Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Epigenome editing reveals core DNA methylation for imprinting control in the Dlk1-Dio3 imprinted domain.

The Dlk1-Dio3 imprinted domain is controlled by an imprinting control region (ICR) called IG-DMR that is hypomethylated on the maternal allele and hypermethylated on the paternal allele. Although several genetic mutation experiments have shown that IG-DMR is essential for imprinting control of the domain, how DNA methylation itself functions has not been elucidated. Here, we performed both gain and loss of DNA methylation experiments targeting IG-DMR by transiently introducing CRISPR/Cas9 based-targeted DNA methylation editing tools along with one guide RNA into mouse ES cells. Altered DNA methylation, particularly at IG-DMR-Rep, which is a tandem repeat containing ZFP57 methylated DNA-binding protein binding motifs, affected the imprinting state of the whole domain, including DNA methylation, imprinted gene expression, and histone modifications. Moreover, the altered imprinting states were persistent through neuronal differentiation. Our results suggest that the DNA methylation state at IG-DMR-Rep, but not other sites in IG-DMR, is a master element to determine whether the allele behaves as the intrinsic maternal or paternal allele. Meanwhile, this study provides a robust strategy and methodology to study core DNA methylation in cis-regulatory elements, such as ICRs and enhancers.

Expression Analyses of Rich2/Arhgap44, a Rho Family GTPase-Activating Protein, during Mouse Brain Development.

Rho family small GTPases, such as Rho, Rac, and Cdc42, play essential roles during brain development, by regulating cellular signaling and actin cytoskeletal reorganization. Rich2/Arhgap44, a Rac- and Cdc42-specific GTPase-activating protein, has been reported to be a key regulator for dendritic spine morphology and synaptic function. Given the essential roles of Rac and Cdc42 in brain development, Rich2 is supposed to take part in brain development. However, not only the molecular mechanism involved but also the expression profile of Rich2 during neurodevelopment has not yet been elucidated. In this study, we carried out expression analyses of Rich2 by focusing on mouse brain development. In immunoblotting, Rich2 exhibited a tissue-dependent expression profile in the young adult mouse, and the expression was increased during brain development. In immunohistochemical analyses, Rich2 was observed in the cytoplasm of cortical neurons at postnatal day (P) 0 and then came to be enriched in the nucleus with moderate distribution in neuropils at P7. Later at P30, a complex immunostaining pattern of Rich2 was observed; Rich2 was distributed in the nucleus, cytoplasm, and neuropils in many cortical neurons, whereas other neurons frequently displayed little expression. In the hippocampus at P7, Rich2 was distributed mainly in the cytoplasm of excitatory neurons in the cornu ammonis regions, while it was moderately detected in the nucleus in the dentate granule cells. Notably, Rich2 was distributed in excitatory synapses of the cornu ammonis 1 region at P30. Biochemical fractionation analyses also detected Rich2 in the postsynaptic density. Taken together, Rich2 is found to be expressed in the central nervous system in a developmental stage-dependent manner and may be involved in synapse formation/maintenance in cortical neurons.

Initial clinical trial of a novel hemostat, TDM-621, in the endoscopic treatments of the gastric tumors.

BACKGROUND AND AIM: The feasibility of TDM-621, the synthetic infectious agent-free peptides, was tested in hemostasis of the bleeding after endoscopic treatments of the gastric tumors. METHODS: The patients who underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) were enrolled in the present study. The subject of hemostasis was the oozing after the EMR or ESD. The hemostatic effect, the secondary hemorrhage from one postoperative day to the day before discharge and operability were studied. RESULTS: The hemostatic effects were assessed in 12 patients. It was "remarkably effective" in 11 patients and "effective" in 1 patient. The operability was "very easy" in two patients, "easy" in eight patients and "acceptable" in two patients. No secondary hemorrhage was observed in all of 12 patients. No adverse effect considered to be related to TDM-621 was observed. CONCLUSION: It was shown that hemostasis using TDM-621 was feasible after endoscopic treatments of the gastric tumors without any technical trouble or adverse event.

[A case of postmenopausal breast cancer becoming HER2 positive after neoadjuvant hormone therapy].

