Longitudinal changes of cerebral glutathione (GSH) levels associated with the clinical course of disease progression in patients with secondary progressive multiple sclerosis

Abstract

Background Increased oxidative stress leads to loss of glutathione (GSH). We have reported lower cerebral GSH in patients with secondary progressive multiple sclerosis (SPMS), indicating the involvement of oxidative stress in MS pathophysiology. Objective This study expanded upon our earlier work by examining longitudinal changes in cerebral GSH in patients with SPMS in relation to their clinical status. Methods Thirteen patients with SPMS (EDSS=4.0–6.5; MS duration=21.2±8.7 years) and 12 controls were studied over 3–5 years. GSH mapping was acquired from frontal and parietal regions using a multiple quantum chemical shift imaging technique at 3T. Clinical assessments of the patient’s disability included EDSS, gait, motor strength, ataxia, tremor, brainstem function and vision changes. Results Brain GSH concentrations in patients were lower than those in controls for both baseline and 3–5 year follow-ups. Longitudinal GSH changes of patients were associated with their neurologist’s blinded appraisal of their clinical progression. Patients judged to have worsening clinical status had significantly greater declines in frontal GSH concentrations than those with stable clinical status. Conclusion GSH provides a distinct measure associated with the disease progression in SPMS, possibly due to its dynamic alignment with pathogenic processes of MS related to oxidative stress.

Extracellular free water and glutathione in first-episode psychosis—a multimodal investigation of an inflammatory model for psychosis

“…Several interacting homeostatic mechanisms regulate brain tissue GSH levels, tending to keep them within a range of normal values 78, 79 . Some inflammatory processes can alter this process sufficiently to cause low GSH levels, such as in multiple sclerosis 80, 81 . Some inflammatory processes do not have this effect, and GSH levels remain normal, as in ALS, for example 82, 83 .…”

Quantifying the Metabolic Signature of Multiple Sclerosis by in vivo Proton Magnetic Resonance Spectroscopy: Current Challenges and Future Outlook in the Translation From Proton Signal to Diagnostic Biomarker

“…Like GABA, glutathione possesses a low-amplitude spectral signature that overlaps heavily with metabolites of much higher brain concentrations, therefore requiring spectral editing for accurate quantification by one-dimensional 1 H-MRS. Previous research employing this editing has suggested that multiple sclerosis is associated with glutathione decreases in gray but not white matter voxels measured superior to the ventricles (104); some evidence also exists of reduced glutathione concentration in secondary progressive mixed-tissue voxels in the frontal (151, 152) and parietal (152) cortex.…”

“…Similarly, studies on mixed-tissue voxels in secondary progressive multiple sclerosis have reported decreases in N-acetyl aspartate referenced to creatine (71, 73, 84, 85, 88) and otherwise (88, 134, 135), as well as increases in creatine (84, 135) and inositol referenced to creatine or otherwise (84), and decreases in GABA (134) but have not replicated relapsing-remitting findings of decreased creatine-referenced choline (144, 145), glutamate (149), or glutamate-glutamine (124, 149). Secondary progressive but not relapsing-remitting patients have, however, exhibited decreases in mixed-tissue creatine (88) and glutathione (151, 152) as well as increases in choline (135). The handful of analyses concomitantly examining mixed-tissue voxels in both phenotypes have reported decreases in N-acetyl aspartate in either both patient groups (71) or secondary progressive multiple sclerosis only (84, 85, 88) and increases in creatine-referenced inositol in both patient groups, in addition to increases in inositol and creatine in secondary progressive but not relapsing-remitting multiple sclerosis (84).…”

“…Among these, at least 26 publications (23, 24, 27, 35, 46, 53, 69, 77, 79, 90–93, 95, 106, 116, 138, 139, 147, 153, 154, 160, 172, 216–219) employed Stimulated Echo Acquisition Mode (STEAM) localization instead of the more commonly used Point-RESolved Spectroscopy (PRESS), of which the former facilitates lower echo times and enables a sharper volume profile at the expense of 50% signal loss relative to the latter. Other short- and long- T E spectral acquisition sequences used have included PRESS with spectral editing (MEscher-GArwood Point-RESolved Spectroscopy or MEGA-PRESS) for GABA (107, 134, 150), chemical shift imaging (CSI) with multiple quantum filtering (151, 152) or band-selective inversion (104) for glutathione, and diffusion-weighted PRESS (38, 103, 206) or STEAM (220), though the latter was used to probe diffusion properties rather than metabolite concentrations.…”

Advances in Imaging Multiple Sclerosis

“…48 Glutathione, an antioxidant against reactive oxygen species, was found to be reduced in the frontal lobes in patients with SPMS and associated with clinical disease progression. 49 Monitoring of metabolites, such as GABA and glutathione, is particularly interesting, as these could represent potential therapeutic targets for neuroprotection. Technical issues limit the routine use of MRS, including poor resolution, signal to noise ratio, and complex processing.…”