Mar 3, 2018 - Paulo; 2Núcleo de Cognição e Sistemas Complexos Centro de. Matemática, Computação e Cognição Universidade Federal do.
Posters (Monday) S239 is unclear. Recent studies showed that a known schizophrenia candidate gene Neuregulin 1 (NRG1) may have a neuroprotective role by stimulating antioxidant synthesis and increasing glutathione (Zhang et al 2016). At least in the periphery, NRG1 is also known to modulate a key enzyme, glutathione reductase, for glutathione redox (Timolati et al 2006). Therefore, we tested the hypothesis that NRG1 may contribute to glutathione levels in the brain. Methods: In this preliminary study that included 129 Caucasians (43 schizophrenia spectrum disorder patients and 86 controls), we measured glutathione levels in the anterior cingulate/medial frontal region by 1H MRS using a very short echo time (TE) phase rotation sequence (Wijtenburg et al 2014) in a 3T scanner. Using genotype data obtained from the Omni2.5–8 Bead Chip Kit panel (Illumina), we identified a putatively functional nonsynonymous SNP rs3924999 previously found to be related to schizophrenia and performed an association analysis with glutathione. Results: This NRG1 nonsynonymous SNP was associated with the level of glutathione in the combined sample (ΔR2 = 6.0%, t = −2.85, P = .005) after covarying out age, sex and diagnosis. Analyzing the 2 groups separately, the findings remained significant in the controls (ΔR2 = 6.9%, t = −2.50, P = .014). The finding was not significant in the patient group (ΔR2 = 4.5%, t = −1.39, P = .17), although the effect was in the same direction. The SNP did not deviate from Hardy-Weinberg equilibrium (P = .71). Conclusion: Abnormal glutathione redox has been implicated in schizophrenia. Our preliminary analysis of the NRG1 effect on glutathione levels, previously only studied in peripheral systems, appears to support that a similar effect may be present in the brain. As NRG1 is a strong candidate gene for schizophrenia, further analysis of the neuregulin 1 - glutathione connection may provide new insight into the mechanism of oxidative stress dysfunction in schizophrenia.
M79. WHITE MATTER CHANGES IN SCHIZOPHRENIA ASSOCIATED WITH ILLNESS DURATION OR AN EFFECT OF AGE? Idaiane Assunção Leme1, André Zugman1, Luciana Moura2, João Sato1, Cristiano Noto1, Rodrigo Bressan1, Andrea Jackowski1, Ary Gadelha3, and Bruno Ortiz*,1 1 Laboratório Interdisciplinar de Neurociências Clínicas(LiNC), Universidade Federal de São Paulo, Universidade Federal de São Paulo; 2Núcleo de Cognição e Sistemas Complexos Centro de Matemática, Computação e Cognição Universidade Federal do ABC (UFABC); 3Laboratório Interdisciplinar de Neurociências Clínicas(LiNC), Universidade Federal de São Paulo(UNIFESP); Universidade Federal de São Paulo(UNIFESP); Universidade Federal de São Paulo(UNIFESP); 4Universidade Federal de São Paulo Background: Several studies have shown diffusion tensor imaging abnormalities in the brain of schizophrenia patients; including decrease prefrontal and temporal lobe fractional anisotropy (FA). The aim of this study was to evaluate regions of interest (ROI) of white matter fiber tracts interconnecting brain regions in relation to duration of illness. Methods: Diffusion MRI data were obtained on schizophrenia patients 90 (59 males) and healthy controls 75(49 males), collected on a Siemens 1.5T MRI scanner. Analysis of diffusion parameters was performed using tract-based spatial statistics (TBSS). Thus, the automated extraction of FA values from ROIs genu (GCC), body (BCC) and splenium (SCC) of corpus callosum, fornix, cingulate gyrus bilateral, uncinate fasciculus bilateral, and average FA from each subject has been performed. Results: Schizophrenia patients and healthy controls presented no significant difference between age (37.40 y ± 10.13 vs 35.97 y ± 10.72) and, duration of illness (14.22 y ± 8.20). A negative correlation between duration of illness and FA measures were found with average FA (r2 = −.295, P = .005),
GCC (r2 = −.372, P < .001), BCC (r2 = −.212, P = .047), SCC (r2 = −.261, P = .014), fornix (r2 = −.454, P < .001), cingulate gyrus right (r2 = −.254, P = .017). No positive significant correlations were found. When performing a GLM adding age as covariate, none correlation for duration of illness remained significant. No correlations were found between the age and the FA measures in the control group. Conclusion: Our findings suggest that the white matter diffusion deficits in schizophrenia overlaps with expected changes during aging, a possibility is that neuroprogression in schizophrenia leads to accelerated aging changes.
