Hyperhomocysteinämie und B-Vitaminmangel bei neurologischen und psychiatrischen Erkrankungen

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
• 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
• 3 Kessler H, Bleich S, Falkai P, Supprian T. Homocysteine and dementia.  Fortschr Neurol Psychiatr. 2003;  71 150-156
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 12 Griffiths R, Tudball N. Observations on the fate of cystathionine in rat brain.  Life Sci. 1976;  19 1217-1224
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 35 McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B(12) deficiency and Alzheimer disease.  Neurology. 2002;  58 1395-1399
• 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
• 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
• 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
• 39 Fassbender K, Mielke O, Bertsch T, Nafe B, Froschen S, Hennerici M. Homocysteine in cerebral macroangiography and microangiopathy.  Lancet. 1999;  353 1586-1587
• 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
• 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
• 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
• 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
• 44 Sachdev P S. Homocysteine and brain atrophy.  Prog Neuropsychopharmacol Biol Psychiatry. 2005;  29 1152-1161
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 52 Malouf R, Grimley E J. The effect of vitamin B₆ on cognition.  Cochrane Database Syst Rev. 2003;  CD004393 1-26
• 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
• 54 Homocysteine Studies Collaboration . Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA. 2002;  288 2015-2022
• 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
• 56 McCully K S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;  56 111-128
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 76 Kuhn W, Roebroek R, Blom H, van O D, Muller T. Hyperhomocysteinaemia in Parkinson's disease.  J Neurol. 1998;  245 811-812
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 90 Aita J F. Why patients with Parkinson's disease fall.  JAMA. 1982;  247 515-516
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 104 Murata S, Naritomi H, Sawada T. MRI in subacute combined degeneration.  Neuroradiology. 1994;  36 408-409
• 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
• 106 Osmond H, Smythies J. Schizophrenia: a new approach.  J Ment Sci. 1952;  98 309-315
• 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
• 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
• 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
• 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
• 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
• 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
• 113 Reynolds E H, Carney M W, Toone B K. Methylation and mood.  Lancet. 1984;  2 196-198
• 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
• 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
• 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
• 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
• 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
• 119 Coppen A, Chaudhry S, Swade C. Folic acid enhances lithium prophylaxis.  J Affect Disord. 1986;  10 9-13
• 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
• 121 Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B₁₂.  J Psychopharmacol. 2005;  19 59-65
• 122 bou-Saleh M T, Coppen A. Folic acid and the treatment of depression.  J Psychosom Res. 2006;  61 285-287
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 130 Neubauer C. Mental deterioration in epilepsy due to folate deficiency.  Br Med J. 1970;  2 759-761
• 131 Freed W J. Selective inhibition of homocysteine-induced seizures by glutamic acid diethyl ester and other glutamate esters.  Epilepsia. 1985;  26 30-36
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 141 Billings R E. Decreased hepatic 5, 10-methylenetetrahydrofolate reductase activity in mice after chronic phenytoin treatment.  Mol Pharmacol. 1984;  25 459-466
• 142 Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation.  J Biol Chem. 2003;  278 27 586-27 592
• 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
• 144 Morrell M J. Guidelines for the care of women with epilepsy.  Neurology. 1998;  51 S21-S27
• 145 Reynolds E H. Mental effects of anticonvulsants, and folic acid metabolism.  Brain. 1968;  91 197-214
• 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
• 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
• 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
• 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
• 150 Hultberg B, Berglund M, Andersson A, Frank A. Elevated plasma homocysteine in alcoholics.  Alcohol Clin Exp Res. 1993;  17 687-689
• 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
• 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
• 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
• 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
• 155 Cooper B A, Rosenblatt D S. Inherited defects of vitamin B₁₂ metabolism.  Annu Rev Nutr. 1987;  7 291-320
• 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
• 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
• 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
• 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
• 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
• 161 Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications.  CMAJ. 2006;  174 341-348
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 170 Sachdev P. Homocysteine, cerebrovascular disease and brain atrophy.  J Neurol Sci. 2004;  226 25-29
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 181 Troen A M. The central nervous system in animal models of hyperhomocysteinemia.  Prog Neuropsychopharmacol Biol Psychiatry. 2005;  29 1140-1151
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 190 Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia.  FEBS Lett. 2006;  580 2994-3005
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 201 McCaddon A. Homocysteine and cognitive impairment; a case series in a General Practice setting.  Nutr J. 2006;  5 6