Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: Review and treatment recommendations

Expert Review of Neurotherapeutics

Volumn 9, Issue 9, 2009, Pages 1393-1412

  Stanger, Olaf ^a   Fowler, Brian ^b   Pietrzik, Klaus ^c   Huemer, Martina ^d   Haschke Becher, Elisabeth ^a   Semmler, Alexander ^e   Lorenzl, Stefan ^f   Linnebank, Michael ^e  

^a PARACELSUS MEDICAL UNIVERSITY   (Austria)

^b UNIVERSITY CHILDREN S HOSPITAL   (Switzerland)

^c UNIVERSITY OF BONN   (Germany)

^d Hospital Bregenz   (Austria)

^e UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^f LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

Author keywords

Dementia; Folate; Homocysteine; Neuropsychiatric disease; Stroke; Vitamin B 12

Indexed keywords

1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM); ADENOSINE TRIPHOSPHATE; ADENOSYLHOMOCYSTEINASE; AMYLOID BETA PROTEIN; BETA SECRETASE; CALCIUM ION; CATECHOL METHYLTRANSFERASE; COPPER; CYANOCOBALAMIN; CYCLIN B; CYCLIN E; DNA; FOLIC ACID; GAMMA SECRETASE; GLUTAMIC ACID; HOMOCYSTEINE; IRON; MATRIX METALLOPROTEINASE; METHYLMALONIC ACID; METHYLTRANSFERASE; N METHYL DEXTRO ASPARTIC ACID; N(G),N(G) DIMETHYLARGININE; NEUROTRANSMITTER; PROTEIN; REACTIVE OXYGEN METABOLITE; S ADENOSYLMETHIONINE; TETRAHYDROBIOPTERIN; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG;

ALZHEIMER DISEASE; CEREBROVASCULAR DISEASE; DEGENERATIVE DISEASE; DEMENTIA; DEPRESSION; HEALTH CARE COST; HUMAN; MENTAL DISEASE; NEUROLOGIC DISEASE; NEUROPSYCHIATRY; PARKINSON DISEASE; PATHOGENESIS; QUALITY OF LIFE; REVIEW; STROKE; VITAMIN DEFICIENCY;

FOLIC ACID; HOMOCYSTEINE; HUMANS; MENTAL DISORDERS; NERVOUS SYSTEM DISEASES; VITAMIN B 12;

EID: 70349456782     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.09.75     Document Type: Review

References (244)

