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Lymphocyte Oxidative DNA Damage and Plasma Antioxidants in Alzheimer Disease
Patrizia Mecocci, MD, PhD;
M. Cristina Polidori, MD;
Antonio Cherubini, MD, PhD;
Tiziana Ingegni, MD;
Paola Mattioli, MD;
Marco Catani, MD;
Patrizia Rinaldi, MD;
Roberta Cecchetti, BSc;
Wilhelm Stahl, PhD;
Umberto Senin, MD;
M. Flint Beal, MD
Arch Neurol. 2002;59:794-798.
ABSTRACT
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Context A large body of experimental evidence suggests that in Alzheimer disease
(AD) pathogenesis an important role is played by oxidative stress, but there
is still a lack of data on in vivo markers of free radical–induced damage.
Objectives To evaluate levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a
marker of oxidative damage to DNA, in peripheral lymphocytes; to measure plasma
concentrations of several nonenzymatic antioxidants; and to assess the relationships
between any observed changes in lymphocyte DNA 8-OHdG content and plasma antioxidant
levels in patients with AD and healthy aged control subjects.
Subjects Forty elderly outpatients with AD and 39 healthy age- and sex-matched
controls were studied.
Main Outcome Measures The level of 8-OHdG was determined in DNA extracted from lymphocytes
and plasma levels of vitamin C, vitamin A, vitamin E, and carotenoids (zeaxanthin,  -cryptoxanthin,
lycopene, lutein, and  - and -carotene) were measured by high-performance
liquid chromatography.
Results Lymphocyte DNA 8-OHdG content was significantly higher and plasma levels
of antioxidants (with the exception of lutein) were significantly lower in
patients with AD compared with controls. In patients with AD, a significant
inverse relationship between lymphocyte DNA 8-OHdG content and plasma levels
of lycopene, lutein, -carotene, and -carotene, respectively,
was observed.
Conclusions Markers of oxidative damage are increased in AD and correlate with decreased
levels of plasma antioxidants. These findings suggest that lymphocyte DNA
8-OHdG content in patients with AD reflects a condition of increased oxidative
stress related to a poor antioxidant status.
INTRODUCTION
A LARGE body of research suggests that oxidative stress, a condition
representing an imbalance between oxidants and antioxidants in favor of the
oxidants,1 plays an important role in the pathogenesis
of Alzheimer disease (AD).2 The brain is particularly
susceptible to the attack of free radicals caused by its low content of antioxidants,
by the considerable content of polyunsaturated fatty acid side chains of the
neuronal membrane lipids, and by its high oxygen consumption rate.2-3 Furthermore, aging—a major risk
factor for AD—is known to be associated with increased free radical
production, and markers of oxidative DNA damage have been found to be increased
in cerebral tissue of healthy aged subjects4
and even more so in patients with AD.5 The
initial idea of a link between increased free radical production and AD6 is now supported by studies showing a potential vicious
circle between free radical–induced -amyloid formation and -amyloid–related
oxidative stress.7
Although the brain is the most affected organ in AD, several studies
showed structural or functional alterations in peripheral tissues. In patients
with AD, alterations of -amyloid metabolism8
or of glutamate uptake9 were detected in platelets
and increased isoprostane levels in urine, blood, and cerebrospinal fluid.10 We also found a higher level of oxidative damage
to DNA in lymphocytes.11 Recently, a reduced
expression of heme-oxygenase messenger RNA in lymphocytes was reported.12
The aims of the present study were (1) to evaluate levels of 8-hydroxy-2'-deoxyguanosine
(8-OHdG)—a well-established marker of oxidative stress in DNA—in
peripheral lymphocytes; (2) to measure plasma concentrations of several nonenzymatic
antioxidants; and (3) to assess the relationships between any observed changes
in lymphocyte DNA 8-OHdG content and plasma antioxidant levels in elderly
subjects and patients with late-onset AD.
