The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases

Clinical Chemistry and Laboratory Medicine

Volumn 45, Issue 12, 2007, Pages 1590-1606

  Obeid, Rima ^a   McCaddon, Andrew ^b   Herrmann, Wolfgang ^a  

^a SAARLAND UNIVERSITY   (Germany)

^b CARDIFF UNIVERSITY SCHOOL OF MEDICINE   (United Kingdom)

Author keywords

Brain atrophy; Depression; Epilepsy; Homocysteine; Neurodegeneration; Vitamin B group

Indexed keywords

ACETYLCYSTEINE; ANTICONVULSIVE AGENT; ANTIOXIDANT; CATECHOL METHYLTRANSFERASE INHIBITOR; CYANOCOBALAMIN; FLUOXETINE; FOLIC ACID; FOLIC ACID DERIVATIVE; HOMOCYSTEINE; LEVODOPA; LITHIUM; METHOTREXATE; METHYLFOLATE; PYRIDOXINE; RIBOFLAVIN; UNCLASSIFIED DRUG; VALPROIC ACID; VITAMIN B GROUP;

ALZHEIMER DISEASE; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM DISEASE; COGNITION; CONFERENCE PAPER; CYANOCOBALAMIN DEFICIENCY; DEGENERATIVE DISEASE; DEMENTIA; DEPRESSION; EPILEPSY; FOLIC ACID DEFICIENCY; HUMAN; HYPERHOMOCYSTEINEMIA; MENTAL DISEASE; MICROANGIOPATHY; MULTIPLE SCLEROSIS; NEUROLOGIC DISEASE; NEUROTOXICITY; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; RETROSPECTIVE STUDY; STROKE; VASCULAR DISEASE; VITAMIN DEFICIENCY; VITAMIN INTAKE; VITAMIN SUPPLEMENTATION;

CENTRAL NERVOUS SYSTEM DISEASES; HUMANS; HYPERHOMOCYSTEINEMIA; MENTAL DISORDERS; VITAMIN B DEFICIENCY;

EID: 36849077234     PISSN: 14346621     EISSN: 14374331     Source Type: Journal    
DOI: 10.1515/CCLM.2007.356     Document Type: Conference Paper

References (172)

1. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985;37:1-31.
2. Obeid R, Schorr H, Eckert R, Herrmann W. Vitamin B12 status in the elderly as judged by available biochemical markers. Clin Chem 2004;50:238-41.
3. 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;84:1406-11.
4. Goodwin JS, Goodwin JM, Garry PJ. Association between nutritional status and cognitive functioning in a healthy elderly population. J Am Med Assoc 1983;249:2917-21.
5. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-8.
6. Shorvon SD, Carney MW, Chanarin I, Reynolds EH. The neuropsychiatry of megaloblastic anaemia. Br Med J 1980;281:1036-8.
7. Masalha R, Chudakov B, Muhamad M, Rudoy I, Volkov I, Wirguin I. Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency. Isr Med Assoc J 2001;3:701-3.
8. Lorenzl S, Vogeser M, Muller-Schunk S, Pfister HW. Clinically and MRI documented funicular myelosis in a patient with metabolical vitamin B12 deficiency but normal vitamin B12 serum level. J Neurol 2003;250:1010-1.
9. Chadwick LH, McCandless SE, Silverman GL, Schwartz S, Westaway D, Nadeau JH. Betaine-homocysteine methyltransferase-2: cDNA cloning, gene sequence, physical mapping, and expression of the human and mouse genes. Genomics 2000;70:66-73.
10. Scott JM, Molloy AM, Kennedy DG, Kennedy S, Weir DG. Effects of the disruption of transmethylation in the central nervous system: an animal model. Acta Neurol Scand Suppl 1994;154:27-31.
11. Ho PI, Ashline D, Dhitavat S, Ortiz D, Collins SC, Shea TB, et al. Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine. Neurobiol Dis 2003;14:32-42.
12. Quinn CT, Griener JC, Bottiglieri T, Arning E, Winick NJ. Effects of intraventricular methotrexate on folate, adenosine, and homocysteine metabolism in cerebrospinal fluid. J Pediatr Hematol Oncol 2004;26:386-8.
13. 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;338:1547-50.
14. Heinonen K. Studies on cystathionase activity in rat liver and brain during development. Effects of hormones and amino acids in vivo. Biochem J 1973;136:1011-5.
15. Griffiths R, Tudball N. Observations on the fate of cystathionine in rat brain. Life Sci 1976;19:1217-24.
16. 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;35:1331-8.
17. 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;22:11-8.
18. Vitvitsky V, Thomas M, Ghorpade A, Gendelman HE, Banerjee R. A functional transsulfuration pathway in the brain links to glutathione homeostasis. J Biol Chem 2006;281:35785-93.
19. Grieve A, Butcher SP, Griffiths R. Synaptosomal plasma membrane transport of excitatory sulphur amino acid transmitter candidates: kinetic characterisation and analysis of carrier specificity. J Neurosci Res 1992;32:60-8.
20. 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;42:577-82.
21. Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol 1997;26:301-7.
22. 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;77:1836-43.
23. Obeid R, Kostopoulos P, Knapp JP, Kasoha M, Becker G, Fassbender K, et al. Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid. Clin Chem 2007;53:326-33.
24. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-7.
25. Morris MS. Homocysteine and Alzheimer's disease. Lancet Neurol 2003;2:425-8.
26. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr 2000;71:614-20S.
27. Riggs KM, Spiro A III, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 1996;63:306-14.
28. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005;82:636-43.
29. Ramos MI, Allen LH, Mungas DM, Jagust WJ, Haan MN, Green R, et al. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2005;82:1346-52.
30. McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B(12) deficiency and Alzheimer disease. Neurology 2002;58:1395-9.
31. Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 1990;53:1096-8.
32. Serot JM, Christmann D, Dubost T, Bene MC, Faure GC. CSF-folate levels are decreased in late-onset AD patients. J Neural Transm 2001;108:93-9.
33. Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004;80:114-22.
34. Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A, Pennisi G. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med 2004;42:1032-5.
35. Fassbender K, Mielke O, Bertsch T, Nafe B, Froschen S, Hennerici M. Homocysteine in cerebral macroangiography and microangiopathy. Lancet 1999;353:1586-7.
36. Wright CB, Lee HS, Paik MC, Stabler SP, Allen RH, Sacco RL. Total homocysteine and cognition in a tri-ethnic cohort: the Northern Manhattan Study. Neurology 2004;63:254-60.
37. Lehrner J, Gufler R, Guttmann G, Maly J, Gleiss A, Auff E, et al. 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;117:629-35.
38. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476-83.
39. McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 2001;12:309-13.
40. Nurk E, Refsum H, Tell GS, Engedal K, Vollset SE, Ueland PM, et al. Plasma total homocysteine and memory in the elderly: The Hordaland Homocysteine Study. Ann Neurol 2005;58:847-57.
41. Duthie SJ, Whalley LJ, Collins AR, Leaper S, Berger K, Deary IJ. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 2002;75:908-13.
42. Lehmann M, Gottfries CG, Regland B. Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement Geriatr Cogn Disord 1999;10:12-20.
43. Nilsson K, Gustafson L, Hultberg B. Relation between plasma homocysteine and Alzheimer's disease. Dement Geriatr Cogn Disord 2002;14:7-12.
