Associations between antipsychotics-induced weight gain and brain networks of impulsivity.

Given the unpredictable rapid onset and ubiquitous consequences of weight gain induced by antipsychotics, there is a pressing need to get insights into the underlying processes at the brain system level that will allow stratification of "at risk" patients. The pathophysiological hypothesis at hand is focused on brain networks governing impulsivity that are modulated by neuro-inflammatory processes. To this aim, we investigated brain anatomy and functional connectivity in patients with early psychosis (median age: 23 years, IQR = 21-27) using anthropometric data and magnetic resonance imaging acquired one month to one year after initiation of AP medication. Our analyses included 19 patients with high and rapid weight gain (i.e., ≥5% from baseline weight after one month) and 23 patients with low weight gain (i.e., <5% from baseline weight after one month). We replicated our analyses in young (26 years, IQR = 22-33, N = 102) and middle-aged (56 years, IQR = 51-62, N = 875) healthy individuals from the general population. In early psychosis patients, higher weight gain was associated with poor impulse control score (ß = 1.35; P = 0.03). Here, the observed brain differences comprised nodes of impulsivity networks - reduced frontal lobe grey matter volume (Pcorrected = 0.007) and higher striatal volume (Pcorrected = 0.048) paralleled by disruption of fronto-striatal functional connectivity (R = -0.32; P = 0.04). Weight gain was associated with the inflammatory biomarker plasminogen activator inhibitor-1 (ß = 4.9, P = 0.002). There was no significant association between increased BMI or weight gain and brain anatomy characteristics in both cohorts of young and middle-aged healthy individuals. Our findings support the notion of weight gain in treated psychotic patients associated with poor impulse control, impulsivity-related brain networks and chronic inflammation.

MiR-22 Deficiency Fosters Hepatocellular Carcinoma Development in Fatty Liver.

MiR-22 is mostly considered as a hepatic tumor-suppressor microRNA based on in vitro analyses. Yet, whether miR-22 exerts a tumor-suppressive function in the liver has not been investigated in vivo. Herein, in silico analyses of miR-22 expression were performed in hepatocellular carcinomas from human patient cohorts and different mouse models. Diethylnitrosamine-induced hepatocellular carcinomas were then investigated in lean and diet-induced obese miR-22-deficient mice. The proteome of liver tissues from miR-22-deficient mice prior to hepatocellular carcinoma development was further analyzed to uncover miR-22 regulated factors that impact hepatocarcinogenesis with miR-22 deficiency. MiR-22 downregulation was consistently observed in hepatocellular carcinomas from all human cohorts and mouse models investigated. The time of appearance of the first tumors was decreased and the number of tumoral foci induced by diethylnitrosamine was significantly increased by miR-22-deficiency in vivo, two features which were further drastically exacerbated with diet-induced obesity. At the molecular level, we provide evidence that the loss of miR-22 significantly affects the energetic metabolism and mitochondrial functions of hepatocytes, and the expression of tumor-promoting factors such as thrombospondin-1. Our study demonstrates that miR-22 acts as a hepatic tumor suppressor in vivo by restraining pro-carcinogenic metabolic deregulations through pleiotropic mechanisms and the overexpression of relevant oncogenes.

Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis.

Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. Since PRSs are rarely used to reveal biological functions or to validate candidate pathways, to fill this gap, we investigated whether their predictive ability could be improved by building genome-wide (GW-PRSs) and pathway-specific PRSs, using distance- or expression quantitative trait loci (eQTLs)- based mapping between genetic variants and genes. We focused on five pathways (glutamate, oxidative stress, GABA/interneurons, neuroimmune/neuroinflammation and myelin) which belong to a critical hub of schizophrenia pathophysiology, centred on redox dysregulation/oxidative stress. Analyses were first performed in the Lausanne Treatment and Early Intervention in Psychosis Program (TIPP) study (n = 340, cases/controls: 208/132), a sample of first-episode of psychosis patients and matched controls, and then validated in an independent study, the epidemiological and longitudinal intervention program of First-Episode Psychosis in Cantabria (PAFIP) (n = 352, 224/128). Our results highlighted two main findings. First, GW-PRSs for schizophrenia were significantly associated with early psychosis status. Second, oxidative stress was the only significantly associated pathway that showed an enrichment in both the TIPP (p = 0.03) and PAFIP samples (p = 0.002), and exclusively when gene-variant linking was done using eQTLs. The results suggest that the predictive accuracy of polygenic risk scores could be improved with the inclusion of information from functional annotations, and through a focus on specific pathways, emphasizing the need to build and study functionally informed risk scores.

