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Increase of Brain Oxidative Stress in Mild Cognitive Impairment
A Possible Predictor of Alzheimer Disease
Domenico Praticò, MD;
Christopher M. Clark, MD;
Feyan Liun, MD;
Virginia Y.-M. Lee, PhD;
John Q. Trojanowski, MD, PhD
Arch Neurol. 2002;59:972-976.
ABSTRACT
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Background The isoprostane 8,12-iso-iPF2 -VI,
a specific marker of in vivo lipid peroxidation, is increased in Alzheimer
disease (AD). The pathological changes associated with AD have a long silent
phase before the appearance of clinical symptoms. Several studies have shown
that AD is preceded by a prodromal phase characterized by mild cognitive impairment
(MCI).
Objective To investigate levels of this biomarker in subjects with MCI.
Design and Main Outcome Measures Using gas chromatography–mass spectrometry analysis, we measured
8,12-iso-iPF2-VI levels in urine,
plasma, and cerebrospinal fluid of patients with AD, subjects with MCI, and
cognitively normal elderly subjects.
Setting and Patients Subjects attending the Memory Disorders Clinic.
Results We found significantly higher 8,12-iso-iPF2-VI levels in cerebrospinal fluid, plasma, and urine of subjects
with MCI compared with cognitively normal elderly subjects.
Conclusions These results imply that individuals with MCI have increased brain oxidative
damage before the onset of symptomatic dementia. Measurement of this isoprostane
may identify a subgroup of patients with MCI with increased lipid peroxidation
who are at increased risk to progress to symptomatic AD.
INTRODUCTION
ALZHEIMER DISEASE (AD) is the most common cause of dementia in the elderly
and may have a long stage of neuropathological changes and cognitive decline
before it is diagnosed.1 An increasing number
of studies clearly indicate that the onset of AD is typically preceded by
an interim phase known as mild cognitive impairment (MCI).2-3
In its amnestic version, MCI is characterized primarily by a memory deficit
without clinically meaningful functional impairment.4
Typically, the onset of MCI is marked by a measurable memory loss that is
abnormal for an individual's age and education and is corroborated by an informant.5
Non-Alzheimer dementia may have a prodromal phase that differs in its
cognitive profile. Despite potential heterogeneity of an MCI diagnosis, recent
data have suggested that it is associated with up to a 50% probability of
progressing to symptomatic AD within a 4-year period.6
Thus, the rate of progression from MCI to AD is approximately 12% per year,
supporting the concept that MCI, at least in part, represents the prodromal
stage of AD.7
For these reasons it is important to identify and biochemically characterize
these patients in the earliest phase of their illness, since it is in this
phase that interventional therapy should have the greatest potential to slow
down disease progression. Factors associated with a more rapid progression
from MCI to AD include the presence of an apolipoprotein E  4 allele
and a small hippocampus as measured on magnetic resonance imaging.8-9
We have recently reported that isoprostanes (iPs), sensitive and specific
markers of in vivo lipid peroxidation,10 are
increased in cerebrospinal fluid (CSF), blood, and urine of patients with
a clinical diagnosis of AD. These levels were highly correlated with other
biomarkers of AD pathology and with the severity of the disease.11
Since individuals with MCI are believed to be at high risk to progress to
a clinical diagnosis of AD, we investigated whether they, like patients with
AD, have high levels of this marker.
SUBJECTS AND METHODS
SUBJECTS
This study was reviewed and approved by the institutional review board
of the University of Pennsylvania, Philadelphia. Subjects were recruited from
the University Alzheimer's Disease Center Memory Disorders Clinic (MDC) between
May 1, 1998, and February 28, 2001. Informed consent was obtained from all
participants and their caregivers.
The clinical diagnosis of probable AD was based on the National Institute
of Neurological and Communicative Diseases and Stroke–Alzheimer's Disease
and Related Disorders Association criteria.12
Criteria for the diagnosis of MCI were the following: (1) memory complaint
documented by the patient or collateral source; (2) scores on standardized
cognitive testing that were 2 SDs below age- and education-adjusted normal
values in 1 domain or 1 SD below normal in 2 domains; (3) Clinical Dementia
Rating of 0.5 or more; and (4) no symptoms of dementia based on a clinical
examination and an extensive interview with a knowledgeable informant.
