8-OHdG in Cerebrospinal Fluid as a Marker of Oxidative Stress in Various Neurodegenerative Diseases

Gmitterová, Karin; Heinemann, Uta; Gawinecka, Joanna; Varges, Daniela; Ciesielczyk, Barbara; Valkovič, Peter; Benetin, Ján; Zerr, Inga

doi:10.1159/000237221

Cited by 63 publications

(41 citation statements)

References 67 publications

(53 reference statements)

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“…16,21,22 Interestingly, in other studies, 8OHdG was elevated in leukocytes in Alzheimer disease and in urine in Friedreich ataxia 30,31 and was higher in CSF from patients with Parkinson disease without dementia than in controls, but there were no differences between levels in controls and those with Parkinson disease without dementia, Alzheimer disease, or dementia with Lewy bodies. 32 Furthermore, 8OHdG was higher in CSF, urine, and plasma from patients with amyotrophic lateral sclerosis compared with controls, whereas only the plasma levels and not the urine or CSF levels were elevated in a group of participants with other neurologic disorders. 33 Identification and validation of biomarkers for HD clinical trials is extremely important and remains a challenging goal; this was a principal goal of the prospective, longitudinal, observational TRACK-HD study.…”

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confidence: 82%

8OHdG is not a biomarker for Huntington disease state or progression

et al. 2013

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Objective: To evaluate plasma 8-hydroxy-deoxy-guanosine (8OHdG) levels as a potential biomarker of premanifest and early Huntington disease (HD).Methods: Personnel from 2 independent laboratories quantified 8OHdG in blinded longitudinal plasma samples taken 24 months apart from 160 TRACK-HD participants, as well as samples containing control plasma with added ("spiked") 8OHdG. One laboratory used a liquid chromatography-electrochemical array (LCECA) assay, and the other used liquid chromatography-mass spectrometry (LCMS).Results: The LCMS assay was more accurate than the LCECA assay for measurements of "spiked" 8OHdG levels in plasma. Neither assay demonstrated cross-sectional differences in plasma 8OHdG among controls, premanifest HD, and early symptomatic HD. Similarly, neither assay showed longitudinal changes in any disease group over 24 months.Conclusions: Plasma concentration of 8OHdG is not a biomarker of disease state or progression in HD. We recommend that future putative biomarker studies use blinded sample analysis, standard curves, independent analytical methods, and strict quality control of sample collection and storage. Huntington disease (HD), an autosomal dominant neurodegenerative disease, is caused by an abnormally expanded trinucleotide (CAG) repeat in the huntingtin (HTT) gene. 1 The disorder is typically diagnosed at onset of motor symptoms, but there is a "premanifest" period associated with clinical signs, including brain atrophy, psychiatric symptoms, and cognitive decline. [2][3][4] PREDICT-HD 5 and TRACK-HD, 6 both longitudinal observational studies, aim to identify early HD biomarkers. These and other studies have shown differences in neuroimaging, cognitive, and motor measures among control, premanifest, and clinically diagnosed cohorts. 7,8 Although premanifest and clinically diagnosed groups show robust longitudinal changes in neuroimaging measures, the latter shows more easily detectable declines in other measures compared with controls and premanifest HD (preHD). 9-14Currently, there are no validated candidate blood, CSF, or urine biomarkers that track the progression of HD.15 8-Hydroxy-deoxy-guanosine (8OHdG) has been proposed as a biomarker of HD progression.16 8OHdG is a product of the oxidation of guanine by reactive oxygen species, and its levels in blood and urine may correlate with the degree of oxidative DNA damage. 17,18 Although increased levels of 8OHdG have been reported in patients with HD and mouse models indicating such oxidative DNA damage, the role of such damage in HD pathogenesis remains obscure. [19][20][21][22][23] Using our recently developed liquid chromatography-mass spectrometry (LCMS) assay, we were unable to replicate the modest increase previously demonstrated with the liquid chromatographyFrom CHDI Management/CHDI Foundation (B.B., J.W., C.S.),

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confidence: 82%

8OHdG is not a biomarker for Huntington disease state or progression

et al. 2013

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“…However, immunoassays for measurement of 8-OHdG and F2-isoP have been criticized, although results employing this technology being widely published. [26][27][28] Recent publications critiquing ELISA-based 8-OHdG methods suggest that ELISA-based values tended to be higher values than ''gold-standard'' LC/ MS-based measurement. 29 However, several steps were taken in this trial protocol to reduce sources of variability that should have improved the ability to detect a trend for change, if one was present.…”

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confidence: 99%

Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress Biomarkers in Human Volunteers

