Download PDF
Fortschr Neurol Psychiatr 2007; 75(9): e1-e18
DOI: 10.1055/s-2007-980112
Übersicht
© Georg Thieme Verlag Stuttgart · New York

Hyperhomocysteinämie und B-Vitaminmangel bei neurologischen und psychiatrischen Erkrankungen

Aktueller Kenntnisstand und vorläufige EmpfehlungenReview of the Role of Hyperhomocysteinemia and B-Vitamin Deficiency in Neurological and Psychiatric DisordersCurrent Evidence and Preliminary RecommendationsW.  Herrmann1 , S.  Lorenzl2 , R.  Obeid1
  • 1Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum des Saarlandes, Homburg
  • 2Neurologische Klinik, Interdisziplinäres Zentrum für Palliativmedizin, Klinikum Großhadern, München
Further Information

Publication History

Publication Date:
28 August 2007 (online)

    Permissions and Reprints

Zusammenfassung

Hyperhomocysteinämie (HHcy) (Plasmakonzentration > 12 µmol/l) ist in vielen Studien mit Erkrankungen des zentralen Nervensystems in Verbindung gebracht worden. Mehrere epidemiologische Studien zeigen eine positive, dosisabhängige Beziehung zwischen dem Homocysteinspiegel (Hcy) und dem Risiko neurodegenerative Erkrankungen zu entwickeln. Hcy ist ein Marker für B-Vitaminmangel (Folat, B12, B6). Die Verminderung des Risikos für die Entwicklung von neurodegenerativen wie psychiatrischen Erkrankungen durch eine Hcy-Senkung mit B-Vitaminen ist in vielen aber nicht allen Studien gezeigt worden. Jüngste Studien und eine Metaanalyse belegen, dass eine Hcy-senkende Behandlung mit B-Vitaminen in der Primär- und Sekundärprävention von Schlaganfällen gute Resultate zeigt. HHcy und erniedrigtes Serumfolat sind bei Patienten mit Morbus Parkinson, multipler Sklerose und Depressionen häufig anzutreffen. Aufgrund klinischer Studien wird der HHcy bei der Entwicklung von Epilepsie ebenfalls eine kausale Rolle zugesprochen. Durch bestimmte Anti-Epileptika kann weiterhin die HHcy verstärkt werden. Bei Kindern mit unerklärbaren neurologischen Symptomen, Antriebsarmut oder schlechten intellektuellen Leistungen sollte ein Mangel an B-Vitaminen ausgeschlossen und ggf. behandelt werden. Für die Primär- und Sekundärprävention von verschiedenen neuropsychiatrischen Erkrankungen ist eine genügende Vitaminaufnahme mit der Nahrung wie auch Supplementation mit B-Vitaminen von Bedeutung, vor allem bei Personen mit ungenügender Vitaminaufnahme oder niedrigem Vitaminstatus.

Abstract

Elevated concentration of total homocysteine (Hcy) in plasma (> 12 µmol/l) is a risk factor for several diseases of the central nervous system. Epidemiological studies have shown a dose-dependent relationship between concentrations of Hcy and the risk for neurodegenerative diseases. Hcy is a marker for B-vitamin deficiency (folate, B12, B6). Hyperhomocysteinemia (HHcy) causes hypomethylation which is an important mechanism that links Hcy to dementia. Supplementation with vitamins B aims at reducing the risk of neurodegenerative diseases. Current evidence suggests that Hcy-lowering treatment has a positive effect for the secondary and primary prevention of stroke. HHcy is very common in patients with Parkinson disease particularly those who receive L-dopa treatment. Furthermore, a positive association has been reported between HHcy and multiple sclerosis. Moreover, HHcy and vitamin B deficiency are reported to have a causal role in depression, and epilepsy. In addition several anti-epileptic drugs cause secondary HHcy. Therefore, sufficient intakes of the vitamins are recommended for patients who have already developed neuropsychiatric diseases. Vitamin B deficiency should be suspected in children with development disorders, failure to thrive and unexplained neurological manifestations. Elderly people are also an important at-risk group where vitamin B deficiency and HHcy have been linked to neurodegenerative diseases. Treatment with folate, B12, and B6 can improve cerebral function. Preventive vitamin B supplementation and sufficient intake seem very important for secondary and primary prevention of neuropsychiatric disorders, especially in subjects with a low intake or status of the vitamins.