As part of their routine cognitive assessment, all patients underwent
the Consortium to Establish a Registry for Alzheimer's Disease psychometric
battery, which assesses memory, language, and constructional praxis,13 plus additional tests of memory (Logical Memory I
and II), visual memory (Constructional Praxis recall and recognition), and
attention (Digit Symbol Substitution). Additional measures included the Mini-Mental
State Examination14 and Dementia Severity Rating
Scale.15 Routine laboratory studies, including
magnetic resonance imaging, were performed to exclude other causes of cognitive
impairment.
To the best of our knowledge, no subject with familial AD was included
in the study. Subjects were also excluded if they had evidence of an acute
infectious or inflammatory disease, chronic hepatic disease, chronic obstructive
pulmonary disease, alcoholism, or cancer, since these conditions may affect
F2-iPs biosynthesis.10 Urine and
blood samples were obtained from 50 patients with AD, 33 with MCI, and 40
control subjects. In addition, within 2 weeks, CSF was obtained from 28 of
the 50 patients with AD, 17 of the 33 subjects with MCI, and 18 of the control
subjects. A second urine sample was collected at this time. The elderly control
subjects were recruited from a cohort of cognitively normal individuals followed
up by the Alzheimer's Disease Center and from cognitively normal spouses of
patients with AD or MCI attending the Memory Disorders Clinic. During the
follow-up period, 5 subjects with MCI progressed to AD.
ISOPROSTANE ANALYSIS
Samples were collected into tubes containing 0.1% of the antioxidant
butylated hydroxytoluene and stored at -80°C until analysis. They
were spiked with a fixed amount of internal standard
(d4-8,12-iso-iPF2-VI)
and extracted on a C18 cartridge column. After the pentafluorobenzyl derivative was made, the eluate
was purified by thin-layer chromatography. Next, the trimethylsilyl derivative
was made, and finally the sample was assayed by negative ion chemical ionization
gas chromatography–mass spectrometry.10, 16
Blood, anticoagulated with edetic acid, was immediately centrifuged at 3000
rpm for 15 minutes at 4°C to obtain plasma and stored at -80°C.
The CSF was collected visually free of blood contamination and sedimented
at 1500 rpm for 15 minutes, and then an aliquot (1 mL) was frozen immediately
at -80°C. All assays were performed without knowledge of the clinical
diagnosis of the patient.
CSF-tau, CSF Aß1-40, AND Aß1-42
Tau protein levels were measured by sandwich enzyme-linked immunosorbent
assay (ELISA) with a kit (Innotest hTAU-Antigen kit; Innogenetics, Zwijndrecht,
Belgium).11, 17 Aß1-40 and Aß1-42 levels were measured by a previously well-characterized
sandwich ELISA using monoclonal antibodies specific for each of these Aß
species.11, 18 Synthetic Aß1-40 and Aß1-42 peptides were used to generate standard
curves. The Aß and tau sandwich ELISA have detection limits of less than
1 fmol of synthetic Aß and less than 75 pg/mL of tau per sample. Both
assays were performed in duplicate, and the variation between samples in the
duplicate assays was less than 10% for each. All assays were performed without
knowledge of the clinical diagnosis of the patient.
APOLIPOPROTEIN E GENOTYPE
DNA was extracted from peripheral leukocytes and apolipoprotein E genotyping
was performed as previously described,11 without
knowledge of the patient's clinical diagnosis.
STATISTICAL ANALYSIS
Comparisons among groups were performed by nonparametric 1-way analysis
of variance (Kruskal-Wallis test) with the use of Dunn posttest. Correlation
was studied by linear regression analysis. Statistical significance was set
at P<.05. Data are given as mean ± SE,
unless otherwise indicated.
RESULTS
Table 1 represents the clinical
characteristics of the population studied. There was no significant difference
among the 3 groups with respect to age and years of education (Table 1), plasma cholesterol level, triglycerides level, diabetes,
or smoking habit (not shown). Similarly, there was no difference among the
3 groups with respect to diet, weight, and vitamin intake (not shown). Apolipoprotein
E 2, 3, and 4 allele distribution in the patients with AD
and MCI are shown in Table 1.
Patients with probable AD had urinary 8,12-iso-iPF2-VI levels significantly greater than that of control subjects
(4.6 ± 0.2 vs 1.5 ± 0.1 ng/mg of creatinine) (P<.001) and patients with MCI (3.6 ± 0.3 ng/mg of creatinine)
(P = .01) (Figure
1, A). Patients with MCI had higher urinary 8,12-iso-iPF2-VI levels than control subjects (3.6 ±
0.3 vs 1.5 ± 0.1 ng/mg of creatinine) (P<.001).
