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L-Methylfolate, Methylcobalamin, and N-Acetylcysteine in the Treatment of Alzheimer's Disease-Related Cognitive Decline

Published online by Cambridge University Press:  07 November 2014

Andrew McCaddon  and
Peter R. Hudson
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Extract

Almost 36 million people will have dementia in 2010—an alarming figure set to double every 20 years with the “greying” of the world population. Alzheimer's disease (AD) and dementia have enormous financial and social impacts on society. Prevention or illness delay of even a small percentage of cases would provide significant cost benefits for health-care systems. This review considers the rationale for a combined B-vitamin and antioxidant supplement (Cerefolin NAC) in treating and slowing AD-related cognitive decline.

Vitamin B12 and folate deficiencies are associated with various cognitive disorders, including dementia. In the 1980s, plasma total homocysteine (tHcy) assays were introduced to assist in diagnosing these deficiencies. Hey is derived from dietary methionine. Cells re-methylate Hey to methionine using B12-dependent methionine synthase; 5-methyltetrahydrofolate (5-MTHF) acts as a methyl donor (Figure 1A). Alternatively, Hey is converted to cystathionine, and ultimately cysteine, by B6-dependent cystathionine β-synthase. Blood Hey levels rise in B6, B6, and folate deficiencies.Higher levels are also associated with aging, smoking, male gender, renal impairment, and drugs including methotrexate, metformin, and levodopa.

Using tHcy as a marker, B vitamin deficiencies were found to be highly prevalent in the elderly. This led to speculation that elevated blood Hey, hyperhomocysteinemia, might occur commonly in dementias, including AD. Hyperhomocysteinemia implies impaired meth-ylation reactions (hypomethylation), with predictable adverse effects for neurotransmitter synthesis and AD neuropathology. Hey is also associated with vascular disease, itself a risk factor for dementia.

Evidence for the “homocysteine hypothesis of dementia” came with reports of hyperhomocysteinemia in patients with clinically and pathologically confirmed AD. Raised blood levels were also observed in mild cognitive impairment (MCI) and vascular dementia. Although elevated Hey could be a consequence of, or coincidental with, dementia hyperhomocysteinemia, it is now recognised to be associated with an increased risk for both cognitive decline and incident dementia.

Type
Expert Review Supplement
Information
CNS Spectrums , Volume 15 , Issue S1: Exploring Novel Treatment Options: Cognitive Decline in Alzheimer's Disease , January 2010 , pp. 2 - 5
Copyright
Copyright © Cambridge University Press 2010

