BackgroundSchizophrenia is a chronic debilitating mental disorder. Children with schizophrenia have been found having potentially greater loading of family histories for schizophrenia and more severe premorbid neurodevelopmental abnormalities, worse long-term outcome, and higher rates of mental disability than their adult counterparts. Accumulating evidences demonstrated that abnormal neurodevelopment plays a key role in the etiology of schizophrenia, and it may refer as abnormalities of brain structure and function. Neurological soft signs(NSS) are subtle signs of brain funtion disorders, and are associated with abnormal neurodevelopment of mental illness. NSS are considered as the endophenotype of schizophrenia. Disrupted-in-schizophrenia-1(DISC1) is a strong susceptibility gene of schizophrenia and plays a key role in neuronal development processes such as neural precursor proliferation, neuronal migration and maturation.Objectives1. To investigate the prevalence of NSS in children with schizophrenia.2. To analysis the associations of NSS with brain stucture in children with schizophrenia.3. To explore associations of NSS and brain stucture with DISC1rs4658971polymorphism in children with schizophrenia.4. To explore the associations of DISC1rs4658971polymorphism with schizophrenia.Methods 1. The severity of NSS was measured with the soft signs assessment subscales of the Cambridge Neurological Inventory (CNI) in both192schizophrenia children and196age-and gender-matched healthy children.2.307schizophrenia children whose course of disease was less than24months were measured employing structural magnetic resonance imaging (MR1) at0.2Tesla. Measuring diameters comprised transverse diameter of third ventricle, distance from lateral wall of third ventricle to left surface of insula, distance from lateral wall of third ventricle to right surface of insula, width of lateral ventricle anterior horn, largest width of lateral ventricle body, width of left temporal horn, width of right temporal horn, width of left lateral fissure, width of right lateral fissure, width of frontal sulci, width of parietal sulci, width of fissura longitudinalis cerebri, width of left head of caudate nucleus, width of right head of caudate nucleus, depth of corpus callosum.3. In this case-control study, DISCI rs4658971polymorphism of445children with schizophrenia and432healthy adult controls were examined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.4. Psychotic symptoms were assessed using Positive and Negative Symptom Scale (PANSS) in445children with schizophrenia.5. Chi-square test was used to compare the differences of positive rates of neurological soft signs between schizophrenia patients and healthy children controls and among patients of different genotypes of DISCI rs4658971, genotype and allele frequencies between schizophrenia patients and healthy adult comparison subjects. Spearman correlation analysis(rs represents correlation coefficent) was used to analyze the relationships of NSS scores with both brain structure measurement values and PANSS scores. Pearson correlation analysis (r represents correlation coefficent) was used to analyze the relationships between brain structure measurement values and PANSS scores. Mann-Whitney U test was usd to compare the differences of neurological soft signs scores between schizophrenia patients and healthy children controls, NSS scores among patients of different genotypes of DISCI rs4658971. T test was used to compare the differences of PANSS scores among patients of different genotypes of DISCI rs4658971. Analysis of covariance(age as a covariate) was used to compare the differences of brain structure measurement values among patients of different genotypes of DISCI rs4658971. Inspection level alpha was0.05, two-sided test. In order to avoid errors due to multiple factors, multiple test correction was conducted.Results1. The comparison of NSS between children with schizophrenia and healthy children controls(1) Positive rates of neurological soft signs in children with schizophrenia and healthy children controls were7.8%-66.7%,2.6%-34.7%. The comparison of positive rates of neurological soft signs between children with schizophrenia and healthy children controls showed that schizophrenia patients had higher positive rates of neurological soft signs in the items of left and right finger-thumb tapping(χ2=16.98,5.18), left and right finger thumb opposition(χ2=25.25,13.82), left and right diadochokinesis(χ2=17.59,15.91), left and right fist-edge-palm test(χ2=37.26,39.67), oseretsky test(χ2=32.03), right finger agnosia(χ2=4.36), left and right graphesthesia(χ2=24.12,12.97), right mirror movement of finger thumb opposition(χ2=4.88), saccade head(χ2=6.25), wink(χ2=8.12);the diferences were statistially significant(P<0.05). After multiple test correction, schizophrenia patients had higher positive rates in the terms of left finger-thumb tapping, left and right finger thumb opposition, left and right diadochokinesis, left and right fist-edge-palm test, oseretsky test, left and right graphesthesia than children controls.