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MEDICAL HYPOTHESIS: A. McCaddon, B. Regland, P. Hudson, and G. Davies Functional vitamin B12 deficiency and Alzheimer disease Neurology 2002; 58: 1395-1399 [Abstract] [Full text] [PDF]

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Reply to Fuchs

Andrew McCaddon, Bjorn Regland, Peter Hudson, Gareth Davies.   (30 September 2002)

Functional vitamin B12 deficiency and Alzheimer disease

Dietmar Fuchs, Katharina Schroecksnadel, Barbara Frick   (12 September 2002)

Reply to Fuchs 30 September 2002
Andrew McCaddon, Honorary Research Fellow University of Wales College of Medicine, Bjorn Regland, Peter Hudson, Gareth Davies. Send Correspondence to journal: Re: Reply to Fuchs andrew{at}mccaddon.demon.co.uk Andrew McCaddon, et al.	Fuchs, Schroecksnadel and Frick make the interesting and important observation that oxidative stress may have an additional impact on the methionine synthase reaction by irreversibly oxidizing methyl-folate. We agree that this would contribute to methionine synthase inactivation. Following our publication, we learned that the zinc site in methionine synthase, essential for binding and activating homocysteine, might also be oxidized. Current experiments in E.coli indicate that this site is readily oxidized on treatment of cells to induce oxidative stress [1]. It seems likely that, for a variety of reasons, the methionine synthase reaction will be physiologically compromised by oxidative stress. The differential effects of such stress on this enzyme and cystathionine beta synthase may explain the observed age-related decline in methionine synthase activity and the switch from methionine conservation to transsulfuration with aging [2]. Tissues without an alternative means of metabolizing homocysteine will be particularly affected by such stress. Their consequent increased cellular export of homocysteine might contribute to elevated plasma levels. Neurones and vascular endothelium both lack an intact transsulfuration pathway and also lack the B12 and folate independent enzyme betaine:homocysteine methyltransferase. Homocysteine levels in these tissues should therefore prove to be an excellent marker of oxidative stress. Rather than constituting a “risk-factor” for vascular disease, dementia and other neurological conditions, elevated plasma homocysteine might best be considered a “risk-marker” signifying the effects of oxidative stress in such diseases. 1) E. Manning and R. G. Matthews, unpublished data. 2) J.Finkelstein. Regulation of Homocysteine Metabolism. In: Carmel R, Jacobsen DW, eds. Homocysteine in Health and Disease. Cambridge University Press, 2001: 92-99.
Functional vitamin B12 deficiency and Alzheimer disease 12 September 2002
Dietmar Fuchs, Professor University of Innsbruck, Katharina Schroecksnadel, Barbara Frick Send Correspondence to journal: Re: Functional vitamin B12 deficiency and Alzheimer disease dietmar.fuchs{at}uibk.ac.at Dietmar Fuchs, et al.	We read with interest the hypothesis by McCaddon et al [1] in which oxidative stress discussed underlying moderate hyperhomocysteinemia in AD. It is suggested that the oxidation-sensitive intermediate form of vitamin B12 (cob[I]alamin) will be destroyed thereby impairing remethylation of homocysteine and giving rise to moderate hyperhomocysteinemia. The authors further speculate that cerebral oxidative stress plays a major role. These assumptions confirm our findings that oxidative stress may underlie moderate hyperhomocysteinemia. [2,3] Not only the intermediate form of vitamin B12 but also methyl- tetrahydrofolate, the second necessary cofactor in the remethylation of homocysteine, is very sensitive to oxidation and as a 6-substituted pteridinederivative is irreversibly degraded once oxidized. This may impact other clinical conditions such as atherosclerosis, depression and even cancer, [2-4] which are often associated with moderate hyperhomocysteinemia. Interestingly, folate deficiency is detected more often in patients than vitamin B12 deficiency, further supporting the concept that also degradation of folate is important. The results confirm a state of chronic immune activation in patients with AD. [5] Homocysteine concentrations correlate with the degree of immune activation as measured by, for example, neopterin concentrations. [3] This association is also found in other clinical conditions with hyperhomocysteinemia. [3,4] Activation of immunocompetent cells like T-lymphocytes and macrophages is associated with the production of large amounts of oxidizing compounds, indicating oxidative stress. The immunopathogenetic background of oxidative stress resulting in vitamin depletion and thus hyperhomocysteinemia is likely and would confirm the concept proposed by McCadden et al. References 1. McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B(12) deficiency and Alzheimer disease. Neurology 2002;58:1395-9. 2. Widner B, Fuchs D, Leblhuber F, Sperner-Unterweger B. Does disturbed homocysteine and folate metabolism in depression result from enhanced oxidative stress? J Neurol Neurosurg Psych 2001;70:419. 3. Fuchs D, Jaeger M, Widner B, Wirleitner B, Artner-Dworzak E, Leblhuber F. Is hyperhomocysteinemia due to oxidative depletion of folate rather than insufficient dietary intake. Clin Chem Lab Med 2001;39:691-4. 4. Frick B, Schröcksnadel K, Fuchs D. Folate and homocysteine levels in head and neck squamous cell carcinoma. Cancer (in press). 5. Leblhuber F, Walli J, Demel U, Tilz GP, Widner B, Fuchs D: Increased serum neopterin concentrations in patients with Alzheimer's disease. Clin Chem Lab Med 1999;37: 429-31.