Evidence of oxidative injury of the spinal cord in 2 horses with equine degenerative myeloencephalopathy.

The cervical spinal cords of 2 horses with equine degenerative myeloencephalopathy (EDM) were evaluated for evidence of oxidative damage to the central nervous system (CNS) using immunohistochemical staining for 3-nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE). Neurons of the CNS from horses with EDM had positive immunohistochemical staining, whereas control samples did not, thus supporting the theory that oxidative damage is a potential underlying factor in horses with EDM. In addition, serum vitamin E concentration was low in both EDM-affected horses, and vitamin E concentration was also deficient in the cerebrospinal fluid in 1 EDM horse, further supporting the association between low vitamin E concentrations and oxidative damage to the CNS. Continued research is necessary to further define the pathophysiologic mechanisms of EDM.

Analysis of postmortem ventricular cerebrospinal fluid from patients with and without dementia indicates association of vitamin E with neuritic plaques and specific measures of cognitive performance.

Ventricular cerebrospinal fluid (vCSF) obtained at autopsy from 230 participants in the Religious Orders Study was analyzed for alpha tocopherol (αT, vitamin E) and gamma tocopherol (γT) in relation to brain tissue neuropathological diagnoses (NIA-Reagan criteria); neuritic plaque density and neurofibrillary tangle state (Braak stage); and cognitive function proximate to death. Neither vCSF αT nor γT was related to the pathological diagnosis of Alzheimer's disease, but vCSF αT concentration was inversely related to neuritic plaque density (ß = -0.21, SE = 0.105, p = 0.04) in regression models adjusted for age, gender, education, and APOE-4. Ventricular CSF αT concentration was positively associated with perceptual speed (ß = 0.27, SE = 0.116, p = 0.02) whereas the γT/αT ratio was negatively associated with episodic memory (ß = -0.037, SE = 0.017, p = 0.04). Only vCSF αT, but not γT, was correlated with postmortem interval (PMI). Adjustment for PMI had no effect on significance of associations between αT and perceptual speed or γT/αT and episodic memory, but after this adjustment the αT concentration was no longer significantly associated with neuritic plaques. These data suggest that vCSF αT, but not γT, is weakly associated with less Alzheimer's disease neuropathology, specifically neuritic plaques, and correlates with better performance on tests of perceptual speed.

[Serum and cerebrospinal fluid concentration of vitamins A, E and C in patients with tick-borne encephalitis]. / Stezenie witamin A, E oraz C w surowicy krwi i plynie mózgowo-rdzeniowym chorych z kleszczowym zapaleniem mózgu--doniesienie wstepne.

We included in our study 18 patients hospitalized because of tick borne encephalitis (tbc) at the Departament of Infectious Diseases and Neuroinfections of Medical University of Bialystok. In this group, concentration of vitamins A, E and C in serum and cerebrospinal fluid (CSF) was measured before and after treatment. The control group consisted of 11 patients with no inflammatory changes in CSF were observed. We did not observe significant differences in concentration of vitamins in serum and CSF before and after treatment comparing to controls. However, we showed significant increase in concentration of vitamin E before and after treatment in both serum and CSF in patients with tbc in comparison with control group.

Associative and predictive biomarkers of dementia in HIV-1-infected patients.