(2) Nonparameter test results showed that NSS total scores, motor oordination scores, sensory integration scores, disinhibition scores (Z=-8.535,-9.133,-5.125,-3.639) of schizophrenia patients was higher than healthy children controls; the diferences were statistially significant(P<0.01).2. The correlation analyses among NSS, brain structure and psychotic symptoms (1) Spearman correlation analysis showed that NSS total scores were inversely correlated with distance from lateral wall of third ventricle to left surface of insula (rs=-0.253) and positively correlated with transverse diameter of third ventricle (rs=0.285), width of left and right lateral fissure (rs=0.197,0.189). Motor coordination scores were positively correlated with transverse diameter of third ventricle, largest width of lateral ventricle body, width of right lateral fissure, width of frontal sulci(rs=0.291,0.241,0.206,0.206). Sensory integration scores were inversely correlated with distance from lateral wall of third ventricle to left surface of insula (rs=-0.250) and positively correlated with width of left lateral fissure (rs=0.215). Disinhibition scores were positively correlated with transverse diameter of third ventricle (rs=0.184). correlation coefficent test was statistially significant(P<0.05). After multiple test correction, NSS total scores and motor coordination scores were positively correlated with transverse diameter of third ventricle.(2) Spearman correlation analysis showed that PANSS total scores were positively correlated with width of frontal sulci (rs=0.015), negative symptom scores are positively correlated with width of left temporal horn, width of frontal sulci (rs=0.055,0.281). General psychopathology scores were positively correlated with width of frontal sulci; correlation coefficent test was statistially significant(P<0.05).(3) Pearson correlation analysis showed that PANSS total scores were positively correlated with width of right lateral fissure (rs=0.141); positive symptom scores were inversely correlated with distance from lateral wall of third ventricle to right surface of insula(rs=-0.188); negative symptom scores were positively correlated with transverse diameter of third ventricle and width of left temporal horn(rs=0.127,0.122) and inversely correlated with width of left and right head of caudate nucleus (rs=-0.146,-0.120); correlation coefficent test was statistially significant(P<0.05). After multiple test correction, positive symptom scores were inversely correlated with distance from lateral wall of third ventricle to right surface of insula.3. The comparision of NSS, brain structure measurements and psychotic symptoms among patients of different genotypes of DISCI rs4658971(1) Positive rate of neurological soft signs in DISCI rs4658971T allele carriers was9.0%~79.8%, which in CC genotype patients was6.8%~55.3%. The comparison showed that T allele carriers had higher positive rates of neurological soft signs than CC gentotype patinets in the items of left and right finger thumb opposition(χ2=8.22,5.82), left and right fist-edge-palm test(χ2=13.10,12.83), left and right graphesthesia(χ2=18.09,5.79), right mirror movement of finger thumb opposition(χ2=4.35), saccade head(χ2=8.29), wink(χ2=12.27); the diferences were statistially significant(P<0.05). After multiple test correction, DISCI rs4658971T allele carriers had higher positive rates in the terms of left and right fist-edge-palm test, left graphesthesia, wink.Nonparameter test results showed that NSS total scores, motor coordination scores, sensory integration scores, disinhibition scores (Z=-6.233,-3.418,-3.272,-4.516) of T allele carriers was higher than CC genotype patients.(2) Analysis of covariance (age as covariate) showed that there was statistically significant difference among different genotypes in the items of transverse diameter of third ventricle (F=126.070), width of left and right temporal horn (F=4.796,4.989), width of left lateral fissure (F=8.115), width of frontal sulci(F=7.498), width of parietal sulci (F=13.199), width of left and right head of caudate nucleus (F=11.463,4.032). Multiple test ajustment showed that transverse diameter of third ventricle of T allele carriers were larger than CC genotype patients; width of right head of caudate nucleuswere smaller than CC genotype patients.(3) T test results showed that PANSS total scores, positive symptom scores, negative symptom scores and general psychopathology scores (t=4.809,2.622,3.717,2.243) of T allele carriers were higher than CC genotype patients.4. The comparision of differences of DISCI rs4658971genotype and allele frequencies between schizophrenia patients and healthy adultThere were no associations in the distribution of genotype and allele frequencies of DISCI SNPrs4658971between children with schizophrenia and healthy adult controls(χ2=2.70,2.28; P=0.26,0.13).Conclusions1. Children with schizophrenia had more obvious neurological soft signs than healthy children controls.2. Children with schizophrenia whose positive rates and scores were higher had larger ventricle and more obvious brain structure.3. DISCI rs4658971T allele carriers had more obvious NSS and ventricles enlargement, and smaller head of caudate nucleus, and more severe psychotic symptoms than CC genotype patients.4. This study didn’t support that DISCI rs4658971polymorphsim was associatede with childhood shizophrenia. |