Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study

Wang, Min; Barker, Peter B.; Cascella, Nicola G.; Coughlin, Jennifer M.; Nestadt, Gerald; Nucifora, Frederick C.; Sedlak, Thomas W.; Kelly, Alexandra; Younes, Laurent; Geman, Donald; Sawa, Akira; Yang, Kun

doi:10.1101/2020.08.25.267419

Cited by 8 publications

(8 citation statements)

References 42 publications

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“…Under such premise, we used classification models with trait markers to evaluate the performance of individual markers as well as the combination of them. Our previous longitudinal assessment for the same cohort used in the present study showed that the ACC-GSH levels were stable in patients between 15-35 years of age [52]. Using the same analytic pipeline that we used to assess longitudinal changes in the ACC-GSH level [52], we found that the right HP volume and the left SFG volume were also stable in FEP patients ( Table S6 : see also details in the supplementary methods).…”

Section: Resultssupporting

confidence: 58%

A multimodal study of a first episode psychosis cohort: potential markers of antipsychotic treatment resistance

Yang

Longo

Narita

et al. 2021

Preprint

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Treatment resistant (TR) psychosis is considered to be a significant cause of disability and functional impairment. Numerous efforts have been made to identify the clinical predictors of TR. However, the exploration of molecular and biological markers is still at an early stage. To understand the TR condition and identify potential molecular and biological markers, we analyzed demographic information, clinical data, structural brain imaging data, and molecular brain imaging data in 7 Tesla magnetic resonance spectroscopy, from a first episode psychosis cohort that includes 138 patients. Age, gender, race, smoking status, duration of illness, and antipsychotic dosages were controlled in the analyses. We found that TR patients had a younger age at onset, more hospitalizations, more severe negative symptoms, a significant reduction in the volumes of the hippocampus (HP) and superior frontal gyrus (SFG), and a significant reduction in glutathione (GSH) levels in the anterior cingulate cortex (ACC), when compared to non-TR patients. The combination of multiple markers provided a better classification between TR and non-TR patients compared to any individual marker. Our study shows that ACC GSH, HP and SFG volumes, and age at onset could potentially be trait biomarkers for TR diagnosis, while hospitalization and negative symptoms could be used to evaluate the progression of the disease. Multimodal cohorts are essential in obtaining a comprehensive understanding of brain disorders.

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Section: Resultssupporting

confidence: 58%

A multimodal study of a first episode psychosis cohort: potential markers of antipsychotic treatment resistance

Yang

Longo

Narita

et al. 2021

Preprint

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“…The same stability in GSH levels was also seen in the 10 demographically healthy controls scanned at 2 time points (Mean(SD) at baseline =1.64 (0.25), at 6-months = 1.63 (0.32)) [84]. In a larger sample of 38 patients with first episode psychosis (onset within 2 years) and 48 healthy controls followed up over 4 years [85], GSH levels was found to have a near zero change in all 5 studied brain regions (ACC, thalamus, DLPFC, centrum semiovale and orbitofrontal cortex) over time, strongly arguing for a 'trait-like' stability of GSH levels compared to other metabolites. These observations do not rule out within-individual differences over time, and the possibility of an early excess in untreated state; but provide a strong support for the presence of a distinct subgroup with GSH-deficit that is over-represented in more established phase of schizophrenia, in association with reduced treatment responsiveness and poor functional outcomes.…”

Section: Intracortical Gsh In Schizophrenia: Mrs Studiesmentioning

confidence: 52%

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

Palaniyappan¹,

Park²,

Jeon³

et al. 2021

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Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical glutathione (GSH). A large body of pre-clinical data has suggested the possibility of notable GSH-deficit in a subgroup of patients with schizophrenia. Nevertheless, studies of intracortical GSH are not conclusive in this regard. In this review, we highlight the recent ultra-high field magnetic resonance spectroscopic studies linking GSH to critical outcome measures across various stages of schizophrenia. We discuss the methodological steps required to conclusively establish or refute the persistence of GSH-deficit subtype and clarify the role of the central antioxidant system in disrupting the brain structure and connectivity in the early stages of schizophrenia. We propose in-vivo GSH quantification for patient selection in forthcoming antioxidant trials in psychosis. This review offers directions for a promising non-dopaminergic early intervention approach in schizophrenia.

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“…Support for this explanation comes from the existing longitudinal studies of ACC GSH in schizophrenia which do not reveal a picture of dynamic change in GSH levels. Instead, existing longitudinal MRS (44,45) as well as genetic studies (31) indicate a constitutional deficit of GSH, at least in some individuals with schizophrenia. The modest effect-size of the reported GSH deficit even in the chronic and partially treatment-resistant samples (7,46), suggests that either (1) only a small number of patients belong to the putative FIGURE 2 | (A) In this model, a primary defect in glutathione generation is thought to contribute to NMDA hypofunction in cortical microcircuits, leading to relative glutamatergic excess via disinhibition of pyramidal neurons.…”

Section: Discussionmentioning

confidence: 99%

Schizophrenia Increases Variability of the Central Antioxidant System: A Meta-Analysis of Variance From MRS Studies of Glutathione

Palaniyappan

Sabesan

et al. 2021

Front. Psychiatry

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Patients with schizophrenia diverge in their clinical trajectories. Such diverge outcomes may result from the resilience provided by antioxidant response system centered on glutathione (GSH). Proton Magnetic Resonance Spectroscopy (1H-MRS) has enabled the precise in vivo measurement of intracortical GSH; but individual studies report highly variable results even when GSH levels are measured from the same brain region. This inconsistency could be due to the presence of distinct subgroups of schizophrenia with varying GSH-levels. At present, we do not know if schizophrenia increases the interindividual variability of intracortical GSH relative to matched healthy individuals. We reviewed all 1H-MRS GSH studies in schizophrenia focused on the Anterior Cingulate Cortex published until August 2021. We estimated the relative variability of ACC GSH levels in patients compared to control groups using the variability ratio (VR) and coefficient of variation ratio (CVR). The presence of schizophrenia significantly increases the variability of intracortical GSH in the ACC (logVR = 0.12; 95% CI: 0.03–0.21; log CVR = 0.15; 95% CI = 0.06–0.23). Insofar as increased within-group variability (heterogeneity) could result from the existence of subtypes, our results call for a careful examination of intracortical GSH distribution in schizophrenia to seek redox-deficient and redox-sufficient subgroups. An increase in GSH variability among patients also indicate that the within-group predictability of adaptive response to oxidative stress may be lower in schizophrenia. Uncovering the origins of this illness-related reduction in the redox system stability may provide novel treatment targets in schizophrenia.

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Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study

Cited by 8 publications

References 42 publications

A multimodal study of a first episode psychosis cohort: potential markers of antipsychotic treatment resistance

A multimodal study of a first episode psychosis cohort: potential markers of antipsychotic treatment resistance

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

Schizophrenia Increases Variability of the Central Antioxidant System: A Meta-Analysis of Variance From MRS Studies of Glutathione

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