Ability to Care for an Ill Loved One During the First COVID-19 Lockdown: Mediators of Informal Caregivers' Stress in Europe.

Informal caregivers are overlooked, healthcare actors. They are at particular risk of distress and suffer from poor mental health. This study aimed to investigate the perceived stress and modulating factors during the first COVID-19 lockdown in Europe, regardless of the illness that care recipients suffer from. Sociodemographic data, coping resources, and perceived stress level using the Perceived Stress Scale (PSS-10) questionnaire were assessed using a web-based survey in Switzerland, France, and Belgium with 232 informal caregivers. Mediation analyses were used to identify the factors that modulate stress. Higher perceived stress among informal caregivers was associated with a younger age for the care recipient, family relationship with the care recipient, cohabitation, and female sex of the informal caregiver. These associations were partially mediated by the fear of getting ill (age, cohabitation), the conviction that lockdowns had a negative impact on health (age, kinship), and the perceived deterioration of the care recipient's health (gender). The fear of losing the ability to cope with caregiving tasks due to an illness (COVID-19 and/or other) and the negative impact of the lockdown on care recipients' health, particularly on the mental health of young care recipients, increased the stress of informal caregivers. Our results emphasize the importance of informal caregiving support to prevent heightened stress in lockdown conditions, regardless of care recipient illness or kinship.

Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk.

Liver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secreted hepatic factors improving metabolic homeostasis. Our results indicated that protein factors, rather than specific metabolites, released by PTEN-deficient hepatocytes trigger an improved muscle insulin sensitivity and a decreased adiposity in LPTENKO. In this regard, a proteomic analysis of conditioned media from PTEN-deficient primary hepatocytes identified seven hepatokines whose expression/secretion was deregulated. Distinct expression patterns of these hepatokines were observed in hepatic tissues from human/mouse with NAFLD. The expression of specific factors was regulated by the PTEN/PI3K, PPAR or AMPK signaling pathways and/or modulated by classical antidiabetic drugs. Finally, loss-of-function studies identified FGF21 and the triad AHSG, ANGPTL4 and LECT2 as key regulators of insulin sensitivity in muscle cells and in adipocytes biogenesis, respectively. These data indicate that hepatic PTEN deficiency and steatosis alter the expression/secretion of hepatokines regulating insulin sensitivity in muscles and the lipid metabolism in adipose tissue. These hepatokines could represent potential therapeutic targets to treat obesity and insulin resistance.

TIA1 Loss Exacerbates Fatty Liver Disease but Exerts a Dual Role in Hepatocarcinogenesis.

Alterations in specific RNA-binding protein expression/activity importantly contribute to the development of fatty liver disease (FLD) and hepatocellular carcinoma (HCC). In particular, adenylate-uridylate-rich element binding proteins (AUBPs) were reported to control the post-transcriptional regulation of genes involved in both metabolic and cancerous processes. Herein, we investigated the pathophysiological functions of the AUBP, T-cell-restricted intracellular antigen-1 (TIA1) in the development of FLD and HCC. Analysis of TIA1 expression in mouse and human models of FLD and HCC indicated that TIA1 is downregulated in human HCC. In vivo silencing of TIA1 using AAV8-delivered shRNAs in mice worsens hepatic steatosis and fibrosis induced by a methionine and choline-deficient diet and increases the hepatic tumor burden in liver-specific PTEN knockout (LPTENKO) mice. In contrast, our in vitro data indicated that TIA1 expression promoted proliferation and migration in HCC cell lines, thus suggesting a dual and context-dependent role for TIA1 in tumor initiation versus progression. Consistent with a dual function of TIA1 in tumorigenesis, translatome analysis revealed that TIA1 appears to control the expression of both pro- and anti-tumorigenic factors in hepatic cancer cells. This duality of TIA1's function in hepatocarcinogenesis calls for cautiousness when considering TIA1 as a therapeutic target or biomarker in HCC.