Similarly, there was a significant difference in plasma isoprostane levels
between patients with AD (0.61 ± 0.03 ng/mL) and MCI (0.44 ±
0.03 ng/mL) (P<.03) and between patients with
MCI and control subjects (0.19 ± 0.01 ng/mL) (P<.001)
(Figure 1, B). There were no significant
clinical or demographic differences in age, symptom severity, or disease duration
between those members who did or did not undergo lumbar puncture in each of
the 3 groups. Likewise, there was no difference in the urinary 8,12-iso-iPF2-VI levels measured at the time
of lumbar puncture compared with the initial sample (data not shown). A significant
increase in CSF 8,12-iso-iPF2-VI
levels in both the AD and MCI groups compared with the control group was found
(P<.001) (Figure
1, C). In particular, patients with AD had a level of 68 ±
6.3 pg/mL compared with 44 ± 7.1 pg/mL for patients with MCI (P = .03) and 15 ± 1.2 pg/mL for control subjects.
There was a direct correlation between CSF and urinary levels of 8,12-iso-iPF2-VI and between CSF and plasma
8,12-iso-iPF2-VI levels. The coefficient
of correlation (r2) for each was 0.55
and 0.64, respectively (both P<.001).
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Table 1. Demographic Characteristics of the Population Studied*
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Urinary (A), plasma (B), and cerebrospinal fluid (C) 8,12-iso-iPF2-VI (a specific marker of in vivo peroxidation
isoprostane) levels in patients with Alzheimer disease (AD), mild cognitive
impairment (MCI), and matched control subjects.
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As would be consistent with the selection criteria, the patients with
AD had impaired cognitive function as shown by the Mini-Mental State Examination
and Dementia Severity Rating Scale assessments (Table 1). By contrast, subjects with MCI performed slightly more
poorly on these measures than the controls subjects but were superior to the
patients with AD. The CSF tau protein level was elevated, whereas the percentage
ratio between CSF Aß1-40 and Aß1-42was lower
in patients with AD than in patients with MCI and matched control subjects
(Table 2). In particular, patients
with AD had significantly higher CSF tau levels and lower percentage of Aß1-42 than control subjects. By contrast, only CSF tau levels, but not
the percentage of Aß1-42, were significantly higher in AD
than in MCI. Moreover, no statistically significant difference was observed
between patients with MCI and matched control subjects for both variables
(Table 2). Finally, no difference
in 8,12-iso-iPF2-VI levels was
found between patients homozygous for apolipoprotein E 4 allele and
those with 1 or no 4 allele (not shown).
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Table 2. Cerebrospinal Fluid tau Levels and Aß1-40
and Aß1-42 Percentage Ratio in AD, MCI, and Control Groups*
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COMMENT
In this study we show that patients who meet standardized clinical criteria
for MCI have increased CSF, plasma, and urinary levels of 8,12-iso-iPF2-VI, a reliable marker of in vivo lipid peroxidation.10 At the same time, we confirm our previous finding
that subjects with AD have higher levels of this marker. Patients with MCI
constitute an important group to study for both theoretical and practical
reasons. This is a group with well-characterized clinical diagnostic criteria.4-5 In particular, most of these patients
have a memory impairment that is beyond normal limits and yet are functioning
independently. These individuals are at high risk to progress to meet clinical
criteria for AD and do so at a rate of 10% to 12% per year,6-7
and therefore it is important to identify them as they represent an ideal
target for preventive strategies.
A consistent body of evidence clearly indicates that oxidative stress
is increased in brains of patients with AD as well as in living patients with
probable AD.19-20 Previously,
our group reported that patients with AD have elevated levels of 8,12-iso-iPF2-VI in CSF, plasma, and urine
when compared with control subjects,11 suggesting
that lipid peroxidation is an early event in AD and that measurement of this
isoprostane could be a sensitive marker of brain oxidative damage. This observation
was confirmed by Tuppo et al,21 who measured
urinary levels of another distinct F2-isoprostane, iPF2-III, in patients with AD. However, another group, by measuring total
F2-isoprostane levels, failed to find a difference in urinary and
plasma levels in AD and found such a difference only in CSF.22
It is possible that methodologic differences explain these contrasting results.
Our finding that levels of this specific isoprostane are significantly
elevated in subjects who meet clinical criteria for MCI adds further support
to the notion that oxidative damage is an early pathological change in AD.
