Dementia and Neurocognitive Disorders (대한치매학회지)

Korean Dementia Association (대한치매학회)
권호 표지

Uric Acid as a Compensator for Oxidative Stress in Alzheimer's Disease

알츠하이머병 환자에서 산화적 스트레스에 대한 요산의 보상적 역할

  • Kim, Sang-Dae (Public Health Center, Hongseong) ;
  • Yang, Ji-Won (Department of Neurology, Gachon University, Gil Medical Center) ;
  • Youn, Bang Bu (The Gachon Brain Health Center, Gachon University, Gil Medical Center) ;
  • Park, Kee Hyung (Department of Neurology, Gachon University, Gil Medical Center)
  • 김상대 (홍성군보건소) ;
  • 양지원 (가천의대 길병원 신경과학교실) ;
  • 윤방부 (가천의대 뇌건강센터) ;
  • 박기형 (가천의대 길병원 신경과학교실)
  • Published : 2011.06.30
⟨ Previous Next ⟩

Abstract

Background: Uric acid (UA) is known to have neuroprotective effects by acting as a major plasma antioxidant. However, it is also known to be a pro-oxidant under certain circumstances. In this study, we analysed the association between UA and homocystein, which is a well-known pro-oxidant, as well as the association between UA and cognitive function in order to evaluate the neuroprotective function of UA in neurodegenerative disease progression. Methods: Plasma UA and homocystein, along with the two other major plasma antioxidants albumin and bilirubin, were measured in 133 Alzhiemer's disease (AD) patients, 98 Mild cognitive impairment (MCI) patients, and 77 normal elderly controls. The cognitive function of the subjects was evaluated by Mini Mental Status Examination (MMSE). By using linear regression analysis, we investigated the association between UA with homocystein in each of these groups. Furthermore, the association between UA levels and the MMSE score was also analyzed. All analyses were adjusted for age, sex, education, hypertension, and diabetes mellitus. Results: Homocystein increased in MCI, AD group compared with the control group. In the AD group, there was a statistically significant increase of UA compared with the MCI group, after adjusting for age, gender, hypertension, diabetes mellitus, and education (p=0.017). Linear regression analysis showed that increasing homocystein predicted increasing UA in MCI and AD patients (${\beta}$=1.12, SE=0.36, p=0.002; ${\beta}$=1.79, SE=0.43, p<0.001, respectively). Furthermore, increasing UA predicted increasing MMSE in AD patients (${\beta}$=0.48, SE=0.21, p=0.02), but not in MCI patients when adjusted for confounders. Conclusions: We suggest that UA might be related to neuroprotective compensation for oxidative stress which would reduce the rate of cognitive decline in AD patients.