A 75-year-old woman presented to a local doctor with a lump in the right breast. On physical examination, a tumor measuring 24mm was palpable in the BD area of her right breast. Mammography showed category 5 disease, and ultrasonography revealed a tumor measuring 24×16 mm. A mammotome biopsy provided a diagnosis of invasive ductal carcinoma of the breast(ER 7/PgR 4/HER2 1+), and the tumor was classified as stage IIA(T2N0M0)according to the UICC-TNM classification. She was recommended surgery but she rejected this option and underwent hormone therapy with anastrozole (1mg/day). One year and 8months after beginning the treatment, ultrasonography showed the tumor to measure 7.0×5.7 mm, and hormone therapy resulted in a partial response(PR). The patient hoped to undergo an operation, so she was referred to our hospital, and a right partial mastectomy and sentinel node biopsy was performed. A histopathological exami- nation indicated scirrhous carcinoma, 18mm, nuclear grade 1, f, ly1, v0, n0, ER 3/PgR 3/HER2 3+. The curative effect was grade 1a. The tumor had become HER2 positive, so the patient was then administered radiotherapy and trastuzumab and anastrozole as adjuvant therapy. Herein, we report our experience with a case of breast cancer that only became HER2 positive after hormone therapy, and also provide some bibliographic comments on this occurrence.

Quantitative trait loci mapping of innate fear behavior in day-old F2 chickens of Japanese Oh-Shamo and White Leghorn breeds using restriction site-associated DNA sequencing.

Understanding the genetic mechanisms that underlie innate fear behavior is essential for improving the management and performance of the poultry industry. This study aimed to map QTL associated with innate fear responses in open field (OF) and tonic immobility (TI) tests, using an F2 chicken intercross population between 2 behaviorally distinct breeds: the aggressive Japanese Oh-Shamo (OSM) and the docile White Leghorn T-line (WL-T). Genome-wide QTL analysis for the OF and TI traits was conducted using 2,109 single nucleotide polymorphism (SNP) markers obtained through restriction site-associated DNA sequencing (RAD-seq). While several suggestive QTL were identified for TI and OF traits at genome-wide 20% significance threshold levels, the analysis revealed 2 significant QTL for 2 OF traits (total distance and maximum speed) at genome-wide 5% significance threshold levels. These significant QTL were located between 12.34 and 30.49 megabase (Mb) on chromosome 1 and between 40.02 and 63.38 Mb on chromosome 2, explaining 6.75 to 7.40% of the total variances. These findings provide valuable insights for the poultry industry, particularly in refining chicken management strategies and informing targeted breeding efforts.

ISWI chromatin remodeling complexes recruit NSD2 and H3K36me2 in pericentromeric heterochromatin.

Histone H3 lysine36 dimethylation (H3K36me2) is generally distributed in the gene body and euchromatic intergenic regions. However, we found that H3K36me2 is enriched in pericentromeric heterochromatin in some mouse cell lines. We here revealed the mechanism of heterochromatin targeting of H3K36me2. Among several H3K36 methyltransferases, NSD2 was responsible for inducing heterochromatic H3K36me2. Depletion and overexpression analyses of NSD2-associating proteins revealed that NSD2 recruitment to heterochromatin was mediated through the imitation switch (ISWI) chromatin remodeling complexes, such as BAZ1B-SMARCA5 (WICH), which directly binds to AT-rich DNA via a BAZ1B domain-containing AT-hook-like motifs. The abundance and stoichiometry of NSD2, SMARCA5, and BAZ1B could determine the localization of H3K36me2 in different cell types. In mouse embryos, H3K36me2 heterochromatin localization was observed at the two- to four-cell stages, suggesting its physiological relevance.

[Three patients with local recurrence of ER-positive breast cancer for whom anastrozole was clinically effective].

We treated three postmenopausal female patients with unresectable local recurrence from breast cancer. All pathological diagnoses of the local recurrence lesions were ER-positive breast cancer. For treatment, we administered anastrozole to these three patients. One has been stable disease for 25 months after taking anastrozole. Another has also showed stable disease for 18 months, and the last patient has been a partial response. We performed a biopsy from a recurring lesion on these three patients, and made a diagnosis of ER-positive breast cancer. This strategy of unresectable local recurrence revealed that these three patients could have had a stable condition for a long duration by taking anastrozole.

Development of a quantitative analysis method for assessing patient body surface deformation using an optical surface tracking system.

