Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology

Abstract

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using 1H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) 1H MRSI to measure CSF lactate; (ii) single-voxel 1H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) 31P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

“…Oxidative imbalance has been detected in striated muscle and was correlated with empirical markers of muscle fatigability in the patients examined [289]. Finally, a relatively recent study utilizing NMR spectroscopy reported significantly impaired production of cortical glutathione in people diagnosed with CFS [283].…”

“…Chronically elevated oxidative stress is almost universally reported by authors investigating this phenomenon in CFS patients, with established highly significant associations between O&NS biomarkers and CFS symptom [208,[279][280][281][282][283][284][285][286]. In an elegant study, Miwa and Fujita showed that a sharp decrease in oxidative stress was associated with clinical remission [287].…”

“…In an elegant study, Miwa and Fujita showed that a sharp decrease in oxidative stress was associated with clinical remission [287]. Studies have shown increases in systemic O&NS biomarkers in CFS patients, including isoprostane, MDA, 2,3-diphosphoglyceric acid, 8-OH-deoxyguanosine, thiobutyric acid, and protein carbonyls [208,[279][280][281][282][283][284][285][286]. NO synthesis is also significantly upregulated in many patients with a diagnosis of CFS compared with healthy controls [37,288].…”

The Emerging Role of Glutathione in Alzheimer's Disease

“…Recent developments in MRS spectra have enabled in vivo quantification of GSH from specific brain regions [81]. Only a small handful of studies have assessed in vivo brain GSH levels by MRS in patients with CNS conditions-epilepsy [83,84], schizophrenia [85][86][87], multiple sclerosis [88,89], bipolar disorder [90,91], and mood depressive disorder [91,92]. Recent work has added to this body of work by assessing GSH levels in brains of MCI and AD patients [68,69].…”

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

“…[1][2][3] Infection has been reported with a wide range of viruses and bacteria, 4 including Epstein-Barr virus, [5][6][7][8] human herpes viruses 6 and 7, [9][10][11] enteroviruses, 7,12 cytomegalovirus 13,14 and lentiviruses, 15 as well as chlamydia, 7 mycoplasma 16 and borrelia species. 17 An association of ME/CFS with central nervous system (CNS) dysfunction is supported by imaging studies documenting cerebral hypoperfusion and increased white matter T2 signal consistent with chronic inflammation 18 in addition to regional differences in gray 19 and/ or white matter. 19,20 Routine cerebrospinal fluid (CSF) studies in patients with ME/ CFS, including white blood cell count, glucose and protein, are typically unremarkable; 21 however, high resolution mass spectrometry has shown abnormalities in the CSF proteome, including an increase in proteins related to the complement cascade.…”