Keywords

References

  1. Patterson RA, Horsely ET, Leake DS. Prooxidant and antioxidant properties of human serum ultrafiltrates toward LDL: important role of uric acid. J Lipid Res 2003; 44: 521-21.
  2. Maxwell SR, Thomason H, Sandler D, Leguen C, Baxter MA, Thorpe GH. Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin dependent diabetes mellitus. Eur J Clin Invest 1997; 27: 484-90. https://doi.org/10.1046/j.1365-2362.1997.1390687.x
  3. Becker BF. Towards the physiological function of uric acid. Free Radic Biol Med 1993; 14: 615-31. https://doi.org/10.1016/0891-5849(93)90143-I
  4. Kim TS, Pae CE, Yoon SJ, Jang WY, Lee NJ, Kim JJ, et al. Decreased plasma antioxidants in patients with Alzheimer's disease. Int J Geriatr Psychiatry 2006; 21: 344-8. https://doi.org/10.1002/gps.1469
  5. Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease. Neurobiol Aging 2003; 24: 915-9. https://doi.org/10.1016/S0197-4580(03)00031-9
  6. Li J, Dong BR, Lin P, Zhang J, Liu GJ. Association of cognitive function with serum uric acid level among Chinese nonagenarians and centenarians. Exp Gerontol 2010; 45: 331-5. https://doi.org/10.1016/j.exger.2010.01.005
  7. Irizarry MC, Raman R, Schwarzschild MA, Becerra LM, Thomas RG, Peterson RC, et al. Plasma urate and progression of mild cognitive impairment. Neurodegener Dis 2009; 6: 23-8. https://doi.org/10.1159/000170883
  8. Schretlen DJ, Inscore AB, Jinnah HA, Rao V, Gordon B, Pearlson GD. Serum uric acid and cognitive function in community-dwelling older adults. Neuropsychology 2007; 21: 136-40.
  9. Vannorsdall TD, Hinnah HA, Gordon B, Kraut M, Schretlen DJ. Cerebral ischemia mediates the effect of serum uric acid on cognitive function. Stroke 2008; 39: 3418-20. https://doi.org/10.1161/STROKEAHA.108.521591
  10. Cherubini A, Polidori MC, Bregnocchi M, Pezzuto S, Cecchetti R, Ingegni T. Antioxidant profile and early outcome in stroke patients. Stroke 2000; 31: 2295-300. https://doi.org/10.1161/01.STR.31.10.2295
  11. McKhan 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: 939-44. https://doi.org/10.1212/WNL.34.7.939
  12. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001; 58: 1985-92. https://doi.org/10.1001/archneur.58.12.1985
  13. Kang Y, Na DL. Seoul Neuropsychological Screening Battery (SNSB) Seoul: Human Brain Research & Consulting Co; 2003.
  14. Robbins TW, James M, Owen AM, Sahakian BJ, Lawrence AD, McInnes L, et al. A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. Cambridge neuropsychological test automated battery. J Int Neuropsychol Soc 1998; 4: 474-90.
  15. Hink HU, Santanam N, Dikalov S, McCann L, Nguyen AD, Parthasarathy S, et al. Peroxidase properties of extracellular superoxide dismutase: role of uric acid in modulating in vivo activity. Arterioscler Thromb Vasc Biol 2002; 22: 1402-8. https://doi.org/10.1161/01.ATV.0000027524.86752.02
  16. Hayden MR, Tyaqi SC. Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: the urate redox shuttle. Nutr Metlab 2004; 19: 1-10
  17. Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res 1998; 53: 613-25. https://doi.org/10.1002/(SICI)1097-4547(19980901)53:5<613::AID-JNR11>3.0.CO;2-1
  18. Kono H, Chen CJ, Ontiveros F, Rock KL. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J Clin Invest 2010; 120: 1939-49. https://doi.org/10.1172/JCI40124
  19. Euser SM, Hofman A, Westendorp RG, Breteler MM. Serum uric acid and cognitive function and dementia. Brain 2009; 132(Pt 2): 377-82.
  20. Schretlen DJ, Inscore AB, Vannorsdall TD, Kraut M, Pearlson GD, Gordon B, et al. Serum uric acid and brain ischemia in normal elderly adults. Neurology 2007 2; 69: 1418-23. https://doi.org/10.1212/01.wnl.0000277468.10236.f1
  21. Bos MJ, Koudstaal PJ, Hofman A, Witteman JCM, Breteler MMB. Uric acid is a risk factor for myocardial infarction and stroke; The Rotterdam Study. Stroke 2006; 37: 1503. https://doi.org/10.1161/01.STR.0000221716.55088.d4
  22. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002; 346: 476-83. https://doi.org/10.1056/NEJMoa011613
  23. Cho SY, Kim SB, Lee MS, Kim HJ, Yun J, Kim K, et al. Association between elevated homocysteine concentration and Alzheimer's disease, Vascular dementia, and Mild cognitive impairment. J Korean Neurol Assoc 2006; 24: 231-8.
  24. Herrmann W, Obeid R. Homocysteine: a biomarker in neurodegenerative disease. Clin Chem Lab Med 2011; 49: 435-41.
  25. Yoon B, Kim YD, Yang DW, Shim YS. Serum uric acid level according to the severity of white matter changes in Alzheimer's disease. Dementia and Neurocognitive Disorders 2009; 8: 79-83.
  26. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer's disease. J Neuropathol Exp Neurol 2001; 60: 759-67. https://doi.org/10.1093/jnen/60.8.759