This study aimed to develop a new method to quantitatively analyze body shape changes in patients during radiotherapy without additional radiation exposure using an optical surface tracking system. This method's accuracy was evaluated using a cubic phantom with a known shift. Surface images of three-dimensionally printed phantoms, which simulated the head and neck shapes of real patients before and after treatment, were used to create a deformation surface area histogram. The near-maximum deformation value covering an area of 2 cm2 in the surface image (Def-2cm2) was calculated. A volumetric modulated arc therapy (VMAT) plan was also created on the pre-treatment phantom, and the dose distribution was recalculated on the post-treatment phantom to compare the dose indices. Surface images of four patients were analyzed to evaluate Def-2cm2 and examine whether this method can be used in clinical cases. Experiments with the cubic phantom resulted in a mean deformation error of 0.08 mm. With head and neck phantoms, the Def-2cm2 value was 17.5 mm, and the dose that covered 95% of the planning target volume in the VMAT plan decreased by 11.7%, indicating that deformation of the body surface may affect the dose distribution. Although analysis of the clinical data showed no clinically relevant deformation in any of the cases, slight skin sagging and respiratory changes in the body surface were observed. The proposed method can quantitatively and accurately evaluate the deformation of a body surface. This method is expected to be used to make decisions regarding modifications to treatment plans.

The Effect of Roxadustat on Transfusion-Dependent Myelodysplastic Syndrome Complicated by Chronic Kidney Disease.

Haematopoietic insufficiency is the treatment target of lower-risk myelodysplastic syndrome (MDS). Although erythropoiesis-stimulating agents (ESAs) are generally effective for treating anaemia, resistance can develop. Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) improves renal anaemia by promoting endogenous erythropoietin production and normalizing iron metabolism. HIF-PH inhibitors could be used to treat MDS, but their efficacy and safety have not been studied. A 78-year-old female patient with essential thrombocythemia gradually developed anaemia and was diagnosed with therapy-related MDS 4 years later. The anaemia temporarily improved with ESAs, but the patient became transfusion dependent. At the same time, anaemia and chronic renal failure due to nephrosclerosis progressed, and the patient was diagnosed with MDS with renal anaemia. After switching from ESAs to roxadustat, an HIF-PH inhibitor, anaemia improved, and the patient was no longer transfusion dependent. No progression of the underlying disease or any adverse events was observed 4 months after initiating roxadustat.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection: In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Critical examination of a correlation between brain gamma-aminobutyric acid (GABA) concentrations and a personality trait of extroversion in healthy volunteers as measured by a 3 Tesla proton magnetic resonance spectroscopy study.

We hypothesized that brain gamma-aminobutyric acid (GABA) levels are associated with neuroticism, a trait associated with depression and anxiety disorders. We examined the correlation between brain GABA concentrations and the five factors included in the NEO Five-Factor Inventory (NEO-FFI) in healthy volunteers using magnetic resonance spectroscopy (MRS) at 3 T. Forty-one healthy subjects (21 males, 20 females; age: 35+/-7 years) were enrolled in this study. Each subject underwent a 3T 1H-MRS study with a MEGA-PRESS sequence. Spectroscopy voxels (3 cm x 3 cm x 3 cm) were placed in the frontal lobe and the parieto-occipital lobe. A negative correlation was found between the GABA/creatine ratios in the frontal lobe and scores of extroversion on the NEO-FFI. These results suggest that GABAergic neurons are related to personality traits of healthy subjects.

[International cooperation for prosthetics and orthotics in Myanmar].

"Effectiveness of the sole protection and the plantar ulcer treatment of Micro Cellular Rubber (MCR) sandals" was investigated as a part of research enterprise "Research concerning the diagnosis, treatment, and the prevention of disability of an effective Leprosy in Myanmar" of the international medical treatment cooperation for three years since 2007. Furthermore "Introduction of Orthotics for the footdrop" was recently attempted through those activities. We participated for two research items from 2007, and reported on the research content and the result. We discussed the ideal way of international technical support for the developing countries in the future. Conclusively we recognized further expected works in this field 1) to train more numbers of orthotic practitioners for MCR sandals; 2) to make them skillful; 3) to train Prosthetists and Orthotists (PO) in Myanmar leaders; and 4) to organize helpers in Japan including preparation for publishing guidelines for PO workers.

