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. 2012 Sep;25(9):1073-87.
doi: 10.1002/nbm.2772. Epub 2012 Jan 27.

Increased Ventricular Lactate in Chronic Fatigue Syndrome. III. Relationships to Cortical Glutathione and Clinical Symptoms Implicate Oxidative Stress in Disorder Pathophysiology

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Free PMC article

Increased Ventricular Lactate in Chronic Fatigue Syndrome. III. Relationships to Cortical Glutathione and Clinical Symptoms Implicate Oxidative Stress in Disorder Pathophysiology

Dikoma C Shungu et al. NMR Biomed. .
Free PMC article

Abstract

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1)H 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) (1)H MRSI to measure CSF lactate; (ii) single-voxel (1)H 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) (31)P 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.

Figures

Figure 1
Figure 1
(A) Prescription of the slice(s) of interest for 1H and 31P MRSI scans. (B) Sample 1H spectrum from a voxel (see box in A) in the lateral ventricle of a patient with chronic fatigue syndrome (CFS) showing a clear lactate doublet peak at 1.33 ppm; also shown are contaminating resonances for N-acetylaspartate (NAA), total creatine (tCr) and total choline (tCho) from surrounding brain tissue as a result of partial volume averaging. (C) The filled structure, which is also shown in (A), depicts the ventricular region of interest from which lactate levels were obtained. The volume of this region of interest was determined by manual delineation of tissue-segmented volumetric MR images to enable the adjustment of lactate for partial volume effects.
Figure 2
Figure 2
Sample 31P MRSI grid overlaid on a corresponding axial-oblique localizer MR image. Insets show the spectral quality for several voxels across the brain. Baseline distortions in each spectrum introduced by the large first-order phase corrections needed to account for the finite delay between the single slice-selective excitation pulse and signal acquisition were removed by interpolation. The following phosphate resonances are identified (inset B): phosphomonoesters (PME), inorganic orthophosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr) and the α, β and γ moieties of nucleoside triphosphate (NTP).
Figure 3
Figure 3
(A) Location of a 2.0 × 3.0 × 3.0-cm3 occipital lobe voxel in which glutathione (GSH) was measured. (B) Demonstration of in vivo human brain GSH detection by 1H MRS: spectra a and b, single-voxel subspectra acquired in 15 min with the editing pulse on and off and 290 (580 total) interleaved averages; spectrum c, difference between spectra a and b showing the edited brain GSH resonance; spectrum d, model fitting of spectrum c to obtain the GSH peak area; spectrum e, residual of the difference between spectra c and d. (C) Stacked plots of edited spectra obtained as in (B) from five randomly selected subjects showing clear and consistent detection of GSH. NAA, N-acetylaspartate; tCho, total choline; tCr, total creatine.
Figure 4
Figure 4
Scatter plots comparing ventricular lactate (A) and occipital glutathione (GSH) levels (B) in patients with chronic fatigue syndrome (CFS) or major depressive disorder (MDD) and in healthy volunteers (HV).
Figure 5
Figure 5
Correlation of occipital glutathione (GSH) and ventricular lac-tate levels across all chronic fatigue syndrome (CFS) (▶), major depressive disorder (MDD) (○) and healthy volunteer (HV) (●) groups.
Figure 6
Figure 6
Associations between ventricular lactate and glutathione (GSH) in chronic fatigue syndrome (CFS) (▶), major depressive disorder (MDD) (○) and healthy volunteer (HV) (●) groups and the following selected clinical variables: (A) total RAND SF-36 (36-Item Short Form Health Survey by the RAND Corporation, Santa Monica, CA, USA) scores; (B) Sheehan Disability Scale (SDS); (C) US Centers for Disease Control and Prevention (CDC) CFS Symptom Inventory.
Figure 7
Figure 7
Regional cerebral blood flow (rCBF) maps showing regions of statistically significant hypoperfusion in patients with chronic fatigue syndrome (CFS) relative to healthy volunteers (HV): left panel, left anterior cingulate cortex (p = 0.039); right panel, right lingual region (p = 0.016).
Figure 8
Figure 8
(A) Percentage regional cerebral blood flow (rCBF) changes (%ΔrCBF) between CFS and HV, CFS and MDD, and MDD and HV, normalized to HV, in 43 brain regions across both hemispheres. For nearly all regions, rCBF changes vary numerically as CFS < MDD < HV. (B) Comparison of mean percentage global CBF change (%ΔgCBF) between CFS and HV, MDD and HV, and CFS and MDD. CFS, chronic fatigue syndrome; HV, healthy volunteer; MDD, major depressive disorder.
Figure 9
Figure 9
Proposed pathophysiological model of chronic fatigue syndrome (CFS) investigated in this study, which may explain the observed cross-sectional elevations of ventricular lactate. Highlighted are the experimentally measurable items, with the red arrows showing the model-predicted outcomes. In this and in two previous studies (3,4), we aimed to validate the model by measuring each item and comparing the results with the predictions, except for the isoprostanes, which have been reported previously (6,7) to be increased significantly in CFS (see text for details). AA, arachidonic acid; GSH, glutathione; NAA, N-acetylaspartate; ROS/RNS, reactive oxygen/nitrogen species;

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