Folic acid, ageing, depression, and dementia
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7352.1512 (Published 22 June 2002) Cite this as: BMJ 2002;324:1512All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
EDITOR, - EH Reynolds discusses a role of folate deficiency in the
pathogenesis of depression and dementia.1 There is no doubt about the
crucial importance of folic acid for the functioning of the central
nervous system, and indeed folate deficiency can cause several neurologic
and psychiatric symptoms especially in the elderly.
However, the article
of EH Reynolds does not provide a rationale for the development of folate
deficiency in such patients, and it appears that besides side effects of
drugs, primarily insufficient dietary intake of the vitamin is considered
to underlie central nervous disturbances. Still the question remains
whether folate deficiency is primary or whether other causes may
contribute to it. Actually immune activation and oxidative stress could
play a role. On the one hand, immune activation is associated with
tryptophan degradation which interferes with the biosynthesis of
neurotransmitter serotonin.2 On the other hand, it might be an important
source for the overwhelming production of oxidizing compounds and thereby
contribute to the depletion of antioxidants.3 Consequently the demand of
vitamins especially of those sensitive to oxidation like vitamins C and E
is increasing. Also the 5,6,7,8-tetrahydro-derivatives of folate, which
are the active cofactors required for C1 group metabolism and for
remethylation of homocysteine, are very susceptible to oxidation.
Importantly immune activation and oxidative stress could contribute to
folate deficiency even in the case when dietary intake is sufficient.
Chronic immune activation is found in patients with depression and
dementia,3-5 and it might provide an explanation why supplementation with
antioxidant vitamins but also treatment with anti-inflammatory drugs has
some capacity to slow-down progression of symptoms in patients.
Katharina Schroecksnadel, research assistant, Barbara Frick, research
assistant,
Dietmar Fuchs, professor of medical chemistry, Institute of Medical
Chemistry and Biochemistry, Leopold Franzens University, A-6020 Innsbuck,
Austria,
1 Reynolds Eh. Folic acid, ageing, depression, and dementia. BMJ
2002; 324:1512-5.
2 Widner B, Ledochowski M, Fuchs D. Interferon-gamma-induced tryptophan
degradation: neuropsychiatry and immunological consequences. Curr Drug
Metabol 2000; 1: 193-204.
5 van West D, Maes M. Activation of the inflammatory response system: A
new look at the etiopathogenesis of major depression. Neuroendocrinol Lett
1999; 20:11-7.
Competing interests: 4 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.
More and more evidence is accumulating on the numerous and various
deleterious effects of Hyperhomocystinemia. Elderly LTC patients with
Oropharyngeal Dysphagia (up to 70% of the institutionalized patients ) are
in high risk of Hyperhomocystinemia as we recently published in the
Journal of Parenteral and Enteral Nutrition. Affected could be their
cognition,their extrapiramidal system , their ability to swallow ,the
affect as well as an increased risk for Cardio-vascular complications.
This growing segment of feeding dependent patients deserve special
attention as to the food suplimentation they receive.
Competing interests: No competing interests
Sir,
The consequence of a deficiency of folate is well known.
My daughter took folate according to doctor's instructions and lost
her conceptus in a worrying fashion.
The next pregnancy very soon after without any folate supplements
went to term and my grandaughter is now a very healthy 18 month baby.
For a normal, well fed, mother to be, can we have too much of a good
thing?
John Fryter (Chemist)
Competing interests: No competing interests
Dementia and metabolism of homocysteine in brain tissue
EDITOR- We read with great interest the article on folic acid,
ageing, depression, and dementia by Reynolds(1). We would like to make
some comments that may be of interest about the neurochemical aspects of
his article. As Dr. Reynolds states, unusually, folic acid in the form of
methylfolate is present in cerebrospinal fluid in humans in concentrations
three times greater than in serum. Brain tissue does not contain two of
the major metabolic routes for the elimination of homocysteine, as the
betaine-mediated conversion and the transsulfuration pathway(2,3). Thus,
in the circumstances of folate deficiency, homocysteine can be
eliminated only by export from the neuron. However, this mechanism may be
hindered because homocysteic acid, a metabolite of homocysteine,
stimulates N-methyl-D-aspartate receptors and may cause neuronal injury
by glutamate excitotoxicity(4). In this way, the decline of folic acid
concentrations in cerebrospinal fluid may contribute to the onset and
progression of neurodegenerative process. Perhaps, the greater levels of
folic acid in cerebrospinal fluid represent a way to compensate the
limited capacity of brain tissue to metabolize homocysteine.
References
1 Reynolds EH. Folic acid, ageing, depression, and dementia. BMJ
2002;324:1512-5.
2 McKeever MP, Weir DG, Molloy A, Scott JM. Betaine-homocysteine
methyltransferase: organ distribution in man, pig and rat and subcellular
distribution in the rat. Clin Sci (Lond) 1991;81:551-6
3 Finkelstein JD. The metabolism of homocysteine: pathways and regulation.
Eur J Pediatr 1998;157:Suppl 2:S40-S44.
4 Loscalzo J. Perspective: homocysteine and dementias. N Engl J Med
2002;346:466-8.
Francisco José Fernández–Fernández, staff internist.
Hospital Arquitecto Marcide, 15405 Ferrol, Spain.
Pascual Sesma, M.D., associate professor of medicine
Department of Medicine, University of Santiago de Compostela, Spain.
Competing interests: No competing interests