Developmental oxidative stress leads to T-type Ca2+ channel hypofunction in thalamic reticular nucleus of mouse models pertinent to schizophrenia.

Impairment of parvalbumin interneurons induced by oxidative stress (OxS) is a "hub" on which converge several genetic and environmental risk factors associated with schizophrenia. In patients, this could be a mechanism leading to anomalies of the thalamic reticular nucleus (TRN) whose major neuronal population expresses parvalbumin. The TRN shapes the information flow within thalamo-cortical circuits. The low-threshold voltage-gated T-type Ca2+ (T-Ca2+) channels (CaV3.2, CaV3.3) contribute to the excitability and rhythmic bursting of TRN neurons which mediates cortical sleep spindles, known to be affected in schizophrenia. Here, we investigated the impact of OxS during postnatal development and adulthood on firing properties and T-Ca2+ channels of TRN neurons. In Gclm knock-out (KO) mice, which display GSH deficit and OxS in TRN, we found a reduction of T-Ca2+ current density in adulthood, but not at peripuberty. In KO adults, the decreased T-Ca2+ currents were accompanied with a decrease of CaV3.3 expression, and a shift towards more hyperpolarized membrane potentials for burst firing leading to less prominent bursting profile. In young KO mice, an early-life oxidative challenge precipitated the hypofunction of T-Ca2+ channels. This was prevented by a treatment with N-acetylcysteine. The concomitant presence of OxS and hypofunction of T-Ca2+ channels were also observed in TRN of a neurodevelopmental model relevant to psychosis (MAM mice). Collectively, these data indicate that OxS-mediated T-Ca2+ hypofunction in TRN begins early in life. This also points to T-Ca2+ channels as one target of antioxidant-based treatments aiming to mitigate abnormal thalamo-cortical communication and pathogenesis of schizophrenia.

Mitochondrial, exosomal miR137-COX6A2 and gamma synchrony as biomarkers of parvalbumin interneurons, psychopathology, and neurocognition in schizophrenia.

Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients' blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients' group with mitochondrial dysfunction "Psy-D", having high miR-137 and low COX6A2 levels in exosomes, and (b) a "Psy-ND" subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials.

Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis.

The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development-contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC.

mTOR Repression in Response to Amino Acid Starvation Promotes ECM Degradation Through MT1-MMP Endocytosis Arrest.

Under conditions of starvation, normal and tumor epithelial cells can rewire their metabolism toward the consumption of extracellular proteins, including extracellular matrix-derived components as nutrient sources. The mechanism of pericellular matrix degradation by starved cells has been largely overlooked. Here it is shown that matrix degradation by breast and pancreatic tumor cells and patient-derived xenograft explants increases by one order of magnitude upon amino acid and growth factor deprivation. In addition, it is found that collagenolysis requires the invadopodia components, TKS5, and the transmembrane metalloproteinase, MT1-MMP, which are key to the tumor invasion program. Increased collagenolysis is controlled by mTOR repression upon nutrient depletion or pharmacological inhibition by rapamycin. The results reveal that starvation hampers clathrin-mediated endocytosis, resulting in MT1-MMP accumulation in arrested clathrin-coated pits. The study uncovers a new mechanism whereby mTOR repression in starved cells leads to the repurposing of abundant plasma membrane clathrin-coated pits into robust ECM-degradative assemblies.

Heat-stability study of various insulin types in tropical temperature conditions: New insights towards improving diabetes care.

