Xueli Sun

Changes of brain morphometry in first-episode, drug-naïve, non-late-life adult patients with major depression: an optimized voxel-based morphometry study.

BACKGROUND Previous structural imaging studies found evidence of brain morphometric changes in major depression (MD) patients, but they rarely excluded compounding effects of some important factors, such as medication and brain degeneration. This study sought to explore the brain morphometric changes of first-episode, drug-naïve, non-late-life adult MD patients with optimized voxel-based morphometry (VBM) method. METHODS Twenty-three first-episode, drug-naïve, non-late-life adult depressed patients and 23 healthy control subjects were enrolled in this study. Subjects underwent high-resolution magnetic resonance imaging, and optimized VBM was performed to analyze the morphometric data. A partial correlation model was used to analyze associations of morphometric changes with Hamilton Depression Rating Scale scores and illness duration. RESULTS Depressed patients showed significant gray matter volume reduction in the bilateral limbic system, especially in hippocampus. These changes did not significantly correlate with symptom severity or illness duration. CONCLUSIONS Our findings provided new evidence of gray matter deficits in first-episode, drug-naïve, non-late-life adult MD patients. It supported that the reduction of hippocampal volume is a trait for MD patients and further highlighted the important role of the limbic system, particularly hippocampus in the pathophysiology of MD.

Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population

Haploinsufficiency for or mutation in at least one gene from the velocardiofacial syndrome (VCFS) region at chromosome 22q11 is implicated in psychosis. Linkage disequilibrium mapping of the region in patients identified a segment containing two genes, proline dehydrogenase (PRODH) and DGCR6, as candidates [Liu et al., 2002a ] and by analysis of additional polymorphisms the PRODH gene was associated with schizophrenia in adult and early onset patients. In the present study we provide additional evidence in support of genetic association between PRODH and schizophrenia in a Chinese population. We analyzed the PRODH gene in a samples of schizophrenic patients and their families from Sichuan, SW China consisting of 528 family trios and sibling pairs. We genotyped six SNPs, PRODH*1195C → T, PRODH*1482C → T, PRODH*1483A → G, PRODH*1766A → G, PRODH*1852G → A PRODH*1945T → C, two of which (PRODH*1483A → G and PRODH*1852G → A) have not been previously reported. We found association with schizophrenia for two haplotypes consisting of PRODH*1945T → C and PRODH*1852G → A (Global P = 0.006), and PRODH*1852G → A and PRODH*1766A → G (Global P = 0.01) which include one of the newly identified markers. After six‐fold Bonferroni correction for multiple testing the PRODH*1945T‐C/PRODH*1852G‐A haplotypes remained significant. This is a sub‐haplotype of the PRODH haplotype previously associated with schizophrenia and it also maps to the 3′ region of the gene, indicating that this is the region most likely to contain the underlying risk alleles. Overall this finding supports a role for the PRODH locus in schizophrenia.

Abnormal neural activities in first-episode, treatment-naïve, short-illness-duration, and treatment-response patients with major depressive disorder: A resting-state fMRI study

BACKGROUND Abnormality of limbic-cortical networks was postulated in depression. Using a regional homogeneity (ReHo) approach, we explored the regional homogeneity (ReHo) of the brain regions in patients with first-episode, treatment-naïve, short-illness-duration, and treatment-response depression in resting state to test the abnormality hypothesis of limbic-cortical networks in major depressive disorder (MDD). METHODS Seventeen patients with treatment-response MDD and 17 gender-, age-, and education-matched healthy subjects participated in the resting-state fMRI scans. RESULTS CONCLUSIONS Our findings suggested the abnormality of limbic-cortical networks in first-episode, treatment-naïve, short-illness-duration, and treatment-response MDD patients, and added an expanding literature to the abnormality hypothesis of limbic-cortical networks in MDD.