Chromatin integration labeling for mapping DNA-binding proteins and modifications with low input.

Cell identity is determined by the selective activation or silencing of specific genes via transcription factor binding and epigenetic modifications on the genome. Chromatin immunoprecipitation (ChIP) has been the standard technique for mapping the sites of transcription factor binding and histone modification. Recently, alternative methods to ChIP have been developed for addressing the increasing demands for low-input epigenomic profiling. Chromatin integration labeling (ChIL) followed by sequencing (ChIL-seq) has been demonstrated to be particularly useful for epigenomic profiling of low-input samples or even single cells because the technique amplifies the target genomic sequence before cell lysis. After labeling the target protein or modification in situ with an oligonucleotide-conjugated antibody (ChIL probe), the nearby genome sequence is amplified by Tn5 transposase-mediated transposition followed by T7 RNA polymerase-mediated transcription. ChIL-seq enables the detection of the antibody target localization under a fluorescence microscope and at the genomic level. Here we describe the detailed protocol of ChIL-seq with assessment methods for the key steps, including ChIL probe reaction, transposition, in situ transcription and sequencing library preparation. The protocol usually takes 3 d to prepare the sequencing library, including overnight incubations for the ChIL probe reaction and in situ transcription. The ChIL probe can be separately prepared and stored for several months, and its preparation and evaluation protocols are also documented in detail. An optional analysis for multiple targets (multitarget ChIL-seq) is also described. We anticipate that the protocol presented here will make the ChIL technique more widely accessible for analyzing precious samples and facilitate further applications.

Associations between plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and negative symptoms or cognitive impairments in early-stage schizophrenia.

Schizophrenic patients demonstrate a variety of cognitive deficits, including attention, executive functions, and working memory, even in the early stage of disease. In the present study, we examined the association between blood levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), or brain-derived neurotrophic factor (BDNF) and scores on the Wisconsin Card Sorting Test (WCST) in patients with early-stage schizophrenia. We also investigated the association between frontal GABA levels using 1H-magnetic resonance spectroscopy (MRS) at 3T and scores on the WCST in the same patients. Blood levels of BDNF and catecholamine metabolites and brain GABA levels using 1H-MRS were measured in 18 schizophrenic patients (nine males, nine females; age range 13-52 year). A significantly positive correlation was observed between plasma MHPG levels and %PEM (rho = -0.686, p = 0.0047). A trend toward negative correlation was found between frontal lobe GABA levels and the per cent of preservation error (%PEM) in the early stage of schizophrenia (rho = -0.420, p = 0.0836). These results suggest that noradrenergic neurons might be involved in neuropsychological functions in early-stage of schizophrenia.

Plasma levels of 3-methoxy-4-hydroxyphenylglycol are associated with microstructural changes within the cerebellum in the early stage of first-episode schizophrenia: a longitudinal VBM study.

The aims of this study are to determine how the interval changes of the brain structures in the early stage of first-episode schizophrenia relate to the interval changes in the clinical data, including the clinical symptoms of schizophrenia and catecholaminergic measures (plasma homovanillic acid [HVA] and 3-methoxy-4-hydroxyphenylglycol [MHPG]). Regional brain volumes and fractional anisotropy (FA)/mean diffusivity (MD) with diffusion tensor imaging (DTI) were measured at baseline and 6-month follow-up in a 3T magnetic resonance imaging (MRI) system in a cohort of 16 schizophrenic patients, who were in their first episode at the time of baseline MRI. At the time of baseline and follow-up MRI, all 16 patients underwent evaluations that included a psychopathological assessment (Positive and Negative Syndrome Scale [PANSS]) and peripheral catecholaminergic measures (plasma MHPG or HVA). For interval changes between baseline and follow-up MRI data (morphological change, MD, and FA), the correlation/regression analysis was performed as a series of single regression correlations in Statistical Parametric Mapping 5, with the interval changes in PANSS or plasma HVA and MHPG as the covariates of interest. Positive and inverse correlations contrasts were created, and in this preliminary analysis, a family-wise error-corrected threshold of P<0.05 was considered significant. In the correlation/regression analysis, a positive correlation between the FA in the right cerebellar vermis and the MHPG was observed. No significant correlations between the brain volume or MD and any laboratory data (plasma HVA and MHPG) were found. During the 6-month follow-up in the early stage of first-episode schizophrenia, the MHPG changes were correlated with the microstructural FA changes in the cerebellum, which may reflect the functional connections of the noradrenergic system in the cerebellum.