Strict storage recommendations for insulin are difficult to follow in hot tropical regions and even more challenging in conflict and humanitarian emergency settings, adding an extra burden to the management of people with diabetes. According to pharmacopeia unopened insulin vials must be stored in a refrigerator (2-8°C), while storage at ambient temperature (25-30°C) is usually permitted for the 4-week usage period during treatment. In the present work we address a critical question towards improving diabetes care in resource poor settings, namely whether insulin is stable and retains biological activity in tropical temperatures during a 4-week treatment period. To answer this question, temperature fluctuations were measured in Dagahaley refugee camp (Northern Kenya) using log tag recorders. Oscillating temperatures between 25 and 37°C were observed. Insulin heat stability was assessed under these specific temperatures which were precisely reproduced in the laboratory. Different commercialized formulations of insulin were quantified weekly by high performance liquid chromatography and the results showed perfect conformity to pharmacopeia guidelines, thus confirming stability over the assessment period (four weeks). Monitoring the 3D-structure of the tested insulin by circular dichroism confirmed that insulin monomer conformation did not undergo significant modifications. The measure of insulin efficiency on insulin receptor (IR) and Akt phosphorylation in hepatic cells indicated that insulin bioactivity of the samples stored at oscillating temperature during the usage period is identical to that of the samples maintained at 2-8°C. Taken together, these results indicate that insulin can be stored at such oscillating ambient temperatures for the usual four-week period of use. This enables the barrier of cold storage during use to be removed, thereby opening up the perspective for easier management of diabetes in humanitarian contexts and resource poor settings.

A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia.

Involvement of oxidative stress in the pathophysiology of schizophrenia (SZ) is suggested by studies of peripheral tissue. Nonetheless, it is unclear how such biological changes are linked to relevant, pathological neurochemistry, and brain function. We designed a multi-faceted study by combining biochemistry, neuroimaging, and neuropsychology to test how peripheral changes in a key marker for oxidative stress, glutathione (GSH), may associate with central neurochemicals or neuropsychological performance in health and in SZ. GSH in dorsal anterior cingulate cortex (dACC) was acquired as a secondary 3T 1H-MRS outcome using a MEGA-PRESS sequence. Fifty healthy controls and 46 patients with SZ were studied cross-sectionally, and analyses were adjusted for effects of confounding variables. We observed lower peripheral total GSH in SZ compared to controls in extracellular (plasma) and intracellular (lymphoblast) pools. Total GSH levels in plasma positively correlated with composite neuropsychological performance across the total population and within patients. Total plasma GSH levels were also positively correlated with the levels of Glx in the dACC across the total population, as well as within each individual group (controls, patients). Furthermore, the levels of dACC Glx and dACC GSH positively correlated with composite neuropsychological performance in the patient group. Exploring the relationship between systemic oxidative stress (in particular GSH), central glutamate, and cognition in SZ will benefit further from assessment of patients with more varied neuropsychological performance.

Tristetraprolin Promotes Hepatic Inflammation and Tumor Initiation but Restrains Cancer Progression to Malignancy.

BACKGROUND & AIMS: Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular carcinoma (HCC). METHODS: TTP expression was investigated in mouse/human models of hepatic metabolic diseases and cancer. The role of TTP in nonalcoholic steatohepatitis and HCC development was further examined through in vivo/vitro approaches using liver-specific TTP knockout mice and a panel of hepatic cancer cells. RESULTS: Our data demonstrate that TTP loss in vivo strongly restrains development of hepatic steatosis and inflammation/fibrosis in mice fed a methionine/choline-deficient diet, as well as HCC development induced by the carcinogen diethylnitrosamine. In contrast, low TTP expression fostered migration and invasion capacities of in vitro transformed hepatic cancer cells likely by unleashing expression of key oncogenes previously associated with these cancerous features. Consistent with these data, TTP was significantly down-regulated in high-grade human HCC, a feature further correlating with poor clinical prognosis. Finally, we uncover hepatocyte nuclear factor 4 alpha and early growth response 1, two key transcription factors lost with hepatocyte dedifferentiation, as key regulators of TTP expression. CONCLUSIONS: Although TTP importantly contributes to hepatic inflammation and cancer initiation, its loss with hepatocyte dedifferentiation fosters cancer cells migration and invasion. Loss of TTP may represent a clinically relevant biomarker of high-grade HCC associated with poor prognosis.