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References

1.Alzheimer's Disease International. World Alzheimer Report. 1–96.21-9-2009.Google Scholar
2.Smith, AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 2OO8;29:S143–S172.CrossRefGoogle Scholar
3.Moretti, R, Torre, P, Antonello, RM, Cattaruzza, T, Cazzato, G, Bava, A. Vitamin B12 and folate depletion in cognition: a review. Neurol India. 2004;52:310–318.Google ScholarPubMed
4.Homocysteine in Health and Disease. Cambridge University Press. 2001.Google Scholar
5.Pennypacker, LC, Allen, RH, Kelly, JP, et al.High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc. 1992;40:1197–1204.CrossRefGoogle ScholarPubMed
6.Seihub, J, Jacques, PFWilson, PW, Rush, D. Rosenberg, IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693–2698.Google Scholar
7.McCaddon, A, Kelly, CL. Alzheimer's disease: a ‘cobalaminergic’ hypothesis. Med Hypotheses 1992;37:161–165.CrossRefGoogle ScholarPubMed
8.Regland, B, Gottfries, CG. Slowed synthesis of DNA and methionine is a pathogenetic mechanism common to dementia in Down's syndrome, AIDS and Alzheimer's disease? Med Hypotheses. 1992;38:11–19.CrossRefGoogle ScholarPubMed
9.Rosenberg, IH, Miller, J. Nutritional factors in physical and cognitive functions of elderly people. Am J Clin Nutr. 1992;55:1237s–1243s.CrossRefGoogle ScholarPubMed
10.Miller, AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003;8:7–19.Google ScholarPubMed
11.Zhou, J, Austin, RC. Contributions of hyperhomocysteinemia to atherosclerosis: causal relationship and potential mechanisms. Biofactors. 2009;35:120–129.CrossRefGoogle ScholarPubMed
12.Diu, C, Kivipelto, M, von Strauss, E. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies Toward intervention. Dialogues Clin Neurosci. 2009;11:111–128.Google Scholar
13.McCaddon, A, Davies, G, Hudson, P. Tandy, S, Cattell, H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry. 1998;13:235–239.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
14.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;55:1449–1455.CrossRefGoogle ScholarPubMed
15.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.CrossRefGoogle ScholarPubMed
16.Malaguarnera, M, Ferri, R. Bella, R, Alagona, G, Carnemolla, APennisi, G. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med. 2004;42:1032–1035.CrossRefGoogle ScholarPubMed
17.McCaddon, A, Hudson, RDavies, G, Hughes, A, Williams, JH, Wilkinson, C. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord. 2001;12:309–313.CrossRefGoogle ScholarPubMed
18.Seshadri, S, Beiser, A, Seihub, J, et al.Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346:476–483.CrossRefGoogle ScholarPubMed
19.Ravaglia, G, Forti, P, Maioli, F. et al.Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005;82:636–643.CrossRefGoogle ScholarPubMed
20.Karnaze, DS, Carmel, R. Low serum cobalamin levels in primary degenerative dementia. Do some patients harbor atypical cobalamin deficiency states? Arch Intern Med. 1987;147:429–431.CrossRefGoogle ScholarPubMed
21.McCaddon, A, Tandy, S, Hudson, P, et al.Absence of macrocytic anaemia in Alzheimer's disease. Clin Lab Haematol. 2004;26:250–263.CrossRefGoogle ScholarPubMed
22.Mcllroy, SP, Dynan, KB, Lawson, JT, Patterson, CC, Passmore, ARModerately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke. 2002;33:2351–2356.CrossRefGoogle Scholar
23.McCaddon, A, Regland, B, Hudson, PDavies, G. Functional vitamin B(12) deficiency and Alzheimer disease. Neurology. 2002;58:1390–1399.CrossRefGoogle ScholarPubMed
24.Fuchs, D. Jaeger, M, Widner, B, Wirleitner, B, Artner-Dworzak, E, Leblhuber, F. Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake? Clin Chem Lab Med. 2001;39:691–694.CrossRefGoogle Scholar
25.Sultana, R, Butterfield, DA. Role of oxidative stress in the progression of Alzheimer's disease. J Alzheimers Dis. Eupb 2009 Sep 11.Google Scholar
26.Lovell, MA, Markesbery, WR. Oxidative damage in mild cognitive impairment and early Alzheimer's disease. J Neurosci Res. 2007;85:3036–3040.CrossRefGoogle ScholarPubMed
27.Markesbery, WR, Kryscio, RJ, Lovell, MA, Morrow, JD. Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment. Ann Neurol. 2005;58:730–735.CrossRefGoogle ScholarPubMed
28.McNaull, BB, Todd, S, McGuinness, B, Passmore, ARInflammation and anti-inflammatory strategies for Alzheimer's disease - a mini-review. Gerontology. Epub 2009 Sep 10.Google Scholar
