Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2014, Article ID 182303, 14 pages
http://dx.doi.org/10.1155/2014/182303
Review Article

The Roles of Biomarkers of Oxidative Stress and Antioxidant in Alzheimer’s Disease: A Systematic Review

1Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung District, Kaohsiung 833, Taiwan
2Department of Biological Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
3Department of Emergency Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung District, Kaohsiung 833, Taiwan
4Department of Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung District, Kaohsiung 833, Taiwan
5Department of Radiology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung District, Kaohsiung 833, Taiwan

Received 25 February 2014; Accepted 27 March 2014; Published 14 May 2014

Academic Editor: Hung-Chen Wang

Copyright © 2014 Ya-Ting Chang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose. Oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). This paper aims to examine whether biomarkers of oxidative stress and antioxidants could be useful biomarkers in AD, which might form the bases of future clinical studies. Methods. PubMed, SCOPUS, and Web of Science were systematically queried to obtain studies with available data regarding markers of oxidative stress and antioxidants from subjects with AD. Results and Conclusion. Although most studies show elevated serum markers of lipid peroxidation in AD, there is no sufficient evidence to justify the routine use of biomarkers as predictors of severity or outcome in AD.

1. Introduction

Alzheimer’s disease is the most common form of dementia in the elderly and is characterized by a progressive loss of cognitive capacity and severe neurodegeneration. The pathophysiologic process is posited to be initiated by extracellular fibrillary β-amyloid deposition, with subsequent intraneuronal hyperphosphorylated tau protein aggregation [1]. Mutations in the amyloid precursor protein (APP), presenilin-1 (PS1), or PS2 that alter APP metabolism favor the production of a fibrillary form, Aβ. Such findings form the basis of the amyloid cascade hypothesis of AD pathophysiology [2].

Although this amyloid cascade hypothesis may be the underlying pathogenesis for the familial form of AD, increasing evidence suggests that oxidative stress has a key role in late-onset sporadic forms, which are the majority of AD cases. Abnormal levels of oxidative stress have been reported in Alzheimer’s disease in both the brain and blood stream [3, 4]. Changes in Alzheimer’s disease that produce a prooxidative imbalance have been attributed to decrease in antioxidant defenses, toxicity related to amyloid-β, and/or altered metal metabolism in the brain and peripheral tissues [3, 4] (Figure 1).

182303.fig.001
Figure 1: Oxidative stress in Alzheimer’s dementia. APP: amyloid precursor protein; BACE: beta-secretase; ROS: reactive oxygen species; RNS: reactive nitrogen species; Aβ: amyloid β.

Oxidative stress, a pathophysiologic imbalance between oxidants and antioxidants in favor of the former, with potential damage, has been shown in the blood, cerebrospinal fluid (CSF), and brain of neurologic patients with probable AD [512]. Biomarkers of oxidative stress in subjects with AD are classified as lipid peroxidation, protein oxidation, DNA oxidation, superoxide dismutase, and glutathione system [5, 1316]. Biomarkers of oxidative damage to lipids include thiobarbituric acid-reactive substances (TBARS) and oxidized-LDL (ox-LDL) [7, 17]. The level of TBARS can be measured in plasma, serum, erythrocytes, and leukocytes [7], while ox-LDL is mostly measured in serum [17]. Oxidative attack on proteins results in the formation of protein carbonyls and protein nitration [18, 19]. Protein carbonyls and nitrated protein can be measured in plasma, serum, CSF, and brain tissue [18]. Regarding nucleic acids, 8-hydroxy-2-deoxyguanosine (8-OHdG) is one of the most commonly used markers of oxidative nucleic acid damage and can be measured in lymphocytes, leukocytes, and the brain [16].

The possible benefits of biomarkers in clinical practice include outcome prediction in AD patients that may further influence therapeutic regimens. The aim of this review is to determine whether biomarkers of oxidative stress can play an important prognostic role in the outcome of AD. The successful translation of these approaches to the clinics offers the promise of not only improving outcome prediction but also a more scientific basis for therapeutic options.

2. Methods

Studies were identified from a systematic search of PubMed, Scopus databases, Google Scholar, and the reference lists of all included studies and major relevant review papers. To find all of the relevant articles, PubMed was searched using the key words: “TBARS,” “oxidized LDL,” “protein carbonyls,” “8-HOG,” “antioxidant,” and “Alzheimer’s disease” in various combinations. Case-control studies with human subjects were considered for inclusion. The articles selected were published in English between January 1985 and September 2013.

