Homozystein und Demenzerkrankungen

 

 Buy Article Permissions and Reprints

Zusammenfassung

Homozystein stellt einen Risikofaktor für atherosklerotische Gefäßerkrankungen einschließlich zerebraler Makro- und Mikroangiopathie dar. Darüber hinaus wird auch ein Zusammenhang mit kognitiven Störungen einschließlich Alzheimer- und vaskulärer Demenz diskutiert. Eine Hyperhomozysteinämie könnte indirekter Marker eines einer kognitiven Störung zugrunde liegenden intrazellulären Vitaminmangels (Vitamin B₁₂, Vitamin B₆, Folsäure) sein, welcher aus einer verminderten Aufnahme oder aus einem gestörten Transport der Vitamine zum ZNS resultieren könnte. Eine weitere Möglichkeit ist ein direkter schädigender Einfluss von Homozystein auf die Kognition über vaskuläre und neurotoxische Pathomechanismen. Da es sich bei der Hyperhomozysteinämie möglicherweise um einen bereits vor der klinischen Manifestation kognitiver Störungen identifizierbaren und potenziell reversiblen Risikofaktor handelt, könnte durch prospektive Interventionsstudien geprüft werden, ob durch Senkung des Homozysteinspiegels mittels einer Vitaminergänzungsbehandlung die Inzidenz und die Progression kognitiver Störungen reduziert werden kann.

Abstract

Homocysteine is a vascular risk factor including cerebral macroangiopathy and microangiopathy. Furthermore, there might also be an association with cognitive disorders including vascular dementia and Alzheimer's disease. Hyperhomocysteinemia linked with cognitive impairment might be an indirect marker for low concentrations of vitamine B₁₂, vitamine B₆ or folate, resulting from low intake or from an impaired transport of the vitamines to the brain. Another possibility is a direct harmful effect of homocysteine to cognition via vascular and neurotoxic pathophysiologic mechanisms. Because hyperhomocysteinemia is a potentially reversible risk factor and can be identified early, it should be investigated by prospective intervention studies whether lowering homocysteine levels by vitamine supplementation could reduce incidence and progression of cognitive disorders.