29.Wyss-Coray, T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006;12:1005–1015.Google ScholarPubMed
30.Moreira, PI, Zhu, X, Liu, Q, et al.Compensatory responses induced by oxidative stress in Alzheimer disease. Biol Res. 2006;39:7–13.CrossRefGoogle ScholarPubMed
31.Banerjee, RV, Matthews, RG. Cobalamin-dependent methionine synthase. FASEB J. 1990;4:1450–1459.CrossRefGoogle ScholarPubMed
32.Scott, JM, Weir, DG. The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia, Lancet. 1981;2:337–340.CrossRefGoogle Scholar
33.Molloy, A, Weir, G. Homocysteine and the nervous system. In: Carmel, R, Jacobsen, DW, eds. Homocysteine in Health and Disease.Cambridge University Press: Cambridge; 2001:183–197.Google Scholar
34.Onyango, IG, Khan, SM. Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer's disease. Curr Alzheimer Res. 2006;3:339–349.CrossRefGoogle ScholarPubMed
35.Pavlov, PF, Petersen, CH, Glaser, E, Ankarcrona, M. Mitochondrial accumulation of APP and Abeta: Significance for Alzheimer disease pathogenesis. J Cell Mol Med. Epub 2009 Sep 1.CrossRefGoogle ScholarPubMed
36.Singh, P, Suman, S, Chandna, S, Das, TK. Possible rale of amyloid-beta, adenine nucleotide translocase ana cyclophilin-D interaction in mitochondrial dysfunction of Alzheimer's disease. Bioinformation. 2009;3:440–445.CrossRefGoogle Scholar
37.Gibson, GE, Starkov, A, Blass, JP, Ratan, RR, Beal, MF. Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochem biophys Acta. 2010;1802:122–134.Google ScholarPubMed
38.Green, R, Miller, JW. Vitamin B12. In: Zempleni, J, Rucker, RB, eds. Handbook of Vitamins. Taylor and Francis: Boca Raton. Florida: 2007:413–457.Google Scholar
39.Hubbard, PA, Padovani, D, Labunska, T, Mahlstedt, SA, Banerjee, R, Drennan, CL. Crystal structure and mutagenesis of the metallochaperone MeaB: insight into the causes of methylmalonic aciduria. J Biol Chem. 2007;282:31308–31316.CrossRefGoogle ScholarPubMed
40.Kolker, S, Schwab, M, Horster, F, et al.Methylmalonic acid, a biochemical hallmark of methylmalonic acidurias but no inhibitor of mitochondrial respiratory chain. J Biol Chem. 2003;278:47388–47393.CrossRefGoogle ScholarPubMed
41.McCracken, C, Hudson, PEllis, R, McCaddon, A. Methylmalonic acid and cognitive function in the Medical Research Council Cognitive Function and Aging Study. Am J Clin Nutr. 2006;84:1406–1411.CrossRefGoogle Scholar
42.Feijoo, C, Campbell, DG, Jakes, R, Goedert, M, Cuenda, A. Evidence that phosphorylation of the microtu-bule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci. 2005;118:397–406.CrossRefGoogle ScholarPubMed
43.Stoothoff, WH, Johnson, GV. Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta. 2005;1739:280–297.CrossRefGoogle ScholarPubMed
44.Wang, JZ. Grundke-lqbal, I, Iqbal, K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci. 2007;25:59–68.CrossRefGoogle ScholarPubMed
45.Vafai, SB, Stock, JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's Disease. FEBS Lett. 2002;518:1–4.CrossRefGoogle ScholarPubMed
46.Obeid, R. Kasoha, M, Knapp, JP, et al.Folate and methylation status in relation to phosphorylated tau protein(181P) and {beta}-amyloid(1-42) in cerebrospinal fluid. Clin Chem. 2007;53:1129–1136.CrossRefGoogle ScholarPubMed
47.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. 2007;27:2751–2759.CrossRefGoogle ScholarPubMed
48.Sontag, JM, Nunbhakdi-Craig, VMontgomery, L, Arning, E, Bottiglieri, T, Sontag, E. Folate deficiency induces in vitro and mouse brain region-specific downregufation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpna) subunit expression that correlate with enhanced tau phosphorylation. J Neurosci. 2008;28:11477–11487.CrossRefGoogle Scholar
49.Zhang, CE, Tian, Q, Wei, W, et al.Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus. Neurobiol Aging. 2008;29:1654–1665.CrossRefGoogle ScholarPubMed
50.Chan, A, Rogers, E, Shea, TB. Dietary deficiency in folate and vitamin E under conditions of oxidative stress increases pnospho-tau Levels: potentiation by ApoE4 and alleviation by s-adenosylmethionine. J Alzheimers Dis. 2009;110:831–836.Google Scholar
51.Nicolia, V, Fuso, A, Cavallaro, RA, Di Luzio, A, Scarpa, S. B vitamin deficiency promotes tau phosphorylation through regulation of GSK3beta and PP2A. J Alzheimers Dis. Epub 2009 Nov 17.Google Scholar