BACKGROUND: Infection with HIV can result in a debilitating CNS disorder known as HIV dementia (HIV-D). Since the advent of highly active antiretroviral therapy (HAART), the incidence of HIV-D has declined, but the prevalence continues to increase. In this new era of HIV-D, traditional biomarkers such as CSF viral load and monocyte chemotactic protein 1 levels are less likely to be associated with dementia in patients on HAART and biomarkers that can predict HIV-D have not yet been identified. OBJECTIVE: To identify biomarkers that are associated with and can predict HIV-D. METHODS: We grouped patients with HIV based on changes in cognitive status over a 1-year period and analyzed sphingolipid, sterol, triglyceride, antioxidant, and lipid peroxidation levels in CSF. RESULTS: We found that increased levels of the vitamin E and triglyceride C52 predicted the onset or worsening of dementia. Elevated levels of sphingomyelin were associated with inactive dementia. Elevated levels of ceramide and the accumulation of 4-hydroxynonenals were associated with active dementia. CONCLUSIONS: We interpret these findings to indicate that early in the pathogenesis of HIV dementia, there is an up-regulation of endogenous antioxidant defenses in brain. The failure of this attempted neuroprotective mechanism leads to the accumulation of sphingomyelin and moderate cognitive dysfunction. The breakdown of this enlarged pool of sphingomyelin to ceramide and the accumulation of highly reactive aldehydes are associated with declining cognitive function. Thus, elevations in endogenous protective mechanisms may identify patients who are at increased risk of the development of HIV dementia.

Vitamin E in neurodegenerative disorders: Alzheimer's disease.

Oxidative stress is important in the pathogenesis of Alzheimer's disease (AD). The brain contains high levels of oxidizable lipids that must be protected by antioxidants. Low concentrations of vitamin E, quantitatively the major lipophilic antioxidant in the brain, are frequently observed in cerebrospinal fluid (CSF) of AD patients, suggesting that supplementation with vitamin E might delay the development of AD. In a placebo-controlled trial, vitamin E (2000 IU/day, 2 years) slowed (-53%) functional deterioration in patients with moderate AD (Sano et al., N. Engl. J. Med. 336: 1216-1222, 1997). Recently, use of vitamin E and vitamin C supplements in combination was found to be associated with reduced prevalence (-78%) and incidence (-64%) of AD in elderly population (Zandi et al., Arch. Neurol. 61: 82-88, 2004). These results are consistent with the ability of the supplementation with vitamin E (400 IU/day, 1 month) to increase its levels in CSF (123%) and plasma (145%) of AD patients and, in combination with vitamin C (1000 g/day), to decrease the susceptibility of CSF lipoproteins (up to -32%) to in vitro oxidation (Kontush et al., Free Radic. Biol. Med. 31: 345-354, 2001). In addition, vitamin E reduced lipid peroxidation and amyloid deposition in a transgenic mice model of AD (Sung et al., FASEB J. 18: 323-325, 2004). Computer modeling of the influence of vitamin E on lipoprotein oxidation reveals that the vitamin develops antioxidative activity in CSF lipoproteins in the presence of physiologically relevant, low amounts of oxidants. By contrast, under similar conditions, vitamin E behaves as a pro-oxidant in plasma lipoproteins, consistent with the model of tocopherol-mediated peroxidation (Stocker, Curr. Opin. Lipidol. 5: 422-433, 1994). This distinction is related to major differences in the levels of vitamin E (50 nM vs. 30 microM) and oxidizable lipids (4 microM vs. 2.5 mM) between CSF and plasma, which result in major differences in oxidative conditions (per unit of vitamin E) between CSF and plasma in the presence of similar amounts of oxidants. Altogether, these data suggest that vitamin E may be effective against in vivo oxidation of CSF lipoproteins and brain lipids, and offer new perspectives in the treatment of AD and other neurodegenerative disorders.

Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease.

Because increased oxidation is an important feature of Alzheimer's disease (AD) and low concentrations of antioxidant vitamins C and E have been observed in cerebrospinal fluid (CSF) of AD patients, supplementation with these antioxidants might delay the development of AD. Major targets for oxidation in brain are lipids and lipoproteins. We studied whether supplementation with antioxidative vitamins E and C can increase their concentrations not only in plasma but also in CSF, and as a consequence decrease the susceptibility of lipoproteins to in vitro oxidation. Two groups, each consisting of 10 patients with AD, were for 1 month supplemented daily with either a combination of 400 IU vitamin E and 1000 mg vitamin C, or 400 IU vitamin E alone. We found that supplementation with vitamin E and C significantly increased the concentrations of both vitamins in plasma and CSF. Importantly, the abnormally low concentrations of vitamin C were returned to normal level following treatment. As a consequence, susceptibility of CSF and plasma lipoproteins to in vitro oxidation was significantly decreased. In contrast, the supplementation with vitamin E alone significantly increased its CSF and plasma concentrations, but was unable to decrease the lipoprotein oxidizability. These findings document a superiority of a combined vitamin E + C supplementation over a vitamin E supplementation alone in AD and provide a biochemical basis for its use.