Literatur

• 1 Ueland P M, Refsum H, Stabler S P, Malinow M R, Andersson A, Allen R H. Total homocysteine in plasma or serum: methods and clinical applications.  Clin Chem. 1993;  39 1764-1779
  PubMedGoogle Scholar
• 2 Jacobsen D W, Gatautis V J, Green R, Robinson K, Savon S R, Secic M, Ji J, Otto J M, Taylor Jr L M. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects.  Clin Chem. 1995;  41 340-342
  PubMedGoogle Scholar
• 3 Graeme J H, Eikelboom J W. Homocysteine and vascular disease.  Lancet. 1999;  354 407-413
  CrossrefPubMedGoogle Scholar
• 4 Ubbink J B, Becker P J, Vermaak W J, Delport R. Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine.  Clin Chem. 1995;  41 1033-1037
  PubMedGoogle Scholar
• 5 Stabler S P, Marcell P D, Podell E R, Allen R H, Savage D G, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry.  J Clin Invest. 1988;  81 466-474
  CrossrefPubMedGoogle Scholar
• 6 Nilsson K, Gustafson L, Hultberg B. Plasma homocysteine is a sensitive marker for tissue deficiency of both cobalamines and folates in a psychogeriatric population.  Dement Geriatr Cogn Disord. 1999;  10 476-482
  CrossrefPubMedGoogle Scholar
• 7 Frosst P, Blom H J, Milos R, Goyette P, Sheppard C A, Matthews R G, Boers G JH, den Heijer M, Kluijtmans L AJ, van den Heuvel L P, Rozen R A. Candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase.  Nat Genet. 1995;  10 111-113
  CrossrefPubMedGoogle Scholar
• 8 Rozen R. Genetic modulation of homocysteinemia.  Semin Thromb Hemost. 2000;  26 255-261
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Rady P L, Szucs S, Grady J, Hudnall S D, Kellner L H, Nitowsky H, Tyring S K, Matalon R K. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A.  Am J Med Genet. 2002;  107 162-168
  CrossrefPubMedGoogle Scholar
• 10 Bleich S, Degner D, Kropp S, Rüther E, Kornhuber J. Red wine, spirits, beer and serum homocysteine.  Lancet. 2000;  356 (9228) 512
  PubMedGoogle Scholar
• 11 Bleich S, Bleich K, Kropp S, Degner D, Bittermann H J, Sperling W, Rüther E, Kornhuber J. Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the “French paradox”?.  Alcohol Alcohol. 2001;  36 189-192
  CrossrefPubMedGoogle Scholar
• 12 Bleich S, Spilker K, Kurth C, Degner D, Quintela-Schneider M, Javaheripour K, Rüther E, Kornhuber J, Wiltfang J. Oxidative stress and an altered methionine metabolism in alcoholism.  Neurosci Lett. 2000;  293 171-174
  CrossrefPubMedGoogle Scholar
• 13 Bleich S, Degner D, Javaheripour K, Kurth C, Kornhuber J. Homocysteine and alcoholism.  J Neural Transm. 2000;  60 187-196
  PubMedGoogle Scholar
• 14 Varela-Moreiras G. Nutritional regulation of homocysteine: effects of drugs.  Biomed Pharmacother. 2001;  55 448-453
  CrossrefPubMedGoogle Scholar
• 15 Selhub J, Jacques P F, Wilson P W, Rush D, Rosenberg I H. Vitamin status and intake as primary determinants of homocysteinemia in a elderly population.  JAMA. 1993;  270 2693-2698
  CrossrefPubMedGoogle Scholar
• 16 Nilsson K, Gustafson L, Fäldt R, Andersson A, Brattstrom L, Lindgren A, Israelsson B, Hultberg B. Hyperhomocysteinaemia - a common finding in a psychogeriatric population.  Eur J Clin Invest. 1996;  26 853-859
  PubMedGoogle Scholar
• 17 Ueland P M, Nygård O, Vollset S E, Refsum H. The Hordaland Homocysteine Studies.  Lipids. 2001;  36 33-39
  PubMedGoogle Scholar
• 18 Abou-Saleh M T, Coppen A. The biology of folate in depression: implications for nutritional hypotheses of the psychoses.  J Psychiatr Res. 1986;  20 91-101
  CrossrefPubMedGoogle Scholar
• 19 Martin D C. B₁₂ and folate deficiency dementia.  Clin Geriatr Med. 1988;  4 814-852
  PubMedGoogle Scholar
• 20 Sauberlich H E. Relationship of vitamin B₆, vitamin B₁₂, and folate to neurological and neuropsychiatric disorders. In: Bendich A, Butterworth CE Jr, eds.: Micronutrients in Health and in Disease Prevention. New York: Marcel Dekker, Inc 1991: 187-218
  Google Scholar
• 21 Goodwin J S, Goodwin J M, Garry P J. Association between nutritional status and cognitive functioning in a healthy elderly population.  JAMA. 1983;  249 (21) 2917-2921
  CrossrefPubMedGoogle Scholar
• 22 McCully K S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;  56 111-128
  Google Scholar
