Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter

IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

See all formats and pricing
More options …
Volume 43, Issue 10


Homocysteine in relation to cognitive performance in pathological and non-pathological conditions

Charlotte E. Teunissen
  • Department of Molecular Cell Biology and Immunology, Amsterdam, and VUmc Medical Center Amsterdam, Amsterdam, The Netherlands
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Martin P. J. van Boxtel
  • Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jellemer Jolles
  • Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jan de Vente
  • Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Fred Vreeling / Frans Verhey / Chris H. Polman / Christine D. Dijkstra
  • Department of Molecular Cell Biology and Immunology, Amsterdam, and VUmc Medical Center Amsterdam, Amsterdam, The Netherlands
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Henk J. Blom
  • Laboratory of Pediatrics and Neurology, University Medical Center Nijmegen, Nijmegen, The Netherlands
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2011-09-21 | DOI: https://doi.org/10.1515/CCLM.2005.190


Elevated serum homocysteine has been associated with increased risk of Alzheimer's disease. Furthermore, elevated homocysteine levels are related to cognitive dysfunction in the elderly. The aim of the present study was to explore the disease specificity of the relation between serum total homocysteine levels and cognitive function. For this, we summarize data from several studies on homocysteine levels in both normal and pathological conditions performed in our laboratories and evaluate possible mechanisms of effects of elevated homocysteine levels in the central nervous system. Total homocysteine levels were measured in serum of: 1) healthy aging individuals; 2) patients with Alzheimer's and Parkinson's disease and patients with other cognitive disorders; and 3) patients with multiple sclerosis. Increased serum homocysteine concentration was related to worse cognitive performance over a 6-year period in the normal aging population (r=−0.36 to −0.14, p<0.01 for the Word learning tests; r=0.76, p<0.05 for the Stroop Colored Word test). Homocysteine was only increased in patients with Parkinson's disease on L-Dopa therapy (18.9 vs. 16.5μmol/L in healthy controls), and not in dementia patients. Homocysteine was elevated in patients with progressive multiple sclerosis (15.0μmol/L, n=39, compared to 12.0 μmol/L in 45 controls) and correlated to both cognitive and motor function (r=−0.33 and −0.33, p<0.05, respectively). The relationship between homocysteine and cognitive function in non-pathological and pathological situations indicates that changes in its levels may play a role in cognitive functioning in a broad spectrum of conditions.

Keywords: aging; cognition; dementia; homocysteine; multiple sclerosis


  • 1.

    Regland B, Abrahamsson L, Gottfries CG, Magnus E. Vitamin B12 analogues, homocysteine, methylmalonic acid, and transcobalamins in the study of vitamin B12 deficiency in primary degenerative dementia. Dementia 1990; 1:272–7.Google Scholar

  • 2.

    Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998; 55:1449–55.CrossrefGoogle Scholar

  • 3.

    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.Google Scholar

  • 4.

    Budge M, Johnston C, Hogervorst E, de Jager C, Milwain E, Iversen SD, et al. Plasma total homocysteine and cognitive performance in a volunteer elderly population. Ann NY Acad Sci 2000; 903:407–10.Google Scholar

  • 5.

    Kalmijn S, Launer LJ, Lindemans J, Bots ML, Hofman A, Breteler MM. Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study. Am J Epidemiol 1999; 150:283–9.Google Scholar

  • 6.

    Morris MS, Jacques PF, Rosenberg IH, Selhub J. Hyper-homocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2001; 73:927–33.Google Scholar

  • 7.

    Duthie SJ, Whalley LJ, Collins AR, Leaper S, Berger K, Deary IJ. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 2002; 75:908–13.Google Scholar

  • 8.

    Riggs KM, Spiro A III, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 1996; 63:306–14.Google Scholar

  • 9.

    McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 2001; 12:309–13.CrossrefGoogle Scholar

  • 10.

    Teunissen CE, Blom AH, Van Boxtel MP, Bosma H, de Bruijn C, Jolles J, et al. Homocysteine: a marker for cognitive performance? A longitudinal follow-up study. J Nutr Health Aging 2003; 7:153–9.Google Scholar

  • 11.

    Jolles J, Houx PJ, van Boxtel MP, Ponds RW. The Maastricht Aging Study. Determinants of cognitive aging. Maastricht: Neuropsych Publishers, 1995.Google Scholar

  • 12.

    van Boxtel MP, Gaillard C, Houx PJ, Buntinx F, de Leeuw PW, Jolles J. Is nondipping in 24 h ambulatory blood pressure related to cognitive dysfunction? J Hypertens 1998; 16:1425–32.CrossrefGoogle Scholar

  • 13.

    Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med 2005; 118:161–7.Google Scholar

  • 14.

    Chertkow H. Mild cognitive impairment. Curr Opin Neurol 2002; 15:401–7.CrossrefGoogle Scholar

  • 15.

    Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R. Plasma homocysteine levels and risk of Alzheimer disease. Neurology 2004; 62:1972–6.CrossrefGoogle Scholar

  • 16.

    Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004; 80:114–22.Google Scholar

  • 17.

    Ariogul S, Cankurtaran M, Dagli N, Khalil M, Yavuz B. Vitamin B(12), folate, homocysteine and dementia: are they really related? Arch Gerontol Geriatr 2005; 40:139–46.CrossrefGoogle Scholar

  • 18.

    O'Suilleabhain P, Diaz-Arrastia R. Levodopa elevates homocysteine: is this a problem? Arch Neurol 2004; 61:633–4.CrossrefGoogle Scholar

  • 19.

    Postuma RB, Lang AE. Homocysteine and levodopa: should Parkinson disease patients receive preventative therapy? Neurology 2004; 63:886–91.CrossrefGoogle Scholar

  • 20.

    Bleich S, Otto M, Zerr I, Kropp S, Kretzschmar HA, Wiltfang J. Creutzfeldt-Jakob disease and homocysteine levels in plasma and cerebrospinal fluid. Gerontology 2005; 51:142–4.CrossrefGoogle Scholar

  • 21.

    Teunissen CE, Lutjohann D, von Bergmann K, Verhey F, Vreeling F, Wauters A, et al. Combination of serum markers related to several mechanisms in Alzheimer's disease. Neurobiol Aging 2003; 24:893–902.CrossrefGoogle Scholar

  • 22.

    Benedict RH, Weinstock-Guttman B, Fishman I, Sharma J, Tjoa CW, Bakshi R. Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden. Arch Neurol 2004; 61:226–30.CrossrefGoogle Scholar

  • 23.

    Amato MP, Bartolozzi ML, Zipoli V, Portaccio E, Mortilla M, Guidi L, et al. Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment. Neurology 2004; 63:89–93.CrossrefGoogle Scholar

  • 24.

    Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991; 41:685–91.CrossrefGoogle Scholar

  • 25.

    Bobholz JA, Rao SM. Cognitive dysfunction in multiple sclerosis: a review of recent developments. Curr Opin Neurol 2003; 16:283–8.CrossrefGoogle Scholar

  • 26.

    Savettieri G, Messina D, Andreoli V, Bonavita S, Caltagirone C, Cittadella R, et al. Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis. J Neurol 2004; 251:1208–14.Google Scholar

  • 27.

    Teunissen CE, Dijkstra CD, Polman CH. Biological markers in CSF and blood for axonal degeneration in multiple sclerosis. Lancet Neurol 2005; 4:32–41.CrossrefGoogle Scholar

  • 28.

    Goodkin DE, Jacobsen DW, Galvez N, Daughtry M, Secic M, Green R. Serum cobalamin deficiency is uncommon in multiple sclerosis. Arch Neurol 1994; 51:1110–4.CrossrefGoogle Scholar

  • 29.

    Reynolds EH. Multiple sclerosis and vitamin B12 metabolism. J Neuroimmunol 1992; 40:225–30.Google Scholar

  • 30.

    Besler HT, Comoglu S. Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis. Nutr Neurosci 2003; 6:189–96.CrossrefGoogle Scholar

  • 31.

    Vrethem M, Mattsson E, Hebelka H, Leerbeck K, Osterberg A, Landtblom AM, et al. Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler 2003; 9:239–45.CrossrefGoogle Scholar

  • 32.

    Kado DM, Bucur A, Selhub J, Rowe JW, Seeman T. Homocysteine levels and decline in physical function: MacArthur Studies of Successful Aging. Am J Med 2002; 113:537–42.Google Scholar

  • 33.

    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.Google Scholar

  • 34.

    Robert K, Vialard F, Thiery E, Toyama K, Sinet PM, Janel N, et al. Expression of the cystathionine beta synthase (CBS) gene during mouse development and immunolocalization in adult brain. J Histochem Cytochem 2003; 51:363–71.CrossrefGoogle Scholar

  • 35.