Depressive Disorders: Focally Altered Cerebral Perfusion Measured with Arterial Spin-labeling MR Imaging

PURPOSE To assess focal cerebral perfusion in patients with refractory depressive disorder (RDD), patients with nonrefractory depressive disorder (NDD), and healthy control subjects by using arterial spin-labeling (ASL) magnetic resonance (MR) imaging. MATERIALS AND METHODS This study was approved by the local ethical committee, and written informed consent was obtained from all participants. Twenty-four patients with RDD, 37 patients with NDD, and 42 healthy control subjects were included. From February 2006 to July 2007, all participants were imaged with a 3-T MR system. ASL and echo-planar images were subtracted and averaged to give perfusion-weighted images. Voxel-based analysis was performed. Region-of-interest analysis was applied to the bilateral hippocampi, thalami, and lentiform nuclei. RESULTS Patients with NDD showed reduced perfusion in the left prefrontal cortex versus control subjects and increased perfusion mainly in the limbic-striatal areas (P < .05). In contrast, patients with RDD had decreased perfusion predominantly in the bilateral frontal and bilateral thalamic regions (P < .05). Compared with patients with RDD, patients with NDD showed higher perfusion mainly in the limbic-striatal areas (P < .05). In region-of-interest analysis, the NDD group showed higher regional cerebral blood flow than both RDD and control groups in the left hippocampus (P = .045), right hippocampus (P = .001), and right lentiform nucleus (P = .049). CONCLUSION This study revealed alterations of regional perfusion in the brains of patients with RDD that differed from those in patients with NDD. These results are consistent with the concept that RDD is associated with decreased activity of the bilateral prefrontal areas; and NDD, with decreased activity of left frontal areas in conjunction with overactivity of the bilateral limbic system.

Neurocognitive deficits in first-episode schizophrenic patients and their first-degree relatives

Some neuropsychological abilities, particularly those affecting memory, attention and executive function, are impaired amongst both schizophrenic patients and their unaffected relatives, implying that these deficits are at least partly genetic in origin. However neuropsychological performance can be altered by medication, and has rarely been examined in first onset, drug naive patients. The objective of this study was to determine whether selected neurocognitive abilities are impaired in first‐onset schizophrenic patients and their relatives compared to controls. We examined attention and speed of information processing, memory and learning, verbal function, visuoconstructive abilities and executive function in 207 first‐episode schizophrenic patients (163 of whom were drug naïve), 322 of their first‐degree relatives and 133 unrelated normal controls. The data were subjected to multilevel modeling to compare neurocognitive performance between schizophrenic probands, relatives and controls while taking into account potential correlations among members of the same family; age, gender, and years of education were included as covariates. Of the three groups, schizophrenic patients performed poorest at all neuropsychological tests, suggestive of a broad range of neurocognitive deficits. Their first‐degree relatives showed a narrower pattern of poor performance at Digit Symbol, Digit Span, Trail Making, Verbal Fluency test, Tower of Hanoi, and WCST‐M tests. Our findings show that selected neurocognitive deficits especially attention and executive function are impaired in the families of schizophrenic patients. These patterns of neurocognitive deficits may represent “endophenotypes” denoting varying degrees of vulnerability to schizophrenia and may be of value in future molecular genetic studies.

Identifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations

The dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP ‘A’) in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia.

Abnormal neural activity of brain regions in treatment-resistant and treatment-sensitive major depressive disorder: A resting-state fMRI study

BACKGROUND Patients with treatment-resistant depression (TRD) and those with treatment-sensitive depression (TSD) responded to antidepressants differently. Previous studies have commonly shown that patients with TRD or TSD had abnormal neural activity in different brain regions. In the present study, we used a coherence-based ReHo (Cohe-ReHo) approach to test the hypothesis that patients with TRD or TSD had abnormal neural activity in different brain regions. METHODS Twenty-three patients with TRD, 22 with TSD, and 19 healthy subjects (HS) matched with gender, age, and education level participated in the study. RESULTS ANOVA analysis revealed widespread differences in Cohe-ReHo values among the three groups in different brain regions which included bilateral superior frontal gyrus, bilateral cerebellum, left inferior temporal gyrus, left occipital cortex, and both sides of fusiform gyrus. Compared to HS, lower Cohe-ReHo values were observed in TRD group in bilateral superior frontal gyrus and left cerebellum; in contrast, in TSD group, lower Cohe-ReHo values were mainly found in bilateral superior frontal gyrus. Compared to TSD group, TRD group had lower Cohe-ReHo in bilateral cerebellum and higher Cohe-ReHo in left fusiform gyrus. There was a negative correlation between Cohe-ReHo values of the left fusiform gyrus and illness duration in the pooled patients (r = 0.480, p = 0.001). The sensitivity and specificity of cerebellar Cohe-ReHo values differentiating TRD from TSD were 83% and 86%, respectively. CONCLUSIONS Compared to healthy controls, both TRD and TSD patients shared the majority of brain regions with abnormal neural activity. However, the lower Cohe-ReHo values in the cerebellum might be as a marker to differentiate TRD from TSD with high sensitivity and specificity.