3. Results

3.1. Biomarkers of Lipid Peroxidation

Lipid peroxidation is one of the major consequences of oxidative imbalance-mediated injury to the brain. It causes changes in the fluidity and permeability of cell membranes and impairs the activity of membrane-bound enzymes. Lipid peroxidation also leads to the production of conjugated diene hydroperoxides and unstable substances that disintegrate into various aldehydes like malondialdehyde, 4-hydroxynonenal, and TBARS.

Several studies demonstrate that serum or plasma TBARS level in AD subjects is significantly higher than in controls [7, 13, 15, 2028], while others observe no significant difference between AD subjects and controls [2935] (Table 1). Results regarding erythrocyte TBARS level in AD are also controversial. Some studies observe higher erythrocyte TBARS levels in AD [5, 7, 31], while others observe no difference between AD and controls [6, 15, 29, 36]. A meta-analysis regarding blood TBARS level in AD and mild cognitive impairment reveals that TBARS levels are significantly elevated in Alzheimer’s disease plasma/serum [37]. However, findings may vary by different patients selection criteria: some researchers observe AD subjects with MMSE 7–24 points do not have significantly higher serum TBARS than controls [34], while others observe AD subjects with 7–20 points as well as ADAS-cog 10–35 points have significantly higher serum TBARS than controls [20]. These suggest that MMSE alone is not enough to discriminate those with higher TBARS from those with lower TBARS. The lack of a link between MMSE and TBARS is also reported by another study, which suggests that MMSE is not correlated with TBARS [7], while plasma TBARS level may actually increase with the severity of cognitive dysfunction in AD [7].

tab1
Table 1: Studies exploring the predictive capacity of biomarkers of lipid peroxidation in AD.

Ox-LDL has been suggested to be produced by oxidized phospholipids released from brain tissue into circulation [38]. Ox-LDL is a promising marker of oxidative injury of the whole body. It may also be a peripheral marker that is linked to the severity of oxidative damage in the presence of dementia [23, 39, 40]. Serum ox-LDL level is universally higher in AD than in controls in the three studies.

3.2. Biomarkers of Protein Oxidation

Two different biomarkers of free-radical damage against protein have been suggested: protein oxidation that leads to the production of protein carbonyls [7, 14, 17, 18, 23, 28, 4047] and protein peroxidation that leads to the production of nitrated protein [18, 19, 43, 46, 4850] (Table 2). As a peripheral marker of oxidative stress in the brain, higher serum/plasma protein carbonyls level in AD is demonstrated in several studies despite varying patient selection criteria [7, 18, 4043, 46]. Only two studies show no significant difference in serum/plasma protein carbonyls level between AD and controls [17, 23].

tab2
Table 2: Studies exploring the predictive capacity of biomarkers of protein peroxidation in AD.
3.3. Biomarkers of Antioxidants

Antioxidants are suggested as potential indirect markers of oxidative stress processing in the brain of patients with AD (Table 3). Oxidative stress has been speculated to cause antioxidant consumption and thus, a decline in antioxidant levels [51]. Nonenzymatic compounds with antioxidant properties include vitamin A/carotenoids, vitamins C and E, and uric acid. On the other hand, antioxidant enzymes that vary on condition of oxidative stress in AD remain unsettled, since antioxidant enzymes like glutathione peroxidase (GPx) and superoxide dismutase (SOD) may be induced by oxidative stress (to increase their level or activity) or consumed (to decrease their level or activity) [37].

tab3
Table 3: Studies exploring the predictive capacity of antioxidant in AD.
3.3.1. Uric Acid

Three studies elaborate that plasma or serum uric acid level is significantly lower in AD [5254], while three other studies do not observe this difference [29, 55, 56]. It is possible that excluding patients with metabolic syndrome plays an important role in measurements of significantly lower uric acid level in AD [52, 54]. This suggests that metabolic syndrome may interfere with the level of uric acid as an indirect marker of oxidative stress in AD.

3.3.2. Vitamin E

Most of the studies in the literature report that plasma or serum vitamin E level is significantly lower in AD [7, 9, 10, 15, 16, 25, 54, 5760]. However, vitamin E supplementation does not seem to improve prognosis in AD [61]. So far, erythrocyte and platelet vitamin E levels are not different between AD and controls [15, 29].