Topology predicts long-term functional outcome in early psychosis.

Early intervention in psychosis is crucial to improving patient response to treatment and the functional deficits that critically affect their long-term quality of life. Stratification tools are needed to personalize functional deficit prevention strategies at an early stage. In the present study, we applied topological tools to analyze symptoms of early psychosis patients, and detected a clear stratification of the cohort into three groups. One of the groups had a significantly better psychosocial outcome than the others after a 3-year clinical follow-up. This group was characterized by a metabolic profile indicative of an activated antioxidant response, while that of the groups with poorer outcome was indicative of oxidative stress. We replicated in a second cohort the finding that the three distinct clinical profiles at baseline were associated with distinct outcomes at follow-up, thus validating the predictive value of this new stratification. This approach could assist in personalizing treatment strategies.

Genetic Ablation of MiR-22 Fosters Diet-Induced Obesity and NAFLD Development.

miR-22 is one of the most abundant miRNAs in the liver and alterations of its hepatic expression have been associated with the development of hepatic steatosis and insulin resistance, as well as cancer. However, the pathophysiological roles of miR-22-3p in the deregulated hepatic metabolism with obesity and cancer remains poorly characterized. Herein, we observed that alterations of hepatic miR-22-3p expression with non-alcoholic fatty liver disease (NAFLD) in the context of obesity are not consistent in various human cohorts and animal models in contrast to the well-characterized miR-22-3p downregulation observed in hepatic cancers. To unravel the role of miR-22 in obesity-associated NAFLD, we generated constitutive Mir22 knockout (miR-22KO) mice, which were subsequently rendered obese by feeding with fat-enriched diet. Functional NAFLD- and obesity-associated metabolic parameters were then analyzed. Insights about the role of miR-22 in NAFLD associated with obesity were further obtained through an unbiased proteomic analysis of miR-22KO livers from obese mice. Metabolic processes governed by miR-22 were finally investigated in hepatic transformed cancer cells. Deletion of Mir22 was asymptomatic when mice were bred under standard conditions, except for an onset of glucose intolerance. However, when challenged with a high fat-containing diet, Mir22 deficiency dramatically exacerbated fat mass gain, hepatomegaly, and liver steatosis in mice. Analyses of explanted white adipose tissue revealed increased lipid synthesis, whereas mass spectrometry analysis of the liver proteome indicated that Mir22 deletion promotes hepatic upregulation of key enzymes in glycolysis and lipid uptake. Surprisingly, expression of miR-22-3p in Huh7 hepatic cancer cells triggers, in contrast to our in vivo observations, a clear induction of a Warburg effect with an increased glycolysis and an inhibited mitochondrial respiration. Together, our study indicates that miR-22-3p is a master regulator of the lipid and glucose metabolism with differential effects in specific organs and in transformed hepatic cancer cells, as compared to non-tumoral tissue.

S100A11/ANXA2 belongs to a tumour suppressor/oncogene network deregulated early with steatosis and involved in inflammation and hepatocellular carcinoma development.

OBJECTIVE: Hepatocellular carcinoma (HCC) development occurs with non-alcoholic fatty liver disease (NAFLD) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC. However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD, thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations. DESIGN: The proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD/HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses. RESULTS: A whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD. Alterations of these TSs/ONCs were preserved or even exacerbated in HCC. Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline/methionine-deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration. CONCLUSION: Cellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis. Among those, overexpression of the oncogenic factor S100A11 promotes inflammation/fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis.

Redox dysregulation as a link between childhood trauma and psychopathological and neurocognitive profile in patients with early psychosis.