M80. GLOBAL MICRO-STRUCTURAL WHITE MATTER ALTERATIONS IN THE FIRST-EPISODE ANTIPSYCHOTIC-NAIVE SCHIZOPHRENIA PATIENTS AFTER 6 WEEKS OF SELECTIVE D2/3 RECEPTOR BLOCKADE Jayachandra Mitta Raghava*,1, Bjørn H. Ebdrup2, Mette Ø. Nielsen2, Egill Rostrup1, René C. W. Mandl3, and Birte Y. Glenthøj2 1 University of Copenhagen; 2Centre for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup; University of Copenhagen; 3Brain Center Rudolf Magnus Background: Preclinical and clinical studies have reported subtle white matter alterations after antipsychotic exposure (Dorph-Petersen et al 2005; Ho et al 2011). It has been debated whether these changes reflect a regulatory effect on oligodendroglial development (Ren et al 2013), or should be ascribed an anti-inflammatory effect due to the inhibition of microglial activation (Kato et al., 2008). In initially antipsychotic naïve patients with schizophrenia, we have previously demonstrated a decreased radial diffusivity (RD) after 6 weeks of treatment with the relative selective D2/3 antagonist, amisulpride (Ebdrup et al, 2015). It is however not clear whether this decrease in RD is due to reduced inflammation or increased myelination. To identify the specific mechanism driving these changes, we combined diffusion tensor imaging (DTI) with magnetization transfer imaging (MTI) in a multi-model design and re-analyzed the effect of 6 weeks of medication. Methods: Thirty-two anti-psychotic naïve patients with schizophrenia and 32 matched healthy controls were scanned on a Philips 3T MR scanner for DWI and for MTI at baseline and after 6 weeks of monotherapy with amisulpride. Only patients have undergone treatment. Brain DWI were skull stripped, corrected for head motion, eddy current distortion and susceptibility artifacts. Using the MTI images the magnetization transfer ratio (MTR) was computed. DTI maps comprising fractional anisotropy (FA), mean diffusivity (MD), mode (MO), and MTR data were skeletonized using tract-based spatial statistics (TBSS) and were residualized for age, gender and motion effects. These residual skeleton images were z-transformed. The change over time in imaging data is calculated by voxel wise subtraction of baseline data from 6-week follow-up data. We used mean-centered partial least squares (PLS) analysis DTI and MTR data to assess the change in WM structural connectivity across 4 different measures (FA, MD, MO, MTR), 2 groups (patients, controls) to deduce latent variables (LV) and brain scores. Results: Longitudinal PLS analyses using DTI and MTR maps of the whole brain identified one significant (P = .031, cross-block covariance 36.68%) latent variable (LV1) representing a global pattern of increase in FA, and decreased MD, MO, MTR within patients when compared to controls. Conclusion: The observed pattern of increased FA, and decreased MD, MO, MTR does not reflect an increase in myelination. Instead, this pattern is consistent with a reduction in free water content, which may reflect inflammatory changes (Mandl et al, 2013). Thus, the preliminary results indicate that changes in white matter microstructure during treatment may be due to a decrease in inflammation in the patients. We find that multi-modal
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