3.3.3. Vitamin C

Vitamin C concentration in plasma or serum is also found to be significantly lower in AD in most literature [10, 16, 25, 54, 60, 62, 63]. Furthermore, vitamin C is especially significantly lower in moderate and severe AD [62].

3.3.4. Vitamin A

All of the studies on serum or plasma vitamin A levels establish a significant difference between AD and control [10, 16, 25, 54, 63, 64].

3.3.5. Superoxide Dismutase (SOD)

As an antioxidant enzyme, SOD may be induced or consumed by oxidative stress [65]. It is one of the most studied antioxidant enzymes in AD. Several studies find no difference in SOD between AD and controls [15, 29, 31, 36, 66]. Some find significantly lower erythrocyte level [5, 11, 54, 67] and plasma/serum level [11, 26] in AD, while others find significantly higher erythrocyte [6, 7, 21, 22, 6871] and plasma [28] levels in AD. However, only three among these studies have a case number more than 80 [7, 22, 68] and all of them either include only mild-to-moderate AD [22, 68] or have clear severity-classification of AD [7]. All three demonstrate significantly higher erythrocyte SOD level in AD [7, 21, 22]. One study further establishes that leukocyte SOD level is higher in moderate AD than in mild AD, higher in mild AD than in controls, and higher in mild AD than in severe AD [7]. This suggests that SOD level is induced by oxidative stress in the early stages of AD and is consumed in the later stage. Studies with different findings may be due to limitations of small sample size [26, 66] or loose inclusion criteria [15, 21, 29, 36, 54].

3.3.6. Glutathione Peroxidase (GPx)/Reduced Glutathione (GSH)

Glutathione peroxidase, another antioxidant enzyme, may be also induced or consumed under conditions of oxidative stress [65]. Some studies demonstrate no difference in GPx level between AD and controls [15, 22, 29, 31]. Some demonstrate lower GPx in AD [2628, 36, 54], while others observe higher GPx [5, 7, 24, 27]. As for the balance between reduced and oxidized GSH (GSSG), some studies show no significant difference between AD and controls [6, 20, 29], while others demonstrate a balance towards GSSG in AD with statistical significance [7, 32, 41, 72, 73]. The only study with a case number more than 100 demonstrates significantly higher plasma, erythrocyte, and leukocyte GPx and GSSG levels in severe AD than in moderate AD, in moderate AD than in mild AD, and in mild AD than in controls [7]. Other studies may be limited by their small sample size [6, 15, 26] or different patient characteristics [20, 31, 54].

3.4. Biomarkers of DNA Oxidation

8-OHdG is the most commonly studied biomarker for oxidative DNA. Most studies in the literature reveal significantly higher 8-OHdG in AD [4, 16, 74]. Among the three, two studies demonstrated significantly higher peripheral 8-OHdG in lymphocytes and leukocytes [4, 16].

3.5. Biomarkers of Central Nervous System

As for CSF antioxidant, the difference of vitamin E level between AD and controls remains controversial [58, 64]. Although one study shows no difference in CSF vitamin C level between AD and controls [75], two other studies reveal that CSF vitamin C level is lower [60, 64] and one study even has negative findings, which may be due to the small sample size [75]. Only one study about CSF vitamin A level shows no difference between AD and control [64].

In terms of markers of oxidative stress measured closer to the brain, one of the studies that measured brain 8-OHdG directly found elevated 8-OHdG in AD [74]. CSF protein carbonyl level is universally significantly higher in AD than in controls [18, 45, 46]. Furthermore, several studies measure protein carbonyls directly in the brain postmortem [14, 43, 47]. Although most studies on the hippocampus have found exclusively significantly higher protein carbonyl levels in AD, one study on other brain regions such as the neocortex, amygdala, brainstem, and cerebellum has also found significantly increased protein carbonyl levels in AD [47].

Regarding nitrated protein that represents protein peroxidation, there is no consistency among different research groups on assessing nitrated protein level in AD. Although direct measurement from brain tissue postmortem reveals consistently significantly higher nitrated protein in AD [19, 43, 49], only two studies demonstrate significantly higher CSF nitrate protein level in AD [46, 48]. Two other studies report no difference between AD and controls [18, 50].

4. Conclusions

Most studies show that serum markers of lipid peroxidation are elevated in Alzheimer’s disease. However, there is insufficient evidence to justify the routine use of biomarkers as predictors of severity or outcome in AD.