SUBJECTS AND METHODS
Forty elderly outpatients (20 women and 20 men; mean [SD] age, 75.9
[5.4] years) with mild to moderate AD (mean [SD] Mini-Mental State Examination
score, 17.3 [2.1] points; range, 14-23 points) diagnosed on the basis of DSM IV-R13 and of NINCDS-ADRDA
(National Institutes of Neurological and Communicative Disorders and Stroke/Alzheimer's
Disease and Related Disorders Association) criteria14
were included in this study. Patients were compared with 39 healthy aged subjects
(20 women and 19 men; mean [SD] age, 74.8 [6.3] years) with a Mini-Mental
State Examination score ranging between 27 and 30 points. Patients and controls
with a history of having a smoking habit and/or alcohol abuse, major organ
failure, dyslipidemia, or alteration of protein metabolism, as well as those
taking iron or antioxidant supplements were excluded. The Mini Nutritional
Assessment15 was administered to all participants.
Body mass index (calculated as weight in kilograms divided by height in meters,
squared), plasma albumin, and transferrin were evaluated in all subjects with
the aim to select well-nourished persons. A semiquantitative food frequency
questionnaire was used to evaluate the dietary habits of patients and controls.
After giving informed consent, patients and controls underwent a 20-mL
blood sample withdrawal for measurement of 8-OHdG in lymphocytes, and of vitamin
C (ascorbic acid), vitamin A (retinol), vitamin E (-tocopherol), and
carotenoids (namely, zeaxanthin, -cryptoxanthin, lycopene, lutein, -carotene,
and -carotene) in plasma.
Lymphocytes were separated, DNA was extracted, and 8-OHdG was assayed
as previously described.11 Briefly, freshly
obtained blood was layered on Lymphoprep (Gibco BRL, Bethesda, Md), centrifuged
and washed, and the pellet was stored at -80°C until analysis. DNA
was extracted from the cells with DNAzol (Gibco BRL), resuspended with 10mM
of Tris hydrochloride and 1 mM of EDTA, and enzymatically hydrolyzed. Both
8-OHdG and deoxyguanosine (dG) were measured by high-performance liquid chromatography
with electrochemical and UV detection, respectively. Results are expressed
as 8OHdG molecules per 105dG molecule (8OHdG-dG ratio).
Vitamin C was detected by high-performance liquid chromatography with
electrochemical detection according to Kutnink et al16
with a Supelco C18 column (250 mm x 4.6 inner diameter) and a Supelco
C18 guard column (20 mm x 4.6 inner diameter). Vitamins A and E were
measured, after extraction with ethanol and hexane, by high-performance liquid
chromatography with UV detection at 280 nm17
with a Waters Simmetry C8 column (150 mm x 4.6 inner diameter). Carotenoids
were detected after extraction with hexane-dichloromethane (5:1) by high-performance
liquid chromatography at 450 nm using a Supelco C18 column (250 mm x
4.6 inner diameter).18
Statistical analysis was performed with the program StatView 4.5 (Abacus
Concept; SAS Institute, Cary, NC). All data are presented as mean (SD). Nonparametric
Mann-Whitney test was used for comparisons between groups and  2 analysis for frequency evaluation. Spearman rank test was performed
to evaluate the relationship between variables. Since considering the ratio
between plasma vitamin E/vitamin A/carotenoids/and total cholesterol level
did not alter results, data are expressed as total plasma levels of these
compounds.
RESULTS
As shown in Figure 1, DNA
extracted from lymphocytes of patients with AD contained significantly higher
amounts of 8-OHdG (4.79 [1.08] 8-OHdG/105 dG; range, 2.5-6.6 8-OHdG/105 dG) compared with controls (2.72 [0.78] 8-OHdG/105 dG;
range, 1.3-4.1 8-OHdG/105 dG) (P<.001).
Plasma levels of vitamin C, vitamin A, vitamin E, and the carotenoids are
listed in Table 1. Mean plasma
antioxidant levels were lower in patients compared with controls. Differences
reached statistical significance for all compounds measured, with the exception
of lutein.