• 23 McCully K S. Atherogenesis and the chemical pathology of homocysteine.  Review Eur J Lab Med. 1996;  4 121-128
  PubMedGoogle Scholar
• 24 Stampfer M J, Malinow M R, Willett W C, Newcomer L M, Upson B, Ullmann D, Tishler P V, Hennekens C H. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.  JAMA. 1992;  268 877-881
  CrossrefPubMedGoogle Scholar
• 25 Arnesen E, Refsum H, Bonaa K H, Ueland P M, Forde O H, Nordrehaug J E. Serum total homocysteine and coronary heart disease.  Int J Epidemiol. 1995;  24 704-709
  CrossrefPubMedGoogle Scholar
• 26 Bostom A G, Silbershatz H, Rosenberg I H, Selhub J, D'Agostino R B, Wolf P A, Jacques P F, Wilson P W. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women.  Arch Intern Med. 1999;  159 1077-1080
  CrossrefPubMedGoogle Scholar
• 27 Kang S S, Wong P W, Malinow M R. Hyperhomocyst(e)inemia as risk factor for occlusive vascular disease.  Ann Rev Nutr. 1992;  12 279-298
  Google Scholar
• 28 Selhub J, Jacques P F, Bostom A G, D'Agostino R B, Wilson P W, Belanger A J, O'Leary D H, Wolf P A, Schaefer E J, Rosenberg I H. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis.  N Engl J Med. 1995;  332 286-291
  CrossrefPubMedGoogle Scholar
• 29 Perry I J, Refsum H, Morris R W, Ebrahim S B, Ueland P M, Shaper A G. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men.  Lancet. 1995;  346 1395-1398
  CrossrefPubMedGoogle Scholar
• 30 Bostom A G, Rosenberg I H, Silbershatz H, Jacques P F, Selhub J, D'Agostino R B, Wilson P W, Wolf P A. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study.  Ann Intern Med. 1999;  131 352-355
  PubMedGoogle Scholar
• 31 Agency for Health Care Policy and Research (AHCPR) .Recognition and initial assessment of Alzheimer's disease and related dementias. Clinical Practice Guideline No. 19; AHCPR Public. No. 97-0702. Nov. 1996
  Google Scholar
• 32 Bell I R, Edman J S, Selhub J, Morrow F D, Marby D W, Kayne H L, Cole J O. Plasma homocysteine in vascular disease and in nonvascular dementia of depressed elderly people.  Acta Psychiatr Scand. 1992;  86 386-390
  PubMedGoogle Scholar
• 33 Riggs K M, Spiro A, Tucker K, Rush D. Relations of vitamin B₁₂, vitamin B₆, folate and homocysteine to cognitive performance in the Normative Aging Study.  Am J Clin Nutr. 1996;  63 306-314
  PubMedGoogle Scholar
• 34 Jensen E, Dehlin O, Erfurth E M, Hagberg B, Samuelsson G, Svensson T, Hultberg B. Plasma homocysteine in 80-year-olds: relationships to medical, psychological and social variables.  Arch Gerontol Geriatr. 1998;  26 215-226
  PubMedGoogle Scholar
• 35 McCaddon A, Hudson P, Davies G, Hughes A, Williams J HH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly.  Dement Geriatr Cogn Disord. 2001;  12 309-313
  CrossrefPubMedGoogle Scholar
• 36 Morris M S, Jacques P F, Rosenberg I H, Selhub J. Hyperhomocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey.  Am J Clin Nutr. 2001;  73 927-933
  PubMedGoogle Scholar
• 37 Lehmann M, Gottfries C G, Regland B. Identification of cognitive impairment in the elderly: Homocysteine is an early marker.  Dement Geriatr Cogn Disord. 1999;  10 12-20
  CrossrefPubMedGoogle Scholar
• 38 Duthie S J, Whalley L J, Collins A R, Leaper S, Berger K, Deary I J. Homocysteine, B vitamin status and cognitive function in the elderly.  Am J Clin Nutr. 2002;  75 908-913
  PubMedGoogle Scholar
• 39 McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type.  Int J Geriat Psychiatry. 1998;  13 235-239
  CrossrefPubMedGoogle Scholar
• 40 Budge M, Johnston C, Hogervorst E, de Jager C, Milwain E, Iversen S D, Barneston L, King E, Smith A D. Plasma total homocysteine and cognitive performance in a volunteer elderly population.  Ann N Y Acad Sci. 2000;  903 407-410
  PubMedGoogle Scholar
• 41 Faßbender K, Mielke O, Bertsch T, Nafe B, Fröschen S, Hennerici M. Homocysteine in cerebral macroangiopathy and microangiopathy.  Lancet. 1999;  353 1586-1587
  CrossrefPubMedGoogle Scholar
• 42 Joosten E, Lesaffre E, Riezler R, Ghekiere V, Dereymaeker L, Pelemans W, Dejaeger E. Is metabolic evidence for vitamin B₁₂ and folate deficiency more frequent in elderly patients with Alzheimer's disease?.  J Gerontol A Biol Sci Med. 1997;  52 M76-79
  PubMedGoogle Scholar