Conflict of Interests

The authors declare that they have no competing interests.

Acknowledgment

The authors wish to thank Dr. Gene Alzona Nisperos for editing and reviewing the paper for English language considerations.

References

  1. M. W. Weiner, D. P. Veitch, P. S. Aisen et al., “The Alzheimer's disease neuroimaging initiative: a review of papers published since its inception,” Alzheimer's and Dementia, vol. 8, no. 1, supplement, pp. S1–S68, 2012. View at Publisher · View at Google Scholar · View at Scopus
  2. J. A. Hardy and G. A. Higgins, “Alzheimer's disease: the amyloid cascade hypothesis,” Science, vol. 256, no. 5054, pp. 184–185, 1992. View at Google Scholar · View at Scopus
  3. M. A. Smith, C. A. Rottkamp, A. Nunomura, A. K. Raina, and G. Perry, “Oxidative stress in Alzheimer's disease,” Biochimica et Biophysica Acta, vol. 1502, no. 1, pp. 139–144, 2000. View at Google Scholar
  4. L. Migliore, I. Fontana, F. Trippi et al., “Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients,” Neurobiology of Aging, vol. 26, no. 5, pp. 567–573, 2005. View at Publisher · View at Google Scholar · View at Scopus
  5. Á. Casado, M. Encarnación López-Fernández, M. Concepción Casado, and R. De La Torre, “Lipid peroxidation and antioxidant enzyme activities in vascular and alzheimer dementias,” Neurochemical Research, vol. 33, no. 3, pp. 450–458, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. J. A. Serra, R. O. Domínguez, E. S. De Lustig et al., “Parkinson's disease is associated with oxidative stress: comparison of peripheral antioxidant profiles in living Parkinson's, Alzheimer's and vascular dementia patients,” Journal of Neural Transmission, vol. 108, no. 10, pp. 1135–1148, 2001. View at Publisher · View at Google Scholar · View at Scopus
  7. D. O. Cristalli, N. Arnal, F. A. Marra, M. J. T. De Alaniz, and C. A. Marra, “Peripheral markers in neurodegenerative patients and their first-degree relatives,” Journal of the Neurological Sciences, vol. 314, no. 1-2, pp. 48–56, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. M. Carantoni, G. Zuliani, M. R. Munari, K. D'Elia, E. Palmieri, and R. Fellin, “Alzheimer disease and vascular dementia: relationships with fasting glucose and insulin levels,” Dementia and Geriatric Cognitive Disorders, vol. 11, no. 3, pp. 176–180, 2000. View at Google Scholar · View at Scopus
  9. A. J. Sinclair, A. J. Bayer, J. Johnston, C. Warner, and S. R. Maxwell, “Altered plasma antioxidant status in subjects with Alzheimer's disease and vascular dementia,” International Journal of Geriatric Psychiatry, vol. 13, no. 12, pp. 840–845, 1998. View at Google Scholar
  10. C. J. Foy, A. P. Passmore, M. D. Vahidassr, I. S. Young, and J. T. Lawson, “Plasma chain-breaking antioxidants in Alzheimer's disease, vascular dementia and Parkinson's disease,” QJM, vol. 92, no. 1, pp. 39–45, 1999. View at Google Scholar · View at Scopus
  11. Y. Ihara, T. Hayabara, K. Sasaki et al., “Free radicals and superoxide dismutase in blood of patients with Alzheimer's disease and vascular dementia,” Journal of the Neurological Sciences, vol. 153, no. 1, pp. 76–81, 1997. View at Publisher · View at Google Scholar · View at Scopus
  12. I. Guidi, D. Galimberti, S. Lonati et al., “Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease,” Neurobiology of Aging, vol. 27, no. 2, pp. 262–269, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. P. Bermejo, P. Gomez-Serranillos, J. Santos, E. Pastor, P. Gil, and S. Martin-Aragon, “Determination of malonaldehyde in Alzheimer's disease: a comparative study of high-performance liquid chromatography and thiobarbituric acid test,” Gerontology, vol. 43, no. 4, pp. 218–222, 1997. View at Google Scholar · View at Scopus
  14. M. Y. Aksenov, M. V. Aksenova, D. A. Butterfield, J. W. Geddes, and W. R. Markesbery, “Protein oxidation in the brain in Alzheimer's disease,” Neuroscience, vol. 103, no. 2, pp. 373–383, 2001. View at Publisher · View at Google Scholar · View at Scopus