1. Mental and neurological disorders. World Health Organization fact sheet no.265 December 2001. Indian J. Med. Sci. 56(1), 25-29 (2002).
2. Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur. J. Neurol. 12(Suppl. 1), 1-27 (2005).
3. Murray CJL, Lopez AD. The Global Burden of Disease: a Comprehensive Assesment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020. Global Burden of Disease and Injury Series, Volume 1. Harvard School of Public Health on behalf of the World Health Organization and the World Bank. Harvard University Press, Cambridge, MA, USA (1996).
4. Truelsen T, Piechowski-Jozwiak B, Bonita R, Mathers C, Bogousslavsky J, Boysen G. Stroke incidence and prevalence in Europe: a review of available data. Eur. J. Neurol. 13(6), 581-598 (2006). (Pubitemid 43873630)
5. de Bree A, van Dusseldorp M, Brouwer IA, van het Hof KH, Steegers-Theunissen RP. Folate intake in Europe: recommended, actual and desired intake. Eur. J. Clin. Nutr. 51(10), 643-660 (1997).
6. Eichholzer M, Tonz O, Zimmermann R. Folic acid: a public-health challenge. Lancet 367(9519), 1352-1361 (2006).
7. Al-Tahan J, Gonzalez-Gross M, Pietrzik K. B-vitamin status and intake in European adolescents. A review of the literature. Nutr. Hosp. 21(4), 452-465 (2006). (Pubitemid 44912128)
8. Okun JG, Horster F, Farkas LM et al. Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity. J. Biol. Chem. 277(17), 14674-14680 (2002). (Pubitemid 34952536)
9. Ho PI, Ashline D, Dhitavat S et al. Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine. Neurobiol. Dis. 14(1), 32-42 (2003). (Pubitemid 37103177)
10. Zieminska E, Matyja E, Kozlowska H, Stafiej A, Lazarewicz JW. Excitotoxic neuronal injury in acute homocysteine neurotoxicity: role of calcium and mitochondrial alterations. Neurochem. Int. 48(6-7), 491-497 (2006).
11. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 580(13), 2994-3005 (2006). (Pubitemid 43744523)
12. Bisschops RH, van der Graaf Y, Mali WP, van der Grond J. Elevated levels of plasma homocysteine are associated with neurotoxicity. Atherosclerosis 174(1), 87-92 (2004).
13. Selhub J. Public health significance of elevated homocysteine. Food Nutr. Bull. 29(2 Suppl.), S116-S125 (2008).
14. Obeid R, McCaddon A, Herrmann W. The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. Clin. Chem. Lab. Med. 45(12), 1590-1606 (2007). (Pubitemid 350232981)
15. Fowler B. Homocysteine: overview of biochemistry, molecular biology, and role in disease processes. Semin. Vasc. Med. 5(2), 77-86 (2005). (Pubitemid 40944284)
16. Chiang PK, Gordon RK, Tal J et al. S-adenosylmethionine and methylation. FASEB J. 10(4), 471-480 (1996).
17. Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 48(2), 137-152 (1994). (Pubitemid 24260350)
18. Axelrod J. Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol. Rev. 18(1), 95-113 (1966).
19. McKeever M, Molloy A, Weir DG et al. An abnormal methylation ratio induces hypomethylation in vitro in the brain of pig and man, but not in rat. Clin. Sci. (Lond.) 88(1), 73-79 (1995).
20. Weir DG, Molloy AM, Keating JN et al. Correlation of the ratio of S-adenosyl-lmethionine to S-adenosyl-l-homocysteine in the brain and cerebrospinal fluid of the pig: implications for the determination of this methylation ratio in human brain. Clin. Sci. (Lond.) 82(1), 93-97 (1992).
21. Smulders YM, Smith DE, Kok RM et al. Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap. Br. J. Haematol. 132(5), 623-629 (2006).
22. Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338(8782-8783), 1550-1554 (1991).
23. Sunden SL, Renduchintala MS, Park EI, Miklasz SD, Garrow TA. Betainehomocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene. Arch. Biochem. Biophys. 345(1), 171-174 (1997).
24. Finkelstein JD. Pathways and regulation of homocysteine metabolism in mammals. Semin. Thromb. Hemost. 26(3), 219-225 (2000).
25. Vitvitsky V, Thomas M, Ghorpade A, Gendelman HE, Banerjee R. A functional transsulfuration pathway in the brain links to glutathione homeostasis. J. Biol. Chem. 281(47), 35785-35793 (2006). (Pubitemid 46041310)
26. Spector R, Coakley G, Blakely R. Methionine recycling in brain: a role for folates and vitamin B-12. J. Neurochem. 34(1), 132-137 (1980). (Pubitemid 10172688)
27. Cobalamin deficiency and neuropsychiatric disorders. N. Engl. J. Med. 319(26), 1733-1735 (1988).
28. Kolker S, Ahlemeyer B, Krieglstein J, Hoffmann GF. Methylmalonic acid induces excitotoxic neuronal damage in vitro. J. Inherit. Metab. Dis. 23(4), 355-358 (2000). (Pubitemid 30364770)
29. Kamen BA, Smith AK. A review of folate receptor a cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv. Drug Deliv. Rev. 56(8), 1085-1097 (2004).
30. Wollack JB, Makori B, Ahlawat S et al. Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model. J. Neurochem. 104(6), 1494-1503 (2008). (Pubitemid 351316763)
31. Ramaekers VT, Blau N. Cerebral folate deficiency. Dev. Med. Child Neurol. 46(12), 843-851 (2004).
32. Reynolds EH, Gallagher BB, Mattson RH, Bowers M, Johnson AL. Relationship between serum and cerebrospinal fluid folate. Nature 240(5377), 155-157 (1972).
33. Spector R, Eells J. Deoxynucleoside and vitamin transport into the central nervous system. Fed. Proc. 43(2), 196-200 (1984). (Pubitemid 14185137)
34. Spector R, Johanson CE. Vitamin transport and homeostasis in mammalian brain: focus on vitamins B and E. J. Neurochem. 103(2), 425-438 (2007). (Pubitemid 47498022)
35. Sharma P, Senthilkumar RD, Brahmachari V et al. Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies. Lipids Health Dis. 5, 1 (2006).