44. Hogervorst E, Ribeiro HM, Molyneux A, Budge M, Smith AD. Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol 2002;59:787-93.
45. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449-55.
46. Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology 2004;63:1187-92.
47. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev 2003;CD004514.
48. Stott DJ, MacIntosh G, Lowe GD, Rumley A, McMahon AD, Langhorne P, et al. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr 2005;82:1320-6.
49. Eussen SJ, de Groot LC, Joosten LW, Bloo RJ, Clarke R, Ueland PM, 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;84:361-70.
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. Malouf R, Grimley EJ. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev 2003;CD004393.
52. Polyak Z, Stern F, Berner YN, Sela BA, Gomori JM, 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.
53. 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;32:1116-9.
54. Bots ML, Launer LJ, Lindemans J, Hoes AW, Hofman A, Witteman JC, 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.
55. Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994;25:1924-30.
56. Sacco RL, Anand K, Lee HS, Boden-Albala B, Stabler S, Allen R, et al. Homocysteine and the risk of ischemic stroke in a triethnic cohort: the Northern Manhattan Study. Stroke 2004;35:2263-9.
57. Giles WH, Croft JB, Greenlund KJ, Ford ES, Kittner SJ. Total homocyst(e)ine concentration and the likelihood of nonfatal stroke: results from the Third National Health and Nutrition Examination Survey, 1988-1994. Stroke 1998;29:2473-7.
58. Vermeer SE, van Dijk EJ, Koudstaal PJ, Oudkerk M, Hofman A, Clarke R, et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Ann Neurol 2002;51:285-9.
59. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J 2002;325:1202.
60. Vermeulen EG, Stehouwer CD, Valk J, van der Knaap M, van den Berg M, Twisk JW, 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;34:256-61.
61. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, 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. J Am Med Assoc 2004;291:565-75.
62. Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention for Stroke Prevention trial: an efficacy analysis. Stroke 2005;36:2404-9.
63. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567-77.
64. Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 2006;113:1335-43.
65. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, 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:e873-923.
66. Blandini F, Fancellu R, Martignoni E, Mangiagalli A, Pacchetti C, Samuele A, et al. Plasma homocysteine and L-dopa metabolism in patients with Parkinson disease. Clin Chem 2001;47:1102-4.
67. Yasui K, Kowa H, Nakaso K, Takeshima T, Nakashima K. Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD. Neurology 2000;55:437-40.
68. de Lau LM, Koudstaal PJ, Witteman JC, Hofman A, Breteler MM. Dietary folate, vitamin B12, and vitamin B6 and the risk of Parkinson disease. Neurology 2006;67:315-8.
69. Yasui K, Nakaso K, Kowa H, Takeshima T, Nakashima K. Levodopa-induced hyperhomocysteinaemia in Parkinson's disease. Acta Neurol Scand 2003;108:66-7.
70. Liu XX, Wilson K, Charlton CG. Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa. Life Sci 2000;66:2277-88.
71. Zhao WQ, Latinwo L, Liu XX, Lee ES, Lamango N, Charlton CG. L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase. Exp Neurol 2001;171:127-38.
72. Werner P, Di Rocco A, Prikhojan A, Rempel N, Bottiglieri T, Bressman S, et al. COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against L-dopa toxicity in vitro. Brain Res 2001;893:278-81.
73. Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, de Mari M, et al. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson's disease patients. Mov Disord 2005;20:69-72.
74. 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;11:253-6.
75. Ostrem JL, Kang GA, Subramanian I, Guarnieri M, Hubble J, Rabinowicz AL, et al. The effect of entacapone on homocysteine levels in Parkinson disease. Neurology 2005;64:1482.
76. Lamberti P, Zoccolella S, Armenise E, Lamberti SV, Fraddosio A, de Mari M, et al. Hyperhomocysteinemia in L-dopa treated Parkinson's disease patients: effect of cobalamin and folate administration. Eur J Neurol 2005;12:365-8.
77. Postuma RB, Espay AJ, Zadikoff C, Suchowersky O, Martin WR, Lafontaine AL, et al. Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study. Neurology 2006;66:1941-3.
78. Irizarry MC, Gurol ME, Raju S, az-Arrastia R, Locascio JJ, Tennis M, et al. Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease. Neurology 2005;65:1402-8.
79. Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL, Mattson MP. Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease. J Neurochem 2002;80:101-10.
80. Lee ES, Chen H, Soliman KF, Charlton CG. Effects of homocysteine on the dopaminergic system and behavior in rodents. Neurotoxicology 2005;26:361-71.
81. O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L, Dewey RB Jr, Bottiglieri T, et al. Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations. Arch Neurol 2004;61:865-8.
82. Rogers JD, Sanchez-Saffon A, Frol AB, az-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease. Arch Neurol 2003;60:59-64.
83. 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;118:1250-5.
84. Aita JF. Why patients with Parkinson's disease fall. J Am Med Assoc 1982;247:515-6.
85. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004;350:2033-41.
86. McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004;350:2042-9.
87. O'Suilleabhain PE, Oberle R, Bartis C, Dewey RB Jr, Bottiglieri T, az-Arrastia R. Clinical course in Parkinson's disease with elevated homocysteine. Parkinsonism Relat Disord 2006;12:103-7.
88. Chen H, Zhang SM, Schwarzschild MA, Hernan MA, Logroscino G, Willett WC, et al. Folate intake and risk of Parkinson's disease. Am J Epidemiol 2004;160:368-75.
89. Nijst TQ, Wevers RA, Schoonderwaldt HC, Hommes OR, de Haan AF. 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;53:951-4.
90. Ramsaransing GS, Fokkema MR, Teelken A, Arutjunyan AV, Koch M, De Keyser J. Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry 2006;77:189-92.
91. Reynolds EH. Multiple sclerosis and vitamin B12 metabolism. J Neuroimmunol 1992;40:225-30.
92. Goodkin DE, Jacobsen DW, Galvez N, Daughtry M, Secic M, Green R. Serum cobalamin deficiency is uncommon in multiple sclerosis. Arch Neurol 1994;51:1110-4.
93. Vrethem M, Mattsson E, Hebelka H, Leerbeck K, Osterberg A, Landtblom AM, 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. Mult Scler 2003;9:239-45.
94. Dalal S, Parkin SM, Homer-Vanniasinkam S, Nicolaou A. Effect of homocysteine on cytokine production by human endothelial cells and monocytes. Ann Clin Biochem 2003;40:534-41.
95. Kim JK, Mastronardi FG, Wood DD, Lubman DM, Zand R, Moscarello MA. Multiple sclerosis: an important role for post-translational modifications of myelin basic protein in pathogenesis. Mol Cell Proteomics 2003;2:453-62.
96. Baldwin GS, Carnegie PR. Specific enzymic methylation of an arginine in the experimental allergic encephalomyelitis protein from human myelin. Science 1971;171:579-81.
97. Mowen KA, Tang J, Zhu W, Schurter BT, Shuai K, Herschman HR, et al. Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription. Cell 2001;104:731-41.
98. Murata S, Naritomi H, Sawada T. MRI in subacute combined degeneration. Neuroradiology 1994;36:408-9.
99. Wade DT, Young CA, Chaudhuri KR, Davidson DL. 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;73:246-9.
100. Osmond H, Smythies J. Schizophrenia: a new approach. J Ment Sci 1952;98:309-15.
101. Cohen SM, Nichols A, Wyatt R, Pollin W. The administration of methionine to chronic schizophrenic patients: a review of ten studies. Biol Psychiatry 1974;8:209-25.
102. Ramos MI, Allen LH, Haan MN, Green R, Miller JW. Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification. Am J Clin Nutr 2004;80:1024-8.
103. Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. 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;157:715-21.
104. Hvas AM, 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;81:269-73.
105. 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;80:1574-8.
106. Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry 2002;159:2099-101.
107. Morris MS, Fava M, Jacques PF, Selhub J, Rosenberg IH. Depression and folate status in the US population. Psychother Psychosom 2003;72:80-7.
108. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228-32.
109. Reynolds EH, Carney MW, Toone BK. Methylation and mood. Lancet 1984;2:196-8.
110. Bottiglieri T, Hyland K, Laundy M, Godfrey P, Carney MW, Toone BK, et al. Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med 1992;22:871-6.
111. Hvas AM, Juul S, Bech P, Nexo E. Vitamin B6 level is associated with symptoms of depression. Psychother Psychosom 2004;73:340-3.
112. 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;76:1158-61S.
113. Kufferle B, Grunberger J. Early clinical double-blind study with S-adenosyl-L-methionine: a new potential antidepressant. Adv Biochem Psychopharmacol 1982;32:175-80.
114. Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 1990;147:591-5.
115. Bell KM, Plon L, Bunney WE Jr, Potkin SG. S-adenosylmethionine treatment of depression: a controlled clinical trial. Am J Psychiatry 1988;145:1110-4.
116. Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336:392-5.
117. Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol 2005;19:59-65.
118. Abou-Saleh MT, Coppen A. Folic acid and the treatment of depression. J Psychosom Res 2006;61:285-7.
119. Freed WJ. Selective inhibition of homocysteine-induced seizures by glutamic acid diethyl ester and other glutamate esters. Epilepsia 1985;26:30-6.
120. 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.
121. 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;46:1677-83.
122. Elliott JO, Jacobson MP, Haneef Z. Homocysteine and bone loss in epilepsy. Seizure 2007;16:22-34.
123. Herrmann M, Wildemann B, Claes L, Klohs S, Ohnmacht M, Taban-Shomal O, et al. Experimental hyperhomocysteinemia reduces bone quality in rats. Clin Chem 2007;53:1455-61.
124. Verrotti A, Pascarella R, Trotta D, Giuva T, Morgese G, Chiarelli F. Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine. Epilepsy Res 2000;41:253-7.
125. Apeland T, Mansoor MA, Strandjord RE, Kristensen O. Homocysteine concentrations and methionine loading in patients on antiepileptic drugs. Acta Neurol Scand 2000;101:217-23.
126. Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology 1992;42:17-24.
127. Reynolds EH. Mental effects of anticonvulsants, and folic acid metabolism. Brain 1968;91:197-214.
128. Edeh J, Toone BK. Antiepileptic therapy, folate deficiency, and psychiatric morbidity: a general practice survey. Epilepsia 1985;26:434-40.
129. Rosche J, Uhlmann C, Froscher W. Low serum folate levels as a risk factor for depressive mood in patients with chronic epilepsy. J Neuropsychiatry Clin Neurosci 2003;15:64-6.