Schlüsselwörter

B-Vitamine - Homocystein - Neurodegeneration - Demenz - Alzheimer - Epilepsie

Key words

B-vitamins - homocysteine - neurodegeneration - dementia - Alzheimer - epilepsy

Literatur

  • 1 Mudd S H, Finkelstein J D, Irreverre F, Laster L. Homocystinuria: an enzymatic defect.  Science. 1964;  143 1443-1445
    Google Scholar
  • 2 Mudd S H, Skovby F, Levy H L, Pettigrew K D, Wilcken B, Pyeritz R E. et al . The natural history of homocystinuria due to cystathionine beta-synthase deficiency.  Am J Hum Genet. 1985;  37 1-31
    Google Scholar
  • 3 Kessler H, Bleich S, Falkai P, Supprian T. Homocysteine and dementia.  Fortschr Neurol Psychiatr. 2003;  71 150-156
    Google Scholar
  • 4 Streck E L, Delwing D, Tagliari B, Matte C, Wannmacher C M, Wajner M, Wyse A T. Brain energy metabolism is compromised by the metabolites accumulating in homocystinuria.  Neurochem Int. 2003;  43 597-602
    Google Scholar
  • 5 Lindenbaum J, Healton E B, Savage D G, Brust J C, Garrett T J, Podell E R. et al . Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis.  N Engl J Med. 1988;  318 1720-1728
    Google Scholar
  • 6 McCracken C, Hudson P, Ellis R, McCaddon A. Methylmalonic acid and cognitive function in the Medical Research Council Cognitive Function and Ageing Study.  Am J Clin Nutr. 2006;  84 1406-1411
    Google Scholar
  • 7 Goodwin J S, Goodwin J M, Garry P J. Association between nutritional status and cognitive functioning in a healthy elderly population.  JAMA. 1983;  249 2917-2921
    Google Scholar
  • 8 Obeid R, Schorr H, Eckert R, Herrmann W. Vitamin B12 status in the elderly as judged by available biochemical markers.  Clin Chem. 2004;  50 238-241
    Google Scholar
  • 9 Ho P I, Ashline D, Dhitavat S, Ortiz D, Collins S C, Shea T B, Rogers E. Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine.  Neurobiol Dis. 2003;  14 32-42
    Google Scholar
  • 10 Ichinohe A, Kanaumi T, Takashima S, Enokido Y, Nagai Y, Kimura H. Cystathionine beta-synthase is enriched in the brains of Down's patients.  Biochem Biophys Res Commun. 2005;  338 1547-1550
    Google Scholar
  • 11 Heinonen K. Studies on cystathionase activity in rat liver and brain during development. Effects of hormones and amino acids in vivo.  Biochem J. 1973;  136 1011-1015
    Google Scholar
  • 12 Griffiths R, Tudball N. Observations on the fate of cystathionine in rat brain.  Life Sci. 1976;  19 1217-1224
    Google Scholar
  • 13 Awata S, Nakayama K, Suzuki I, Sugahara K, Kodama H. Changes in cystathionine gamma-lyase in various regions of rat brain during development.  Biochem Mol Biol Int. 1995;  35 1331-1338
    Google Scholar
  • 14 Kranich O, Dringen R, Sandberg M, Hamprecht B. Utilization of cysteine and cysteine precursors for the synthesis of glutathione in astroglial cultures: preference for cystine.  Glia. 1998;  22 11-18
    Google Scholar
  • 15 Vitvitsky V, Thomas M, Ghorpade A, Gendelman H E, Banerjee R. A functional transsulfuration pathway in the brain links to glutathione homeostasis.  J Biol Chem. 2006;  281 35 785-35 793
    Google Scholar
  • 16 Scott J M, Molloy A M, Kennedy D G, Kennedy S, Weir D G. Effects of the disruption of transmethylation in the central nervous system: an animal model.  Acta Neurol Scand Suppl. 1994;  154 27-31
    Google Scholar
  • 17 Quinn C T, Griener J C, Bottiglieri T, Arning E, Winick N J. Effects of intraventricular methotrexate on folate, adenosine, and homocysteine metabolism in cerebrospinal fluid.  J Pediatr Hematol Oncol. 2004;  26 386-388
    Google Scholar
  • 18 Surtees R, Bowron A, Leonard J. Cerebrospinal fluid and plasma total homocysteine and related metabolites in children with cystathionine beta-synthase deficiency: the effect of treatment.  Pediatr Res. 1997;  42 577-582
    Google Scholar
  • 19 Grieve A, Butcher S P, Griffiths R. Synaptosomal plasma membrane transport of excitatory sulphur amino acid transmitter candidates: kinetic characterisation and analysis of carrier specificity.  J Neurosci Res. 1992;  32 60-68
    Google Scholar
  • 20 Obeid R, Kostopoulos P, Knapp J P, Kasoha M, Becker G, Fassbender K, Herrmann W. Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid.  Clin Chem. 2007;  53 326-333
    Google Scholar
  • 21 Eto K, Asada T, Arima K, Makifuchi T, Kimura H. Brain hydrogen sulfide is severely decreased in Alzheimer's disease.  Biochem Biophys Res Commun. 2002;  293 1485-1488
    Google Scholar
  • 22 Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag L E, Gottfries C G. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome.  Scand J Rheumatol. 1997;  26 301-307
    Google Scholar
  • 23 Regland B, Abrahamsson L, Blennow K, Grenfeldt B, Gottfries C G. CSF-methionine is elevated in psychotic patients.  J Neural Transm. 2004;  111 631-640
    Google Scholar
  • 24 Yanai Y, Shibasaki T, Kohno N, Mitsui T, Nakajima H. Concentrations of sulfur-containing free amino acids in lumbar cerebrospinal fluid from patients with consciousness disturbances.  Acta Neurol Scand. 1983;  68 386-393
    Google Scholar
  • 25 Isobe C, Murata T, Sato C, Terayama Y. Increase of total homocysteine concentration in cerebrospinal fluid in patients with Alzheimer's disease and Parkinson's disease.  Life Sci. 2005;  77 1836-1843
    Google Scholar
  • 26 Heijer T den, Vermeer S E, Clarke R, Oudkerk M, Koudstaal P J, Hofman A, Breteler M M. Homocysteine and brain atrophy on MRI of non-demented elderly.  Brain. 2003;  126 170-175
    Google Scholar
  • 27 Wright C B, Paik M C, Brown T R, Stabler S P, Allen R H, Sacco R L, DeCarli C. Total homocysteine is associated with white matter hyperintensity volume: the Northern Manhattan Study.  Stroke. 2005;  36 1207-1211