Six-month treatment with atypical antipsychotic drugs decreased frontal-lobe levels of glutamate plus glutamine in early-stage first-episode schizophrenia.

OBJECTIVE: To study the effects of treatment with atypical antipsychotic drugs on brain levels of glutamate plus glutamine in early-stage first-episode schizophrenia. PARTICIPANTS: Sixteen patients (eight males, eight females; aged 30 ± 11 years) completed the study. METHODS: We used administered 6 months of atypical antipsychotic drugs and used proton magnetic resonance spectroscopy to evaluate the results. RESULTS: We found that the administration of atypical antipsychotic drugs for 6 months decreased the glutamate plus glutamine/creatine ratio in the frontal lobe. These results suggest that the administration of atypical antipsychotic drugs for at least 6 months decreased glutamatergic neurotransmissions in the frontal lobe in early-stage first-episode schizophrenia, but there was no difference in frontal-lobe levels between patients and control subjects before administration. CONCLUSION: Taking these findings into account, the glutamatergic and GABAergic neurons are implicated in early-stage first-episode schizophrenia, but in complex ways.

No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage first-episode schizophrenia.

We investigated the effects of atypical antipsychotic drugs on GABA concentrations in early-stage, first-episode schizophrenia patients. Sixteen (8 males, 8 females; age, 30±11 years old) patients were followed up for six months. We also included 18 sex- and age-matched healthy control subjects. All patients were treated with atypical antipsychotic drugs (5 patients with risperidone, 5 patients with olanzapine, 4 patients with aripiprazole, and 2 patients with quetiapine). In all three regions measured (frontal lobe, left basal ganglia, and parieto-occipital lobe), no differences in GABA concentrations were observed in a comparison of pre-treatment levels and those six months after treatment. These results suggest that relatively short-term treatment with atypical antipsychotic drugs may not affect GABAergic neurotransmission; however, it is also possible that such treatment prevents further reductions in brain GABA levels in people with early-stage, first-episode schizophrenia.

Gray and white matter volumetric and diffusion tensor imaging (DTI) analyses in the early stage of first-episode schizophrenia.

PURPOSE: To determine whether statistical analyses of quantitative MR imaging data, including morphological changes, mean diffusivity (MD), and fractional anisotropy (FA), could provide useful biomarkers in early stage of first-episode schizophrenia. MATERIALS AND METHODS: Twenty-three patients, who met all the criteria in the DSM-IV-TR category for schizophrenia excluding the duration of the disease (less than 6 months of follow-up), were examined by MR imaging during the initial consultation. Nineteen of the 23 patients were finally diagnosed to have schizophrenia after a 6-month follow-up, and they were included in this study as having been in the early stage of first-episode schizophrenia. Nineteen healthy volunteers also underwent MR imaging as age-matched controls. Three-dimensional spoiled gradient recalled acquisition with steady state (3D-SPGR) and diffusion tensor imaging (DTI) were performed at 3T. Image processing for voxel-based morphometry, a fully automatic technique for a computational analysis of differences in regional brain volume throughout the entire brain, was conducted using the Statistical Parametric Mapping 5 software package (SPM5). The 3D-SPGR images in the native space were bias-corrected; spatially normalized; segmented into gray matter, white matter, and cerebrospinal fluid images; and intensity-modulated using SPM5. A voxel-based analysis was conducted using both the MD and FA maps computed from DTI. The customized MD and FA template specific to this study was created from all participants. Thereafter, all the MD and FA maps in the native space were transformed onto the stereotactic space by registering each of the images to the customized MD and FA template. The two groups were compared using SPM5. Age and sex were treated as confounding covariates. RESULTS: The patients demonstrated a significant increase in the MD of the left parahippocampal gyrus, left insula, and right anterior cingulate gyrus in comparison to the control subjects (FDR corrected p<0.05). No significant difference was observed in the correlation between the gray/white matter volume and FA. CONCLUSION: These findings suggest that structural abnormalities in the brain are present during the early stage of first-episode schizophrenia and MD might therefore be a sensitive marker for the detection of these abnormalities.