Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy.

INTRODUCTION: The finding of mutations of the COQ2 gene and reduced coenzyme Q10 levels in the cerebellum in multiple system atrophy (MSA) suggest that coenzyme Q10 is relevant to MSA pathophysiology. Two recent studies have reported reduced coenzyme Q10 levels in plasma and serum (respectively) of MSA patients compared to Parkinson's disease and/or control subjects, but with largely overlapping values, limited comparison with other parkinsonisms, or dependence on cholesterol levels. We hypothesized that cerebrospinal fluid (CSF) is reliable to assess reductions in coenzyme Q10 as a candidate biomarker of MSA. METHODS: In this preliminary cross-sectional study we assessed CSF coenzyme Q10 levels in 20 patients with MSA from the multicenter Catalan MSA Registry and of 15 PD patients, 10 patients with progressive supranuclear palsy (PSP), and 15 control subjects from the Movement Disorders Unit Biosample Collection of Hospital Clinic de Barcelona. A specific ELISA kit was used to determine CSF coenzyme Q10 levels. CSF coenzyme Q10 levels were compared in MSA vs. the other groups globally, pair-wise, and by binary logistic regression models adjusted for age, sex, disease severity, disease duration, and dopaminergic treatment. RESULTS: CSF coenzyme Q10 levels were significantly lower in MSA than in other groups in global and pair-wise comparisons, as well as in multivariate regression models. Receiver operating characteristic curve analyses yielded significant areas under the curve for MSA vs. PD, PSP and controls. CONCLUSIONS: These findings support coenzyme Q10 relevance in MSA. Low CSF coenzyme Q10 levels deserve further consideration as a biomarker of MSA.

The antioxidant idebenone fails to prevent or attenuate chronic experimental autoimmune encephalomyelitis in the mouse.

Oxidative stress and mitochondrial dysfunction appear to contribute to neurodegenerative processes during multiple sclerosis (MS). Thus, antioxidants may represent a therapeutic option for MS. The antioxidant idebenone was proven to be beneficial in Friedreich's ataxia and Leber's hereditary optic neuropathy, two disorders caused by mitochondrial alterations. Here we showed that idebenone protected neuronal HT22 cells from glutamate-induced death in vitro. However, in experimental autoimmune encephalomyelitis, idebenone failed to affect disease incidence or onset when applied preventively, or to reduce disease severity when applied therapeutically. Histopathological examination of CNS from idebenone treated mice showed no improvement in inflammation, demyelination, or axonal damage. Thus, we hypothesize that idebenone treatment will likely not benefit patients with MS.

Coenzyme Q10 quantification in muscle, fibroblasts and cerebrospinal fluid by liquid chromatography/tandem mass spectrometry using a novel deuterated internal standard.

RATIONALE: Neurological dysfunction is common in primary coenzyme Q10 (2,3-dimethoxy, 5-methyl, 6-polyisoprene parabenzoquinone; CoQ10 ; ubiquinone) deficiencies, the most readily treatable subgroup of mitochondrial disorders. Therapeutic benefit from CoQ10 supplementation has also been noted in other neurodegenerative diseases. CoQ10 can be measured by high-performance liquid chromatography (HPLC) in plasma, muscle or leucocytes; however, there is no reliable method to quantify CoQ10 in cerebrospinal fluid (CSF). Additionally, many methods use CoQ9 , an endogenous ubiquinone in humans, as an internal standard. METHODS: Deuterated CoQ10 (d6 -CoQ10 ) was synthesised by a novel, simple, method. Total CoQ10 was measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) using d6 -CoQ10 as internal standard and 5 mM methylamine as an ion-pairing reagent. Chromatography was performed using a Hypsersil GOLD C4 column (150 × 3 mm, 3 µm). RESULTS: CoQ10 levels were linear over a concentration range of 0-200 nM (R(2) = 0.9995). The lower limit of detection was 2 nM. The inter-assay coefficient of variation (CV) was 3.6% (10 nM) and 4.3% (20 nM), and intra-assay CV 3.4% (10 nM) and 3.6% (20 nM). Reference ranges were established for CoQ10 in CSF (5.7-8.7 nM; n = 17), fibroblasts (57.0-121.6 pmol/mg; n = 50) and muscle (187.3-430.1 pmol/mg; n = 15). CONCLUSIONS: Use of d6 -CoQ10 internal standard has enabled the development of a sensitive LC/MS/MS method to accurately determine total CoQ10 levels. Clinical applications of CSF CoQ10 determination include identification of patients with cerebral CoQ10 deficiency, and monitoring CSF CoQ10 levels following supplementation.

Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2'-deoxyguanosine in the cerebrospinal fluid of patients with living Parkinson's disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process.

The aim of this study was to investigate the possibility that mitochondrial oxidative damage, oxidative DNA damage or both contribute to the neurodegenerative process of Parkinson's disease (PD). We employed high-performance liquid chromatography (HPLC) using an electrochemical detector to measure concentrations of the reduced and oxidized forms of coenzyme Q-10 (CoQ-10) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the cerebrospinal fluid (CSF) of 20 patients with PD and 20 age-matched controls with no neurological disease. The percentage of oxidized to total CoQ-10 (%CoQ-10) in the CSF of the PD group (80.3+/-17.9%) was significantly higher than in the control group (68.2+/-20.4%, P<0.05). In addition, the concentration of 8-OHdG in the CSF of PD patients was greater than in the CSF of controls (P<0.0001) and was positively correlated with the duration of illness (r(s)=0.87, P<0.001). Finally, the %CoQ-10 was correlated with concentrations of 8-OHdG in the CSF of PD patients (r(s)=0.56, P<0.01). The present study suggests that both mitochondrial oxidative damage and oxidative DNA damage play important roles in the pathogenesis of early PD development.

Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2'-deoxyguanosine in the CSF of patients with Alzheimer's disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process.

To investigate the possibility that mitochondrial oxidative damage, oxidative DNA damage or both contribute to the neurodegenerative process of Alzheimer's disease (AD), we employed high-performance liquid chromatography using an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q-10 (CoQ-10) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the cerebrospinal fluid (CSF) of 30 patients with AD and in 30 age-matched controls with no neurological disease. The percentage of oxidized/total CoQ-10 (%CoQ-10) in the CSF of the AD group (78.2 +/- 18.8%) was significantly higher than in the control group (41.3 +/- 10.4%) (P < 0.0001). The concentration of 8-OHdG in the CSF of AD patients was greater than in the CSF of controls (P < 0.0001) and was positively correlated with the duration of illness (r(s) = 0.95, P < 0.0001). The %CoQ-10 was correlated with concentrations of 8-OHdG in the CSF of AD patients (r(s) = 0.66, P < 0.001). The present study suggests that both mitochondrial oxidative damage and oxidative DNA damage play important roles in the pathogenesis of early AD development.

Increase in the oxidized/total coenzyme Q-10 ratio in the cerebrospinal fluid of Alzheimer's disease patients.

BACKGROUND/AIM: The contribution of mitochondrial dysfunction and oxidative stress to the pathogenesis of Alzheimer's disease (AD) has previously been described. We aimed to investigate whether the balance between the oxidized and reduced forms of coenzyme Q-10 (CoQ-10) is related to the pathogenesis of AD. MATERIALS AND METHOD: Thirty patients with AD (69.0 +/- 4.1 years) and 30 healthy control subjects (63.8 +/- 16.4 years) were enrolled in this study. Concentrations of oxidized CoQ-10 and reduced CoQ-10 were measured by high-performance liquid chromatography using an electrochemical detector. RESULTS: The percentage of oxidized/total CoQ-10 in the cerebrospinal fluid (%CoQ-10, CSF) was significantly higher in the untreated AD group (78.2 +/- 18.8%) than in the control group (41.3 +/- 10.4%, p < 0.001), and there was a significant negative correlation between %CoQ-10 and the duration of the illness (r(s) = -0.93, p < 0.001). CONCLUSION: These findings in living AD patients suggest a possible role for %CoQ-10 in the pathogenesis of the early stage of AD development.

Increased mitochondrial oxidative damage in patients with sporadic amyotrophic lateral sclerosis.

To investigate whether mitochondrial oxidative damage contributes to the pathogenesis of sporadic amyotrophic lateral sclerosis (sALS), we used high-performance liquid chromatography with an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q10 (CoQ10) in the cerebrospinal fluid (CSF) of 30 patients with sALS and 17 age-matched controls with no neurological diseases. The percentage of oxidized CoQ10 in the CSF of sALS patients were significantly greater than those in the CSF of controls (P<0.002) and were negatively correlated with duration of illness (rho=-0.64, P<0.001). These results suggest that mitochondrial oxidative damage contributes to the pathogenesis of sporadic amyotrophic lateral sclerosis.

Increase of oxidized/total coenzyme Q-10 ratio in cerebrospinal fluid in patients with Parkinson's disease.

