Background: The biological action of uric acid (UA) in humans is controversial. UA is considered an antioxidant compound, but preclinical evidence suggests a proinflammatory action. Epidemiological studies found that hyperuricemia is associated with conditions leading to dementia. Our aim is to investigate the relationship between UA levels and dementia in older persons. Methods: Cross-sectional study performed in 1,016 community-dwelling older persons participating in the InCHIANTI study. Participants underwent determination of circulating UA levels and neuropsychological evaluation. A multivariate logistic regression model was used to estimate the probability of participants belonging to the highest and middle UA tertile to be affected by dementia compared to those in the lowest tertile. Results: Demented persons had higher UA levels (p = 0.001) and the prevalence of persons affected by dementia increased across UA tertiles (p < 0.0001). Independent of several confounders, persons belonging to the highest UA tertile had a threefold (OR = 3.32; 95% CI: 1.06–10.42) higher probability to suffer from a dementia syndrome while those in the middle UA tertile tended to have a higher probability of being demented compared to those in the lowest tertile. Conclusion: In a population-based sample, high circulating UA levels are associated with an increased likelihood to be affected by a dementia syndrome.
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- Uric acid
- Flirski M, Sobow T: Biochemical markers and risk factors of Alzheimer’s disease. Curr Alzheimer Res 2005;2:47–64.
- Lahiri DK, Maloney B, Basha MR, Ge YW, Zawia NH: How and when environmental agents and dietary factors affect the course of Alzheimer’s disease: the ‘LEARn’ model (latent early-life associated regulation) may explain the triggering of AD. Curr Alzheimer Res 2007;4:219–228.
- Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N: Oxidative damage in Alzheimer’s. Nature 1996;382:120–121.
- Neuroinflammation Working Group: Inflammation and Alzheimer’s disease. Neurobiol. Aging 2000;21:383–421.
- Wu XW, Muzny DM, Lee CC, Caskey CT: Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992;34:78–84.
- Ames BN, Cathcart R, Schwiers E, Hochstein P: Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 1981;78:6858–6862.
- Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA: Uric acid and oxidative stress. Curr Pharm Des 2005;11:4145–4151.
- Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, Davos CH, Cicoira M, Shamim W, Kemp M, Segal R, Osterziel KJ, Leyva F, Hetzer R, Ponikowski P, Coats AJ: Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003;107:1991–1997.
- Ruggiero C, Cherubini A, Ble A, Bos AJ, Maggio M, Dixit VD, Lauretani F, Bandinelli S, Senin U, Ferrucci L: Uric acid and inflammatory markers. Eur Heart J 2006;27:1174–1181.
- Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJ, Anker SD, Hambrecht R: Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure. Circulation 2002;105:2619–2624.
- Johnson RJ, Rodriguez-Iturbe B, Kang DH, Feig DI, Herrera-Acosta J: A unifying pathway for essential hypertension. Am J Hypertens 2005;18:431–440.
- Ford ES, Li C, Cook S, Choi HK: Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents. Circulation 2007;115:2526–2532.
- Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M: Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183 –1190.
- Karagiannis A, Mikhailidis DP, Tziomalos K, Sileli M, Savvatianos S, Kakafika A, Gossios T, Krikis N, Moschou I, Xochellis M, Athyros VG: Serum uric acid as an independent predictor of early death after acute stroke. Circ J 2007;71:1120–1127.
- Fang J, Alderman MH: Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA 2000;283:2404–2410.
- Niskanen LK, Laaksonen DE, Nyyssönen K, Alfthan G, Lakka HM, Lakka TA, Salonen JT: Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med 2004;164:1546–1551.
- Meisinger C, Koenig W, Baumert J, Döring A: Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: the MONICA/KORA cohort study. Arterioscler Thromb Vasc Biol 2008;28:1186–1192.
- 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.
- Ferrucci L, Bandinelli S, Benvenuti E, Di Iorio A, Macchi C, Harris TB, Guralnik JM: Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study. J Am Geriatr Soc 2000;48:1618–1625.
- Pisani P, Faggiano F, Krogh V, Palli D, Vineis P, Berrino F: Relative validity and reproducibility of a food frequency dietary questionnaire for use in the Italian EPIC centers. Int J Epidemiol 1997;26:152–160.
