AUTHORS: Do KQ, Cabungcal JH, Cleusix M, Dwir D, Fournier M, Griffa A, Gruetter R, Hagmann P, Jenni R, Klauser P, Monin A, Mullier E, Steullet P, Xin L, Cuenod M, Conus P

Biological Psychiatry, 89(9): S56, May 2021

ABSTRACT

Background: Redox imbalance/oxidative stress affect oligodendrocytes precursor cells (OPC) and myelination, leading to dysconnectivity.
Methods: Gclm-KO mice with impaired GSH synthesis: Immunohistochemistry; 14T MRS/DTI. Early psychosis patients (EPP): white matter (WM) integrity, fractional anisotropy (FA) by DSI; resting state fMRI; glutathione (GSH) by MRS; GSH peroxidase (GPx) activity, sRAGE; neurocognition.
Results: Oxidative stress impaired OPC proliferation and maturation, a dysregulation mediated by Fyn kinase pathway and reversed by antioxidant GSH precursor N-acetylcysteine (NAC) or Fyn kinase inhibitors. In prefrontal cortex of Gclm-KO, oligodendrocyte and myelin markers were decreased concomitantly with increases of oxidative stress and neuro-inflammation. Translating to EPP, multimodal brain imaging revealed a positive association between prefrontal GSH levels and both WM integrity and resting-state functional connectivity along cingulum bundle. Fyn was impaired in patients’ fibroblasts. The mechanism-based marker of neuroinflammation sRAGE was increased.
In Gclm-KO mice, WM integrity (FA) was reduced in fornix-fimbria. EPP exhibited decreased fornix integrity associated with smaller hippocampus, correlated with higher blood GSH peroxidase (GPx) activity.
In a clinical trial, NAC increased prefrontal GSH levels (target engagement), improved processing speed and positive symptoms in patients with high blood GPx activity. NAC also decreased the neuroinflammation marker sRAGE. NAC improved cingulum connectivity and fornix integrity, in correlation with brain GSH increase and cognition improvement.
Conclusions: Developmental redox dysregulation leads to impairments of myelination, WM maturation, and fiber integrity in both EPP and GSH deficit models. Fyn kinase pathway dysregulation, sRAGE and fornix integrity impairments may constitute markers in EP, paving the way for patient stratification and biomarker-guided treatments.

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