Alzheimer's disease (AD) represents a highly common form of dementia, but can be diagnosed in the earlier stages before dementia onset. Early diagnosis is crucial for successful therapeutic intervention. The introduction of new diagnostic biomarkers for AD is aimed at detecting underlying brain pathology. These biomarkers reflect structural or biochemical changes related to AD. Examination of cerebrospinal fluid has many drawbacks; therefore, the search for sensitive and specific blood markers is ongoing. Investigation is mainly focused on upstream processes, among which oxidative stress in the brain is of particular interest. Products of oxidative stress may diffuse into the blood and evaluating them can contribute to diagnosis of AD. However, results of blood oxidative stress markers are not consistent among various studies, as documented in this review. To find a specific biochemical marker for AD, we should concentrate on specific metabolic products formed in the brain. Specific fluorescent intermediates of brain lipid peroxidation may represent such candidates as the composition of brain phospholipids is unique. They are small lipophilic molecules and can diffuse into the blood stream, where they can then be detected. We propose that these fluorescent products are potential candidates for blood biomarkers of AD.

Department of Medical Chemistry and Biochemistry Charles University Prague 2nd Faculty of Medicine Prague Czech Republic

Zobrazit více v PubMed

McKhann G, Drachman D, Folstein M, et al. 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;34:939–44. PubMed

Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22:2314–24. PubMed

Alberts MJ, Latchaw RE, Jagoda A, et al. Revised and updated recommendations for the establishment of primary stroke centers: a summary statement from the brain attack coalition. Stroke. 2011;42:2651–65. PubMed

McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263–9. PubMed PMC

Hort J, O'Brien JT, Gainotti G, et al. On Behalf of the EFNS Scientist Panel on Dementia. EFNS guidelines for the diagnosis and management of Alzheimer's disease. Eur J Neurol. 2010;17:1236–48. PubMed

Hort J, Glosová L, Vyhnálek M, et al. The liquor tau protein and beta amyloid in Alzheimer's disease. Ces Slov Neurol Neurochir. 2007;70:30–6.

Maruta C, Guerreiro M, de Mendonça A, et al. The use of neuropsychological tests across Europe: the need for a consensus in the use of assessment tools for dementia. Eur J Neurol. 2011;18:279–85. PubMed

Klunk WE. Amyloid imaging as a biomarker for cerebral β-amyloidosis and risk prediction for Alzheimer dementia. Neurobiol Aging. 2011;32:20–36. PubMed PMC

Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C. Biochemical markers related to Alzheimer's dementia in serum and cerebrospinal fluid. Neurobiol Aging. 2002;23:485–508. PubMed

Blennow K. Biomarkers in Alzheimer's disease drug development. Nat Med. 2010;16:1218–22. PubMed

Bonda DJ, Wang X, Perry G, et al. Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology. 2010;59:290–4. PubMed

Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease-systematic review and meta-analysis. Neurobiol Aging. 2009;30:337–52. PubMed

Popescu BO, Toescu EC, Popescu LM, et al. Blood-brain barrier alterations in ageing and dementia. J Neurol Sci. 2009;283:99–106. PubMed

Selkoe DJ. Resolving controversies on the path to Alzheimer's therapeutics. Nat Med. 2011;17:1060–5. PubMed

Shimohama S, Tanino H, Kawakami N, et al. Activation of NADPH oxidase in Alzheimer's disease brains. Biochem Biophys Res Commun. 2000;273:5–9. PubMed

Cagnin A, Brooks DJ, Kennedy AM, et al. In vivo measurement of activated microglia in dementia. Lancet. 2001;358:461–7. PubMed

Varadarajan S, Yatin S, Aksenova M, Butterfield DA. Review: Alzheimer's β-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol. 2000;130:184–208. PubMed

Lynch T, Herny RA, Bush AI. Oxidative processes in Alzheimer's disease: the role of Aβ-metal interactions. Exp Gerontol. 2000;35:445–51. PubMed

Cornet CR, Markesbery WR, Ehmann WD. Imbalances of trace elements related to oxidative damage in Alzheimer's disease brain. Neurotoxicity. 1998;19:339–45. PubMed

Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001;60:759–67. PubMed

Nunomura A, Perry G, Pappolla MA, et al. Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol. 2000;59:1011–7. PubMed

Odetti P, Angelini G, Dapino D, et al. Early glycoxidation damage in brains from Down's syndrome. Biochem Biophys Res Commun. 1998;243:849–51. PubMed

Pratico D, Uryu K, Leight S, et al. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci. 2001;21:4183–7. PubMed PMC

Söderberg M, Edlund C, Kristensson K, Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer disease. Lipids. 1991;26:421–5. PubMed

Lovell MA, Ehmann WD, Butler SM, Markesbery WR. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer's disease. Neurology. 1995;45:1594–601. PubMed

Markesbery WR, Lovell MA. Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease. Neurobiol Aging. 1998;19:33–6. PubMed

Keller JN, Schmitt FA, Scheff SW, et al. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology. 2005;7:1152–6. PubMed

Butterfield DA, Reed T, Perluigi M, et al. Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment. Neurosci Lett. 2006;3:170–3. PubMed

Montine TJ, Quinn J, Kaye J, Morrow JD. F(2)-isoprostanes as biomarkers of late-onset Alzheimer's disease. J Mol Neurosci. 2007;33:114–9. PubMed

Praticò D, Clark CM, Lee VM, et al. Increased 8,12-iso-iPF2alpha-VI in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol. 2000;48:809–12. PubMed

Montine TJ, Markesbery WR, Morrow JD, Roberts LJ., II Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer's disease. Ann Neurol. 1998;44:410–3. PubMed

Markesbery WR, Kryscio RJ, Lovell MA, Morrow JD. Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment. Ann Neurol. 2005;5:730–5. PubMed

Roberts LJ, II, Montine TJ, Markesbery WR, et al. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem. 1998;273:13605–12. PubMed

Ozcankaya R, Delibas N. Malondialdehyde, superoxide dismutase, melatonin, iron, copper, and zinc blood concentrations in patients with Alzheimer disease: cross-sectional study. Croat Med J. 2002;43:28–32. PubMed

Polidori MC, Mecocci P. Plasma susceptibility to free radical-induced antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease. J Alzheimers Dis. 2002;4:517–22. PubMed

Aybek H, Ercan F, Aslan D, Sahiner T. Determination of malondialdehyde, reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer's disease in Denizli, Turkey. Clin Biochem. 2007;40:172–6. PubMed

Bourdel-Marchasson I, Delmas-Beauvieux MC, Peuchant E, et al. Antioxidant defences and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients. Age Ageing. 2001;30:235–41. PubMed

Greilberger J, Koidl C, Greilberger M, et al. Malondialdehyde, carbonyl proteins and albumin-disulphide as useful oxidative markers in mild cognitive impairment and Alzheimer's disease. Free Radic Res. 2008;42:633–8. PubMed

Casado A, Encarnación López-Fernández M, Concepción Casado M, de La Torre R. Lipid peroxidation and antioxidant enzyme activities in vascular and Alzheimer dementias. Neurochem Res. 2008;33:450–8. PubMed

Martín-Aragón S, Bermejo-Bescós P, Benedí J, et al. Metalloproteinase's activity and oxidative stress in mild cognitive impairment and Alzheimer's disease. Neurochem Res. 2009;34:373–8. PubMed

Cecchi C, Fiorillo C, Sorbi S, et al. Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients. Free Radic Biol Med. 2002;15:1372–9. PubMed

Sinem F, Dildar K, Gökhan E, et al. The serum protein and lipid oxidation marker levels in Alzheimer's disease and effects of cholinesterase inhibitors and antipsychotic drugs therapy. Curr Alzheimer Res. 2010;7:463–9. PubMed

Serra JA, Domínguez RO, Marschoff ER, et al. Systemic oxidative stress associated with the neurological diseases of aging. Neurochem Res. 2009;34:2122–32. PubMed

Serra JA, Domínguez RO, de Lustig ES, 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. J Neural Transm. 2001;108:1135–48. PubMed

Kawamoto EM, Munhoz CD, Glezer I, et al. Oxidative state in platelets and erythrocytes in aging and Alzheimer's disease. Neurobiol Aging. 2005;26:857–64. PubMed