36. Gellekink H, den Heijer M, Heil SG, Blom HJ. Genetic determinants of plasma total homocysteine. Semin. Vasc. Med. 5(2), 98-109 (2005). (Pubitemid 40944286)
37. Frosst P, Blom HJ, Milos R et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10(1), 111-113 (1995).
38. Jacques PF, Bostom AG, Williams RR et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93(1), 7-9 (1996).
39. Kauwell GP, Wilsky CE, Cerda JJ et al. Methylenetetrahydrofolate reductase mutation (677C - >T) negatively influences plasma homocysteine response to marginal folate intake in elderly women. Metabolism 49(11), 1440-1443 (2000).
40. Malinow MR, Nieto FJ, Kruger WD et al. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler. Thromb. Vasc. Biol. 17(6), 1157-1162 (1997).
41. Fohr IP, Prinz-Langenohl R, Bronstrup A et al. 5,10- Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am. J. Clin. Nutr. 75(2), 275-282 (2002). (Pubitemid 34101212)
42. de Bree A, Verschuren WM, Bjorke- Monsen AL et al. Effect of the methylenetetrahydrofolate reductase 677C - >T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample. Am. J. Clin. Nutr. 77(3), 687-693 (2003).
43. Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 98(23), 2520-2526 (1998). (Pubitemid 29001189)
44. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C - >T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288(16), 2023-2031 (2002). (Pubitemid 35204693)
45. Harmon DL, Doyle RM, Meleady R et al. Genetic analysis of the thermolabile variant of 5, 10-methylenetetrahydrofolate reductase as a risk factor for ischemic stroke. Arterioscler. Thromb. Vasc. Biol. 19(2), 208-211 (1999). (Pubitemid 29072731)
46. Dierkes J, Jeckel A, Ambrosch A, Westphal S, Luley C, Boeing H. Factors explaining the difference of total homocysteine between men and women in the european investigation into cancer and nutrition potsdam study. Metabolism 50(6), 640-645 (2001). (Pubitemid 32551815)
47. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270(22), 2693-2698 (1993). (Pubitemid 23350966)
48. Norlund L, Grubb A, Fex G et al. The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin. Chem. Lab. Med. 36(3), 175-178 (1998). (Pubitemid 28185327)
49. Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am. J. Clin. Nutr. 73(3), 613-621 (2001). (Pubitemid 32176514)
50. Anello G, Gueant-Rodriguez RM, Bosco P et al. Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer's disease. Neuroreport 15(5), 859-861 (2004). (Pubitemid 38453474)
51. Nishiyama M, Kato Y, Hashimoto M, Yukawa S, Omori K. Apolipoprotein E, methylenetetrahydrofolate reductase (MTHFR) mutation and the risk of senile dementia - an epidemiological study using the polymerase chain reaction (PCR) method. J. Epidemiol. 10(3), 163-172 (2000).
52. Kelly PJ, Rosand J, Kistler JP et al. Homocysteine, MTHFR 677C - >T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology 59(4), 529-536 (2002). (Pubitemid 34919985)
53. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288(16), 2015-2022 (2002).
54. Wullner U, Kolsch H, Linnebank M. Methylenetetrahydrofolate reductase in Parkinson's disease. Ann. Neurol. 58(6), 972-973 (2005).
55. Linnebank M, Linnebank A, Jeub M et al. Lack of genetic dispositions to hyperhomocysteinemia in Alzheimer disease. Am. J. Med. Genet. A. 131(1), 101-102 (2004). (Pubitemid 39434804)
56. Skibola CF, Smith MT, Kane E et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc. Natl Acad. Sci. USA 96(22), 12810-12815 (1999). (Pubitemid 29513584)
57. Matsuo K, Hamajima N, Suzuki R et al. Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. Am. J. Hematol. 77(4), 351-357 (2004). (Pubitemid 39578315)
58. Keku T, Millikan R, Worley K et al. 5,10-methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epidemiol. Biomarkers Prev. 11(12), 1611-1621 (2002). (Pubitemid 36020015)
59. Wang J, Gajalakshmi V, Jiang J et al. Associations between 5,10-methylenetetrahydrofolate reductase codon 677 and 1298 genetic polymorphisms and environmental factors with reference to susceptibility to colorectal cancer: a case- control study in an Indian population. Int. J. Cancer 118(4), 991-997 (2006). (Pubitemid 43157676)
60. van der Put NM, Gabreels F, Stevens EM et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am. J. Hum. Genet. 62(5), 1044-1051 (1998). (Pubitemid 28199004)
61. Linnebank M, Schmidt S, Kolsch H et al. The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma. Br. J. Cancer 90(10), 1969-1971 (2004).
62. Semmler A, Simon M, Moskau S, Linnebank M. The methionine synthase polymorphism c.2756A>G alters susceptibility to glioblastoma multiforme. Cancer Epidemiol. Biomarkers Prev. 15(11), 2314-2316 (2006). (Pubitemid 44877063)
63. Semmler A, Simon M, Moskau S, Linnebank M. Polymorphisms of methionine metabolism and susceptibility to meningioma formation: laboratory investigation. J. Neurosurg. 108(5), 999-1004 (2008). (Pubitemid 351656849)
64. Semmler A, Linnebank M, Krex D et al. Polymorphisms of homocysteine metabolism are associated with intracranial aneurysms. Cerebrovasc. Dis. 26(4), 425-429 (2008).
65. Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. NeuroPediatrics 33(6), 301-308 (2002). (Pubitemid 36222142)
66. Ramaekers VT, Rothenberg SP, Sequeira JM et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N. Engl. J. Med. 352(19), 1985-1991 (2005).
67. Fowler B. Genetic defects of folate and cobalamin metabolism. Eur. J. Pediatr. 157(Suppl. 2), S60-S66 (1998). (Pubitemid 128684219)
68. Yap S, Naughten E. Homocystinuria due to cystathionine β-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J. Inherit. Metab. Dis. 21(7), 738-747 (1998). (Pubitemid 28477146)