    Google Scholar
  • 28 Ferri C P, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M. et al . Global prevalence of dementia: a Delphi consensus study.  Lancet. 2005;  366 2112-2117
    Google Scholar
  • 29 Riggs K M, Spiro III A, 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;  63 306-314
    Google Scholar
  • 30 Clarke R, Smith A 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
    Google Scholar
  • 31 Morris M S, Fava M, Jacques P F, Selhub J, Rosenberg I H. Depression and folate status in the US Population.  Psychother Psychosom. 2003;  72 80-87
    Google Scholar
  • 32 Selhub J, Bagley L C, Miller J, Rosenberg I H. B vitamins, homocysteine, and neurocognitive function in the elderly.  Am J Clin Nutr. 2000;  71 614S-620S
    Google Scholar
  • 33 Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N. et al . Incidence and etiology of dementia in a large elderly Italian population.  Neurology. 2005;  64 1525-1530
    Google Scholar
  • 34 Ramos M I, Allen L H, Mungas D M, Jagust W J, Haan M N, Green R, Miller J W. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging.  Am J Clin Nutr. 2005;  82 1346-1352
    Google Scholar
  • 35 McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B(12) deficiency and Alzheimer disease.  Neurology. 2002;  58 1395-1399
    Google Scholar
  • 36 Gharib A, Chabannes B, Sarda N, Pacheco H. In vivo elevation of mouse brain S-adenosyl-L-homocysteine after treatment with L-homocysteine.  J Neurochem. 1983;  40 1110-1112
    Google Scholar
  • 37 Bottiglieri T, Godfrey P, Flynn T, Carney M W, Toone B K, Reynolds E H. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine.  J Neurol Neurosurg Psychiatry. 1990;  53 1096-1098
    Google Scholar
  • 38 Serot J M, Christmann D, Dubost T, Bene M C, Faure G C. CSF-folate levels are decreased in late-onset AD patients.  J Neural Transm. 2001;  108 93-99
    Google Scholar
  • 39 Fassbender K, Mielke O, Bertsch T, Nafe B, Froschen S, Hennerici M. Homocysteine in cerebral macroangiography and microangiopathy.  Lancet. 1999;  353 1586-1587
    Google Scholar
  • 40 Wright C B, Lee H S, Paik M C, Stabler S P, Allen R H, Sacco R L. Total homocysteine and cognition in a tri-ethnic cohort: the Northern Manhattan Study.  Neurology. 2004;  63 254-260
    Google Scholar
  • 41 Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia.  Am J Clin Nutr. 2004;  80 114-122
    Google Scholar
  • 42 Lehrner J, Gufler R, Guttmann G, Maly J, Gleiss A, Auff E, Dal-Bianco P. Annual conversion to alzheimer disease among patients with memory complaints attending an outpatient memory clinic: the influence of amnestic mild cognitive impairment and the predictive value of neuropsychological testing.  Wien Klin Wochenschr. 2005;  117 629-635
    Google Scholar
  • 43 Nurk E, Refsum H, Tell G S, Engedal K, Vollset S E, Ueland P M. et al . Plasma total homocysteine and memory in the elderly: The Hordaland Homocysteine study.  Ann Neurol. 2005;  58 847-857
    Google Scholar
  • 44 Sachdev P S. Homocysteine and brain atrophy.  Prog Neuropsychopharmacol Biol Psychiatry. 2005;  29 1152-1161
    Google Scholar
  • 45 Seshadri S, Beiser A, Selhub J, Jacques P F, Rosenberg I H, D'Agostino R B. et al . Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.  N Engl J Med. 2002;  346 476-483
    Google Scholar
  • 46 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
    Google Scholar
  • 47 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
    Google Scholar
  • 48 Stott D J, MacIntosh G, Lowe G D, Rumley A, McMahon A D, Langhorne P. et al . Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease.  Am J Clin Nutr. 2005;  82 1320-1326
    Google Scholar
  • 49 Eussen S J, de Groot L C, Joosten L W, Bloo R J, Clarke R, Ueland P M. et al . Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial.  Am J Clin Nutr. 2006;  84 361-370
    Google Scholar
  • 50 Clarke R, Harrison G, Richards S. Effect of vitamins and aspirin on markers of platelet activation, oxidative stress and homocysteine in people at high risk of dementia.  J Intern Med. 2003;  254 67-75
    Google Scholar
  • 51 Vermeulen E G, Stehouwer C D, Valk J, van der K M, van den B M, Twisk J W. et al . Effect of homocysteine-lowering treatment with folic acid plus vitamin B on cerebrovascular atherosclerosis and white matter abnormalities as determined by MRA and MRI: a placebo-controlled, randomized trial.  Eur J Clin Invest. 2004;  34 256-261
    Google Scholar
  • 52 Malouf R, Grimley E J. The effect of vitamin B6 on cognition.  Cochrane Database Syst Rev. 2003;  CD004393 1-26
    Google Scholar
  • 53 McMahon J A, Green T J, Skeaff C M, Knight R G, Mann J I, Williams S M. A controlled trial of homocysteine lowering and cognitive performance.  N Engl J Med. 2006;  354 2764-2772
    Google Scholar
  • 54 Homocysteine Studies Collaboration . Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA. 2002;  288 2015-2022
    Google Scholar
  • 55 Polyak Z, Stern F, Berner Y N, Sela B A, Gomori J M, Isayev M. et al . Hyperhomocysteinemia and vitamin score: correlations with silent brain ischemic lesions and brain atrophy.  Dement Geriatr Cogn Disord. 2003;  16 39-45
    Google Scholar
  • 56 McCully K S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;  56 111-128
    Google Scholar
  • 57 Konrad C, Muller G A, Langer C, Kuhlenbaumer G, Berger K, Nabavi D G. et al . Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections.  Journal of Neurology. 2004;  251 1242-1248
    Google Scholar