Since the earliest neurologic changes of AD begin well before a clinical
diagnosis can be made, there is considerable benefit to the identification
of an easily obtainable biological marker that could identify patients with
MCI who are at highest risk to progress to AD.23-24
Previous works demonstrated that apolipoprotein E 4 carrier status and
the identification of mild memory impairment might predict who is likely to
progress to AD.8, 25 Magnetic resonance
imaging volumetric measurements of the hippocampal formation9
and CSF tau and Aß1-42 levels may also be useful in this task.26
In accordance with previous reports, we found that, among the 3 groups
studied, patients with AD had the highest values for CSF tau and the lowest
percentage ratio between Aß1-40 and Aß1-42,
but no significant difference was observed between subjects with MCI and control
subjects. By contrast, subjects with MCI had CSF 8,12-iso-iPF2-VI levels significantly higher than those of
elderly control subjects. Considering that CSF tau and Aß levels are
thought to be markers of AD neuropathologic changes and disease progression,17 this observation would suggest that brain oxidative
damage is an early event in the development of AD-like pathology. Remarkably,
in our study we found that subjects with MCI are different from elderly control
subjects with respect only to this marker of oxidative stress. This suggests
that measurement of 8,12-iso-iPF2-VI
may provide a reliable biomarker of brain oxidative damage that could help
in identifying, together with hippocampus volumetric analyses and apolipoprotein
E 4 allele analysis, subjects with MCI who are at higher risk to develop
to AD. Parenthetically, 5 of the subjects with MCI, all with high 8,12-iso-iPF2-VI levels, converted to AD during
the follow-up. However, future longitudinal studies are needed to address
this hypothesis.
AUTHOR INFORMATION
Accepted for publication January 9, 2002.
Author contributions: Study concept and design (Drs Praticò and Clark); acquisition of data (Drs Praticò, Clark, and Liun); analysis and interpretation
of data (Drs Praticò, Clark, Lee, and Trojanowski); drafting of the manuscript (Drs Praticò and
Liun); critical revision of the manuscript for important intellectual
content (Drs Praticò, Clark, Lee, and Trojanowski); statistical expertise (Drs Praticò, Clark,
Liun, and Trojanowski); study supervision (Drs Praticò
and Clark).
This study was supported in part by grants AG09215, AG10124, and AG11542
from the National Institutes of Health, Bethesda, Md, and the American Heart
Association, Dallas, Tex.
We thank the patients and all their families who made this research
possible. The assistance of Marianne Watson, RN, Barbara Tournier, RN, and
Susan Leight is greatly appreciated.
Corresponding author and reprints: Domenico Praticò, MD, Center
for Experimental Therapeutics, University of Pennsylvania, BRB II/III, Room
812, 421 Curie Blvd, Philadelphia, PA 19104 (e-mail: domenico{at}spirit.gcrc.upenn.edu).
From the Center for Experimental Therapeutics and Department of Pharmacology
(Drs Praticò and Liun), Department of Neurology (Dr Clark), Center
for Neurodegenerative Disease Research (Drs Lee and Trojanowski), and Alzheimer's
Disease Center (Drs Clark, Lee, and Trojanowski), University of Pennsylvania
School of Medicine, Philadelphia.
REFERENCES
| |
1. Clark CM. Clinical manifestations and diagnostic evaluation of patients with
Alzheimer's disease. In: Clark CM, Trojanowski JQ, eds. Neurodegenerative
Dementias: Clinical Features and Pathological Mechanisms. New York,
NY: McGraw-Hill Co; 2000:95-114.
2. Flicker C, Ferris SH, Reisberg B. Mild cognitive impairment in the elderly: predictors of dementia. Neurology. 1991;41:1006-1009.
FREE FULL TEXT
3. Petersen RC. Normal aging, mild cognitive impairment, and early Alzheimer's disease. Neurologist. 1995;1:326-344.
4. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303-308.
FREE FULL TEXT
5. Tuokko H, Frerichs RJ. Cognitive impairment with no dementia (CIND): longitudinal studies,
the findings, and the issues. Clin Neuropsychol. 2000;14:504-525.
ISI
| PUBMED
6. Dawe B, Procter A, Philpot M. Concepts of mild cognitive impairment in the elderly and their relationship
to dementia: a review. Int J Geriatr Psychiatry. 1992;7:473-479.