69. Yap S. Classical homocystinuria: vascular risk and its prevention. J. Inherit. Metab. Dis. 26(2-3), 259-265 (2003). (Pubitemid 36889746)
70. Lovblad K, Ramelli G, Remonda L, Nirkko AC, Ozdoba C, Schroth G. Retardation of myelination due to dietary vitamin B12 deficiency: cranial MRI findings. Pediatr. Radiol. 27(2), 155-158 (1997). (Pubitemid 27101782)
71. Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin. Hematol. 36(1), 19-34 (1999).
72. Rosenberg IH, Miller JW. Nutritional factors in physical and cognitive functions of elderly people. Am. J. Clin. Nutr. 55(6 Suppl.), 1237S-1243S (1992).
73. Muller WH, Froscher W. Neurologic and psychologic disorders in folic acid deficiency. Fortschr. Neurol. Psychiatr. 57(9), 395-401 (1989). (Pubitemid 19233886)
74. Savage DG, Lindenbaum J. Neurological complications of acquired cobalamin deficiency: clinical aspects. Baillieres Clin. Haematol. 8(3), 657-678 (1995).
75. Lindenbaum J, Healton EB, Savage DG et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N. Engl. J. Med. 318(26), 1720-1728 (1988). (Pubitemid 18156673)
76. Stanger O, Herrmann W, Pietrzik K et al. Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases. Z. Kardiol. 93(6), 439-453 (2004). (Pubitemid 38858323)
77. Clayton PT. B6-responsive disorders: a model of vitamin dependency. J. Inherit. Metab. Dis. 29(2-3), 317-326 (2006).
78. Hvas AM, Juul S, Bech P, Nexo E. Vitamin B6 level is associated with symptoms of depression. Psychother. Psychosom. 73(6), 340-343 (2004). (Pubitemid 39370522)
79. Robinson K, Arheart K, Refsum H et al. Low circulating folate and vitamin B6 concentrations: risk factors for Stroke peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation 97(5), 437-443 (1998). (Pubitemid 28090214)
80. Clarke R, Grimley Evans J, Schneede J et al. Vitamin B12 and folate deficiency in later life. Age Ageing 33(1), 34-41 (2004). (Pubitemid 38111446)
81. Bottiglieri T, Reynolds EH, Laundy M. Folate in CSF and age. J. Neurol. Neurosurg. Psychiatry 69(4), 562 (2000).
82. Reynolds EH. Folic acid, ageing, depression, and dementia. BMJ 324(7352), 1512-1515 (2002).
83. Fabian E, Elmadfa I. Nutritional situation of the elderly in the European Union: data of the European Nutrition and Health Report (2004). Ann. Nutr. Metab. 52(Suppl. 1), 57-61 (2008).
84. Domagala TB, Undas A, Libura M, Szczeklik A. Pathogenesis of vascular disease in hyperhomocysteinaemia. J. Cardiovasc. Risk 5(4), 239-247 (1998).
85. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 365(9455), 224-232 (2005). (Pubitemid 40138016)
86. Wang X, Qin X, Demirtas H et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 369(9576), 1876-1882 (2007).
87. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325(7374), 1202 (2002). (Pubitemid 35398783)
88. Bazzano LA, He J, Ogden LG et al. Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. Stroke 33(5), 1183-1188 (2002).
89. Bostom AG, Rosenberg IH, Silbershatz H et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann. Intern. Med. 131(5), 352-355 (1999). (Pubitemid 29424629)
90. Bots ML, Launer LJ, Lindemans J et al. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study. Arch. Intern. Med. 159(1), 38-44 (1999). (Pubitemid 29044117)
91. Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention For Stroke Prevention trial: an efficacy analysis. Stroke 36(11), 2404-2409 (2005). (Pubitemid 41566967)
92. Lonn E, Yusuf S, Arnold MJ et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N. Engl. J. Med. 354(15), 1567-1577 (2006).
93. Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E. Homocysteinelowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke 40(4), 1365-1372 (2009).
94. Bonaa KH, Njolstad I, Ueland PM et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N. Engl. J. Med. 354(15), 1578-1588 (2006).
95. Yang Q, Botto LD, Erickson JD et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 113(10), 1335-1343 (2006).
96. Clarke R, Lewington S, Sherliker P, Armitage J. Effects of B-vitamins on plasma homocysteine concentrations and on risk of cardiovascular disease and dementia. Curr. Opin. Clin. Nutr. Metab. Care 10(1), 32-39 (2007). (Pubitemid 44901131)
97. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am. Heart J. 151(2), 282-287 (2006).
98. Hofman A, Ott A, Breteler MM et al. Atherosclerosis apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 349(9046), 151-154 (1997). (Pubitemid 27039193)
99. Katzman R. Luigi Amaducci memorial award winner's paper 2003. A neurologist's view of Alzheimer's disease and dementia. Int. Psychogeriatr. 16(3), 259-273 (2004).
100. Sachdev PS, Valenzuela MJ, Brodaty H et al. Homocysteine as a risk factor for cognitive impairment in stroke patients. Dement. Geriatr. Cogn. Disord. 15(3), 155-162 (2003). (Pubitemid 36206645)
101. Longstreth WT Jr, Katz R, Olson J et al. Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons: the Cardiovascular Health Study. Arch. Neurol. 61(1), 67-72 (2004). (Pubitemid 38067416)
102. Fassbender K, Mielke O, Bertsch T, Nafe B, Froschen S, Hennerici M. Homocysteine in cerebral macroangiography and microangiopathy. Lancet 353(9164), 1586-1587 (1999).
103. Kruman, II, Kumaravel TS, Lohani A et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J. Neurosci. 22(5), 1752-1762 (2002). (Pubitemid 35386293)
104. Ho PI, Ortiz D, Rogers E, Shea TB. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J. Neurosci. Res. 70(5), 694-702 (2002). (Pubitemid 35397143)