Increased lipoprotein oxidation in Alzheimer's disease.

Oxidation has been proposed to be an important factor in the pathogenesis of Alzheimer's disease (AD) and amyloid beta is considered to induce oxidation. In biological fluids, including cerebrospinal fluid (CSF), amyloid beta is found complexed to lipoproteins. On the basis of these observations, we investigated the potential role of lipoprotein oxidation in the pathology of AD. Lipoprotein oxidizability was measured in vitro in CSF and plasma from 29 AD patients and found to be significantly increased in comparison to 29 nondemented controls. The levels of the hydrophilic antioxidant ascorbate were significantly lower in CSF and plasma from AD patients. In plasma, alpha-carotene was significantly lower in AD patients compared to controls while alpha-tocopherol levels were indistinguishable between patients and controls. In CSF, a nonsignificant trend to lower alpha-tocopherol levels among AD patients was found. Polyunsaturated fatty acids, the lipid substrate for oxidation, were significantly lower in the CSF of AD patients. Our findings suggest that (i) lipoprotein oxidation may be important in the development of AD and (ii) the in vitro measurement of lipid peroxidation in CSF might become a useful additional marker for diagnosis of AD.

Cerebrospinal fluid levels of alpha-tocopherol in amyotrophic lateral sclerosis.

We compared CSF and serum levels, and the CSF/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 30 patients with sporadic amyotrophic lateral sclerosis (SALS) and 78 matched controls. The mean CSF and serum vitamin E levels did not differ significantly between the 2 study groups. These values were not influenced by the clinical form (spinal versus bulbar) of SALS. CSF alpha-tocopherol levels did not correlate with age, age at onset, and duration of the disease. These results suggest that CSF and serum alpha-tocopherol concentrations are unrelated with the risk for ALS.

Cerebrospinal fluid levels of alpha-tocopherol in patients with multiple sclerosis.

We compared cerebrospinal fluid (CSF) and serum levels, and the CSF/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 36 patients with multiple sclerosis (MS) and 32 matched controls. The mean CSF vitamin E levels and the CSF/serum vitamin E ratio did not differ significantly between the two study groups. The serum levels of vitamin E and the serum vitamin E/cholesterol ratio were significantly lower in MS patients when compared with controls (P < 0.05 and P < 0.01, respectively). These values were not correlated with age, age at onset and duration of the disease in the patients group. These results suggest that CSF vitamin E concentrations are not a marker of activity of MS activity.

Alpha tocopherol in CSF of subjects taking high-dose vitamin E in the DATATOP study. Parkinson Study Group.

Alpha-Tocopherol concentrations were determined in the CSF of patients with early untreated Parkinson's disease receiving 2,000 IU vitamin E orally per day. After treatment the concentrations increased significantly (p < 0.001) by 76+/-10 (SE)%. The net increases in CSF alpha-tocopherol concentrations after treatment showed a significant positive correlation with the number of days of vitamin E ingestion (p < 0.001). Thus, high-dose vitamin E treatment results in elevating CSF vitamin E levels and possibly brain vitamin E levels.

Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Parkinson's disease.

We compared CSF and serum levels, and the CSF/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 34 patients with Parkinson's disease (PD) and 47 controls. CSF and serum vitamin E levels were correlate. The mean CSF and serum vitamin E levels, and the CSF/serum ratio of PD patients did not differ significantly between the groups. There was no influence of antiparkinsonian therapy on CSF vitamin E levels. CSF vitamin E levels did not correlate with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group. These results suggest that CSF vitamin E concentrations are unrelated with the risk for PD.

Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer's disease.

We compared CSF and serum levels, and the CST/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 44 apparently well-nourished patients with Alzheimer's disease (AD) and 37 matched controls. CSF and serum vitamin E levels were correlated, both in AD patients and in controls. The mean CSF and serum vitamin E levels were significantly lower in AD patients, and the CSF/serum ratio of AD patients did not differ significantly between the 2 study groups. CSF vitamin E levels did not correlate with age, age at onset, duration of the disease and score of the Minimental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that low CSF and serum vitamin E concentrations in AD patients could be related with a deficiency of dietary intake of vitamin E.

Alpha-tocopherol in the ventricular cerebrospinal fluid of Parkinson's disease patients: dose-response study and correlations with plasma levels.

OBJECTIVE: To determine if ventricular cerebrospinal fluid (vCSF) alpha-tocopherol levels in Parkinson's disease (PD) patients can be increased by oral alpha-tocopherol supplementation and whether vCSF levels are linearly related to plasma alpha-tocopherol levels. BACKGROUND: In spite of its putative neuroprotective properties, alpha-tocopherol has failed to alter PD clinical progression. However, the ability of supplemental alpha-tocopherol to affect brain or vCSF levels has never been assessed in humans nor has a dose response curve for alpha-tocopherol in vCSF been established. METHODS: Five PD patients with Ommaya catheters received oral dl-alpha-tocopherol over 5 months. Each patient ingested alpha-tocopherol daily with monthly dosage increases (400, 800, 1,600, 3,200, 4,000 IU/day). Plasma and vCSF samples were obtained at baseline and at the end of each month. Alpha-tocopherol levels were determined in triplicate by high-pressure liquid chromatography with fluorometric and electrochemical detection. RESULTS: At baseline, endogenous alpha-tocopherol was detected in plasma and vCSF, with a greater than one-hundred-fold difference between the fluid compartments (mean plasma level 18.76 microM/l (SD +/- 4.69) versus mean CSF level 0.114 microM/l (SD +/- 0.084). A clear dose-response curve occurred in plasma, with statistically significant increases over baseline developing even with 400 IU/d. With higher doses, a significant increase continued without evidence of saturation. However, there was no significant increase in vCSF alpha-tocopherol levels at any dose, including the supraclinical (4,000 IU/d). There was no correlation between plasma and vCSF alpha-tocopherol levels. CONCLUSION: Oral alpha-tocopherol supplementation, even at supraclinical doses, fails to increase vCSF alpha-tocopherol levels. This lack of change may be due to limited passage across the blood-brain barrier or very rapid alpha-tocopherol metabolism. All prior negative studies on efficacy of alpha-tocopherol in PD may need reevaluation in light of these pharmacologic data.

alpha-Tocopherol quinone level is remarkably low in the cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis.

In order to investigate the role of free radicals in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), the concentrations of alpha-tocopherol (alpha-TOH) and its oxidized form alpha-tocopherol quinone (alpha-TQ) in the cerebrospinal fluid (CSF) of SALS patients were determined. The alpha-TOH level was 31% lower (P < 0.05) and the alpha-TQ level was 75% lower (P < 0.001) in SALS patients than in normal subjects. The results of the present study do not support the hypothesis that activated lipid peroxidation accelerates oxidation of alpha-TOH into alpha-TQ in SALS patients.

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.

Reduced and oxidized forms of glutathione and alpha-tocopherol in the cerebrospinal fluid of parkinsonian patients: comparison between before and after L-dopa treatment.