Ahlskog JE, Uitti RJ, Low PA, et al. No evidence for systemic oxidant stress in Parkinson's or Alzheimer's disease. Mov Disord. 1995;10:566–73. PubMed

Ceballos-Picot I, Merad-Boudia M, Nicole A, 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 Radic Biol Med. 1996;20:579–87. PubMed

Fernandes MA, Proenca MT, Nogueira AJ, et al. Influence of apolipoprotein E genotype on blood redox status of Alzheimer's disease patients. Int J Mol Med. 1999;4:179–86. PubMed

Sinclair AJ, Bayer AJ, Johnston J, et al. Altered plasma antioxidant status in subjects with Alzheimer's disease and vascular dementia. Int J Geriatr Psychiatry. 1998;13:840–5. PubMed

McGrath LT, McGleenon BM, Brennan S, et al. Increased oxidative stress in Alzheimer's disease as assessed with 4-hydroxynonenal but not malondialdehyde. QJM. 2001;94:485–90. PubMed

Polidori MC, Mattioli P, Aldred S, et al. Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia. Dement Geriatr Cogn Disord. 2004;18:265–70. PubMed

Selley ML, Close DR, Stern SE. The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease. Neurobiol Aging. 2002;23:383–8. PubMed

Calabrese V, Sultana R, Scapagnini G, et al. Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer's disease. Antioxid Redox Signal. 2006;8:1975–86. PubMed

Praticò D, Clark CM, Liun F, et al. Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol. 2002;59:972–6. PubMed

Irizarry MC, Yao Y, Hyman BT, et al. Plasma F2A isoprostane levels in Alzheimer's and Parkinson's disease. Neurodegener Dis. 2007;4:403–5. PubMed

Feillet-Coudray C, Tourtauchaux R, Niculescu M, et al. Plasma levels of 8-epiPGF2alpha, an in vivo marker of oxidative stress, are not affected by aging or Alzheimer's disease. Free Radic Biol Med. 1999;27:463–9. PubMed

Montine TJ, Quinn JF, Milatovic D, et al. Peripheral F2-isoprostanes and F4-neuroprostanes are not increased in Alzheimer's disease. Ann Neurol. 2002;52:175–9. PubMed

Sundelöf J, Kilander L, Helmersson J, et al. Systemic tocopherols and F2-isoprostanes and the risk of Alzheimer's disease and dementia: a prospective population-based study. J Alzheimers Dis. 2009;18:71–8. PubMed

Hensley K, Hall N, Subramaniam R, et al. Brain regional correspondence between Alzheimer's disease histopathology and biomarkers of protein oxidation. J Neurochem. 1995;65:2146–56. PubMed

Ahmed N, Ahmed U, Thornalley PJ, et al. Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment. J Neurochem. 2005;92:255–63. PubMed

Butterfield DA, Reed TT, Perluigi M, et al. Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease. Brain Res. 2007;1148:243–8. PubMed PMC

Greilberger J, Fuchs D, Leblhuber F, et al. Carbonyl proteins as a clinical marker in Alzheimer's disease and its relation to tryptophan degradation and immune activation. Clin Lab. 2010;56:441–8. PubMed

Bermejo P, Martín-Aragón S, Benedí J, et al. Peripheral levels of glutathione and protein oxidation as markers in the development of Alzheimer's disease from Mild Cognitive Impairment. Free Radic Res. 2008;42:162–70. PubMed

Conrad CC, Marshall PL, Talent JM, et al. Oxidized proteins in Alzheimer's plasma. Biochem Biophys Res Commun. 2000;275:678–81. PubMed

Aldred S, Bennett S, Mecocci P. Increased low-density lipoprotein oxidation, but not total plasma protein oxidation, in Alzheimer's disease. Clin Biochem. 2010;43:267–71. PubMed

Yu HL, Chertkow HM, Bergman H, Schipper HM. Aberrant profiles of native and oxidized glycoproteins in Alzheimer plasma. Proteomics. 2003;3:2240–8. PubMed

Choi J, Malakowsky CA, Talent JM, et al. Identification of oxidized plasma proteins in Alzheimer's disease. Biochem Biophys Res Commun. 2002;293:1566–70. PubMed

Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol. 1994;36:747–51. PubMed

Nunomura A, Perry G, Pappolla MA, et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci. 1999;19:1959–64. PubMed PMC

Mullaart E, Boerrigter ME, Ravid R, et al. Increased levels of DNA breaks in cerebral cortex of Alzheimer's disease patients. Neurobiol Aging. 1990;11:169–73. PubMed

Mecocci P, Polidori MC, Ingegni T, et al. Oxidative damage to DNA in lymphocytes from AD patients. Neurology. 1998;51:1014–7. PubMed

Mecocci P, Polidori MC, Cherubini A, et al. Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease. Arch Neurol. 2002;59:794–8. PubMed

Mórocz M, Kálmán J, Juhász A, et al. Elevated levels of oxidative DNA damage in lymphocytes from patients with Alzheimer's disease. Neurobiol Aging. 2002;23:47–53. PubMed

Kadioglu E, Sardas S, Aslan S, et al. Detection of oxidative DNA damage in lymphocytes of patients with Alzheimer's disease. Biomarkers. 2004;9:203–9. PubMed

Migliore L, Fontana I, Trippi F, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging. 2005;26:567–73. PubMed

Abe T, Tohgi H, Isobe C, et al. Remarkable increase in the concentration of 8-hydroxyguanosine in cerebrospinal fluid from patients with Alzheimer's disease. J Neurosci Res. 2002;70:447–50. PubMed

Foy CJ, Passmore AP, Vahidassr MD, et al. Plasma chain-breaking antioxidants in Alzheimer's disease, vascular dementia and Parkinson's disease. QJM. 1999;92:39–45. PubMed

Jeandel C, Nicolas MB, Dubois F, et al. Lipid peroxidation and free radical scavengers in Alzheimer's disease. Gerontology. 1989;35:275–82. PubMed

Rivière S, Birlouez-Aragon I, Nourhashémi F, Vellas B. Low plasma vitamin C in Alzheimer patients despite an adequate diet. Int J Geriatr Psychiatry. 1998;13:749–54. PubMed

Zaman Z, Roche S, Fielde P, et al. Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease. Age Ageing. 1992;21:91–4. PubMed

Jiménez-Jiménez FJ, de Bustos F, Molina JA, et al. Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer's disease. J Neural Transm. 1997;104:703–10. PubMed

Paraskevas GP, Kapaki E, Libitaki G, et al. Ascorbate in healthy subjects, amyotrophic lateral sclerosis and Alzheimer's disease. Acta Neurol Scand. 1997;96:88–90. PubMed

Repetto MG, Reides CG, Evelson P, et al. Peripheral markers of oxidative stress in probable Alzheimer patients. Eur J Clin Invest. 1999;29:643–9. PubMed

Guidi I, Galimberti D, Lonati S, et al. Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease. Neurobiol Aging. 2006;27:262–9. PubMed

Grünblatt E, Schlösser R, Fischer P, et al. Oxidative stress related markers in the “VITA” and the centenarian projects. Neurobiol Aging. 2005;26:429–38. PubMed

Long EK, Picklo MJ., Sr Trans-4-hydroxy-2-hexenal, a product of n-3 fatty acid peroxidation: make some room HNE. Free Radic Biol Med. 2010;49:1–8. PubMed

Wilhelm J, Brzak P, Rejholcova M. Changes of lipofuscin-like pigments in erythrocytes and spleen after whole-body gamma irradiation of rats. Radiat Res. 1989;120:227–33. PubMed

Skoumalová A, Rofina J, Schwippelová Z, et al. The role of free radicals in canine counterpart of senile dementia of the Alzheimer type. Exp Gerontol. 2003;38:711–9. PubMed

Skoumalová A, Ivica J, Šantorová P, et al. The lipid peroxidation products as possible markers of Alzheimer's disease in blood. Exp Gerontol. 2011;46:38–42. PubMed

Vascular Cognitive Impairment: Information from Animal Models on the Pathogenic Mechanisms of Cognitive Deficits

Analysis of lipophilic fluorescent products in blood of Alzheimer's disease patients