The concentrations of oxidized coenzyme Q-10 (CoQ-10) and reduced CoQ-10 in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) was examined in order to determine whether the balance in oxidized and reduced CoQ-10 is related to the pathogenesis of PD. The percentage of oxidized/total CoQ-10 (%CoQ-10) in the CSF was significantly higher in the untreated PD group (80.3+/-17.9%) compared to the normal control group (68.2+/-20.4%) (p<0.05). The %CoQ-10 in the CSF of PD patients showed significant negative correlation with the duration of illness. These findings in living patients provide in vivo evidence for a possible role for %CoQ-10 in the pathogenesis in the early stages of PD development.

Cerebrospinal fluid concentrations of idebenone in Friedreich ataxia patients.

We studied plasma and cerebrospinal fluid (CSF) concentrations of idebenone in five Friedreich ataxia patients on treatment with this antioxidant, and plasma and CSF ubiquinone-10 (Q (10)) concentrations in 15 controls. CSF idebenone concentrations were below the detection limit in 3 Friedreich ataxia patients and no association could be demonstrated between plasma and CSF idebenone values. Q (10) CSF concentrations (median: 2.25 nmol/L) were approximately 300 times lower than those of plasma (median: 0.77 micro mol/L). No correlation was observed between plasma and CSF Q (10) concentrations. A significantly positive correlation was observed between CSF total protein values (range 8.1 - 107.5 mg/dL; median: 29.5) and CSF Q (10) concentrations (Spearman test: r = 0.664; p = 0.01). Our findings suggest that less idebenone is distributed to the brain than to other tissues, although CSF does not appear to be an appropriate material for treatment monitoring of idebenone and other quinoid compounds.

[An increase in cerebrospinal fluid ubiquitin in human global brain ischemia--a prognostic marker for anoxic-ischemic encephalopathy].

The prognostic value of ubiquitin levels in cerebrospinal fluid (CSF) was studied in human global brain ischemia (anoxic-ischemic encephalopathy). Twenty four samples were collected from 13 patients who were resuscitated from cardio-pulmonary arrest and survived for at least 1 day. The outcome was classified according to the Glasgow Outcome Scale (GOS1-5). The ubiquitin levels (normal: 14.3 +/- 1.1 ng/ml, mean +/- S.E.M.) in neurologically symptomatic patients (GOS1-4) were 151 +/- 32.5 ng/ml on day 1-2 and elevated to 1,960 +/- 849 ng/ml on day 3-4. The Spearman's rank correlation of ubiquitin levels on day 3-4 and the GOS was -0.855, showing a better correlation than CSF neuron-specific enolase levels (r = -0.846). Ubiquitin is a heat shock protein associated with the degradation of abnormal cellular proteins. Thus, the elevation of CSF ubiquitin levels represents both its overproduction by a cytoprotective response to brain ischemia and its leakage from the damaged tissue. The present study suggests that the measurement of CSF ubiquitin level is useful for the early prognostic assessment of global brain ischemia.

The effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity.

Free radicals are thought to be involved in the onset of neuronal disturbances such as Alzheimer's disease, Parkinson's disease, and neuronal ceroid lipofuscinosis. It is also assumed that they play a role in cerebral injury caused by ischemia or trauma. Plasma and cerebrospinal fluid (CSF), Total (peroxyl) Radical-trapping Antioxidant Parameter (TRAP), and the known antioxidant components of TRAP, for instance, ascorbic acid, uric acid, protein sulfhydryl groups, tocopherol, and ubiquinol were analyzed and the remaining unidentified fragment was calculated in five healthy volunteers before and after 4 weeks of ascorbate and ubiquinone (Q-10) supplementation. In CSF, TRAP was significantly lower than in plasma. The major contributor to plasma's antioxidant capacity was uric acid (UA), whereas in CSF it was ascorbic acid (AA). In CSF, AA concentrations were four times higher than in plasma. Oral supplementation of AA (500 mg/d first 2 weeks, 1,000 mg/d following 2 weeks) and Q-10 (100 mg/d first 2 weeks, 300 mg/d following 2 weeks) induced a significant increase in plasma AA and Q-10. Surprisingly, in spite of the high lipophilicity of Q-10, its concentration did not change in CSF. The supplementation of AA increased its concentration in CSF by 28% (p < .05). However, the increase in AA did not result in an increase in CSF TRAP. This indicates that AA had lost one-third of its radical trapping capacity as compared to that in plasma. The facts that AA is the highest contributor to CSF TRAP and its effect on TRAP is concentration dependent could indicate that the peroxyl radical-trapping capacity of CSF is buffered by AA.