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Figure 1. Levels of 8-hydroxy-2|mJ-deoxyguanosine (8-OHdG),
expressed as 8OHdG molecules per 105dG molecule ratio (OHdG), in the
lymphocytes of patients with Alzheimer disease (AD) and control
subjects.
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Plasma Concentrations of Antioxidants in Patients With Alzheimer Disease
(AD) and in Healthy Aged Control Subjects*
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In patients with AD, we found a significant inverse relationship between
the content of 8-OHdG in lymphocyte DNA and plasma levels of lycopene (r = 0.560, P<.001)
(Figure 2A), lutein (r
= 0.577, P<.05) (Figure 2B), -carotene (r = 0.873, P<.01) (Figure 3A),
and -carotene (r = 0.689, P<.01) (Figure 3B). No
correlation was found between the content in 8-OHdG of lymphocyte DNA and
antioxidants in controls.
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Figure 2. Linear regression analysis between
lymphocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) and, respectively, lycopene
(A) and lutein (B) in patients with Alzheimer disease (AD).
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No significant differences were found between the patients with AD and
controls regarding body mass index, plasma albumin and transferrin levels,
Mini Nutritional Assessment scores, and dietary habits (particularly with
respect to frequency of fruit and vegetable intake).
COMMENT
Oxidative damage may play an important role in the pathogenesis of several
neurodegenerative diseases, and growing evidence points to the involvement
of free radicals in mediating neuronal death in these illnesses. Oxygen free
radicals, which are mainly products of mitochondrial activity, react with
all key cellular components. As a consequence of this, damage to purines and
pyrimidines in DNA yielding oxidized bases is produced. Among oxidized bases,
8-OHdG is the most abundant, and it can be measured in both tissue extracts
and cells. It has, therefore, been proposed as a marker of oxidative damage
both in physiological and pathological conditions.
Our prior work and others showed increased amounts of 8-OHdG in mitochondrial
and nuclear DNA from AD-affected brains compared with controls.5, 19
Increased levels of 8-hydroxyguanine were also found in intact DNA isolated
from ventricular cerebrospinal fluid in autoptic samples from subjects with
AD.20 Postmortem studies, however, are not
easy to perform, and the feasibility of detecting 8-OHdG in peripheral cells,
such as lymphocytes, may be useful in evaluating conditions of oxidative stress.
In the present study, we detected significantly increased levels of
8-OHdG in lymphocyte DNA from patients with AD compared with controls. We
found that the increased content of 8-OHdG is significantly correlated with
a decreased content of plasma carotenoids in patients with AD. Although it
has been proposed that carotenoids protect against degenerative conditions,
such as cancer and coronary heart disease, direct evidence of their in vivo
antioxidant activity is limited.21-22
Furthermore, the role of antioxidants in preventing neurodegenerative disorders,
and in particular AD, is scanty.
