affect the cognitive domain in patients with schizophrenia. A total of 58 patients with chronic schizophrenia were included in this cross-sectional study. Plasma advanced glycation end products were measured using high-performance liquid chromatography (HPLC). Neuropsychological and cognitive functions were assessed using the Wechsler Adult Intelligence Scale, Third Version, and the Wisconsin Card Sorting Test Keio-FS version. Multiple regression analysis adjusted for age, sex, body mass index, educational years, daily dose of antipsychotics, and psychotic symptoms revealed that processing speed was significantly associated with plasma pentosidine, a representative advanced glycation end product (standardized ß = -0.425; p = 0.009). Processing speed is the cognitive domain affected by advanced glycation end products. Considering preceding evidence that impaired processing speed is related to poor functional outcome, interventions targeted at reducing advanced glycation end products may contribute to promoting recovery of patients with schizophrenia as well as cognitive function improvement.
Subject(s)
Cognitive Dysfunction/metabolism , Glycation End Products, Advanced/metabolism , Schizophrenia/metabolism , Arginine/analogs & derivatives , Arginine/metabolism , Cognition/physiology , Cross-Sectional Studies , Female , Humans , Lysine/analogs & derivatives , Lysine/metabolism , Male , Middle Aged , Neuropsychological Tests , Receptor for Advanced Glycation End Products/metabolismABSTRACT
Methylglyoxal (MG) is a reactive and cytotoxic α-dicarbonyl byproduct of glycolysis. Our bodies have several bio-defense systems to detoxify MG, including an enzymatic system by glyoxalase (GLO) 1 and GLO2. We identified a subtype of schizophrenia patients with novel mutations in the GLO1 gene that results in reductions of enzymatic activity. Moreover, we found that vitamin B6 (VB6) levels in peripheral blood of the schizophrenia patients with GLO1 dysfunction are significantly lower than that of healthy controls. However, the effects of GLO1 dysfunction and VB6 deficiency on the pathophysiology of schizophrenia remains poorly understood. Here, we generated a novel mouse model for this subgroup of schizophrenia patients by feeding Glo1 knockout mice VB6-deficent diets (KO/VB6(-)) and evaluated the combined effects of GLO1 dysfunction and VB6 deficiency on brain function. KO/VB6(-) mice accumulated homocysteine in plasma and MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed behavioral deficits, such as impairments of social interaction and cognitive memory and a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-sequencing and weighted gene co-expression network analysis (WGCNA). Finally, we demonstrated abnormal mitochondrial respiratory function and subsequently enhanced oxidative stress in the PFC of KO/VB6(-) mice in the PFC. These findings suggest that the combination of GLO1 dysfunction and VB6 deficiency may cause the observed behavioral deficits via mitochondrial dysfunction and oxidative stress in the PFC.
Subject(s)
Lactoylglutathione Lyase , Schizophrenia , Vitamin B 6 Deficiency , Animals , Humans , Lactoylglutathione Lyase/genetics , Lactoylglutathione Lyase/metabolism , Mice , Mitochondria/metabolism , Mitochondria/pathology , Prefrontal Cortex/metabolism , Schizophrenia/geneticsABSTRACT
Case control studies have suggested that advanced glycation end products play a key role in the pathophysiology of chronic schizophrenia. However, the longitudinal association between advanced glycation end products and psychotic symptoms among drug-naïve adolescents remains unclear. This study examined whether advanced glycation end products could predict the trajectory of psychotic symptoms in drug-naive adolescents using data from prospective population-based biomarker subsample study of the Tokyo Teen Cohort. A total of 277 community-dwelling adolescents aged 13 years without antipsychotic medication were analyzed. Fingertip advanced glycation end products were measured in adolescents using noninvasive technology that can be used quickly. The trajectory of psychotic symptoms in a 12-month follow-up was assessed by experienced psychiatrists using a semi-structured interview. Of the 277 participants, 13 (4.7%) experienced persistent psychotic symptoms (psychotic symptoms at baseline and follow-up), 65 (23.5%) experienced transient psychotic symptoms (psychotic symptoms at baseline or follow-up), and 199 (71.8%) did not have psychotic symptoms. Multinomial logistic regression analysis adjusted for age and sex revealed that baseline fingertip advanced glycation end products might predict the risk of persistent psychotic symptoms (odds ratio = 1.68; 95% confidence interval, 1.05-2.69; P = 0.03). Altogether, fingertip advanced glycation end products potentially predicted the trajectory of psychotic symptoms among drug-naive adolescents, which indicated its involvement in the pathophysiology of early psychosis. Further studies are required to identify strategies to reduce adolescent advanced glycation end products, which may contribute to preventing the onset of psychosis.
ABSTRACT
Genomic defects with large effect size can help elucidate unknown pathologic architecture of mental disorders. We previously reported on a patient with schizophrenia and a balanced translocation between chromosomes 4 and 13 and found that the breakpoint within chromosome 4 is located near the LDB2 gene. We show here that Ldb2 knockout (KO) mice displayed multiple deficits relevant to mental disorders. In particular, Ldb2 KO mice exhibited deficits in the fear-conditioning paradigm. Analysis of the amygdala suggested that dysregulation of synaptic activities controlled by the immediate early gene Arc is involved in the phenotypes. We show that LDB2 forms protein complexes with known transcription factors. Consistently, ChIP-seq analyses indicated that LDB2 binds to > 10,000 genomic sites in human neurospheres. We found that many of those sites, including the promoter region of ARC, are occupied by EGR transcription factors. Our previous study showed an association of the EGR family genes with schizophrenia. Collectively, the findings suggest that dysregulation in the gene expression controlled by the LDB2-EGR axis underlies a pathogenesis of subset of mental disorders.