52.Balastik, M, Lim, J, Pastorino, L, Lu, KP. Pin1 in Alzheimer's disease: multiple substrates, one regulatory mechanism? Biochem Biophys Acta. 2007;1772:422–429.Google ScholarPubMed
53.Sultana, R, Boyd-Kimball, D, Poon, HF, et al.Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: a redox proteomics analysis. Neurobiol Aging. 2006;27:918–925.CrossRefGoogle ScholarPubMed
54.Meziane, H, Dodart, JC, Mathis, C, et al.Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci U.S.A. 1998;95:12683–12688.CrossRefGoogle ScholarPubMed
55.Mattson, MP, Cheng, B, Culwell, AR, Esch, FS, Lieberburg, I, Rydel, RE. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron. 1993;10:243–254.CrossRefGoogle ScholarPubMed
56.Finder, VH, Glockshuber, R. Amyloid-beta aggregation. Neurodegener Dis. 2007;4:13–27.CrossRefGoogle ScholarPubMed
57.Butterfield, DA, Poon, HF, St Clair, D, et al.Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease. Neurobiol Dis. 2006;22:223–232.CrossRefGoogle ScholarPubMed
58.Butterfield, DA, Abdul, HM, Opii, W, et al.Pin1 in Alzheimer's disease. J Neurochem. 2006;98:1697–1706.CrossRefGoogle ScholarPubMed
59.Chen, F, Hasegawa, H, Schmitt-Ulms, G, et al.TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature. 2006;440:1208–1212.CrossRefGoogle Scholar
60.Willnow, TE, Andersen, OM. Pin-pointing APP processing. Mol Interv. 2006;6:137–139.CrossRefGoogle ScholarPubMed
61.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.CrossRefGoogle ScholarPubMed
62.Zhang, CE, Wei, W, Liu, YH, et al.Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am J Pathol. 2009;174:1481–1491.CrossRefGoogle ScholarPubMed
63.Ho, PI, Collins, SC, Dhitavat, S, et al.Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem. 2001;78:249–253.CrossRefGoogle ScholarPubMed
64.Hansson, O, Zetterberg, H, Buchhave, P, Londos, E, Blennow, K, Minthon, L. Association between CSF biomark-ers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5:228–234.CrossRefGoogle ScholarPubMed
65.Blennow, K, Zetterberg, H. Cerebrospinal fluid biomarkers for Alzheimer's disease. J Alzheimers Dis. 2009;18:413–417.CrossRefGoogle ScholarPubMed
66.Lanari, A, Parnetti, L. Cerebrospinal fluid biomarkers and prediction of conversion in patients with mild cognitive impairment: 4-year follow-up in a routine clinical setting. ScientificWorldJoumal. 2009;9:961–966.CrossRefGoogle Scholar
67.Mattsson, N, Zetterberg, H, Hansson, O, et al.CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302:385–393.CrossRefGoogle ScholarPubMed
68.Popp, J, Lewczuk, RLinnebank, M, et al.Homocysteine metabolism and cerebrospinal fluid markers for Alzheimer's disease. J Alzheimers Dis. Epub 2009 Aug 3.CrossRefGoogle ScholarPubMed
69.Glodzik-Sobanska, L, Pirraglia, E, Brys, M, et al.The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease. Neurobiol Aging. 2009;30:672–681.CrossRefGoogle ScholarPubMed
70.Williams, TI, Lynn, BC, Markesbery, WR, Lovell, MA. Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in mild cognitive impairment and early Alzheimer's disease. Neurobiol Aging. 2006;27:1094–1099.CrossRefGoogle ScholarPubMed
71.Doraiswamy, PM. Non-cholinergic strategies for treating and preventing Alzheimer's disease. CNS Drugs. 2002;16:811–824.CrossRefGoogle ScholarPubMed
72.Magnusson, KR. The aging of the NMDA receptor complex. Front Biosci. 1998;3:e70–e80.CrossRefGoogle ScholarPubMed
73.Do, KQ, Herrling, PL, Streit, PCuenod, M. Release of neuroactive substances: homocysteic acid as an endogenous agonist of the NMDA receptor. J Neural Transm. 1988;72:185–190.CrossRefGoogle ScholarPubMed
74.Lipton, SA, Kim, WK, Choi, YB, 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.CrossRefGoogle ScholarPubMed
75.Blusztajn, JK, Wurtman, RJ. Choline and cholinergic neurons. Science. 1983;221:614–620.CrossRefGoogle ScholarPubMed
76.Chanarin, I, Deacon, R, Lumb, M, Muir, M, Perry, J. Cobalamin-folate interrelations: a critical review. Blood. 1985;66:479–489.CrossRefGoogle ScholarPubMed
77.Hirata, F, Axelrod, J. Phospholipid methylation and biological signal transmission. Science. 1980;209:1082–1090.CrossRefGoogle ScholarPubMed
78.Pogribny, IP, Basnakian, AG, Miller, BJ, Lopatina, NG, Poirier, LA, James, SJ. Breaks in genomic DNA and within the p53 gene are associated with nypomethylation in livers of folate/methyl-deficient rats. Cancer Res. 1995;55:1894–1901.Google ScholarPubMed
