Study On The Local Consistency Characteristics Of MMP-9 Gene Methylation And Resting State Functional Magnetic Resonance In Defective Schizophrenia

Part I: DNA methylation and gene expression of matrix metalloproteinase-9 gene in deficit and non-deficit schizophreniaBackground The biological pathology of deficit schizophrenia(DS)remains unclear.Matrix metalloproteinase-9(MMP-9)might be associated with neural plasticity and glutamate regulation,involved in schizophrenia pathogenesis.This study explored gene expression and DNA methylation of MMP-9 in peripheral blood mononuclear cells(PBMCs)and their relationship with clinical symptoms in DS and non-deficit schizophrenia(NDS).Materials and Methods Pyrosequencing was used to determine DNA methylation at Cp G sites in exon 4 and exon 5 of MMP-9 gene in 51 DS patients,53 NDS patients and 50 healthy subjects(HC).RT-q PCR was used to detect MMP-9 gene expression.Clinical symptoms were assessed by BPRS,SANS and SAPS scales.Differences of gene expression and DNA methylation between three groups were determined through ANCOVA analyses,post hoc analyses were used to compare differeces between DS and NDS groups.Results MMP-9 gene expression in PBMCs was significantly higher in DS than NDS and HC subjects.Compared to NDS patients,DS patients had significantly lower DNA methylation at individual Cp G sites in exon 4 and exon 5 of MMP-9 gene.Correlation analysis showed that DNA methylation in exon 4 was negatively correlated with gene expression in DS group.Positive correlation was found between MMP-9 gene expression and negative symptoms in total schizophrenic patients.The social amotivation factor of SANS and negative syndrome of BPRS was negatively correlated with DNA methylation of Cp G5-1 in DS patients but not in NDS patients.Conclusions DS patients showed a specific abnormality of peripheral MMP-9 gene expression and DNA methylation,indicating a pathological mechanism underlying DS as a specific subgroup of schizophrenia.Part II: DNA methylation and gene expression of matrix metalloproteinase-9 gene in deficit and non-deficit schizophreniaObjective To identify the characteristics of neurocognitive impairment in patients with deficit schizophrenia.Explore the correlation between neruocognitive function and DNA methylation of MMP-9 gene and in DS and NDS subgroup.Materials and Methods A neuropsychological battery including Spatial Processing Block design,Trail Making Test and Stroop Color-Words Test was used to assess the neurocognitive function in 46 DS patients,51 NDS patients and 44 HC subjects.Pyrosequencing was used to determine DNA methylation at Cp G sites of MMP-9 gene.Stepwise regression and partial correlation analyses were performed to determine the relationship among clinical variables and neurocognitive impairment and DNA methylation of MMP-9 in DS patients and NDS patients respectively.Results Both DS and NDS suffered more severe cognitive impairments than HC and DS patients performed worse than NDS in each neurocognitive component.The SANS scores contributed an effect on each neurocognitive component in DS group,while the clinical variables such as duration,onset and SAPS scores had an effect on TMT-B and Stroop-words in NDS patients.Partial correlation analyses showed that DNA methylation in Cp G4-5 of MMP-9 gene was negatively correlated with timeconsuming of TMT-B test,methylation in Cp G5-4 was positive correlated with scores of Spatial Processing Block design test in DS patients.There is no significant association between neurocognitive impairment and Cp G site methylation of MMP-9 gene in NDS patients.Conclusions DS patients showed a specific abnormality of neurocognitive impairment.The spatial memory and executive function were associated with DNA methylation of individual Cp G site.Indicating a pathological mechanism underlying impairment of neurocognitive in DS patients.Part III: The abnormalities of regional homogeneity in the resting-state functional magnetic resonance imaging were associated with impairment of attention function in deficit schizophreniaObjective To identify the characteristics of regional homogeneity(Re Ho)of resting state brain activity and explore the association with the attention function in patients with deficit schizophrenia(DS).Method The patients were recruited with the diagnosis of schizophrenia according to DSM-IV and divided into DS and non-deficit schizophrenia(NDS)sub-groups according to the Chinese version of the Schedule for the Deficit Syndrome(SDS).30 DS patients and 38 NDS patients,accompanying with 38 healthy controls(HC)who were age-,gender-and handedness-matched with the patients were enrolled.The severity of schizophrenic symptoms was evaluated by the Brief Psychiatric Rating Scale(BPRS),the Scale for the Assessment of Negative Symptoms(SANS),and the Scale for the Assessment of Positive Symptoms(SAPS).The Stroop Color-Word test were used to assess the attention function of subjects.All participants were scanned using a 3.0 T MRI system(GE HDx)for the resting-state f MRI data.The Re Ho was calculated and compared within three groups.A partial correlation analysis was further performed to explore the relationships between these difference Re Ho and attention function within the specific group.Results The Stroop colors,Stroop words,Stroop interference test scores were lower in both DS and NDS groups than healthy controls group.DS patients showed lower scores in Stroop colors,Stroop word test than NDS patients.Compared with NDS patients,DS patients showed significant increased Re Ho in left and right lingual gyrus,left inferior temporal gyrus,right middle temporal gyrus/superior temporal gyrus,right middle occipital gyrus,and the significant decreased Re Ho in left medial superior frontal gyrus/anterior cingulate gyrus,right triangular part of inferior frontal gyrus/middle frontal gyrus,left triangular part of inferior frontal gyrus.The Re Ho of left inferior frontal gyrus triangular was positive correlated with Stroop words test and Stroop interference test and showed no significant correlation with Stroop colors test.There was no significant correlation between the Re Ho and Stroop test scores in other areas.NDS patients showed a negative result in correlation analysis.Conclusion Compared with NDS patients,DS patients exhibited more serious in sustained attention function,which might be related to brain activity regional homogeneity in left triangular part of inferior frontal gyrus.