  • 58 Moller J, Nielsen G M, Tvedegaard K C, Andersen N T, Jorgensen P E. A meta-analysis of cerebrovascular disease and hyperhomocysteinaemia.  Scandinavian Journal of Clinical & Laboratory Investigation. 2000;  60 491-499
    Google Scholar
  • 59 Gallai V, Caso V, Paciaroni M, Cardaioli G, Arning E, Bottiglieri T, Parnetti L. Mild hyperhomocyst(e)inemia - A possible risk factor for cervical artery dissection.  Stroke. 2001;  32 714-718
    Google Scholar
  • 60 Moller J, Nielsen G M, Tvedegaard K C, Andersen N T, Jorgensen P E. A meta-analysis of cerebrovascular disease and hyperhomocysteinaemia.  Scandinavian Journal of Clinical & Laboratory Investigation. 2000;  60 491-499
    Google Scholar
  • 61 Pezzini A, Del Zotto E, Archetti S, Negrini R, Bani P, Albertini A. et al . Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.  Neurology. 2002;  58 A479
    Google Scholar
  • 62 Pezzini A, Del Zotto E, Archetti S, Negrini R, Bani P, Albertini A. et al . Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.  Neurology. 2002;  58 A479
    Google Scholar
  • 63 Matsui T, Arai H, Yuzuriha T, Yao H, Miura M, Hashimoto S. et al . Elevated plasma homocysteine levels and risk of silent brain infarction in elderly people.  Stroke. 2001;  32 1116-1119
    Google Scholar
  • 64 Bots M L, Launer L J, Lindemans J, Hoes A W, Hofman A, Witteman J C. et al . Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study.  Arch Intern Med. 1999;  159 38-44
    Google Scholar
  • 65 Verhoef P, Hennekens C H, Malinow M R, Kok F J, Willett W C, Stampfer M J. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke.  Stroke. 1994;  25 1924-1930
    Google Scholar
  • 66 Sacco R L, Anand K, Lee H S, Boden-Albala B, Stabler S, Allen R, Paik M C. Homocysteine and the risk of ischemic stroke in a triethnic cohort: the NOrthern MAnhattan Study.  Stroke. 2004;  35 2263-9226
    Google Scholar
  • 67 Vermeer S E, Dijk E J van, Koudstaal P J, Oudkerk M, Hofman A, Clarke R, Breteler M M. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study.  Ann Neurol. 2002;  51 285-289
    Google Scholar
  • 68 Toole J F, Malinow M R, Chambless L E, Spence J D, Pettigrew L C, Howard V J. et al . Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.  JAMA. 2004;  291 565-575
    Google Scholar
  • 69 Spence J D, Bang H, Chambless L E, Stampfer M J. Vitamin Intervention For Stroke Prevention trial: an efficacy analysis.  Stroke. 2005;  36 2404-2409
    Google Scholar
  • 70 Lonn E, Yusuf S, Arnold M J, Sheridan P, Pogue J, Micks M. et al . Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med. 2006;  354 1567-1577
    Google Scholar
  • 71 Yang Q, Botto L D, Erickson J D, Berry R J, Sambell C, Johansen H, Friedman J M. Improvement in stroke mortality in Canada and the United States, 1990 to 2002.  Circulation. 2006;  113 1335-1343
    Google Scholar
  • 72 Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y. et al . Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.  Lancet. 2007;  369 1876-1882
    Google Scholar
  • 73 Goldstein L B, Adams R, Alberts M J, Appel L J, Brass L M, Bushnell C D. et al . Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group.  Circulation. 2006;  113 e873-e923
    Google Scholar
  • 74 Blandini F, Fancellu R, Martignoni E, Mangiagalli A, Pacchetti C, Samuele A, Nappi G. Plasma homocysteine and l-dopa metabolism in patients with Parkinson disease.  Clin Chem. 2001;  47 1102-1104
    Google Scholar
  • 75 Yasui K, Kowa H, Nakaso K, Takeshima T, Nakashima K. Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD.  Neurology. 2000;  55 437-440
    Google Scholar
  • 76 Kuhn W, Roebroek R, Blom H, van O D, Muller T. Hyperhomocysteinaemia in Parkinson's disease.  J Neurol. 1998;  245 811-812
    Google Scholar
  • 77 Lamberti P, Zoccolella S, Armenise E, Lamberti S V, Fraddosio A MM de. et al . Hyperhomocysteinemia in L-dopa treated Parkinson's disease patients: effect of cobalamin and folate administration.  Eur J Neurol. 2005;  12 365-368
    Google Scholar
  • 78 Liu X X, Wilson K, Charlton C G. Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa.  Life Sci. 2000;  66 2277-2288
    Google Scholar
  • 79 Miller J W, Shukitt-Hale B, Villalobos-Molina R, Nadeau M R, Selhub J, Joseph J A. Effect of L-Dopa and the catechol-O-methyltransferase inhibitor Ro 41 - 0960 on sulfur amino acid metabolites in rats.  Clin Neuropharmacol. 1997;  20 55-66
    Google Scholar
  • 80 Yassin M S, Cheng H, Ekblom J, Oreland L. Inhibitors of catecholamine metabolizing enzymes cause changes in S-adenosylmethionine and S-adenosylhomocysteine in the rat brain.  Neurochem Int. 1998;  32 53-59
    Google Scholar
  • 81 Werner P, Di R A, Prikhojan A, Rempel N, Bottiglieri T, Bressman S, Yahr M D. COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against L-dopa toxicity in vitro.  Brain Res. 2001;  893 278-281
    Google Scholar
  • 82 Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A MM de, Livrea P. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson"s disease patients.  Mov Disord. 2005;  20 69-72
    Google Scholar
  • 83 Valkovic P, Benetin J, Blazicek P, Valkovicova L, Gmitterova K, Kukumberg P. Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients.  Parkinsonism Relat Disord. 2005;  11 253-256
    Google Scholar
  • 84 Zesiewicz T A, Wecker L, Sullivan K L, Merlin L R, Hauser R A. The controversy concerning plasma homocysteine in Parkinson disease patients treated with levodopa alone or with entacapone: effects of vitamin status.  Clin Neuropharmacol. 2006;  29 106-111
    Google Scholar
