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Background: In general, MR spectroscopy (MRS) studies report alterations of both glutamatergic indices and NAA not only in first episode psychosis and established schizophrenia but also in high risk populations, suggesting that altered excitatory neurotransmission and loss of neuronal integrity are early pathophysiological processes. However, interpretation of these findings is limited by the region-of-interest approach of current MRS techniques, limiting the measurement of metabolites to delimited cerebral volumes, selected by a priori hypotheses. In that context, we developed and implemented a new technique including specific MR sequence and data reconstruction that allows for whole brain high-resolution MRS imaging (MRSI) in two or three dimensions. The results enable the mapping of main metabolites in all brain regions (cortex, white matter, deep grey matter) of youths at clinical high risk for psychosis (CHR-P). Methods: An FID-MRSI (Henning et al. NMR Biomed 2009) sequence with a 3D phase encoding accelerated by compressed-sensing was implemented on a 3T Prisma fit MRI (Siemens, Erlangen, Germany). The echo time (TE) was 0.65 ms, repetition time (TR) was 355 ms and the flip angle 35 degree. FID was acquired with 4 kHz bandwidth. The size of the excited Volume of Interest (VOI) was (A/P-R/L-H/F) 210 mm by 160 mm by 95 mm with a matrix of 42 x 32 x 20 resulting in 5 mm isotropic resolution. After reconstruction (Klauser A et al. Magn Reson Med. 2018), 3D MRSI data were quantified with LCModel to produce 3D metabolite maps. Concentration for total N-acetyl aspartate (tNAA), total creatinine (tCre), choline-containing compounds (Cho), myo-inositol (Ins), glutamate and glutamine (Glx) were calculated in every single voxel. A T1-weighted MPRAGE anatomical scan was acquired for positioning of the 3D MRSI and for the segmentation of the brain. For each participant, brain tissue was segmented into gray and white matter. Cerebral lobes and deep grey mater structures were also delineated using Freesurfer software package. CHR-P individuals were recruited in the service of child and adolescent psychiatry and in the service of general psychiatry, department of psychiatry at Lausanne university hospital. They were help-seeking adolescents and young adults aged between 14 and 35, who presented a psychosisrisk syndrome or basic symptoms as assessed by the Structured Interview for Psychosis-Risk Syndromes (SIPS) and the Schizophrenia Proneness Instrument, Adult (SPI-A) or Child & Youth version (SPI-CY). Healthy controls matched for age and sex were recruited in the general population. Results: Three-dimension MRSI provides spatial specificity by allowing main metabolites (i.e., tNAA, tCre, Cho, Ins and Glx) to be reliably mapped in the volume of the entire brain. The resulting contrast allows the recognition of brain compartments and subcortical structures. Individual brain segments, cerebral lobes and subcortical structures were registered to 3D MRSI data and the mean concentration in each structure was computed to allow group comparisons between CHR-P and HC. Discussion: In general, there is a strong need to develop new tools for the identification and stratification of CHR-P populations. Alterations of gross brain anatomy are relatively late events but early and subtle neurochemical changes and especially those reflecting oxidative stress and concomitant synaptic remodeling are promising candidates. This pilot study illustrates the potential of three-dimension MRSI to detect such alterations in the whole brain and with a good spatial resolution. [ABSTRACT FROM AUTHOR]

Background: The Clinical High Risk state (CHR) concept was implemented to promote the early detection of young help-seeking patients with higher risk of psychotic transition. This category is based on specific clinical criteria (EPA, 2015) and require narrow frequency/duration ratings of subclinical positive psychotic symptoms to allow its definition. Prevalence of CHR “category” appears nevertheless rare in help-seeking young people and the rate of psychotic transition of CHR state is lower than predicted by early studies. Therefore, the binary outcome of transition to psychosis proposed by the “CHR model” actually fails to be an efficient marker to stratify, in neurobiological studies, people with different psychopathological trajectories, notably those who develop psychosis from those who do not. In order to rely on a vulnerability model for schizophrenic psychosis more sensitive to psychosocial functioning and negative dimension, we study prospectively with three years of follow-up a population of helpseekers addressed for clinical suspicion of prodromal state of psychosis. We aimed here to identify subgroups of patients in a sample of subclinical psychotic states using psychological and cognitive outcomes as profiling criteria, focusing not only on transition but also on psychosocial functioning as main outcome. Methods: A total of 32 help-seeking adolescents and young adults aged 14 to 35 were referred by health care providers for a specialized evaluation in case of suspicion of a prodromal psychotic state and/or detected by the French version of the Prodromal Questionnaire (PQ-16; cut-off 6/16). Their CHR status was assessed by the Structured Interview for PsychosisRisk Syndromes (SIPS) and the Schizophrenia Proneness Instrument, Adult (SPI-A). Individuals included in the study presented either a CHR status, a subclinical CHR status or negative symptomatology. All subjects performed an additional neuropsychological battery and blood test for redox markers (Glutathione Peroxidase (GPx) and Glutathione Reductase (GR) activities) (Xin et al, 2016). Based on their clinical profile, we made a stratification of the patients using a Principal Component Analysis. Results: Cognitive and psychological outcome stratification of all help-seekers revealed two subgroups (called group1 and group2) of patients with distinct profiles. Individuals in group1 (n=18) had greater levels of basic symptoms and general symptomatology. On the other hand, in group2 (n=14), individuals showed a weaker self-esteem and a lower rate of “living independently”. Cognitive scores for speed processing, attention, verbal learning and social cognition were significantly lower in group2 compared to group1. In addition, these cognitive outcomes were negatively correlated with negative symptoms only in group2. Analysis of redox markers revealed a positive correlation between GPx and GR activities in group1, a correlation disrupted in group2. Discussion: Stratification of a cohort of young help-seekers with suspicion of prodromal psychosis, regardless of their CHR status, allowed us to distinguish two subgroups with different clinical profiles: group1 with higher levels of basic symptoms and general symptomatology, and group2 with weaker self-esteem, less autonomy and poorer neurocognition. In addition, analysis of redox markers revealed a redox dysregulation in patients with poorer cognitive profile. Considering the impact of neurocognitive impairment on functioning, special focus to patients of group2 is needed, mostly in clinical practice. Moreover, they might benefit of supplementation with antioxidant compounds such as NAC, which may improve cognitive deficits (Conus et al, 2018). [ABSTRACT FROM AUTHOR]