130. Dansky LV, Andermann E, Rosenblatt D, Sherwin AL, Andermann F. Anticonvulsants, folate levels, and pregnancy outcome: a prospective study. Ann Neurol 1987;21:176-82.
131. Hiilesmaa VK, Teramo K, Granstrom ML, Bardy AH. Serum folate concentrations during pregnancy in women with epilepsy: relation to antiepileptic drug concentrations, number of seizures, and fetal outcome. Br Med J (Clin Res Ed) 1983;287:577-9.
132. Sachdev PS, Valenzuela M, Wang XL, Looi JC, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology 2002;58:1539-41.
133. Scott TM, Tucker KL, 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;12:631-8.
134. Sachdev P. Homocysteine, cerebrovascular disease and brain atrophy. J Neurol Sci 2004;226:25-9.
135. Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol 2003;53:214-21.
136. Wong A, Mok V, Fan YH, Lam WW, Liang KS, Wong KS. Hyperhomocysteinemia is associated with volumetric white matter change in patients with small vessel disease. J Neurol 2006;253:441-7.
137. Wright CB, Paik MC, Brown TR, Stabler SP, Allen RH, Sacco RL, et al. Total homocysteine is associated with white matter hyperintensity volume: the Northern Manhattan Study. Stroke 2005;36:1207-11.
138. den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 2003;126:170-5.
139. Williams JH, Pereira EA, Budge MM, Bradley KM. Minimal hippocampal width relates to plasma homocysteine in community-dwelling older people. Age Ageing 2002;31:440-4.
140. 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;61:1369-76.
141. Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, et al. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 2006;107:591-3.
142. Lehmann M, Regland B, Blennow K, Gottfries CG. Vitamin B12-B6-folate treatment improves blood-brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment. Dement Geriatr Cogn Disord 2003;16:145-50.
143. Lipton SA, Kim WK, Choi YB, Kumar S, D'Emilia DM, Rayudu PV, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA 1997;94:5923-8.
144. Parsons RB, Waring RH, Ramsden DB, Williams AC. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines. Neurotoxicology 1998;19:599-603.
145. Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000;20:6920-6.
146. Vitvitsky V, Dayal S, Stabler S, Zhou Y, Wang H, Lentz SR, et al. Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia. Am J Physiol Regul Integr Comp Physiol 2004;287:R39-46.
147. Troen AM. The central nervous system in animal models of hyperhomocysteinemia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1140-51.
148. Watanabe M, Osada J, Aratani Y, Kluckman K, Reddick R, Malinow MR, et al. Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci USA 1995;92:1585-9.
149. Algaidi SA, Christie LA, Jenkinson AM, 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.
150. Streck EL, Bavaresco CS, Netto CA, Wyse AT. Chronic hyperhomocysteinemia provokes a memory deficit in rats in the Morris water maze task. Behav Brain Res 2004;153:377-81.
151. Streck EL, Delwing D, Tagliari B, Matte C, Wannmacher CM, Wajner M, et al. Brain energy metabolism is compromised by the metabolites accumulating in homocystinuria. Neurochem Int 2003;43:597-602.
152. Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003;26:137-46.
153. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992;258:468-71.
154. Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 2001;78:249-53.
155. 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;5:237-43.
156. Fuso A, Seminara L, Cavallaro RA, 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.
157. Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's disease. FEBS Lett 2002;518:1-4.
158. Nilsson K, Gustafson L, Hultberg B. Plasma homocysteine is elevated in elderly patients with memory complaints and vascular disease. Dement Geriatr Cogn Disord 2007;23:321-6.
159. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 2006;580:2994-3005.
160. Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med 2005;118:161-7.
161. Clark MS, Guthrie JR, Dennerstein L. Hyperhomocysteinemia is associated with lower performance on memory tasks in post-menopausal women. Dement Geriatr Cogn Disord 2005;20:57-62.
162. 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;81:1155-62.
163. Elias MF, Robbins MA, Budge MM, Elias PK, Brennan SL, 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;68:547-54.
164. Elias MF, Sullivan LM, D'Agostino RB, Elias PK, Jacques PF, Selhub J, et al. Homocysteine and cognitive performance in the Framingham Offspring Study: age is important. Am J Epidemiol 2005;162:644-53.
165. Miller JW, Green R, Ramos MI, Allen LH, Mungas DM, Jagust WJ, et al. Homocysteine and cognitive function in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2003;78:441-7.
166. 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;77:668-73.
167. McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 2006;354:2764-72.
168. 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;132:1345-56.
169. Hvas AM, 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;253:146-52.
170. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord 2000;60:121-30.
171. Coppen A, Chaudhry S, Swade C. Folic acid enhances lithium prophylaxis. J Affect Disord 1986;10:9-13.
172. McCaddon A. Homocysteine and cognitive impairment; a case series in a General Practice setting. Nutr J 2006;5:6.