    Kennedy BP, Bottiglieri T, Arning E, Ziegler MG, Hansen LA, Masliah E. Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases andcognitive function. J Neural Transm 2004; 111:547–67.Google Scholar

  • 36.

    Refsum H, Ueland PM, Nygard O, Vollset SE. Homo-cysteine and cardiovascular disease. Annu Rev Med 1998; 49:31–62.CrossrefGoogle Scholar

  • 37.

    Vermeer SE, van Dijk EJ, Koudstaal PJ, Oudkerk M, Hofman A, Clarke R, et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Ann Neurol 2002; 51:285–9.CrossrefGoogle Scholar

  • 38.

    Sengupta S, Wehbe C, Majors AK, Ketterer ME, DiBello PM, Jacobsen DW. Relative roles of albumin and ceruloplasmin in the formation of homocystine, homocysteine-cysteine-mixed disulfide, and cystine in circulation. J Biol Chem 2001; 276:46896–904.Google Scholar

  • 39.

    Reis EA, Zugno AI, Franzon R, Tagliari B, Matte C, Lammers ML, et al. Pretreatment with vitamins E and C prevent the impairment of memory caused by homocysteine administration in rats. Metab Brain Dis 2002; 17:211–7.CrossrefGoogle Scholar

  • 40.

    Wyse AT, Zugno AI, Streck EL, Matte C, Calcagnotto T, Wannmacher CM, et al. Inhibition of Na(+),K(+)-ATPase activity in hippocampus of rats subjected to acute administration of homocysteine is prevented by vitamins E and C treatment. Neurochem Res 2002; 27:1685–9.CrossrefGoogle Scholar

  • 41.

    Kubova H, Folbergrova J, Mares P. Seizures induced by homocysteine in rats during ontogenesis. Epilepsia 1995; 36:750–6.CrossrefGoogle Scholar

  • 42.

    Fykse EM, Iversen EG, Fonnum F. Inhibition of L-glutamate uptake into synaptic vesicles. Neurosci Lett 1992; 135:125–8.Google Scholar

  • 43.

    Matte C, Monteiro SC, Calcagnotto T, Bavaresco CS, Netto CA, Wyse AT. In vivo and in vitro effects of homocysteine on Na+, K+-ATPase activity in parietal, prefrontal and cingulate cortex of young rats. Int J Dev Neurosci 2004; 22:185–90.CrossrefGoogle Scholar

  • 44.

    Scholze A, Rinder C, Beige J, Riezler R, Zidek W, Tepel M. Acetylcysteine reduces plasma homocysteine concentration and improves pulse pressure and endothelial function in patients with end-stage renal failure. Circulation 2004; 109:369–74.CrossrefGoogle Scholar

  • 45.

    Chung YH, Hong JJ, Shin CM, Joo KM, Kim MJ, Cha CI. Immunohistochemical study on the distribution of homocysteine in the central nervous system of transgenic mice expressing a human Cu/Zn SOD mutation. Brain Res 2003; 967:226–34.Google Scholar

  • 46.

    Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, Trolliet M, et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest 2000; 106:483–91.CrossrefGoogle Scholar

  • 47.

    Schlaich MP, John S, Jacobi J, Lackner KJ, Schmieder RE. Mildly elevated homocysteine concentrations impair endothelium dependent vasodilation in hypercholesterolemic patients. Atherosclerosis 2000; 153:383–9.Google Scholar

  • 48.

    Zhang F, Slungaard A, Vercellotti GM, Iadecola C. Super-oxide-dependent cerebrovascular effects of homocysteine. Am J Physiol 1998; 274:R1704–11.Google Scholar

  • 49.

    Lee SJ, Kim KM, Namkoong S, Kim CK, Kang YC, Lee H, et al. Nitric oxide inhibition of homocysteine-induced human endothelial cell apoptosis by down-regulation of p53-dependent Noxa expression through the formation of S-nitrosohomocysteine. J Biol Chem 2005; 280:5781–8.Google Scholar

  • 50.

    Kim WK. S-Nitrosation ameliorates homocysteine-induced neurotoxicity and calcium responses in primary culture of rat cortical neurons. Neurosci Lett 1999; 265:99–102.Google Scholar

  • 51.

    D'Emilia DM, Lipton SA. Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures. Neurosci Lett 1999; 265:103–6.Google Scholar

  • 52.

    Contestabile A, Monti B, Ciani E. Brain nitric oxide and its dual role in neurodegeneration/neuroprotection: understanding molecular mechanisms to devise drug approaches. Curr Med Chem 2003; 10:2147–74.CrossrefGoogle Scholar

  • 53.