7. Shah Y, Tangalos EG, Petersen RC. Mild cognitive impairment: when is it a precursor to Alzheimer's disease? Geriatrics. 2000;55:62-68.
ISI
| PUBMED
8. Petersen RC, Smith GE, Ivnik RJ, et al. Apolipoprotein E status as a predictor of the development of Alzheimer's
disease in memory-impaired individuals. JAMA. 1995;273:1274-1278.
ABSTRACT
9. Jack CR, Petersen RC, Xu YC, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive
impairment. Neurology. 1999;52:1397-1403.
FREE FULL TEXT
10. Praticò D. F2-isoprostanes: sensitive and specific non-invasive indices
of lipid peroxidation in vivo. Atherosclerosis. 1999;147:1-10.
FULL TEXT
|
ISI
| PUBMED
11. Praticò D, Clark CM, Lee VM-Y, 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.
FULL TEXT
|
ISI
| PUBMED
12. Radebaugh TS, Buckholz NS, Khachaturian ZS. Fisher symposium: strategies for the prevention of Alzheimer's disease—overview
of research planning meeting III. Alzheimer Dis Assoc Disord. 1996;10(suppl 1):1-5.
13. Welsh KA, Butters N, Mohs RC, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD),
part V: a normative study of the neuropsychological battery. Neurology. 1994;44:609-614.
FREE FULL TEXT
14. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state
of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
FULL TEXT
|
ISI
| PUBMED
15. Clark CM, Ewbank DC. Performance of the Dementia Severity Rating Scale: a caregiver questionnaire
for rating severity in Alzheimer's disease. Alzheimer Dis Assoc Disord. 1996;10:31-39.
ISI
| PUBMED
16. Lawson JA, Li H, Rokach J, et al. Identification of two major F2 isoprostanes, 8,12-iso- and
5-epi-8,12-Iso-isoprostane F2-VI,
in human urine. J Biol Chem. 1998;273:29295-29301.
FREE FULL TEXT
17. Arai H, Terajima M, Miura M, et al. Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer's
disease. Ann Neurol. 1995;38:649-652.
FULL TEXT
|
ISI
| PUBMED
18. Skowronsky DM, Lee VM-Y, Praticò D. Amyloid precursor protein and amyloid ß peptide in human platelets:
role of cyclooxygenase and protein kinase C. J Biol Chem. 2001;276:17036-17043.
FREE FULL TEXT
19. Praticò D, Lee VM-Y, Trojanowski JQ, Rokach J, FitzGerald GA. Increased F2-isoprostanes in Alzheimer's disease: evidence
for enhanced lipid peroxidation in vivo. FASEB J. 1998;12:1777-1783.
FREE FULL TEXT
20. Montine TJ, Markesbery WR, Roberts LJ, Morrow JD. Cerebrospinal fluid F2-isoprostane levels are increased
in Alzheimer's disease. Ann Neurol. 1998;44:410-413.
FULL TEXT
|
ISI
| PUBMED
21. Tuppo EE, Forman LJ, Spur BW, Chan-Ting RE, Chopra A, Cavalieri TA. Sign of lipid peroxidation as measured in the urine of patients with
probable Alzheimer's disease. Brain Res Bull. 2001;54:565-568.
FULL TEXT
| PUBMED
22. Montine TJ, Shinobu L, Montine KS, et al. No difference in plasma or urinary F2-isoprostanes among
patients with Huntington's disease or Alzheimer's disease and controls [letter]. Ann Neurol. 2000;48:950.
FULL TEXT
| PUBMED
23. Friedrich MJ. Mild cognitive impairment raises Alzheimer's disease risk. JAMA. 1999;282:621-622.
FREE FULL TEXT
24. Daly E, Zaitchik D, Copeland M, Schmahmann J, Gunther J, Albert M. Predicting conversion to Alzheimer disease using standardized clinical
information. Arch Neurol. 2000;57:675-680.
FREE FULL TEXT
25. Tierney MC, Szalai JP, Snow WG, et al. A prospective study of the clinical utility of ApoE genotype in the
prediction of outcome in patients with memory impairment. Neurology. 1996;46:149-154.
FREE FULL TEXT
26. Andreasen N, Minthon L, Vanmechelen E, et al. Cerebrospinal fluid tau and Aß42 as predictors of development
of Alzheimer's disease in patients with mild cognitive impairment. Neurosci Lett. 1999;273:5-8.
FULL TEXT
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ISI
| PUBMED
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