In the cerebrospinal fluid of untreated patients with Parkinson's disease (PD) the concentrations of reduced glutathione (GSH) and alpha-tocopherol (alpha-TOH) were unaltered but the concentration of oxidized glutathione (glutathione disulfide, GSSG) (P < 0.001), the GSSG/GSH ratio (P < 0.06), alpha-tocopherol quinone (alpha-TQ) (P < 0.001), and the alpha-TQ/alpha-TOH ratio (P < 0.01) were reduced significantly. In L-dopa-treated patients, the concentrations of GSH, GSSG, and the alpha-TQ concentration and the alpha-TQ/alpha-TOH ratio (P < 0.05) increased compared with untreated PD patients. These results suggest that oxidation of GSH and alpha-TOH is decreased in untreated PD patients, but is activated to a control level or more after L-dopa treatment.

Concentrations of alpha-tocopherol and its quinone derivative in cerebrospinal fluid from patients with vascular dementia of the Binswanger type and Alzheimer type dementia.

We determined the concentrations of alpha-tocopherol (alpha-TOH) and alpha-tocopherol quinone(alpha-TQ), an oxidized derivative of alpha-TOH, in cerebrospinal fluid from patients with Alzheimer type dementia (ATD) and those with vascular dementia of the Binswanger type (VDBT). Compared with results for the controls, the VDBT patients had unaltered concentrations of alpha-TOH, but a statistically significant, 3.6-fold increase of alpha-TQ (P < 0.01) which was significantly correlated with decreases in the Mini-Mental State Examination scores (P < 0.05). In contrast, ATD patients had significantly decreased concentrations of alpha-TOH (P < 0.01), but had unaltered concentrations of alpha-TQ. These results suggest that there is greater oxidation of alpha-TOH to alpha-TQ in VDBT brain, but are inconclusive about the occurrence of peroxidation in ATD brains.

The total peroxyl radical-trapping ability of plasma and cerebrospinal fluid in normal and preeclamptic parturients.

Plasma and cerebrospinal fluid total peroxyl radical-trapping antioxidative parameter (TRAP) and the main antioxidant components of TRAP (vitamin E, ascorbic acid, uric acid, protein sulfhydryl groups, and the unidentified antioxidant proportion) were analyzed in 11 preeclamptic parturients, 9 healthy parturients with an uncomplicated pregnancy, and 10 healthy nonpregnant women. In addition, the possible effects of ongoing labor were studied in 10 healthy parturients. The samples of plasma and cerebrospinal fluid (CSF) were collected at cesarean section (pregnant women) or minor surgical procedure (nonpregnant women). Normal pregnancy or ongoing labor induced no significant changes in total TRAP, as compared with nonpregnant women, but significant changes in the percentage contributions of individual antioxidants were noted in plasma and CSF. In preeclampsia, a significant increase in TRAP was noted in both plasma and CSF. This increase was mainly due to an increased proportion of uric acid and unidentified antioxidants in plasma samples, and an increased proportion of unidentified antioxidants in CSF. The concentration of CSF ascorbic acid was decreased in preeclampsia, and a negative correlation between CSF ascorbic acid and blood pressure was observed.

Vitamin E (tocopherols) in human cerebrospinal fluid.

Cerebrospinal fluid (CSF) and blood were obtained at the time of myelographic examinations from 40 adult, male, human subjects with no neurologic or metabolic abnormalities. Vitamin E (tocopherols) concentrations were determined by liquid chromatography. In subjects with normal concentrations of CSF protein (n = 22), the alpha- and gamma-tocopherol concentrations were 29.2 +/- 9.5 (mean +/- SD) and 6.5 +/- 3.6 nmol/L, respectively, in CSF and 26.0 +/- 8.1 and 6.0 +/- 3.6 mumol/L, respectively, in serum. The concentrations of alpha-tocopherol in CSF correlated significantly (P less than 0.001) with both total protein and albumin concentrations, suggesting that tocopherol transport into CSF is linked with that of plasma proteins. In vitro oxidation of vitamin E in CSF by the free-radical generator 2,2'-azobis-(2-amidinopropane) hydrochloride showed a measurable induction (lag) period. This is due to the presence of other antioxidants in human CSF.