Allen

Bradley

2011

The Journal of Alternative and Complementary Medicine

134

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Background: The tripeptide glutathione (GSH) is the most abundant free radical scavenger synthesized endogenously in humans. Increasing mechanistic, clinical, and epidemiological evidence demonstrates that GSH status is significant in acute and chronic diseases. Despite ease of delivery, little controlled clinical research data exist evaluating the effects of oral GSH supplementation. Objectives: The study objectives were to determine the effect of oral GSH supplementation on biomarkers of systemic oxidative stress in human volunteers. Design: This was a randomized, double-blind, placebo-controlled clinical trial. Setting/location: The study was conducted at Bastyr University Research Institute, Kenmore, WA and the Bastyr Center for Natural Health, Seattle, WA. Subjects: Forty (40) adult volunteers without acute or chronic disease participated in this study. Intervention: Oral GSH supplementation (500 mg twice daily) was given to the volunteers for 4 weeks. Outcome measures: Primary outcome measures included change in creatinine-standardized, urinary F2-isoprostanes (F2-isoP) and urinary 8-hydroxy-2¢-deoxyguanosine (8-OHdG). Changes in erythrocyte GSH concentrations, including total reduced glutathione (GSH), oxidized glutathione (GSSG), and their ratio (GSH:GSSG) were also measured by tandem liquid chromatography/mass spectrometry. Analysis of variance was used to evaluate differences between groups. Results: There were no differences in oxidative stress biomarkers between treatment groups at baseline. Thirtynine (39) participants completed the study per protocol. Changes in creatinine standardized F2-isoP (ng/mg creatinine) (0.0 -0.1 versus 0.0 -0.1, p = 0.38) and 8-OHdG (lg/g creatinine) (-0.2 -3.3 versus 1.0 -3.2, p = 0.27) were nonsignificant between groups at week 4. Total reduced, oxidized, and ratio measures of GSH status were also unchanged. Conclusions: No significant changes were observed in biomarkers of oxidative stress, including glutathione status, in this clinical trial of oral glutathione supplementation in healthy adults.

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“…TAC includes antioxidant activities of non-enzymatic low molecular weight substances such as glutathione, ascorbic acid, uric acid, α-tocopherol, and coenzyme Q (Alho et al, 1998; Bartosz, 2003); a reduction in TAC could alter the balance between ROS levels and mechanisms which protect against their cytotoxic effects, in favor of oxidative damage. The concentration of 8-OHdG has been reported to be increased in PD cerebrospinal fluid (CSF) (Kikuchi et al, 2002; Abe et al, 2003; Gmitterová et al, 2009; Isobe et al, 2010). We found no reports of 8-ISO or TAC measurements in PD CSF; however, 8-ISO in the PD SNC has been reported to be unchanged (Fessel et al, 2003), while TAC in the PD SNC is reported to be decreased (Sofic et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Increased Oxidative Stress Markers in Cerebrospinal Fluid from Healthy Subjects with Parkinson’s Disease-Associated LRRK2 Gene Mutations

Loeffler

Klaver

Coffey

et al. 2017

Front. Aging Neurosci.

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of inherited Parkinson’s disease (PD). The most common PD-associated LRRK2 mutation, G2019S, induces increased production of reactive oxygen species in vitro. We therefore hypothesized that individuals with PD-associated LRRK2 mutations might have increased concentrations of oxidative stress markers and/or decreased total antioxidant capacity (TAC) in their cerebrospinal fluid (CSF). We measured two oxidative stress markers, namely 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO), and TAC in CSF from LRRK2 mutation-bearing PD patients (LRRK2 PD = 19), sporadic PD patients (sPD = 31), and healthy control subjects with or without these mutations (LRRK2 CTL = 30, CTL = 27). 8-OHdG and 8-ISO levels were increased in LRRK2 CTL subjects, while TAC was similar between groups. 8-ISO was negatively correlated, and TAC was positively correlated, with Montreal Cognitive Assessment scores in LRRK2 PD, LRRK2 CTL, and CTL subjects. Correlations in both groups of PD patients between the two oxidative stress markers and Unified Parkinson Disease Rating Scale Total scores were weak, while TAC was negatively correlated with these scores. These findings suggest that oxidative stress may be increased in the CNS in healthy individuals with PD-associated LRRK2 mutations. Further, TAC may decrease in the CNS with the progression of PD, and when cognitive impairment is present regardless of the presence or absence of PD.

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8-OHdG in Cerebrospinal Fluid as a Marker of Oxidative Stress in Various Neurodegenerative Diseases

Cited by 63 publications

References 67 publications

8OHdG is not a biomarker for Huntington disease state or progression

8OHdG is not a biomarker for Huntington disease state or progression

Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress Biomarkers in Human Volunteers

Increased Oxidative Stress Markers in Cerebrospinal Fluid from Healthy Subjects with Parkinson’s Disease-Associated LRRK2 Gene Mutations

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