• 43 Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger G, Fuchs D. Hyperhomocysteinemia in dementia.  J Neural Transm. 2000;  107 1469-1474
  CrossrefPubMedGoogle Scholar
• 44 Clarke R, Smith D, Jobst K A, Refsum H, Sutton L, Ueland P M. Folate, Vitamin B₁₂, and serum total homocysteine levels in confirmed Alzheimer disease.  Arch Neurol. 1998;  55 1449-1455
  CrossrefPubMedGoogle Scholar
• 45 Kalmijn S, Launer L J, Lindemans J, Bots M L, Hofman A, Breteler M MB. Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study.  Am J Epidemiol. 1999;  150 283-289
  PubMedGoogle Scholar
• 46 Seshadri S, Beiser A, Selhub J, Jacques P F, Rosenberg I H, D'Agostino R B, Wilson P WF, Wolf P A. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.  N Engl J Med. 2002;  346 476-483
  CrossrefPubMedGoogle Scholar
• 47 Wang H X, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B₁₂ and folate in relation to the development of Alzheimer's disease.  Neurology. 2001;  56 1188-1194
  PubMedGoogle Scholar
• 48 Snowdon D A, Tully C L, Smith C D, Riley K P, Markesbery W R. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun Study.  Am J Clin Nutr. 2000;  71 (4) 993-998
  PubMedGoogle Scholar
• 49 Ikeda T, Furukawa Y, Mashimoto S, Takahashi K, Yamada M. Vitamin B₁₂ levels in serum and cerebrospinal fluid of people with Alzheimer's disease.  Acta Psychiatr Scand. 1990;  82 327-329
  PubMedGoogle Scholar
• 50 Welch G N, Loscalzo J. Homocysteine and atherothrombosis.  N Engl J Med. 1998;  338 1042-1050
  Google Scholar
• 51 Starkebaum G, Harlan J M. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine.  J Clin Invest. 1986;  77 1370-1376
  CrossrefPubMedGoogle Scholar
• 52 D'Emilia D M, Lipton S A. Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures.  Neurosci Lett. 1999;  265 103-106
  CrossrefPubMedGoogle Scholar
• 53 Hirano K, Miki M, Yasuda H, Tamai H, Kawamura N, Mino M. Homocysteine induces iron-catalyzed lipid peroxidation of low-density lipoprotein that is prevented by alpha-tocopherol.  Free Rad Res. 1994;  21 267-276
  PubMedGoogle Scholar
• 54 Jones B G, Rose F A, Tudball N. Lipid peroxidation and homocysteine induced toxicity.  Atherosclerosis. 1994;  105 165-170
  CrossrefPubMedGoogle Scholar
• 55 Lander H M. An essential role for free radicals and derived species in signal transduction.  FASEB J. 1997;  11 118-124
  PubMedGoogle Scholar
• 56 Harker L A, Ross R, Slichter S J, Scott C R. Homocystine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis.  J Clin Invest. 1976;  58 731-741
  PubMedGoogle Scholar
• 57 Celermajer D S, Sorensen K, Ryalls M, Robinson J, Thomas O, Leonhard J V, Deanfiled J E. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents.  J Am Coll Cardiol. 1993;  22 854-858
  CrossrefPubMedGoogle Scholar
• 58 van den Berg M, Boers G H, Franken D G, Blom H J, van Kamp G J, Jakobs C, Rauwerda J A, Kluft C, Stehouwert C D. Hyperhomocysteinemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease.  Eur J Clin Invest. 1995;  25 176-181
  PubMedGoogle Scholar
• 59 Ashfield-Watt P A, Moat S J, Doshi S N, McDowell I F. Folate, homocysteine, endothelial function and cardiovascular disease. What is the link?.  Biomed Pharmacother. 2001;  55 425-433
  CrossrefPubMedGoogle Scholar
• 60 Stamler J S, Osborne J A, Jaraki O, Rabbani L E, Mullins M, Singel D, Loscalzo J. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen.  J Clin Invest. 1993;  91 308-318
  PubMedGoogle Scholar
• 61 Tsai J C, Wang H, Perrella M A, Yoshizumi M, Sibinga N E, Tan L C, Haber E, Chang T H, Schlegel R, Lee M E. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells.  J Clin Invest. 1996;  97 146-153
  PubMedGoogle Scholar
• 62 Silverman M D, Tumuluri R J, Davis M, Lopez G, Rosenbaum J T, Lelkes P I. Homocysteine upregulates vascular cell adhesion molecule-1 expression in cultured human aortic endothelial cells and enhances monocyte adhesion.  Arterioscler Thromb Vasc Biol. 2002;  22 (4) 587-892
  PubMedGoogle Scholar
• 63 Jakubowski H, Zhang L, Bardeguez A, Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells. Implications for Atherosclerosis.  Circ Res. 2000;  87 45-51
  CrossrefPubMedGoogle Scholar