Measurement of peripheral antioxidants is considered an appropriate
way of looking at oxidative stress in various disease states in humans.23 In our study, all measured plasma antioxidants were
significantly lower in patients with AD than in healthy controls. A potential
explanation of the low levels of antioxidants in patients with AD is that
these patients are malnourished. Our patients, however, did not differ from
controls with respect to dietary habits, Mini Nutritional Assessment score,
body mass index, or plasma albumin and transferrin levels. Low plasma levels
of vitamin C, moreover, were found in AD despite an adequate diet.24 Another possible explanation for low levels of plasma
antioxidants in AD is that they might be consumed because of a disease-related
higher rate of free radical production. In AD, decreased cytochrome c oxidase activity has been shown both in cerebral tissue25 and peripheral cells,26
as well as a pro-oxidant activity that has been attributed to -amyloid.27 Some epidemiological studies showed that low plasma
levels of antioxidant vitamins are a risk factor for cognitive impairment,28-31 and
that oxidative stress markers are associated with cognitive decline.32 We also found high levels of vitamin A and vitamin
E in plasma samples of mentally healthy centenarians,33
suggesting a protective role of these nutrients in the oldest-old. Antioxidant
vitamin supplementation seems to decrease the risk of cognitive impairment,
as suggested by studies in which ascorbic acid and -tocopherol administration
lowered the risk of suffering from AD34 or,
more generally, from dementia.35 Therapeutic
use of antioxidants (-tocopherol and/or selegiline) has been also proposed
to slow the course of AD.36 Although there
are only few studies on the relationship between plasma and brain concentration
of antioxidants, it has been demonstrated that supplementation or depletion
of vitamin E results in marked changes in vitamin E levels in the rat brain37-38 and -tocopherol and ascorbic
acid supplementation has been shown to increase the concentrations of both
vitamins not only in plasma, but also in cerebrospinal fluid.39
The relationship between markers of oxidative stress in the brain and at the
peripheral level has been studied in a transgenic mouse model of AD amyloidosis
by Praticó et al40 who measured isoprostanes-specific
and -sensitive markers of in vivo lipid peroxidation in cerebral tissue, plasma,
and urine. In these animals, brain, plasma, and urine isoprostanes levels
were higher compared with control mice and also brain levels were positively
correlated to amyloid deposition. Other data have also shown that oxidative
stress increases intracellular amyloid.41-42
Several researchers show that biomarkers of oxidative stress are present
in AD peripheral tissues.43 In particular,
increased concentrations of isoprostanes were detected in urine, plasma, and
cerebrospinal fluid samples of patients with AD. A direct correlation was
found between plasma and cerebrospinal fluid levels, suggesting that plasma
levels may reflect brain oxidative stress.10
It is possible that AD-affected lymphocytes are genetically prone to oxidative
stress. It has been recently shown that peripheral lymphocytes from presenilin-1
transgenic mice have an enhanced vulnerability to cell death, which was associated
with an increased production of reactive oxygen species and altered calcium
regulation,44 linking a genetic cause of AD
to a condition of oxidative stress in peripheral cells. It was also found
that glutathione S-transferase polymorphisms influence the level of oxidative
DNA damage in lymphocytes. The damage was more marked if subjects had poor
antioxidant status.45 So it is conceivable
that the oxidative DNA damage, such as lymphocyte 8-OHdG, could result from
co-occurrence of pro-oxidant genetic and environmental factors.
In the present study, we observed an inverse trend between plasma antioxidants
and the content of 8-OHdG in lymphocyte DNA of patients with AD. There was
a strong, significant relationship for lycopene, lutein, and - and -carotenes.
A significant negative correlation between concentrations of serum carotenoids
and oxidized pyrimidines was found in lymphocytes of healthy humans,46 suggesting that some nutritional factors may protect
from oxidative DNA damage (as assessed by the presence of DNA strand breaks
measured with the comet assay). In another study, Lenton et al47
showed that naturally occurring levels of intracellular antioxidants (glutathione
and vitamin C) were negatively correlated with oxidative damage in human lymphocytes,
as assessed by levels of 5-hydroxy-2'-deoxycytidine and of 8-oxo-dG.