105. Linnebank M, Lutz H, Jarre E et al. Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells. Neurobiol. Dis. 23(3), 725-730 (2006). (Pubitemid 44234108)
106. Evin G, Zhu A, Holsinger RM, Masters CL, Li QX. Proteolytic processing of the Alzheimer's disease amyloid precursor protein in brain and platelets. J. Neurosci. Res. 74(3), 386-392 (2003). (Pubitemid 37362815)
107. Gopalakrishnan S, Van Emburgh BO, Robertson KD. DNA methylation in development and human disease. Mutat. Res. 647(1-2), 30-38 (2008).
108. Finkelstein JD. The metabolism of homocysteine: pathways and regulation. Eur. J. Pediatr. 157 (Suppl. 2) S40-S44 (1998).
109. Yi P, Melnyk S, Pogribna M, Pogribny IP, Hine RJ, James SJ. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J. Biol. Chem. 275(38), 29318-29323 (2000). (Pubitemid 32043802)
110. Scarpa S, Fuso A, D'Anselmi F, Cavallaro RA. Presenilin 1 gene silencing by S-adenosylmethionine: a treatment for Alzheimer disease? FEBS Lett. 541(1-3), 145-148 (2003). (Pubitemid 36428933)
111. 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 β-amyloid production. Mol. Cell. Neurosci. 28(1), 195-204 (2005). (Pubitemid 39656023)
112. Chan A, Shea TB. Folate deprivation increases presenilin expression, γ-secretase activity, and Aβ levels in murine brain: potentiation by ApoE deficiency and alleviation by dietary S-adenosyl methionine. J. Neurochem. 102(3), 753-760 (2007). (Pubitemid 47057297)
113. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 5(3), 228-234 (2006). (Pubitemid 43238346)
114. Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's disease. FEBS Lett. 518(1-3), 1-4 (2002).
115. Sontag E, Nunbhakdi-Craig V, Lee G, Bloom GS, Mumby MC. Regulation of the phosphorylation state and microtubulebinding activity of Tau by protein phosphatase 2A. Neuron 17(6), 1201-1207 (1996). (Pubitemid 27021104)
116. Sontag E, Nunbhakdi-Craig V, Sontag JM et al. Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J. Neurosci. 27(11), 2751-2759 (2007). (Pubitemid 46438990)
117. Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. J. Neurochem. 67(3), 1328-1331 (1996).
118. Bottiglieri T, Reynolds EH, Toone BK, Carney MW. CSF S-adenosylmethionine in neuropsychiatric disorders. Lancet 338(8759), 121 (1991).
119. Kennedy BP, Bottiglieri T, Arning E, Ziegler MG, Hansen LA, Masliah E. Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function. J. Neural Transm. 111(4), 547-567 (2004). (Pubitemid 38478922)
120. Shea TB, Chan A. S-adenosyl methionine: a natural therapeutic agent effective against multiple hallmarks and risk factors associated with Alzheimer's disease. J. Alzheimers Dis. 13(1), 67-70 (2008).
121. Topal G, Brunet A, Millanvoye E et al. Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. Free Radic. Biol. Med. 36(12), 1532-1541 (2004). (Pubitemid 38746561)
122. Finkelstein JD. Methionine metabolism in mammals. J. Nutr. Biochem. 1(5), 228-237 (1990).
123. Ishii I, Akahoshi N, Yu XN et al. Murine cystathionine gamma-lyase: complete cDNA and genomic sequences, promoter activity, tissue distribution and developmental expression. Biochem. J. 381(Pt 1), 113-123 (2004). (Pubitemid 38932217)
124. Vitvitsky V, Dayal S, Stabler S et al. Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287(1), R39-R46 (2004). (Pubitemid 38856309)
125. Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am. J. Clin. Nutr. 55(1), 131-138 (1992).
126. Mudd SH, Levy HL, Kraus JP. Disorders of transsulfuration. In: The Metabolic and Molecular Bases of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, Vogelstein B. (Eds). McGraw-Hill, NY, USA 2007-2056 (2001).
127. Serot JM, Christmann D, Dubost T, Bene MC, Faure GC. CSF-folate levels are decreased in late-onset AD patients. J. Neural Transm. 108(1), 93-99 (2001). (Pubitemid 32692616)
128. Kristensen MO, Gulmann NC, Christensen JE, Ostergaard K, Rasmussen K. Serum cobalamin and methylmalonic acid in Alzheimer dementia. Acta Neurol. Scand, 87(6), 475-481 (1993). (Pubitemid 23187978)
129. Lewis MS, Miller LS, Johnson MA, Dolce EB, Allen RH, Stabler SP. Elevated methylmalonic acid is related to cognitive impairement in older adults enrolled in an elderly nutrition program. J. Nutr. Elder 24(3), 47-65 (2005).
130. Refsum H, Smith AD. Low vitamin B-12 status in confirmed Alzheimer's disease as revealed by serum holotranscobalamin. J. Neurol. Neurosurg. Psychiatry 74(7), 959-961 (2003). (Pubitemid 36783006)
131. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology 56(9), 1188-1194 (2001).
132. McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B(12) deficiency and Alzheimer disease. Neurology 58(9), 1395-1399 (2002). (Pubitemid 34507168)
133. Leblhuber F, Walli J, Artner-Dworzak E et al. Hyperhomocysteinemia in dementia. J. Neural Transm. 107(12), 1469-1474 (2000).
134. Morris MS. Homocysteine and Alzheimer's disease. Lancet Neurol. 2(7), 425-428 (2003).
135. Lehmann M, Gottfries CG, Regland B. Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement. Geriatr. Cogn. Disord. 10(1), 12-20 (1999). (Pubitemid 28567038)
136. Nilsson K, Gustafson L, Hultberg B. Plasma homocysteine concentration relates to the severity but not to the duration of Alzheimer's disease. Int. J. Geriatr. Psychiatry 19(7), 666-672 (2004). (Pubitemid 38996844)
137. Nilsson K, Gustafson L, Hultberg B. The plasma homocysteine concentration is better than that of serum methylmalonic acid as a marker for sociopsychological performance in a psychogeriatric population. Clin. Chem. 46(5), 691-696 (2000). (Pubitemid 30318425)
138. 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 63(2), 254-260 (2004).