  • 85 Postuma R B, Espay A J, Zadikoff C, Suchowersky O, Martin W R, Lafontaine A L. et al . Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study.  Neurology. 2006;  66 1941-1943
    Google Scholar
  • 86 Duan W, Ladenheim B, Cutler R G, Kruman I I, Cadet J L, Mattson M P. Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease.  J Neurochem. 2002;  80 101-110
    Google Scholar
  • 87 O'Suilleabhain P E, Sung V, Hernandez C, Lacritz L, Dewey Jr. R B, Bottiglieri T, az-Arrastia R. Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations.  Arch Neurol. 2004;  61 865-868
    Google Scholar
  • 88 Rogers J D, Sanchez-Saffon A, Frol A B, az-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease.  Arch Neurol. 2003;  60 59-64
    Google Scholar
  • 89 Sato Y, Iwamoto J, Kanoko T, Satoh K. Homocysteine as a predictive factor for hip fracture in elderly women with Parkinson's disease.  Am J Med. 2005;  118 1250-1255
    Google Scholar
  • 90 Aita J F. Why patients with Parkinson's disease fall.  JAMA. 1982;  247 515-516
    Google Scholar
  • 91 Meurs J B van, Dhonukshe-Rutten R A, Pluijm S M, Klift M van der, de Jonge R, Lindemans J. et al . Homocysteine levels and the risk of osteoporotic fracture.  N Engl J Med. 2004;  350 2033-2041
    Google Scholar
  • 92 McLean R R, Jacques P F, Selhub J, Tucker K L, Samelson E J, Broe K E. et al . Homocysteine as a predictive factor for hip fracture in older persons.  N Engl J Med. 2004;  350 2042-2049
    Google Scholar
  • 93 O'Suilleabhain P E, Oberle R, Bartis C, Dewey Jr. R B, Bottiglieri T, az-Arrastia R. Clinical course in Parkinson's disease with elevated homocysteine.  Parkinsonism Relat Disord. 2006;  12 103-107
    Google Scholar
  • 94 Chen H, Zhang S M, Schwarzschild M A, Hernan M A, Logroscino G, Willett W C, Ascherio A. Folate intake and risk of Parkinson's disease.  Am J Epidemiol. 2004;  160 368-375
    Google Scholar
  • 95 Lamberti P, Zoccolella S, Armenise E, Lamberti S V, Fraddosio A MM de. et al . Hyperhomocysteinemia in L-dopa treated Parkinson's disease patients: effect of cobalamin and folate administration.  Eur J Neurol. 2005;  12 365-368
    Google Scholar
  • 96 Nijst T Q, Wevers R A, Schoonderwaldt H C, Hommes O R, de Haan A F. Vitamin B12 and folate concentrations in serum and cerebrospinal fluid of neurological patients with special reference to multiple sclerosis and dementia.  J Neurol Neurosurg Psychiatry. 1990;  53 951-954
    Google Scholar
  • 97 Ramsaransing G S, Fokkema M R, Teelken A, Arutjunyan A V, Koch M, De K J. Plasma homocysteine levels in multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2006;  77 189-192
    Google Scholar
  • 98 Goodkin D E, Jacobsen D W, Galvez N, Daughtry M, Secic M, Green R. Serum Cobalamin Deficiency Is Uncommon in Multiple-Sclerosis.  Archives of Neurology. 1994;  51 1110-1114
    Google Scholar
  • 99 Vrethem M, Mattsson E, Hebelka H, Leerbeck K, Osterberg A, Landtblom A M. et al . Increased plasma homocysteine levels without signs of vitamin B-12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid.  Multiple Sclerosis. 2003;  9 239-245
    Google Scholar
  • 100 Dalal S, Parkin S M, Homer-Vanniasinkam S, Nicolaou A. Effect of homocysteine on cytokine production by human endothelial cells and monocytes.  Ann Clin Biochem. 2003;  40 534-541
    Google Scholar
  • 101 Kim J K, Mastronardi F G, Wood D D, Lubman D M, Zand R, Moscarello M A. Multiple sclerosis: an important role for post-translational modifications of myelin basic protein in pathogenesis.  Mol Cell Proteomics. 2003;  2 453-462
    Google Scholar
  • 102 Baldwin G S, Carnegie P R. Specific enzymic methylation of an arginine in the experimental allergic encephalomyelitis protein from human myelin.  Science. 1971;  171 579-581
    Google Scholar
  • 103 Mowen K A, Tang J, Zhu W, Schurter B T, Shuai K, Herschman H R, David M. Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription.  Cell. 2001;  104 731-41
    Google Scholar
  • 104 Murata S, Naritomi H, Sawada T. MRI in subacute combined degeneration.  Neuroradiology. 1994;  36 408-409
    Google Scholar
  • 105 Wade D T, Young C A, Chaudhuri K R, Davidson D L. A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the „Cari Loder regime”) in the treatment of multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2002;  73 246-249
    Google Scholar
  • 106 Osmond H, Smythies J. Schizophrenia: a new approach.  J Ment Sci. 1952;  98 309-315
    Google Scholar
  • 107 Cohen S M, Nichols A, Wyatt R, Pollin W. The administration of methionine to chronic schizophrenic patients: a review of ten studies.  Biol Psychiatry. 1974;  8 209-225
    Google Scholar
  • 108 Ramos M I, Allen L H, Haan M N, Green R, Miller J W. Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification.  Am J Clin Nutr. 2004;  80 1024-1028
    Google Scholar
  • 109 Penninx B W, Guralnik J M, Ferrucci L, Fried L P, Allen R H, Stabler S P. Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study.  Am J Psychiatry. 2000;  157 715-721
    Google Scholar
  • 110 Hvas A M, Juul S, Lauritzen L, Nexo E, Ellegaard J. No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study.  J Affect Disord. 2004;  81 269-273
    Google Scholar
  • 111 Tolmunen T, Hintikka J, Voutilainen S, Ruusunen A, Alfthan G, Nyyssonen K. et al . Association between depressive symptoms and serum concentrations of homocysteine in men: a population study.  Am J Clin Nutr. 2004;  80 1574-1578
    Google Scholar
  • 112 Tiemeier H, Tuijl H R van, Hofman A, Meijer J, Kiliaan A J, Breteler M M. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study.  Am J Psychiatry. 2002;  159 2099-2101
    Google Scholar