In particular, the strongest inverse relationship was found between glutathione
and 8-oxo-dG, and, on the basis of these results, the authors suggested that
intracellular glutathione and ascorbate protect human lymphocytes against
oxidative DNA damage.47 Several studies have
shown that dietary supplements including ascorbic acid, -tocopherol,
and -carotene protect lymphocyte DNA against oxidative damage.48 Flavonoids,49 coenzyme
Q10,50 and lycopene contained in tomatoes51 have been shown to exert protective effects against
oxidative DNA damage, either by decreasing DNA strand breaks52
or by increasing DNA resistance to hydrogen peroxide (H2O2)–induced oxidation.50-51
High levels of the xanthophylls lutein and -cryptoxanthin are related
to low levels of lymphocyte 8-OHdG and of urinary 8-epiprostaglandin F2. Supplementation with xanthophylls and lycopene further reduces
the amount of these biochemical markers of oxidation.52 -Carotene
supplementation also reduced oxidative damage in DNA of lymphocytes treated
with H2O2.53 Furthermore,
it was recently shown that exposure of mouse monocytes to oxidized low-density
lipoproteins results in an accumulation of 8-OHdG in DNA and in a down-regulation
of base excision repair activity. Treatment with antioxidants (in this case
ascorbate and -tocopherol) reversed this situation, showing a linkage
between lipid and DNA oxidation and between lipid oxidation.54
CONCLUSIONS
This preliminary study suggests that lymphocyte DNA 8-OHdG levels are
increased in AD and correlate with decreased levels of plasma antioxidants.
These findings suggest that lymphocyte 8-OHdG levels in patients with AD reflects
a condition of increased oxidative stress related to a poor antioxidant status.
It will be important to replicate the findings of this study in other populations
and at different severity stages of dementia.
AUTHOR INFORMATION
Accepted for publication January 10, 2001.
Author contributions: Study concept and design (Drs Mecocci, Polidori, Ingegni, Catani, Rinaldi, Senin, and Beal); acquisition of data (Drs Mecocci, Cherubini, Ingegni,
and Mattioli and Ms Cecchetti); analysis and interpretation of data (Drs Mecocci and Stahl); drafting of the manuscript (Drs Mecocci, Polidori, Ingegni, Rinaldi, and Beal); critical
revision of the manuscript for important intellectual content (Drs Cherubini, Mattioli, Catani, Stahl, Senin, and Beal and Ms Cecchetti); statistical expertise (Dr Cherubini); obtained
funding (Drs Mecocci and Senin); administrative,
technical, and material support (Drs Ingegni and Mattioli); study supervision (Drs Catani and Beal).
This study was supported in part by grants from the Italian National
Research Council, Rome, and the University of Perugia. Dr Polidori is a European
Union Marie-Curie Fellow for the project "Quality of Life and Management of
Living Resources."
We thank Helmut Sies, MD, for critically revising the manuscript.
Corresponding author: Patrizia Mecocci, MD PhD, Institute of Gerontology
and Geriatrics, University of Perugia, Via Eugubina 42, 06122 Perugia, Italy
(e-mail: mecocci{at}unipg.it).
From the Institute of Gerontology and Geriatrics, University of Perugia,
Perugia, Italy (Drs Mecocci, Polidori, Cherubini, Ingegni, Mattioli, Catani,
Rinaldi, Stahl, and Senin and Ms Cecchetti); Institute of Physiological Chemistry,
Heinrich-Heine University, Düsseldorf, Germany (Drs Polidori and Stahl);
and the Department of Neurology and Neuroscience, Weill Medical College of
Cornell University and the New York Hospital, Cornell Medical Center, New
York (Dr Beal).
REFERENCES
| |
1. Sies H. Oxidative stress: introductory remarks. In: Sies H, ed. Oxidative Stress. Orlando,
Fla: Academic Press; 1985:1-8.
2. Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr. 2000;71:621S-629S.
3. Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol. 1995;38:357-366.
FULL TEXT
|
ISI
| PUBMED
4. Mecocci P, MacGarvey U, Kaufman AE, et al. Oxidative damage to mitochondrial DNA shows marked age-dependent increases
in human brain. Ann Neurol. 1993;34:609-616.
FULL TEXT
|
ISI
| PUBMED
5. Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol. 1994;36:747-751.
FULL TEXT
|
ISI
| PUBMED
6. Harman D. A hypothesis on the pathogenesis of Alzheimer's disease. Ann N Y Acad Sci. 1996;786:152-168.
ISI
| PUBMED
7. Stadtman ER, Levine RL. Oxidation of cellular proteins by -amyloid peptide. Neurobiol Aging. 1999;20:331-333.
FULL TEXT
|
ISI
| PUBMED
8. Di Luca M, Pastorino L, Bianchetti A, et al. Differential level of platelet amyloid-beta precursor protein isoforms:
an early marker for Alzheimer disease. Arch Neurol. 1998;55:1195-2000.