- Salvini S: A food composition database for epidemiological studies in Italy. Cancer 1997;114:299–300
- Guralnik JM, Fried LP, Simonsick EM, Kasper JD, Lafferty ME: The Women’s Health and Aging Study: health and social characteristics of older women with disability. Bethesda, National Institute of Aging, 1995.
- Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.
- National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease. Evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1–S266.
- McDermott MM, Guralnik JM, Albay M, Bandinelli S, Miniati B, Ferrucci L: Impairments of muscles and nerves associated with peripheral arterial disease and their relationship with lower extremity functioning: the InCHIANTI Study. J Am Geriatr Soc 2004;52:405–410.
- Cherubini A, Martin A, Andres-Lacueva C, Di Iorio A, Lamponi M, Mecocci P, Bartali B, Corsi A, Senin U, Ferrucci L: Vitamin E levels, cognitive impairment and dementia in older persons: the InCHIANTI study. Neurobiol Aging 2005;26:987–994.
- Richmond W: Preparation and properties of a cholesterol oxidase from Nocardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin Chem 1973;19:1350–1356.
- Cherubini A, Andres-Lacueva C, Martin A, Lauretani F, Di Iorio A, Bartali B, Corsi A, Bandinelli S, Mattson MP, Ferrucci L: Low plasma n–3 fatty acids and dementia in older subjects: the InCHIANTI study. J Gerontol Med Sci 2007;62:1120–1126.
- Wechsler D: Wechsler Memory Scale-Revised Manual. San Antonio, Psychological Corporation, 1987.
- Carlesimo GA, Caltagirone C, Gainotti G: The Mental Deterioration Battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the Mental Deterioration Battery. Eur Neurol 1996;36:378–384.
- Novelli G, Papagno C, Capitani E, Laiacona M, Cappa SF, Vallar G: Three clinical tests of long-term verbal memory. Calibration on normal subjects. Arch Psicol Neurol Psichiatria 1986;47:278–296.
- Stetten D Jr, Hearon JZ: Intellectual level measured by army classification battery and serum uric acid concentration. Science 1959;129:1737.
- Dunn JP, Brooks GW, Mausner J, Rodnan GP, Cobb S: Social class gradient of serum uric acid levels in males. JAMA 1963;185:431–436.
- 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.
- Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG: Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 2000;148:131–139.
- 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.
- 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.
- Shi Y, Evans JE, Rock KL: Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003;425:516–521.
- Ruggiero C, Cherubini A, Miller E 3rd, Maggio M, Najjar SS, Lauretani F, Bandinelli S, Senin U, Ferrucci L: Usefulness of uric acid to predict changes in C-reactive protein and interleukin-6 in 3-year period in Italians aged 21 to 98 years. Am J Cardiol 2007;100:115–121.
- Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado M: Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals. Arterioscler Thromb Vasc Biol 2005;25:1038–1044.
- Viazzi F, Parodi D, Leoncini G, Parodi A, Falqui V, Ratto E, Vettoretti S, Bezante GP, Del Sette M, Deferrari G, Pontremoli R: Serum uric acid and target organ damage in primary hypertension. Hypertension 2005;45:991–996.
- Yu KH, Luo SF, Tsai WP, Huang YY: Intermittent elevation of serum urate and 24-hour urinary uric acid excretion. Rheumatology (Oxford) 2004;43:1541–1545.
- Nakanishi N, Yoshida H, Nakamura K, Suzuki K, Tatara K: Predictors for development of hyperuricemia: an 8-year longitudinal study in middle-aged Japanese men. Metabolism 2001;50:621–626.
Carmelinda Ruggiero, MD, Institute of Geriatrics and Gerontology,
Department of Clinical and Experimental Medicine, University of Perugia
Ospedale S. Maria della Misericordia, Blocco A Piano 4, Piazzale Menghini 1
IT–06156 Perugia (Italy)
Tel. +39 075 5783 722, Fax +39 075 5730 259, E-Mail firstname.lastname@example.org
C. Ruggiero and A. Cherubini contributed equally to the study.
Accepted: November 25, 2008
Published online: April 1, 2009
Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 3, Number of References : 43
Dementia and Geriatric Cognitive Disorders
Vol. 27, No. 4, Year 2009 (Cover Date: April 2009)
Journal Editor: Chan-Palay V. (New York, N.Y.)
ISSN: 1420-8008 (Print), eISSN: 1421-9824 (Online)
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