  • 113 Reynolds E H, Carney M W, Toone B K. Methylation and mood.  Lancet. 1984;  2 196-198
    Google Scholar
  • 114 Bottiglieri T, Laundy M, Crellin R, Toone B K, Carney M W, Reynolds E H. Homocysteine, folate, methylation, and monoamine metabolism in depression.  J Neurol Neurosurg Psychiatry. 2000;  69 228-232
    Google Scholar
  • 115 Hvas A M, Juul S, Bech P, Nexo E. Vitamin B6 level is associated with symptoms of depression.  Psychother Psychosom. 2004;  73 340-343
    Google Scholar
  • 116 Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence.  Am J Clin Nutr. 2002;  76 1158S-1161S
    Google Scholar
  • 117 Kufferle B, Grunberger J. Early clinical double-blind study with S-adenosyl-L-methionine: a new potential antidepressant.  Adv Biochem Psychopharmacol. 1982;  32 175-180
    Google Scholar
  • 118 Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial.  J Affect Disord. 2000;  60 121-130
    Google Scholar
  • 119 Coppen A, Chaudhry S, Swade C. Folic acid enhances lithium prophylaxis.  J Affect Disord. 1986;  10 9-13
    Google Scholar
  • 120 Godfrey P S, Toone B K, Carney M W, Flynn T G, Bottiglieri T, Laundy M. et al . Enhancement of recovery from psychiatric illness by methylfolate.  Lancet. 1990;  336 392-395
    Google Scholar
  • 121 Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12.  J Psychopharmacol. 2005;  19 59-65
    Google Scholar
  • 122 bou-Saleh M T, Coppen A. Folic acid and the treatment of depression.  J Psychosom Res. 2006;  61 285-287
    Google Scholar
  • 123 Levine J, Stahl Z, Sela B A, Gavendo S, Ruderman V, Belmaker R H. Elevated homocysteine levels in young male patients with schizophrenia.  American Journal of Psychiatry. 2002;  159 1790-1792
    Google Scholar
  • 124 Goff D C, Bottiglieri T, Arning E, Shih V, Freudenreich O, Evins A E. et al . Folate, homocysteine, and negative symptoms in schizophrenia.  Am J Psychiatry. 2004;  161 1705-1708
    Google Scholar
  • 125 Muntjewerff J W, Hoogendoorn M L, Kahn R S, Sinke R J, den H M, Kluijtmans L A, Blom H J. Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study.  Am J Med Genet B Neuropsychiatr Genet. 2005;  135 69-72
    Google Scholar
  • 126 Muntjewerff J W, Kahn R S, Blom H J, den H M. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis.  Mol Psychiatry. 2006;  11 143-149
    Google Scholar
  • 127 Devlin A M, Ling E H, Peerson J M, Fernando S, Clarke R, Smith A D, Halsted C H. Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia.  Hum Mol Genet. 2000;  9 2837-2844
    Google Scholar
  • 128 Applebaum J, Shimon H, Sela B A, Belmaker R H, Levine J. Homocysteine levels in newly admitted schizophrenic patients.  J Psychiatr Res. 2004;  38 413-416
    Google Scholar
  • 129 Levine J, Stahl Z, Sela B A, Ruderman V, Shumaico O, Babushkin I. et al . Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia.  Biol Psychiatry. 2006;  60 265-269
    Google Scholar
  • 130 Neubauer C. Mental deterioration in epilepsy due to folate deficiency.  Br Med J. 1970;  2 759-761
    Google Scholar
  • 131 Freed W J. Selective inhibition of homocysteine-induced seizures by glutamic acid diethyl ester and other glutamate esters.  Epilepsia. 1985;  26 30-36
    Google Scholar
  • 132 Verrotti A, Pascarella R, Trotta D, Giuva T, Morgese G, Chiarelli F. Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine.  Epilepsy Res. 2000;  41 253-257
    Google Scholar
  • 133 Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser P A, Walter-Sack I. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment.  Epilepsia. 1999;  40 345-350
    Google Scholar
  • 134 Huemer M, Ausserer B, Graninger G, Hubmann M, Huemer C, Schlachter K. et al . Hyperhomocysteinemia in children treated with antiepileptic drugs is normalized by folic acid supplementation.  Epilepsia. 2005;  46 1677-1683
    Google Scholar
  • 135 Attilakos A, Papakonstantinou E, Schulpis K, Voudris K, Katsarou E, Mastroyianni S, Garoufi A. Early effect of sodium valproate and carbamazepine monotherapy on homocysteine metabolism in children with epilepsy.  Epilepsy Res. 2006;  71 229-232
    Google Scholar
  • 136 Sener U, Zorlu Y, Karaguzel O, Ozdamar O, Coker I, Topbas M. Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12, folic acid and vitamin B6.  Seizure. 2006;  15 79-85
    Google Scholar
  • 137 Kolinova M, Dvorakova J, Hladikova E, Preiss J, Hyanek J. Moderate hyperhomocysteinemia in patients treated for epilepsy.  Prague Med Rep. 2006;  107 227-241
    Google Scholar
  • 138 Gidal B E, Tamura T, Hammer A, Vuong A. Blood homocysteine, folate and vitamin B-12 concentrations in patients with epilepsy receiving lamotrigine or sodium valproate for initial monotherapy.  Epilepsy Res. 2005;  64 161-166
    Google Scholar
  • 139 Apeland T, Mansoor M A, Strandjord R E, Kristensen O. Homocysteine concentrations and methionine loading in patients on antiepileptic drugs.  Acta Neurol Scand. 2000;  101 217-223
    Google Scholar
  • 140 Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis.  Neurology. 1992;  42 17-24
    Google Scholar
  • 141 Billings R E. Decreased hepatic 5, 10-methylenetetrahydrofolate reductase activity in mice after chronic phenytoin treatment.  Mol Pharmacol. 1984;  25 459-466
    Google Scholar
  • 142 Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation.  J Biol Chem. 2003;  278 27 586-27 592
    Google Scholar
  • 143 Onso-Aperte E, Ubeda N, Achon M, Perez-Miguelsanz J, Varela-Moreiras G. Impaired methionine synthesis and hypomethylation in rats exposed to valproate during gestation.  Neurology. 1999;  52 750-756
    Google Scholar