139. den Heijer T, Vermeer SE, Clarke R et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126(Pt 1), 170-175 (2003). (Pubitemid 36068567)
140. Scott TM, Tucker KL, Bhadelia A et al. Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders. Am. J. Geriatr. Psychiatry 12(6), 631-638 (2004). (Pubitemid 41031065)
141. Sachdev P. Homocysteine, cerebrovascular disease and brain atrophy. J. Neurol. Sci. 226(1-2), 25-29 (2004). (Pubitemid 39505400)
142. Snowdon DA, Tully CL, Smith CD, Riley KP, Markesbery WR. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study. Am. J. Clin. Nutr. 71(4), 993-998 (2000).
143. 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. 55(11), 1449-1455 (1998). (Pubitemid 28525506)
144. Williams JH, Pereira EA, Budge MM, Bradley KM. Minimal hippocampal width relates to plasma homocysteine in community-dwelling older people. Age Ageing 31(6), 440-444 (2002).
145. Kado DM, Karlamangla AS, Huang MH 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. 118(2), 161-167 (2005).
146. Maxwell CJ, Hogan DB, Ebly EM. Serum folate levels and subsequent adverse cerebrovascular outcomes in elderly persons. Dement. Geriatr. Cogn. Disord. 13(4), 225-234 (2002).
147. Ravaglia G, Forti P, Maioli F et al. Conversion of mild cognitive impairment to dementia: predictive role of mild cognitive impairment subtypes and vascular risk factors. Dement. Geriatr. Cogn. Disord. 21(1), 51-58 (2006). (Pubitemid 41797971)
148. McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly. Dement. Geriatr. Cogn. Disord. 12(5), 309-313 (2001). (Pubitemid 32656662)
149. Seshadri S, Beiser A, Selhub J et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N. Engl. J. Med. 346(7), 476-483 (2002). (Pubitemid 34441738)
150. Clarke R, Birks J, Nexo E et al. Low vitamin B-12 status and risk of cognitive decline in older adults. Am. J. Clin. Nutr. 86(5), 1384-1391 (2007). (Pubitemid 350126242)
151. Hin H, Clarke R, Sherliker P et al. Clinical relevance of low serum
152. Miller JW, Green R, Ramos MI et al. Homocysteine and cognitive function in the sacramento area latino study on aging. Am. J. Clin. Nutr. 78(3), 441-447 (2003). (Pubitemid 39663511)
153. Haan MN, Miller JW, Aiello AE et al. Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the sacramento area latino study on aging. Am. J. Clin. Nutr. 85(2), 511-517 (2007).
154. Blasko I, Jellinger K, Kemmler G et al. Conversion from cognitive health to mild cognitive impairment and Alzheimer's disease: prediction by plasma amyloid β 42, medial temporal lobe atrophy and homocysteine. Neurobiol. Aging 29(1), 1-11 (2008). (Pubitemid 350102708)
155. Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann. Neurol. 53(2), 214-221 (2003). (Pubitemid 36164003)
156. Luchsinger JA, Tang MX, Miller J, Green R, Mayeux R. Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch. Neurol. 64(1), 86-92 (2007). (Pubitemid 46072428)
157. Durga J, van Boxtel MP, Schouten EG et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 369(9557), 208-216 (2007). (Pubitemid 46107683)
158. Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst. Rev. (4), CD004514 (2008).
159. Elias MF, Sullivan LM, D'Agostino RB et al. Homocysteine and cognitive performance in the Framingham offspring study: age is important. Am. J. Epidemiol. 162(7), 644-653 (2005).
160. 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. 16(3), 145-150 (2003). (Pubitemid 36737000)
161. VanItallie TB. Subsyndromal depression in the elderly: underdiagnosed and undertreated. Metabolism 54(5 Suppl. 1), 39-44 (2005).
162. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J. Neurol. Neurosurg. Psychiatr. 69(2), 228-232 (2000). (Pubitemid 30466029)
163. Carney MW, Chary TK, Laundy M et al. Red cell folate concentrations in psychiatric patients. J. Affect Disord. 19(3), 207-213 (1990). (Pubitemid 20209137)
164. Shorvon SD, Carney MW, Chanarin I, Reynolds EH. The neuropsychiatry of megaloblastic anaemia. Br. Med. J. 281(6247), 1036-1038 (1980).
165. Surtees R, Heales S, Bowron A. Association of cerebrospinal fluid deficiency of 5-methyltetrahydrofolate, but not S-adenosylmethionine, with reduced concentrations of the acid metabolites of 5-hydroxytryptamine and dopamine. Clin. Sci. (Lond.) 86(6), 697-702 (1994). (Pubitemid 24181962)
166. Bottiglieri T, Hyland K, Laundy M et al. Folate deficiency, biopterin and monoamine metabolism in depression. Psychol. Med. 22(4), 871-876 (1992). (Pubitemid 23006998)
167. Wesson VA, Levitt AJ, Joffe RT. Change in folate status with antidepressant treatment. Psychiatry Res. 53(3), 313-322 (1994).
168. Godfrey PS, Toone BK, Carney MW et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336(8712), 392-395 (1990).
169. 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. 15(1), 64-66 (2003). (Pubitemid 36168081)
170. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr. Rev. 55(5), 145-149 (1997).
171. Papakostas GI, Petersen T, Lebowitz BD et al. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int. J. Neuropsychopharmacol. 8(4), 523-528 (2005). (Pubitemid 41400882)
172. Papakostas GI, Petersen T, Mischoulon D et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J. Clin. Psychiatry 65(8), 1096-1098 (2004).
173. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J. Affect Disord. 60(2), 121-130 (2000). (Pubitemid 30680129)
174. 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. 80(4), 1024-1028 (2004).
175. Kendrick T, Dunn N, Robinson S et al. A longitudinal study of blood folate levels and depressive symptoms among young women in the Southampton Women's Survey. J. Epidemiol. Community Health 62(11), 966-972 (2008).
176. Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am. J. Epidemiol. 165(1), 1-13 (2007). (Pubitemid 46026203)
177. Alpert M, Silva RR, Pouget ER. Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. J. Clin. Psychopharmacol. 23(3), 309-313 (2003). (Pubitemid 36807797)
178. Reynolds EH, Carney MW, Toone BK. Methylation and mood. Lancet 2(8396), 196-198 (1984).
179. Otero-Losada ME, Rubio MC. Acute changes in 5-HT metabolism after S-adenosyl-L-methionine administration. Gen. Pharmacol. 20(4), 403-406 (1989).
180. Losada ME, Rubio MC. Acute effects of S-adenosyl-L-methionine on catecholaminergic central function. Eur. J. Pharmacol. 163(2-3), 353-356 (1989).
181. 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. Psychiatr. 53(12), 1096-1098 (1990).
182. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol. Scand. Suppl. 154, 7-14 (1994).
183. Miller DB, O'Callaghan JP. Depression, cytokines, and glial function. Metabolism 54(5 Suppl. 1), 33-38 (2005).
184. Passeri M, Cucinotta D, Abate G et al. Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano) 5(1), 63-71 (1993). (Pubitemid 23117911)
185. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr. Clin. North Am. 19(2), 179-200 (1996).
186. Chen H, Zhang SM, Schwarzschild MA et al. Folate intake and risk of Parkinson's disease. Am. J. Epidemiol. 160(4), 368-375 (2004). (Pubitemid 39045268)
187. 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 67(2), 315-318 (2006).
188. Rogers JD, Sanchez-Saffon A, Frol AB, Diaz-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease. Arch. Neurol. 60(1), 59-64 (2003). (Pubitemid 36078109)
189. O'Suilleabhain PE, Sung V, Hernandez C et al. Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations. Arch. Neurol. 61(6), 865-868 (2004). (Pubitemid 38747325)
190. Muller T, Woitalla D, Hauptmann B, Fowler B, Kuhn W. Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson's disease. Neurosci. Lett. 308(1), 54-56 (2001). (Pubitemid 32607679)
191. Muller T, Werne B, Fowler B, Kuhn W. Nigral endothelial dysfunction, homocysteine, and Parkinson's disease. Lancet 354(9173), 126-127 (1999). (Pubitemid 29313150)
192. Cheng H, Gomes-Trolin C, Aquilonius SM et al. Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adenosylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinson's disease. Exp. Neurol. 145(2 Pt 1), 580-585 (1997). (Pubitemid 27314809)
193. 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. 171(1), 127-138 (2001). (Pubitemid 32848451)
194. Muller T, Woitalla D, Fowler B, Kuhn W. 3-OMD and homocysteine plasma levels in parkinsonian patients. J. Neural Transm. 109(2), 175-179 (2002). (Pubitemid 34185663)
195. Lamberti P, Zoccolella S, Iliceto G et al. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson's disease patients. Mov. Disord. 20(1), 69-72 (2005). (Pubitemid 40277507)
196. Irizarry MC, Gurol ME, Raju S et al. Association of homocysteine with plasma amyloid b protein in aging and neurodegenerative disease. Neurology 65(9), 1402-1408 (2005). (Pubitemid 41552769)
197. Korten A, Lodder J, Vreeling F, Boreas A, van Raak L, Kessels F. Stroke and idiopathic Parkinson's disease: does a shortage of dopamine offer protection against stroke? Mov. Disord. 16(1), 119-123 (2001). (Pubitemid 36041125)
198. McCann SJ, LeCouteur DG, Green AC et al. The epidemiology of Parkinson's disease in an Australian population. Neuroepidemiology 17(6), 310-317 (1998).
199. Emre M. Dementia associated with Parkinson's disease. Lancet Neurol. 2(4), 229-237 (2003).
200. Ozer F, Meral H, Hanoglu L et al. Plasma homocysteine levels in patients treated with levodopa: motor and cognitive associations. Neurol. Res. 28(8), 853-858 (2006). (Pubitemid 44904462)
201. Zoccolella S, Lamberti P, Iliceto G et al. Plasma homocysteine levels in L-dopatreated Parkinson's disease patients with cognitive dysfunctions. Clin. Chem. Lab. Med. 43(10), 1107-1110 (2005). (Pubitemid 41581969)
202. Applebaum J, Shimon H, Sela BA, Belmaker RH, Levine J. Homocysteine levels in newly admitted schizophrenic patients. J. Psychiatr. Res. 38(4), 413-416 (2004). (Pubitemid 38760009)
203. Goff DC, Bottiglieri T, Arning E et al. Folate, homocysteine, and negative symptoms in schizophrenia. Am.J. Psychiatry 161(9), 1705-1708 (2004). (Pubitemid 39201472)
204. Shi J, Gershon ES, Liu C. Genetic associations with schizophrenia: Metaanalyses of 12 candidate genes. Schizophr. Res. 104(1-3), 96-107 (2008).
205. Miodownik C, Lerner V, Vishne T, Sela BA, Levine J. High-dose vitamin B6 decreases homocysteine serum levels in patients with schizophrenia and schizoaffective disorders: a preliminary study. Clin. Neuropharmacol. 30(1), 13-17 (2007). (Pubitemid 46204313)
206. Levine J, Stahl Z, Sela BA et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol. Psychiatry 60(3), 265-269 (2006). (Pubitemid 44093437)
207. Ozbek Z, Kucukali CI, Ozkok E et al. Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives. Prog. Neuropsychopharmacol. Biol. Psychiatry 32(5), 1331-1337 (2008).
208. Reif A, Pfuhlmann B, Lesch KP. Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Prog. Neuropsychopharmacol. Biol. Psychiatry 29(7), 1162-1168 (2005). (Pubitemid 41383515)
209. Dittmann S, Seemuller F, Grunze HC et al. The impact of homocysteine levels on cognition in euthymic bipolar patients: a cross-sectional study. J. Clin. Psychiatry 69(6), 899-906 (2008). (Pubitemid 351944941)
210. Dittmann S, Seemuller F, Schwarz MJ et al. Association of cognitive deficits with elevated homocysteine levels in euthymic bipolar patients and its impact on psychosocial functioning: preliminary results. Bipolar Disord. 9(1-2), 63-70 (2007). (Pubitemid 46671675)