Exposure to childhood trauma (CT) increases the risk for psychosis and affects the development of brain structures, possibly through oxidative stress. As oxidative stress is also linked to psychosis, it may interact with CT, leading to a more severe clinical phenotype. In 133 patients with early psychosis (EPP), we explored the relationships between CT and hippocampal, amygdala, and intracranial volume (ICV); blood antioxidant defenses [glutathione peroxidase (GPx) and thioredoxin/peroxiredoxin (Trx/Prx)]; psychopathological results; and neuropsychological results. Nonadjusted hippocampal volume correlated negatively with GPx activity in patients with CT, but not in patients without CT. In patients with CT with high GPx activity (high-GPx+CT), hippocampal volume was decreased compared with that in patients with low-GPx+CT and patients without CT, who had similar hippocampal volumes. Patients with high-GPx+CT had more severe positive and disorganized symptoms than other patients. Interestingly, Trx and oxidized Prx levels correlated negatively with GPx only in patients with low-GPx+CT. Moreover, patients with low-GPx+CT performed better than other patients on cognitive tasks. Discriminant analysis combining redox markers, hippocampal volume, clinical scores, and cognitive scores allowed for stratification of the patients into subgroups. In conclusion, traumatized EPP with high peripheral oxidation status (high-GPx activity) had smaller hippocampal volumes and more severe symptoms, while those with lower oxidation status (low-GPx activity) showed better cognition and regulation of GPx and Trx/Prx systems. These results suggest that maintained regulation of various antioxidant systems allowed for compensatory mechanisms preventing long-term neuroanatomical and clinical impacts. The redox marker profile may thus represent important biomarkers for defining treatment strategies in patients with psychosis.

N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trial.

Mechanism-based treatments for schizophrenia are needed, and increasing evidence suggests that oxidative stress may be a target. Previous research has shown that N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor almost devoid of side effects, improved negative symptoms, decreased the side effects of antipsychotics, and improved mismatch negativity and local neural synchronization in chronic schizophrenia. In a recent double-blind randomized placebo-controlled trial by Conus et al., early psychosis patients received NAC add-on therapy (2700 mg/day) for 6 months. Compared with placebo-treated controls, NAC patients showed significant improvements in neurocognition (processing speed) and a reduction of positive symptoms among patients with high peripheral oxidative status. NAC also led to a 23% increase in GSH levels in the medial prefrontal cortex (GSHmPFC) as measured by 1H magnetic resonance spectroscopy. A subgroup of the patients in this study were also scanned with multimodal MR imaging (spectroscopy, diffusion, and structural) at baseline (prior to NAC/placebo) and after 6 months of add-on treatment. Based on prior translational research, we hypothesized that NAC would protect white matter integrity in the fornix. A group × time interaction indicated a difference in the 6-month evolution of white matter integrity (as measured by generalized fractional anisotropy, gFA) in favor of the NAC group, which showed an 11% increase. The increase in gFA correlated with an increase in GSHmPFC over the same 6-month period. In this secondary study, we suggest that NAC add-on treatment may be a safe and effective way to protect white matter integrity in early psychosis patients.

Networks of blood proteins in the neuroimmunology of schizophrenia.

Levels of certain circulating cytokines and related immune system molecules are consistently altered in schizophrenia and related disorders. In addition to absolute analyte levels, we sought analytes in correlation networks that could be prognostic. We analyzed baseline blood plasma samples with a Luminex platform from 72 subjects meeting criteria for a psychosis clinical high-risk syndrome; 32 subjects converted to a diagnosis of psychotic disorder within two years while 40 other subjects did not. Another comparison group included 35 unaffected subjects. Assays of 141 analytes passed early quality control. We then used an unweighted co-expression network analysis to identify highly correlated modules in each group. Overall, there was a striking loss of network complexity going from unaffected subjects to nonconverters and thence to converters (applying standard, graph-theoretic metrics). Graph differences were largely driven by proteins regulating tissue remodeling (e.g. blood-brain barrier). In more detail, certain sets of antithetical proteins were highly correlated in unaffected subjects (e.g. SERPINE1 vs MMP9), as expected in homeostasis. However, for particular protein pairs this trend was reversed in converters (e.g. SERPINE1 vs TIMP1, being synthetical inhibitors of remodeling of extracellular matrix and vasculature). Thus, some correlation signals strongly predict impending conversion to a psychotic disorder and directly suggest pharmaceutical targets.

N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis.

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.