• 64 Scheltens P, Barkhof F, Valk J, Algra P R, van der Hoop R G, Nauta J, Wolters E C. White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer's disease: evidence for heterogenity.  Brain. 1992;  115 735-748
  PubMedGoogle Scholar
• 65 Hogervorst E, Ribeiro H M, Molyneux A, Budge M, Smith A D. Plasma homocysteine levels, cerebrovascular risk factors and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease.  Arch Neurol. 2002;  59 787-793
  CrossrefPubMedGoogle Scholar
• 66 Watkins D, Rosenblatt D S. Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity.  Am J Med Genet. 1989;  34 427-434
  CrossrefPubMedGoogle Scholar
• 67 Bleich S, Bandelow B, Javaheripour K, Müller A, Degner D, Wilhelm J, Havemann-Reinecke U, Sperling W, Rüther E, Kornhuber J. Hyperhomocysteinemia - A new risk factor for brain shrinkage in alcoholism.  Neurosci Lett. 2002;  (in press)
  PubMedGoogle Scholar
• 68 Sachdev P S, Valenzuela M, Wang X L, Looi J C, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals.  Neurology. 2002;  58 1539-1541
  PubMedGoogle Scholar
• 69 Schwarz S, Zhou G Z. N-methyl-D-aspartate receptors and CNS symptoms of homocystinuria.  Lancet. 1991;  337 (8751) 1226-1227
  PubMedGoogle Scholar
• 70 Beal M F, Swartz K J, Finn S F, Mazurek M F, Kowall N W. Neurochemical characterization of excitotoxin lesions in the cerebral cortex.  J Neurosci. 1991;  11 147-158
  PubMedGoogle Scholar
• 71 Lipton S A, Kim W K, Choi Y B, Kumar S, Démilia D M, Rayudu P V, Arnelle D R, Stamler J S. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor.  Proc Natl Acad Sci USA. 1997;  94 5923-5928
  CrossrefPubMedGoogle Scholar
• 72 Kornhuber J, Kaiserauer C H, Kornhuber A W, Kornhuber M E. Alcohol consumption and blood-cerebrospinal fluid barrier dysfunction in man.  Neurosci Lett. 1987;  79 218-222
  CrossrefPubMedGoogle Scholar
• 73 Zhang D, Lipton S A. L-homocysteic acid selectively activates N-methyl-D-aspartate receptors of rat retinal ganglion cells.  Neurosci Lett. 1992;  139 173-177
  CrossrefPubMedGoogle Scholar
• 74 Huang R F, Huang S M, Lin B S, Wie J S, Liu T Z. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells.  Life Sci. 2001;  68 2799-2811
  CrossrefPubMedGoogle Scholar
• 75 Kruman I I, Culmsee C, Chan S L, Kruman Y, Guo Z, Penix L, Mattson M P. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensivity to excitotoxicity.  J Neurosci. 2000;  20 6920-6926
  PubMedGoogle Scholar
• 76 Qutinen P A, Sood S K, Liaw P CY, Sarge K D, Maeda N, Hirsh J, Ribau J, Podor T J, Weitz J I, Austin R C. Characterization of the stress-inducing effects of homocysteine.  Biochem J. 1998;  332 213-221
  PubMedGoogle Scholar
• 77 Parsons R B, Waring R H, Ramsden D B, Williams A C. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines.  Neurotoxicology. 1998;  19 599-604
  PubMedGoogle Scholar
• 78 Dalton M L, Gadson Jr P F, Wrenn R W, Rosenquist T H. Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells.  FASEB J. 1997;  11 703-711
  PubMedGoogle Scholar
• 79 Moore P, El-Sherbeny A, Roon P, Schoenlein P, Ganapathy V, Smith S B. Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine.  Exp Eye Res. 2001;  73 45-57
  CrossrefPubMedGoogle Scholar
• 80 Ho P I, Collins S C, Dhitavat S, Ortiz D, Ashline D, Rogers E, Shea T B. Homocysteine potentiates β-amyloid neurotoxicity: role of oxidative stress.  J Neurochem. 2001;  78 249-253
  CrossrefPubMedGoogle Scholar
• 81 White A R, Huang X, Jobling M F, Barrow C J, Beyreuther K, Masters C L, Bush A I, Cappai R. Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer's-type neurodegenerative pathways.  J Neurochem. 2001;  76 1509-1520
  CrossrefPubMedGoogle Scholar
• 82 Saltzman E, Mason J B, Jacques P F, Selhub J, Salem D, Schaefer E J, Turissini C, Bendich A, Rosenberg I H. B vitamin supplementation lowers homocysteine levels in heart disease.  Clin Res. 1994;  42 172A
  PubMedGoogle Scholar
• 83 Jacques P F, Selhub J, Bostom A G, Wilson P W, Rosenberg I H. The effect of folic acid fortification on plasma folate and total homocysteine concentrations.  N Engl J Med. 1999;  340 1449-1454
  CrossrefPubMedGoogle Scholar

Dr. med. H. Kessler

Universitäts-Nervenklinik und Poliklinik · Psychiatrie und Psychotherapie

Kirrberger Straße

66421 Homburg/Saar

Email: nehkes@uniklinik-saarland.de