211. Osher Y, Sela BA, Levine J, Belmaker RH. Elevated homocysteine levels in euthymic bipolar disorder patients showing functional deterioration. Bipolar Disord. 6(1), 82-86 (2004). (Pubitemid 38256508)
212. Miller A, Korem M, Almog R, Galboiz Y. Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. J. Neurol. Sci. 233(1-2), 93-97 (2005). (Pubitemid 40804822)
213. Vrethem M, Mattsson E, Hebelka H et al. Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult. Scler. 9(3), 239-245 (2003). (Pubitemid 36681888)
214. Ramsaransing GS, Fokkema MR, Teelken A, Arutjunyan AV, Koch M, De Keyser J. Plasma homocysteine levels in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 77(2), 189-192 (2006). (Pubitemid 43220840)
215. Reynolds EH, Bottiglieri T, Laundy M, Crellin RF, Kirker SG. Vitamin B12 metabolism in multiple sclerosis. Arch. Neurol. 49(6), 649-652 (1992).
216. Goodkin DE, Jacobsen DW, Galvez N, Daughtry M, Secic M, Green R. Serum cobalamin deficiency is uncommon in multiple sclerosis. Arch. Neurol. 51(11), 1110-1114 (1994). (Pubitemid 24352852)
217. Schroecksnadel K, Frick B, Wirleitner B, Winkler C, Schennach H, Fuchs D. Moderate hyperhomocysteinemia and immune activation. Curr. Pharm. Biotechnol. 5(1), 107-118 (2004).
218. Lawson BR, Manenkova Y, Ahamed J et al. Inhibition of transmethylation downregulates CD4 T cell activation and curtails development of autoimmunity in a model system. J. Immunol. 178(8), 5366-5374 (2007). (Pubitemid 46595323)
219. 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 73(3), 246-249 (2002).
220. van Rensburg SJ, Kotze MJ, Hon D et al. Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metab. Brain Dis. 21(2-3), 121-137 (2006).
221. Grandes P, Kq K, Morino P, Cuenod M, Streit P. Homocysteate, an excitatory transmitter candidate localized in glia. Eur. J. Neurosci. 3(12), 1370-1373 (1991).
222. Neubauer C. Mental deterioration in epilepsy due to folate deficiency. Br. Med. J. 2(5712), 759-761 (1970).
223. Schwaninger M, Ringleb P, Winter R et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 40(3), 345-350 (1999). (Pubitemid 29164801)
224. 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 15(2), 79-85 (2006). (Pubitemid 43192416)
225. Billings RE. Decreased hepatic 5, 10-methylenetetrahydrofolate reductase activity in mice after chronic phenytoin treatment. Mol. Pharmacol. 25(3), 459-466 (1984).
226. Morrell MJ. Guidelines for the care of women with epilepsy. Neurology 51(5 Suppl. 4), S21-S27 (1998).
227. Gidal BE, 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. 64(3), 161-166 (2005). (Pubitemid 40853928)
228. Karabiber H, Sonmezgoz E, Ozerol E, Yakinci C, Otlu B, Yologlu S. Effects of valproate and carbamazepine on serum levels of homocysteine, vitamin B12, and folic acid. Brain Dev. 25(2), 113-115 (2003). (Pubitemid 36170307)
229. Crawford P. Best practice guidelines for the management of women with epilepsy. Epilepsia 46(Suppl. 9), 117-124 (2005). (Pubitemid 44921989)
230. Wilson RD, Davies G, Desilets V et al. The use of folic acid for the prevention of neural tube defects and other congenital anomalies. J. Obstet. Gynaecol. Can. 25(11), 959-973 (2003).
231. Monji A, Yanagimoto K, Maekawa T, Sumida Y, Yamazaki K, Kojima K. Plasma folate and homocysteine levels may be related to interictal "schizophrenia- like" psychosis in patients with epilepsy. J. Clin. Psychopharmacol. 25(1), 3-5 (2005).
232. Edeh J, Toone BK. Antiepileptic therapy, folate deficiency, and psychiatric morbidity: a general practice survey. Epilepsia 26(5), 434-440 (1985). (Pubitemid 16226442)
233. Ali A, Pillai KK, Pal SN. Effects of folic acid and lamotrigine therapy in some rodent models of epilepsy and behavior. J. Pharm. Pharmacol. 55(3), 387-391 (2003). (Pubitemid 36410362)
234. Huemer M, Ausserer B, Graninger G et al. Hyperhomocysteinemia in children treated with antiepileptic drugs is normalized by folic acid supplementation. Epilepsia 46(10), 1677-1683 (2005). (Pubitemid 44921945)
235. Apeland T, Mansoor MA, Pentieva K, McNulty H, Seljeflot I, Strandjord RE. The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs. Epilepsy Res. 51(3), 237-247 (2002). (Pubitemid 35238047)
236. Reynolds EH. Mental effects of anticonvulsants, and folic acid metabolism. Brain 91(2), 197-214 (1968).
237. Smith AD. Folic acid fortification: the good, the bad, and the puzzle of vitamin B-12. Am. J. Clin. Nutr. 85(1), 3-5 (2007).
238. Luebeck EG, Moolgavkar SH, Liu AY, Boynton A, Ulrich CM. Does folic acid supplementation prevent or promote colorectal cancer? Results from modelbased predictions. Cancer Epidemiol. Biomarkers Prev. 17(6), 1360-1367 (2008).
239. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am. J. Clin. Nutr. 87(3), 517-533 (2008).
240. Pitkin RM. Folate and neural tube defects. Am. J. Clin. Nutr. 85(1), 285S-288S (2007).
241. Molloy AM, Kirke PN, Troendle JF et al. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic Acid fortification. Pediatrics 123(3), 917-923 (2009).
242. Butterworth CE Jr, Tamura T. Folic acid safety and toxicity: a brief review. Am. J. Clin. Nutr. 50(2), 353-358 (1989). (Pubitemid 19208755)
243. Herzlich B, Herbert V. Depletion of serum holotranscobalamin II. An early sign of negative vitamin B12 balance. Lab. Invest. 58(3), 332-337 (1988). (Pubitemid 18101863)
244. Baumbach GL, Sigmund CD, Bottiglieri T, Lentz SR. Structure of cerebral arterioles in cystathionine b-synthase deficient mice. Circ. Res. 91(10), 931-937 (2002).