  • 144 Morrell M J. Guidelines for the care of women with epilepsy.  Neurology. 1998;  51 S21-S27
    Google Scholar
  • 145 Reynolds E H. Mental effects of anticonvulsants, and folic acid metabolism.  Brain. 1968;  91 197-214
    Google Scholar
  • 146 Baker H, Leevy C B, DeAngelis B, Frank O, Baker E R. Cobalamin (vitamin B12) and holotranscobalamin changes in plasma and liver tissue in alcoholics with liver disease.  J Am Coll Nutr. 1998;  17 235-238
    Google Scholar
  • 147 Baker H, Frank O, DeAngelis B. Plasma vitamin B12 titres as indicators of disease severity and mortality of patients with alcoholic hepatitis.  Alcohol Alcohol. 1987;  22 1-5
    Google Scholar
  • 148 Eisenga B H, Collins T D, McMartin K E. Effects of acute ethanol on urinary excretion of 5-methyltetrahydrofolic acid and folate derivatives in the rat.  J Nutr. 1989;  119 1498-1505
    Google Scholar
  • 149 McMartin K E, Collins T D, Eisenga B H, Fortney T, Bates W R, Bairnsfather L. Effects of chronic ethanol and diet treatment on urinary folate excretion and development of folate deficiency in the rat.  J Nutr. 1989;  119 1490-1497
    Google Scholar
  • 150 Hultberg B, Berglund M, Andersson A, Frank A. Elevated plasma homocysteine in alcoholics.  Alcohol Clin Exp Res. 1993;  17 687-689
    Google Scholar
  • 151 Bleich S, Bandelow B, Javaheripour K, Muller A, Degner D, Wilhelm J. et al . Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism.  Neurosci Lett. 2003;  335 179-182
    Google Scholar
  • 152 Bleich S, Bayerlein K, Hillemacher T, Degner D, Kornhuber J, Frieling H. An assessment of the potential value of elevated homocysteine in predicting alcohol-withdrawal seizures.  Epilepsia. 2006;  47 934-938
    Google Scholar
  • 153 Wilhelm J, Bayerlein K, Hillemacher T, Reulbach U, Frieling H, Kromolan B. et al . Short-term cognition deficits during early alcohol withdrawal are associated with elevated plasma homocysteine levels in patients with alcoholism.  J Neural Transm. 2006;  113 357-363
    Google Scholar
  • 154 Peters T J, Kotowicz J, Nyka W, Kozubski W, Kuznetsov V, Vanderbist F. et al . Treatment of alcoholic polyneuropathy with vitamin B complex: a randomised controlled trial.  Alcohol Alcohol. 2006;  41 636-642
    Google Scholar
  • 155 Cooper B A, Rosenblatt D S. Inherited defects of vitamin B12 metabolism.  Annu Rev Nutr. 1987;  7 291-320
    Google Scholar
  • 156 Graham S M, Arvela O M, Wise G A. Long-term neurologic consequences of nutritional vitamin B12 deficiency in infants.  J Pediatr. 1992;  121 710-714
    Google Scholar
  • 157 Dagnelie P C, Staveren W A van, Vergote F J, Dingjan P G, Van den B H, Hautvast J G. Increased risk of vitamin B-12 and iron deficiency in infants on macrobiotic diets.  Am J Clin Nutr. 1989;  50 818-824
    Google Scholar
  • 158 Mudd S H, Levy H L, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited disease. New York: McGraw-Hill Publishing Co 1995: 1279-1327
    Google Scholar
  • 159 Hyland K, Smith I, Bottiglieri T, Perry J, Wendel U, Clayton P T, Leonard J V. Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency.  Neurology. 1988;  38 459-462
    Google Scholar
  • 160 Haan E A, Rogers J G, Lewis G P, Rowe P B. 5,10-Methylenetetrahydrofolate reductase deficiency. Clinical and biochemical features of a further case.  J Inherit Metab Dis. 1985;  8 53-57
    Google Scholar
  • 161 Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications.  CMAJ. 2006;  174 341-348
    Google Scholar
  • 162 Zaina S, Lindholm M W, Lund G. Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia?.  J Nutr. 2005;  135 5-8
    Google Scholar
  • 163 James S J, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor D W, Neubrander J A. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.  Am J Clin Nutr. 2004;  80 1611-1617
    Google Scholar
  • 164 Higginbottom M C, Sweetman L, Nyhan W L. A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian.  N Engl J Med. 1978;  299 317-323
    Google Scholar
  • 165 Kuhne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency.  Eur J Pediatr. 1991;  150 205-208
    Google Scholar
  • 166 Schneede J, Dagnelie P C, Staveren W A van, Vollset S E, Refsum H, Ueland P M. Methylmalonic acid and homocysteine in plasma as indicators of functional cobalamin deficiency in infants on macrobiotic diets.  Pediatr Res. 1994;  36 194-201
    Google Scholar
  • 167 Ooylan L M, Hart S, Porter K B, Driskell J A. Vitamin B-6 content of breast milk and neonatal behavioral functioning.  J Am Diet Assoc. 2002;  102 1433-1438
    Google Scholar
  • 168 Refsum H, Grindflek A W, Ueland P M, Fredriksen A, Meyer K, Ulvik A. et al . Screening for serum total homocysteine in newborn children.  Clin Chem. 2004;  50 1769-1784
    Google Scholar
  • 169 Scott T M, Tucker K L, Bhadelia A, Benjamin B, Patz S, Bhadelia R. et al . Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders.  Am J Geriatr Psychiatry. 2004;  12 631-638
    Google Scholar
  • 170 Sachdev P. Homocysteine, cerebrovascular disease and brain atrophy.  J Neurol Sci. 2004;  226 25-29
    Google Scholar
  • 171 Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people.  Ann Neurol. 2003;  53 214-221
    Google Scholar
  • 172 Wong A, Mok V, Fan Y H, Lam W W, Liang K S, Wong K S. Hyperhomocysteinemia is associated with volumetric white matter change in patients with small vessel disease.  J Neurol. 2006;  253 441-447
    Google Scholar
  • 173 Williams L J, Mai C T, Edmonds L D, Shaw G M, Kirby R S, Hobbs C A. et al . Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States.  Teratology. 2002;  66 33-39
    Google Scholar