    O'Brien NC, Charlton B, Cowden WB, Willenborg DO. Inhibition of nitric oxide synthase initiates relapsing remitting experimental autoimmune encephalomyelitis in rats, yet nitric oxide appears to be essential for clinical expression of disease. J Immunol 2001; 167:5904–12.Google Scholar

  • 54.

    Keilhoff G, Fansa H, Wolf G. Nitric oxide synthase, an essential factor in peripheral nerve regeneration. Cell Mol Biol (Noisy-le-grand) 2003; 49:885–97.Google Scholar

  • 55.

    Kruman , II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000; 20:6920–6.Google Scholar

  • 56.

    Axelrod J. Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol Rev 1966; 18:95–113.Google Scholar

About the article

Corresponding author: Dr. Charlotte E. Teunissen, Molecular Cell Biology and Immunology, VU University Medical Center, FdG, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands Phone: +31-20-4448076, Fax: +31-20-4448081,

Published Online: 2011-09-21

Published in Print: 2005-10-01

Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 43, Issue 10, Pages 1089–1095, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/CCLM.2005.190.

Export Citation

©2005 by Walter de Gruyter Berlin New York.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Ebtesam Mohamed Fahmy, Nervana Mohamed Elfayoumy, Ahmed Mohamed Abdelalim, Sahar Abdel-aaty Sharaf, Rania Shehata Ismail, and Haidy Elshebawy
International Journal of Neuroscience, 2018, Page 1
P.E. Lazzerini, P.L. Capecchi, E. Selvi, S. Lorenzini, S. Bisogno, M. Galeazzi, and F. Laghi Pasini
Lupus, 2007, Volume 16, Number 11, Page 852
Andrew McCaddon
Biochimie, 2013, Volume 95, Number 5, Page 1066
Stefano Zoccolella, Carla Tortorella, Pietro Iaffaldano, Vita Direnzo, Mariangela D’Onghia, Damiano Paolicelli, Paolo Livrea, and Maria Trojano
Journal of Neurology, 2012, Volume 259, Number 10, Page 2105
Ying Zhu, Zhi-Yi He, and He-Nan Liu
Journal of Clinical Neuroscience, 2011, Volume 18, Number 7, Page 933
Shih-Jen Tsai, Chen-Jee Hong, Heng-Liang Yeh, Ying-Jay Liou, Albert C. Yang, Mu-En Liu, and Jen-Ping Hwang
Dementia and Geriatric Cognitive Disorders, 2011, Volume 32, Number 3, Page 159
Jonatan R. Ruiz, Ruth Castillo, Idoia Labayen, Luis A. Moreno, Miguel García Fuentes, Domingo González Lamuño, Jesus L. Alvarez Granda, Alejandro Lucia, and Francisco B. Ortega
The Journal of Pediatrics, 2010, Volume 156, Number 6, Page 978
Joshua L. Roffman, Anthony P. Weiss, Thilo Deckersbach, Oliver Freudenreich, David C. Henderson, Donna H. Wong, Charles H. Halsted, and Donald C. Goff
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008, Volume 147B, Number 6, Page 990
A. Pexa, M. Herrmann, O. Taban-Shomal, T. Henle, and A. Deussen
Acta Physiologica, 2009, Volume 197, Number 1, Page 27
Bram Bekaert, Matthew L. Cooper, Fiona R. Green, Helene McNulty, Kristina Pentieva, John M. Scott, Anne M. Molloy, and Margaret P. Rayman
Molecular Nutrition & Food Research, 2008, Volume 52, Number 11, Page 1324
Philippe Robaey, Maja Krajinovic, Sophie Marcoux, and Albert Moghrabi
Developmental Disabilities Research Reviews, 2008, Volume 14, Number 3, Page 211
Jean-Sébastien Vidal, Carole Dufouil, Véronique Ducros, and Christophe Tzourio
Neuroepidemiology, 2008, Volume 30, Number 4, Page 207
C. Russo, F. Morabito, F. Luise, A. Piromalli, L. Battaglia, A. Vinci, V. Trapani Lombardo, V. de Marco, P. Morabito, F. Condino, A. Quattrone, and U. Aguglia
Journal of Neurology, 2008, Volume 255, Number 1, Page 64
International Journal of Geriatric Psychiatry, 2006, Volume 21, Number 5, Page 500

Comments (0)

Please log in or register to comment.
Log in