  15. I. Bourdel-Marchasson, M.-C. Delmas-Beauviex, E. Peuchant et al., “Antioxidant defences and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients,” Age and Ageing, vol. 30, no. 3, pp. 235–241, 2001. View at Publisher · View at Google Scholar · View at Scopus
  16. P. Mecocci, M. Cristina Polidori, A. Cherubini et al., “Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease,” Archives of Neurology, vol. 59, no. 5, pp. 794–798, 2002. View at Google Scholar · View at Scopus
  17. S. Aldred, S. Bennett, and P. Mecocci, “Increased low-density lipoprotein oxidation, but not total plasma protein oxidation, in Alzheimer's disease,” Clinical Biochemistry, vol. 43, no. 3, pp. 267–271, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. M. A. Korolainen and T. Pirttilä, “Cerebrospinal fluid, serum and plasma protein oxidation in Alzheimer's disease,” Acta Neurologica Scandinavica, vol. 119, no. 1, pp. 32–38, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. A. Castegna, V. Thongboonkerd, J. B. Klein, B. Lynn, W. R. Markesberyl, and D. A. Butterfield, “Proteomic identification of nitrated proteins in Alzheimer's disease brain,” Journal of Neurochemistry, vol. 85, no. 6, pp. 1394–1401, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. H. Aybek, F. Ercan, D. Aslan, and T. Şahiner, “Determination of malondialdehyde, reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer's disease in Denizli, Turkey,” Clinical Biochemistry, vol. 40, no. 3-4, pp. 172–176, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. R. Ozcankaya and N. Delibas, “Malondialdehyde, superoxide dismutase, melatonin, iron, copper, and zinc blood concentrations in patients with Alzheimer disease: cross-sectional study,” Croatian Medical Journal, vol. 43, no. 1, pp. 28–32, 2002. View at Google Scholar · View at Scopus
  22. J. A. Serra, R. O. Domínguez, E. R. Marschoff, E. M. Guareschi, A. L. Famulari, and A. Boveris, “Systemic oxidative stress associated with the neurological diseases of aging,” Neurochemical Research, vol. 34, no. 12, pp. 2122–2132, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. F. Sinem, K. Dildar, E. Gökhan, B. Melda, Y. Orhan, and M. Filiz, “The serum protein and lipid oxidation marker levels in Alzheimer's disease and effects of cholinesterase inhibitors and antipsychotic drugs therapy,” Current Alzheimer Research, vol. 7, no. 5, pp. 463–469, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. L. L. Torres, N. B. Quaglio, G. T. De Souza et al., “Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 59–68, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. M. C. Polidori and P. Mecocci, “Plasma susceptibility to free radical-induced antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease,” Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 517–522, 2002. View at Google Scholar · View at Scopus
  26. M. Padurariu, A. Ciobica, L. Hritcu, B. Stoica, W. Bild, and C. Stefanescu, “Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease,” Neuroscience Letters, vol. 469, no. 1, pp. 6–10, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Martín-Aragón, P. Bermejo-Bescós, J. Benedí et al., “Metalloproteinase's activity and oxidative stress in mild cognitive impairment and Alzheimer's disease,” Neurochemical Research, vol. 34, no. 2, pp. 373–378, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. M. C. Puertas, J. M. Martínez-Martos, M. P. Cobo, M. P. Carrera, M. D. Mayas, and M. J. Rami'rez-Expósito, “Plasma oxidative stress parameters in men and women with early stage Alzheimer type dementia,” Experimental Gerontology, vol. 47, no. 8, pp. 625–630, 2012. View at Google Scholar
  29. M. A. Fernandes, M. T. Proenca, A. J. Nogueira et al., “Influence of apolipoprotein E genotype on blood redox status of Alzheimer's disease patients,” International Journal of Molecular Medicine, vol. 4, no. 2, pp. 179–186, 1999. View at Google Scholar · View at Scopus
  30. C. Galbusera, M. Facheris, F. Magni et al., “Increased susceptibility to plasma lipid peroxidation in Alzheimer disease patients,” Current Alzheimer Research, vol. 1, no. 2, pp. 103–109, 2004. View at Google Scholar · View at Scopus
