Free Access
Neurodegenerative Dis 2009;6:23–28
(DOI:10.1159/000170883)

Plasma Urate and Progression of Mild Cognitive Impairment

Irizarry M.C.a · Raman R.c, d · Schwarzschild M.A.a · Becerra L.M.c · Thomas R.G.c, d · Peterson R.C.e · Ascherio A.b · Aisen P.S.d
aDepartment of Neurology, Massachusetts General Hospital,and bDepartment of Epidemiology, Harvard School of Public Health, Boston, Mass., cDivision of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, and dDepartment of Neurosciences, University of California San Diego, San Diego, Calif., and eDepartment of Neurology, Mayo Clinic College of Medicine, Rochester, Minn., USA
email Corresponding Author


 goto top of outline Key Words

  • Alzheimer’s disease
  • Mild cognitive impairment
  • Urate
  • Oxidative stress
  • Biomarkers

 goto top of outline Abstract

Background: Impaired antioxidant defenses are implicated in neurodegenerative disease. The plasma levels of urate, a water-soluble antioxidant, are reduced in Alzheimer’s disease (AD). Objective: We aimed to test the hypotheses that high plasma urate at baseline is associated with: (1) a reduced rate of conversion from mild cognitive impairment (MCI) to AD and (2) a lower rate of cognitive decline in MCI. Methods: Plasma urate was obtained at baseline from 747 participants in a 3-year, randomized, double-blind, placebo-controlled study of donepezil, vitamin E or placebo for delaying the progression of MCI to AD.The association between baseline urate and conversion from MCI to AD was examined by Cox proportional hazards regression. The relationship between baseline urate and cognitive change on the cognitive subscale of the Alzheimer’s Disease Assessment Scale was evaluated by longitudinal analysis. Results: Baseline plasma urate was not associated with the rate of conversion of MCI to AD. In the placebo arm, high plasma urate was related to a slower rate of cognitive decline over 3 years, although this was not reproduced in the other treatment arms. Conclusion: While plasma urate levels did not predict the progression of MCI to AD, high urate may be associated with a reduced rate of cognitive decline in MCI patients not treated with donepezil or vitamin E. The results support the investigation of biomarkers of antioxidant status as risk factors for cognitive decline in MCI.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ, Hebert LE, Hennekens CH, Taylor JO: Prevalence of Alzheimer’s disease in a community population of older persons: higher than previously reported. JAMA 1989;262:2551–2556.
  2. Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST: Practice parameter: early detection of dementia – mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1133–1142.
  3. Irizarry MC, Hyman BT: Alzheimer disease therapeutics. J Neuropathol Exp Neurol 2001;60:923–928.
  4. Butterfield DA: Oxidative stress in neurodegenerative disorders. Antioxid Redox Signal 2006;8:1971–1973.
  5. Pratico D, Clark CM, Liun F, Rokach J, Lee VY, Trojanowski JQ: Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol 2002;59:972–976.
  6. Kim TS, Pae CU, Yoon SJ, Jang WY, Lee NJ, Kim JJ, Lee SJ, Lee C, Paik IH, Lee CU: Decreased plasma antioxidants in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 2006;21:344–348.
  7. Polidori MC, Mattioli P, Aldred S, Cecchetti R, Stahl W, Griffiths H, Senin U, Sies H, Mecocci P: Plasma antioxidant status, immunoglobulin G oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia. Dement Geriatr Cogn Disord 2004;18:265–270.
  8. Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, Catani M, Cecchetti R, Senin U, Mecocci P: Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol Aging 2003;24:915–919.
  9. Weisskopf MG, O’Reilly E, Chen H, Schwarzschild MA, Ascherio A: Plasma urate and risk of Parkinson’s disease. Am J Epidemiol 2007;166:561–567.
  10. Davis JW, Grandinetti A, Waslien CJ, Ross GW, White LR, Morens DM: Observations on Serum uric acid levels and the risk of idiopathic Parkinson’s disease. Am J Epidemiol 1996;144:480–484.
  11. De Lau LM, Koudstaal PJ, Hofman A, Breteler MM: Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 2005;58:797–800.
  12. Schwarzschild MA, Schwid SR, Marek K, Watts A, Lang AE, Oakes D, Shoulson I, Ascherio A, Parkinson’s Study Group PRECEPT Investigators: Serum urate as a predictor of clinical and radiographic progression in Parkinson’s disease. Arch Neurol 2008; 65:716–723.
  13. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ: Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379–2388.
  14. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ: Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379–2388.
  15. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
  16. Schretlen DJ, Inscore AB, Vannorsdall TD, Kraut M, Pearlson GD, Gordon B, Jinnah HA: Serum uric acid and brain ischemia in normal elderly adults. Neurology 2007;69:1418–1423.
  17. Kim TS, Pae CU, Yoon SJ, Jang WY, Lee NJ, Kim JJ, Lee SJ, Lee C, Paik IH, Lee CU: Decreased plasma antioxidants in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 2006;21:344–348.
  18. Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, Catani M, Cecchetti R, Senin U, Mecocci P: Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol Aging 2003;24:915–919.
  19. Ahlskog JE, Uitti RJ, Low PA, Tyce GM, Nickander KK, Petersen RC, Kokmen E: No evidence for systemic oxidant stress in Parkinson’s or Alzheimer’s disease. Mov Disord 1995;10:566–573.
  20. 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;21:136–140.

 goto top of outline Author Contacts

Michael C. Irizarry, MD
WW Epidemiology, GlaxoSmithKline
5 Moore Drive, 17.2123
Research Triangle Park, NC 27709 (USA)
Tel. +1 919 483 7701, Fax +1 919 315 4947, E-Mail michael.c.irizarry@gsk.com


 goto top of outline Article Information

M.C.I. is a stock- and options-holding employee of GlaxoSmithKline.

Received: February 19, 2008
Accepted after revision: May 26, 2008
Published online: November 5, 2008
Number of Print Pages : 6
Number of Figures : 2, Number of Tables : 1, Number of References : 20


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 6, No. 1-2, Year 2009 (Cover Date: December 2008)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660–2854 (Print), eISSN: 1660–2862 (Online)

For additional information: http://www.karger.com/NDD


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