FREE FULL TEXT
9. Ferrarese C, Begni B, Canevari C, et al. Glutamate uptake is decreased in platelets from Alzheimer's disease
patients. Ann Neurol. 2000;47:641-643.
FULL TEXT
|
ISI
| PUBMED
10. Praticò D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA. Increased 8,12-iso-iPF2-VI in Alzheimer's disease:
correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol. 2000;48: 809-812.
11. Mecocci P, Polidori MC, Ingegni T, et al. Oxidative damage to DNA in lymphocytes from AD patients. Neurology. 1998;51:1014-1017.
FREE FULL TEXT
12. Schipper HM, Chertkow H, Mehindate K, Frankel D, Melmed G, Bergman H. Evaluation of heme oxygenase-1 as a systemic biological marker of sporadic
AD. Neurology. 2000;54:1297-1304.
FREE FULL TEXT
13. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Revised. Washington, DC: American Psychiatric Association; 1994.
14. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA
Work Group under the auspices of Department of Health and Human Services Task
Force on Alzheimer's Disease. Neurology. 1984;34:939-944.
FREE FULL TEXT
15. Guigoz Y, Vellas B, Garry PJ. Assessing the nutritional status of the elderly: the Mini Nutritional
Assessment as part of the geriatric evaluation. Nutr Rev. 1996;54(pt 2):S59-S65.
16. Kutnink MA, Hawkes WC, Schaus EE, Omaye ST. An internal standard method for the unattended high-performance liquid
analysis of ascorbic acid in blood components. Anal Biochem. 1987;166:424-430.
FULL TEXT
|
ISI
| PUBMED
17. Nierenberg, DW, Nann SL. A method for determining concentrations of retinol, tocopherol, and
five carotenoids in human plasma and tissue samples. Am J Clin Nutr. 1992;56:417-426.
FREE FULL TEXT
18. Stahl W, Schwarz W, Sundquist AR, Sies H. Cis-trans isomers of lycopene and beta-carotene
in human serum and tissues. Arch Biochem Biophys. 1992;294:173-177.
FULL TEXT
|
ISI
| PUBMED
19. Gabbita SP, Lovell MA, Markesbery WR. Increased nuclear DNA oxidation in the brain in Alzheimer's disease. J Neurochem. 1998;71:2034-2040.
ISI
| PUBMED
20. Lovell MA, Markesbery WR. Ratio of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is
increased in Alzheimer disease ventricular cerebrospinal fluid. Arch Neurol. 2001;58:392-396.
FREE FULL TEXT
21. Halliwell B. Oxidative stress, nutrition and health: experimental strategies for
optimization of nutritional antioxidant intake in humans. Free Radic Res. 1996;25:57-74.
ISI
| PUBMED
22. Cooper DA, Eldridge A, Peters JC. Dietary carotenoids and lung cancer: a review of recent research. Nutr Rev. 1999;57:133-145.
ISI
| PUBMED
23. Polidori MC, Stahl W, Eichler O, Niestroj N, Sies H. Profiles of antioxidants in human plasma. Free Radic Biol Med. 2001;30:456-462.
FULL TEXT
|
ISI
| PUBMED
24. Riviere S, Birlouez-Aragon I, Nourashemi F, Vellas B. Low plasma vitamin C in Alzheimer patients despite an adequate diet. Int J Geriatr Psychiatry. 1998;13:749-754.
FULL TEXT
|
ISI
| PUBMED
25. Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem. 1994;63:2179-2184.
ISI
| PUBMED
26. Parker WD Jr, Filley CM, Parks JK. Cytochrome oxidase deficiency in Alzheimer's disease. Neurology. 1990;40:1302-1303.