  31. I. Ceballos-Picot, M. Merad-Boudia, A. Nicole et al., “Peripheral antioxidant enzyme activities and selenium in elderly subjects and in dementia of Alzheimer's type—place of the extracellular glutathione peroxidase,” Free Radical Biology and Medicine, vol. 20, no. 4, pp. 579–587, 1996. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Gironi, A. Bianchi, A. Russo et al., “Oxidative imbalance in different neurodegenerative diseases with memory impairment,” Neurodegenerative Diseases, vol. 8, no. 3, pp. 129–137, 2011. View at Publisher · View at Google Scholar · View at Scopus
  33. J. Kalman, I. Dey, S. V. Ilona et al., “Platelet membrane fluidity and plasma malondialdehyde levels in Alzheimer's demented patients with and without family history of dementia,” Biological Psychiatry, vol. 35, no. 3, pp. 190–194, 1994. View at Publisher · View at Google Scholar · View at Scopus
  34. L. T. McGrath, B. M. McGleenon, S. Brennan, D. McColl, S. McIlroy, and A. P. Passmore, “Increased oxidative stress in Alzheimer's disease as assessed with 4-hydroxynonenal but not malondialdehyde,” QJM, vol. 94, no. 9, pp. 485–490, 2001. View at Google Scholar · View at Scopus
  35. M. A. Sekler, J. M. Jiménez, L. Rojo et al., “Cognitive impairment and Alzheimer's disease: links with oxidative stress and cholesterol metabolism,” Neuropsychiatric Disease and Treatment, vol. 4, no. 4, pp. 715–722, 2008. View at Google Scholar · View at Scopus
  36. C. Jeandel, M. B. Nicolas, F. Dubois, F. Nabet-Belleville, F. Penin, and G. Cuny, “Lipid peroxidation and free radical scavengers in Alzheimer's disease,” Gerontology, vol. 35, no. 5-6, pp. 275–282, 1989. View at Google Scholar · View at Scopus
  37. M. Schrag, C. Mueller, M. Zabel et al., “Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a meta-analysis,” Neurobiology of Disease, vol. 59, pp. 100–110, 2013. View at Google Scholar
  38. M. Uno, K. T. Kitazato, K. Nishi, H. Itabe, and S. Nagahiro, “Raised plasma oxidised LDL in acute cerebral infarction,” Journal of Neurology Neurosurgery and Psychiatry, vol. 74, no. 3, pp. 312–316, 2003. View at Publisher · View at Google Scholar · View at Scopus
  39. C. E. Teunissen, J. De Vente, H. W. M. Steinbusch, and C. De Bruijn, “Biochemical markers related to Alzheimer's dementia in serum and cerebrospinal fluid,” Neurobiology of Aging, vol. 23, no. 4, pp. 485–508, 2002. View at Publisher · View at Google Scholar · View at Scopus
  40. Z.-Y. Cai, Y. Yan, L. Yan et al., “Serum level of MMP-2, MMP-9 and Ox-LDL in Alzheimer's disease with hyperlipoidemia,” Journal of Medical Colleges of PLA, vol. 22, no. 6, pp. 352–356, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. P. Bermejo, S. Martín-Aragón, J. Benedí et al., “Peripheral levels of glutathione and protein oxidation as markers in the development of Alzheimer's disease from Mild Cognitive Impairment,” Free Radical Research, vol. 42, no. 2, pp. 162–170, 2008. View at Publisher · View at Google Scholar · View at Scopus
  42. C. C. Conrad, P. L. Marshall, J. M. Talent, C. A. Malakowsky, J. Choi, and R. W. Gracy, “Oxidized proteins in Alzheimer's plasma,” Biochemical and Biophysical Research Communications, vol. 275, no. 2, pp. 678–681, 2000. View at Google Scholar
  43. R. Sultana, H. F. Poon, J. Cai et al., “Identification of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach,” Neurobiology of Disease, vol. 22, no. 1, pp. 76–87, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. J. Choi, C. A. Malakowsky, J. M. Talent, C. C. Conrad, and R. W. Gracy, “Identification of oxidized plasma proteins in Alzheimer's disease,” Biochemical and Biophysical Research Communications, vol. 293, no. 5, pp. 1566–1570, 2002. View at Google Scholar
  45. M. A. Korolainen, T. A. Nyman, P. Nyyssönen, E. S. Hartikainen, and T. Pirttilä, “Multiplexed proteomic analysis of oxidation and concentrations of cerebrospinal fluid proteins in Alzheimer disease,” Clinical Chemistry, vol. 53, no. 4, pp. 657–665, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. N. Ahmed, U. Ahmed, P. J. Thornalley, K. Hager, G. Fleischer, and G. Münch, “Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment,” Journal of Neurochemistry, vol. 92, no. 2, pp. 255–263, 2005. View at Publisher · View at Google Scholar · View at Scopus