Association analysis of the RGS4 gene in Han Chinese and Scottish populations with schizophrenia

We investigated the RGS4 as a susceptibility gene for schizophrenia in Chinese Han (184 trios and 138 sibling pairs, a total of 322 families) and Scottish (580 cases and 620 controls) populations using both a family trio and case‐control design. Both the samples had statistical power greater than 70% to detect a heterozygote genotype relative risk of >1.2 for frequent RGS4‐risk alleles. We genotyped four single nucleotide polymorphisms (SNPs) which have previously been associated with schizophrenia as either individually or part of haplotypes. Allele frequencies and linkage disequilibrium between the SNPs was similar in the two populations. In the Chinese sample, no individual SNPs or any of their haplotypes were associated with schizophrenia. In the Scottish population, one SNP (SNP7) was significantly over‐represented in the cases compared with the controls (0.44 vs. 0.38; A allele; χ2 7.08, P = 0.011 after correction for correlation between markers by permutation testing). One two‐marker haplotype, composed of alleles T and A of SNP4 and SNP7, respectively, showed individual significance after correction by permutation testing (χ2 6.8; P = 0.04). None of the full four‐marker haplotypes showed association, including the G‐G‐G‐G haplotype previously associated with schizophrenia in more than one sample and the A‐T‐A‐A haplotype. Thus, our data do not directly replicate previous associations of RGS4, but association with SNP 7 in the Scottish population provides some support for a role in schizophrenia susceptibility. We cannot conclusively exclude RGS4, as associated haplotypes are likely to be surrogates for unknown causative alleles, whose relationship with overlying haplotypes may differ between the population groups. Differences in the association seen across the two populations could result from methodological factors such as diagnostic differences but most likely result from ethnic differences in haplotype structures within RGS4.

Magnetization transfer imaging reveals the brain deficit in patients with treatment-refractory depression

BACKGROUND Studies on treatment resistant depression (TRD) using advanced magnetic resonance imaging techniques are very limited. METHODS A group of 15 patients with clinically defined TRD and 15 matched healthy controls underwent magnetization transfer imaging (MTI) and T1-weighted (T1W) imaging. MTI data were processed and analyzed voxel-wised in SPM2. A voxel based morphometric (VBM) analysis was performed using T1W images. RESULTS Reduced magnetization transfer ratio was observed in the TRD group relative to normal controls in the anterior cingulate, insula, caudate tail and amygdala-parahippocampal areas. All these regions were identified within the right hemisphere. VBM revealed no morphological abnormalities in the TRD group compared to the control group. Negative correlations were found between MRI and clinical measures in the inferior temporal gyrus. LIMITATIONS The cross-sectional design and small sample size. CONCLUSIONS The findings suggest that MTI is capable of identifying subtle brain abnormalities which underlie TRD and in general more sensitive than morphological measures.

Correlation and familial aggregation of dimensions of psychosis in affected sibling pairs from China

BACKGROUND A number of studies with conflicting results have examined the familiality of schizophrenia syndromes in Western populations. AIMS The objective of this study was to determine, using clinical data from concordant sibling pairs, whether symptom dimensions and other clinical characteristics of schizophrenia show familial aggregation and are therefore potentially useful traits in genetic studies. METHOD We measured clinical and demographic features, and symptom dimensions of schizophrenia in 137 families from China who had two or more affected members with schizophrenia. Within-sibling pair correlation was assessed with intraclass correlation coefficient and kappa statistics. RESULTS Global functioning, positive, disorganisation and dysphoric symptoms, premorbid schizotypal and schizoid traits, premorbid social adjustment, type and age at illness onset all showed significant evidence of familial aggregation. DSM-IV schizophrenia subtypes were also found to be familial. CONCLUSIONS This is the first study in a large non-European population to confirm that schizophrenia dimensions and clinical characteristics show significant familiality, implying possible heritability. This supports their use in the delineation of homogeneous subsets for future genetic studies.