  • 174 Sachdev P, Parslow R, Salonikas C, Lux O, Wen W, Kumar R. et al . Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men.  Arch Neurol. 2004;  61 1369-1376
    Google Scholar
  • 175 Kamath A F, Chauhan A K, Kisucka J, Dole V S, Loscalzo J, Handy D E, Wagner D D. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice.  Blood. 2006;  107 591-593
    Google Scholar
  • 176 Lehmann M, Regland B, Blennow K, Gottfries C G. Vitamin B12-B6-folate treatment improves blood-brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment.  Dement Geriatr Cogn Disord. 2003;  16 145-150
    Google Scholar
  • 177 Lipton S A, Kim W K, Choi Y B, Kumar S, D'Emilia D M, Rayudu P V. et al . Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor.  Proc Natl Acad Sci U S A. 1997;  94 5923-5928
    Google Scholar
  • 178 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;  19 599-603
    Google Scholar
  • 179 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 hypersensitivity to excitotoxicity.  J Neurosci. 2000;  20 6920-6936
    Google Scholar
  • 180 Vitvitsky V, Dayal S, Stabler S, Zhou Y, Wang H, Lentz S R, Banerjee R. Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia.  Am J Physiol Regul Integr Comp Physiol. 2004;  287 R39-R46
    Google Scholar
  • 181 Troen A M. The central nervous system in animal models of hyperhomocysteinemia.  Prog Neuropsychopharmacol Biol Psychiatry. 2005;  29 1140-1151
    Google Scholar
  • 182 Watanabe M, Osada J, Aratani Y, Kluckman K, Reddick R, Malinow M R, Maeda N. Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.  Proc Natl Acad Sci USA. 1995;  92 1585-1589
    Google Scholar
  • 183 Algaidi S A, Christie L A, Jenkinson A M, Whalley L, Riedel G, Platt B. Long-term homocysteine exposure induces alterations in spatial learning, hippocampal signalling and synaptic plasticity.  Exp Neurol. 2006;  197 8-21
    Google Scholar
  • 184 Streck E L, Bavaresco C S, Netto C A, Wyse A T. Chronic hyperhomocysteinemia provokes a memory deficit in rats in the Morris water maze task.  Behav Brain Res. 2004;  153 377-381
    Google Scholar
  • 185 Zhang S H, Reddick R L, Piedrahita J A, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.  Science. 1992;  258 468-471
    Google Scholar
  • 186 Ho P I, Collins S C, Dhitavat S, Ortiz D, Ashline D, Rogers E, Shea T B. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress.  J Neurochem. 2001;  78 249-253
    Google Scholar
  • 187 Jara-Prado A, Ortega-Vazquez A, Martinez-Ruano L, Rios C, Santamaria A. Homocysteine-induced brain lipid peroxidation: effects of NMDA receptor blockade, antioxidant treatment, and nitric oxide synthase inhibition.  Neurotox Res. 2003;  5 237-243
    Google Scholar
  • 188 Fuso A, Seminara L, Cavallaro R A, D"Anselmi F, Scarpa S. S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production.  Mol Cell Neurosci. 2005;  28 195-204
    Google Scholar
  • 189 Vafai S B, Stock J B. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's Disease.  FEBS Lett. 2002;  518 1-4
    Google Scholar
  • 190 Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia.  FEBS Lett. 2006;  580 2994-3005
    Google Scholar
  • 191 McCaddon A, Hudson P, Davies G, Hughes A, Williams J H, Wilkinson C. Homocysteine and cognitive decline in healthy elderly.  Dement Geriatr Cogn Disord. 2001;  12 309-313
    Google Scholar
  • 192 Kado D M, Karlamangla A S, Huang M H, Troen A, Rowe J W, Selhub J, Seeman T E. 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;  118 161-167
    Google Scholar
  • 193 Clark M S, Guthrie J R, Dennerstein L. Hyperhomocysteinemia is associated with lower performance on memory tasks in post-menopausal women.  Dement Geriatr Cogn Disord. 2005;  20 57-62
    Google Scholar
  • 194 Lewerin C, Matousek M, Steen G, Johansson B, Steen B, Nilsson-Ehle H. Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study.  Am J Clin Nutr. 2005;  81 1155-1162
    Google Scholar
  • 195 Elias M F, Robbins M A, Budge M M, Elias P K, Brennan S L, Johnston C. et al . Homocysteine, folate, and vitamins B6 and B12 blood levels in relation to cognitive performance: the Maine-Syracuse study.  Psychosom Med. 2006;  68 547-554
    Google Scholar
  • 196 Elias M F, Sullivan L M, D'Agostino R B, Elias P K, Jacques P F, Selhub J. et al . Homocysteine and cognitive performance in the Framingham offspring study: age is important.  Am J Epidemiol. 2005;  162 644-653
    Google Scholar
  • 197 Miller J W, Green R, Ramos M I, Allen L H, Mungas D M, Jagust W J, Haan M N. Homocysteine and cognitive function in the Sacramento Area Latino Study on Aging.  Am J Clin Nutr. 2003;  78 441-447
    Google Scholar
  • 198 Ravaglia G, Forti P, Maioli F, Muscari A, Sacchetti L, Arnone G. et al . Homocysteine and cognitive function in healthy elderly community dwellers in Italy.  Am J Clin Nutr. 2003;  77 668-673
    Google Scholar
  • 199 Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages.  J Nutr. 2002;  132 1345-1356
    Google Scholar
  • 200 Hvas A M, Juul S, Nexo E, Ellegaard J. Vitamin B-12 treatment has limited effect on health-related quality of life among individuals with elevated plasma methylmalonic acid: a randomized placebo-controlled study.  J Intern Med. 2003;  253 146-152
    Google Scholar
  • 201 McCaddon A. Homocysteine and cognitive impairment; a case series in a General Practice setting.  Nutr J. 2006;  5 6
    Google Scholar

Prof. Dr. med. Wolfgang Herrmann

Institut für Kinische Chemie und Laboratoriumsmedizin, Universitätsklinikum des Saarlandes

Kirrberger Straße, Gebäude 57

66421 Homburg

Email: prof.wolfgang.herrmann@uniklinikum-saarland.de

      >