  47. A. Castegna, M. Aksenov, M. Aksenova et al., “Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1,” Free Radical Biology and Medicine, vol. 33, no. 4, pp. 562–571, 2002. View at Publisher · View at Google Scholar · View at Scopus
  48. H. Tohgi, T. Abe, K. Yamazaki, T. Murata, E. Ishizaki, and C. Isobe, “Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease,” Neuroscience Letters, vol. 269, no. 1, pp. 52–54, 1999. View at Publisher · View at Google Scholar · View at Scopus
  49. K. Hensley, M. L. Maidt, Z. Yu, H. Sang, W. R. Markesbery, and R. A. Floyd, “Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation,” Journal of Neuroscience, vol. 18, no. 20, pp. 8126–8132, 1998. View at Google Scholar · View at Scopus
  50. H. Ryberg, A.-S. Söderling, P. Davidsson, K. Blennow, K. Caidahl, and L. I. Persson, “Cerebrospinal fluid levels of free 3-nitrotyrosine are not elevated in the majority of patients with amyotrophic lateral sclerosis or Alzheimer's disease,” Neurochemistry International, vol. 45, no. 1, pp. 57–62, 2004. View at Publisher · View at Google Scholar · View at Scopus
  51. M. C. Polidori, W. Stahl, O. Eichler, I. Niestroj, and H. Sies, “Profiles of antioxidants in human plasma,” Free Radical Biology and Medicine, vol. 30, no. 5, pp. 456–462, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. T.-S. Kim, C.-U. Pae, S.-J. Yoon et al., “Decreased plasma antioxidants in patients with Alzheimer's disease,” International Journal of Geriatric Psychiatry, vol. 21, no. 4, pp. 344–348, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. J. K. Maesaka, G. Wolf-Klein, J. M. Piccione, and C. M. Ma, “Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer's disease,” Journal of the American Geriatrics Society, vol. 41, no. 5, pp. 501–506, 1993. View at Google Scholar · View at Scopus
  54. P. Rinaldi, M. C. Polidori, A. Metastasio et al., “Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease,” Neurobiology of Aging, vol. 24, no. 7, pp. 915–919, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Ruggiero, A. Cherubini, F. Lauretani et al., “Uric acid and dementia in community-dwelling older persons,” Dementia and Geriatric Cognitive Disorders, vol. 27, no. 4, pp. 382–389, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. D. J. Schretlen, A. B. Inscore, H. A. Jinnah, V. Rao, B. Gordon, and G. D. Pearlson, “Serum uric acid and cognitive function in community-dwelling older adults,” Neuropsychology, vol. 21, no. 1, pp. 136–140, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. L. Iuliano, R. Monticolo, G. Straface et al., “Vitamin E and enzymatic/oxidative stress-driven oxysterols in amnestic mild cognitive impairment subtypes and Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1383–1392, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. F. J. Jiménez-Jiménez, F. de Bustos, J. A. Molina et al., “Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer's disease,” Journal of Neural Transmission, vol. 104, no. 6-7, pp. 703–710, 1997. View at Google Scholar
  59. Z. Zaman, S. Roche, P. Fielden, P. G. Frost, D. C. Niriella, and A. C. D. Cayley, “Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease,” Age and Ageing, vol. 21, no. 2, pp. 91–94, 1992. View at Google Scholar · View at Scopus
  60. M. Glasø, G. Nordbø, L. Diep, and T. Bøhmer, “Reduced concentrations of several vitamins in normal weight patients with late-onset dementia of the Alzheimer type without vascular disease,” Journal of Nutrition, Health and Aging, vol. 8, no. 5, pp. 407–413, 2004. View at Google Scholar · View at Scopus
  61. M. Sano, C. Ernesto, R. G. Thomas et al., “A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease,” The New England Journal of Medicine, vol. 336, no. 17, pp. 1216–1222, 1997. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Riviere, I. Birlouez-Aragon, F. Nourhashémi, and B. Vellas, “Low plasma vitamin C in Alzheimer patients despite an adequate diet,” International Journal of Geriatric Psychiatry, vol. 13, no. 11, pp. 749–754, 1998. View at Google Scholar