FREE FULL TEXT
27. Praticò D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on
Alzheimer's disease. Am J Med. 2000;109:577-585.
FULL TEXT
|
ISI
| PUBMED
28. Larue A, Koehler KM, Wayne SJ, Chiulli SJ, Haaland KY, Garry PJ. Nutritional status and cognitive functioning in a normally aging sample:
a 6-year assessment. Am J Clin Nutr. 1997;65:20-29.
FREE FULL TEXT
29. Kalmijn S, Feskens EJM, Launer LJ, Kromhout D. Polyunsaturated fatty acids, antioxidants, and cognitive function in
very old men. Am J Epidemiol. 1997;145:33-41.
FREE FULL TEXT
30. Paleologolos M, Cumming RG, Lazarus R. Cohort study of vitamin C intake and cognitive impairment. Am J Epidemiol. 1998;148:45-50.
FREE FULL TEXT
31. Schmidt R, Hayn M, Reinhart B, et al. Plasma antioxidants and cognitive performance in middle-aged and older
adults: results of the Austrian stroke prevention study. J Am Geriatr Soc. 1998;46:1407-1410.
ISI
| PUBMED
32. Berr C, Balansard B, Arnaud J, Roussel AM, Alpérovitch A for the Etude du Vieillissement Arteriel Study Group. Cognitive decline is associated with systemic oxidative stress: the
EVA study. J Am Geriatr Soc. 2000;48:1285-1291.
ISI
| PUBMED
33. Mecocci P, Polidori MC, Troiano L, et al. Plasma antioxidants and longevity: a study on healthy centenarians. Free Radic Biol Med. 2000;28:1243-1248.
FULL TEXT
|
ISI
| PUBMED
34. Morris MC, Beckett LA, Scherr PA, et al. Vitamin E and vitamin C supplement use and risk of incident Alzheimer
disease. Alzheimer Dis Assoc Disord. 1998;12:121-126.
ISI
| PUBMED
35. Masaki KH, Losonczy KG, Izmirlian G, et al. Association of vitamin E and C supplement use with cognitive function
and dementia in elderly men. Neurology. 2000;54:1265-1272.
FREE FULL TEXT
36. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, -tocopherol, or both as a
treatment for Alzheimer's disease. N Engl J Med. 1997;336:1216-1222.
FREE FULL TEXT
37. Martin A, Janigian D, Shukitt-Hale B, Prior RL, Joseph JA. Effect of vitamin E intake on levels of vitamins E and C in the central
nervous system and peripheral tissues: implications for health recommendations. Brain Res. 1999;845:50-59.
FULL TEXT
|
ISI
| PUBMED
38. Martin A, Prior R, Shukitt-Hale B, Cao G, Joseph JA. Effect of fruits, vegetables, or vitamin E-rich diet on vitamins E
and C distribution in peripheral and brain tissues: implications for brain
function. J Gerontol A Biol Sci Med Sci. 2000;55:B144-B151.
39. Kontush A, Mann U, Arlt S, et al. Influence of vitamin E and C supplementation on lipoprotein oxidation
in patients with Alzheimer's disease. Free Radic Biol Med. 2001;31:345-354.
FULL TEXT
|
ISI
| PUBMED
40. Praticó D, Urvu K, Leight S, Trojanowski JQ, Lee VM. Increased lipid peroxidation precedes amyloid plaque formation in an
animal model of Alzheimer amyloidosis. J Neurosci. 2001;21:4183-4187.
FREE FULL TEXT
41. Paola D, Domenicotti C, Nitti M, et al. Oxidative stress induces increase in intracellular amyloid -protein
production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun. 2000;268:642-646.
FULL TEXT
|
ISI
| PUBMED
42. Misonou H, Morishima-Kawashima M, Ihara Y. Oxidative stress induces intracellular accumulation of amyloid -protein
(Abeta) in human neuroblastoma cells. Biochemistry. 2000;39:6951-6959.
FULL TEXT
| PUBMED
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