79.Fenecn, M. The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res. 2001;475:57–67.CrossRefGoogle Scholar
80.Kruman, II, Culmsee, C, Chan, SL, et al.Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;20:6920–6926.CrossRefGoogle ScholarPubMed
81.Blount, BC, Mack, MM, Wehr, CM, et al.Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA. 1997;94:3290–3295.CrossRefGoogle ScholarPubMed
82.Meli, E, Pangallo, M, Baronti, R, et al.Poly(ADP-ribose) polymerase as a key player in excitotoxicity and post-ischemic brain damage. Toxicol Lett. 2003;139:153–162.CrossRefGoogle ScholarPubMed
83.Stanger, O, Fowler, B, Piertzik, K, et al.Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations. Expert Rev Neurother. 2009;9:1393–1412.CrossRefGoogle ScholarPubMed
84.Morris, MS. Homocysteine and Alzheimer's disease. Lancet Neurol. 2003;2:425–428.CrossRefGoogle ScholarPubMed
85.Sachdev, PS. Homocysteine and brain atrophy. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1152–1161.CrossRefGoogle ScholarPubMed
86.Den Heiier, T, Vermeer, SE, Clarke, R, et al.Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003;126:170–175.CrossRefGoogle Scholar
87.Kamath, AF, Chauhan, AK, Kisucka, J, et al.Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood. 2006;107:591–593.CrossRefGoogle ScholarPubMed
88.Lehmann, M, Regland, B, Blennow, K, Gottfries, CG. Vitamin b(12)-b(6)-folate treatment improves blood-brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment. Dement Geriatr Cogn Disord. 2003;16:145–150.CrossRefGoogle Scholar
89.Smith, DA. Treatment of Alzheimer's disease in the long-term-care setting. Am J Health Syst Pharm. 2009;66:899–907.CrossRefGoogle ScholarPubMed
90.Chan, A, Paskavitz, J, Remington, R, Rasmussen, S, Shea, TB. Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer's disease: a 1-year, open-label pilot study with an 16-month caregiver extension. Am J Alzheimers Dis Other Demen. 2008;23:571–585.CrossRefGoogle ScholarPubMed
91.Remington, R, Chan, A, Paskavitz, J, Shea, TB. Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer's disease: a placebo-controlled pilot study. Am J Alzheimers Dis Other Demen. 2009;24:27–33.CrossRefGoogle ScholarPubMed
92.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. 2008;104:1494–1503.CrossRefGoogle Scholar
93.Atkuri, KR, Mantovani, JJ, Herzenberg, LA, Herzenberg, LA. N-Acetylcysteine-a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007;7:355–359.CrossRefGoogle ScholarPubMed
94.Ventura, P, Panini, R, Abbati, G, Marchetti, G, Salvioli, G. Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy. Pharmacology. 2003;68:105–114.CrossRefGoogle ScholarPubMed
95.Adair, JC, Knoefel, JE, Morgan, N. Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology. 2001;57:1515–1517.CrossRefGoogle ScholarPubMed
96.Butler, CC, Vidal-Alaball, J, Cannings-John, R, et al.Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials. Fam Pract 2006;23:279–285.CrossRefGoogle ScholarPubMed
97.Kim, J, Hannibal, L, Gherasim, C, Jacobsen, DW, Banerjee, R. A human B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem. 2009;284:33418–33424.CrossRefGoogle ScholarPubMed
98.Suarez-Moreira, E, Yun, J, Birch, CS, Williams, JH, McCaddon, A, Brasch, NE. Vitamin B(12) and redox homeostasis: cob(ll)|alamin reacts with superoxide at rates approaching superoxide dismutase (SOD). J Am Chem Soc. 2009;131:15078–15079.CrossRefGoogle ScholarPubMed
99.Birch, CS, Brasch, NE, McCaddon, A, Williams, JH. A novel role for vitamin B(12): Cobalamins are intracellular antioxidants in vitro. Free Radie Biol Med. 2009;47:184–188.CrossRefGoogle ScholarPubMed
100.Richard, E, Jorge-Finnigan, A, Garcia-Villoria, J, et al.Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblc) with homocystinuria (MMACHC). Hum Mutat. 2009;30:1558–1566.CrossRefGoogle ScholarPubMed
101.Maron, BA, Loscalzo, J. The treatment of hyperhomocysteinemia. Annu Rev Med. 2009;60:39–54.CrossRefGoogle ScholarPubMed
102.McCaddon, A. Homocysteine and cognitive impairment; a case series in a general practice setting. Nutr J. 2006;5:6.CrossRefGoogle Scholar
103.McCaddon, A, Davies, G. Co-administration of N-acetylcysteine, vitamin B12 and folate in cognitively impaired hyperhomocysteinaemic patients. Int J Geriatr Psychiatry. 2005;20:998–1000.CrossRefGoogle ScholarPubMed