  63. C. A. von Arnim, F. Herbolsheimer, T. Nikolaus et al., “Dietary antioxidants and dementia in a population-based case-control study among older people in South Germany,” Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 717–724, 2012. View at Google Scholar
  64. S. Schippling, A. Kontush, S. Arlt et al., “Increased lipoprotein oxidation in Alzheimer's disease,” Free Radical Biology and Medicine, vol. 28, no. 3, pp. 351–360, 2000. View at Publisher · View at Google Scholar · View at Scopus
  65. A. Cherubini, C. Ruggiero, M. C. Polidori, and P. Mecocci, “Potential markers of oxidative stress in stroke,” Free Radical Biology and Medicine, vol. 39, no. 7, pp. 841–852, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. N. Tabet, D. Mantle, Z. Walker, and M. Orrell, “Vitamins, trace elements, and antioxidant status in dementia disorders,” International Psychogeriatrics, vol. 13, no. 3, pp. 265–275, 2001. View at Publisher · View at Google Scholar · View at Scopus
  67. J. Snaedal, J. Kristinsson, S. Gunnarsdóttir, Á. Ólafsdóttir, M. Baldvinsson, and T. Jóhannesson, “Copper, ceruloplasmin and superoxide dismutase in patients with Alzheimer's disease. A case-control study,” Dementia and Geriatric Cognitive Disorders, vol. 9, no. 5, pp. 239–242, 1998. View at Publisher · View at Google Scholar · View at Scopus
  68. H. Kharrazi, A. Vaisi-Raygani, Z. Rahimi, H. Tavilani, M. Aminian, and T. Pourmotabbed, “Association between enzymatic and non-enzymatic antioxidant defense mechanism with apolipoprotein E genotypes in Alzheimer disease,” Clinical Biochemistry, vol. 41, no. 12, pp. 932–936, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. R. Perrin, S. Briancon, C. Jeandel et al., “Blood activity of Cu/Zn superoxide dismutase, glutathione peroxidase and catalase in Alzheimer's disease: a case-control study,” Gerontology, vol. 36, no. 5-6, pp. 306–313, 1990. View at Google Scholar · View at Scopus
  70. L. Rossi, R. Squitti, P. Pasqualetti et al., “Red blood cell copper, zinc superoxide dismutase activity is higher in Alzheimer's disease and is decreased by D-penicillamine,” Neuroscience Letters, vol. 329, no. 2, pp. 137–140, 2002. View at Publisher · View at Google Scholar · View at Scopus
  71. M. E. De Leo, S. Borrello, M. Passantino et al., “Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer's disease,” Neuroscience Letters, vol. 250, no. 3, pp. 173–176, 1998. View at Publisher · View at Google Scholar · View at Scopus
  72. M. P. Bowes, J. A. Zivin, G. R. Thomas, H. Thibodeaux, and S. C. Fagan, “Acute hypertension, but not thrombolysis, increases the incidence and severity of hemorrhagic transformation following experimental stroke in rabbits,” Experimental Neurology, vol. 141, no. 1, pp. 40–46, 1996. View at Publisher · View at Google Scholar · View at Scopus
  73. I. Baldeiras, I. Santana, M. T. Proença et al., “Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 15, no. 1, pp. 117–128, 2008. View at Google Scholar · View at Scopus
  74. A. Nunomura, T. Tamaoki, N. Motohashi et al., “The earliest stage of cognitive impairment in transition from normal aging to alzheimer disease is marked by prominent RNA oxidation in vulnerable neurons,” Journal of Neuropathology and Experimental Neurology, vol. 71, no. 3, pp. 233–241, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. G. P. Paraskevas, E. Kapaki, G. Libitaki, C. Zournas, I. Segditsa, and C. Papageorgiou, “Ascorbate in healthy subjects, amyotrophic lateral sclerosis and Alzheimer's disease,” Acta Neurologica Scandinavica, vol. 96, no. 2, pp. 88–90, 1997. View at Google Scholar · View at Scopus
  76. H. Vural, H. Demirin, Y. Kara, I. Eren, and N. Delibas, “Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer’s disease,” Journal of Trace Elements in Medicine & Biology, vol. 24, no. 3, pp. 169–173, 2010. View at Google Scholar