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1 From the Department of Clinical Medicine, Trinity College, and St James's Hospital, Dublin.
2 Address reprint requests to DG Weir, Department of Clinical Medicine, Trinity Centre for Health Sciences, St James's Hospital, James's Street, Dublin 8, Ireland. E-mail: dweir{at}tcd.ie.
See corresponding article on page 993
It has been known since the latter half of the 19th century that cobalamin deficiency produces widespread pathology in the central nervous system (1). However, the role of folate deficiency on the pathogenesis of brain disease is poorly understood, despite the findings of several patient series and population-based studies (2). In the past decade, several investigators have described associations between reduced concentrations of the vitamins folate, cobalamin (vitamin B-12), and pyridoxine (vitamin B-6) and the development of cognitive dysfunction in the elderly.
The publication by Snowdon et al (2) in this issue of the Journal addresses the issue of folate deficiency and the development of dementia. Snowden et al studied a cohort of elderly nuns who had lived in the same convent; thus, all subjects had closely similar dietary and physical lifestyles. In this cohort, serum folate showed a strong negative correlation with the subsequent severity of postmortem atrophy found in the brain neocortex of subjects with significant numbers of Alzheimer disease lesions. As the authors point out, such an association does not prove a causal relation, nor does it offer any evidence that folate supplementation will be protective. However, their paper adds to the evidence that when a pathogenic process inducing dementia such as Alzheimer disease is present, disturbed folate metabolism may exacerbate the condition.
The function of folate in the brain, as elsewhere, is the conveyance of one-carbon units either for the synthesis of nucleic acids from purines and pyrimidines or for the maintenance of methylation reactions of internal metabolism mediated by S-adenosyl-l-methionine (SAM) (1). The former process is especially important during the early development of the brain, whereas the latter methylation processes are essential for the maintenance of normal brain function. Although this methylation process has various checks and counterchecks in organs such as the liver and kidney, in the brain these are severely limited (3).
The predominant source of methyl groups (-CH3) for SAM-dependent methylation processes is 5-methyltetrahydrofolate (5CH3THF). The sole function of this compound is to remethylate homocysteine via cobalamin-dependent methionine synthase (5-methyltetrahydrofolate–homocysteine S-methyltransferase), thereby synthesizing methionine and SAM. SAM-dependent methylations are strongly inhibited by the reaction coproduct, S-adenosylhomocysteine (SAH); thus, the ratio of SAM to SAH under various conditions and to a different extent in individual organs controls the methylation process (3). To maintain a favorable ratio of SAM to SAH, SAH is usually rapidly hydrolyzed to homocysteine and adenosine. However, when homocysteine is not removed, its accumulation in the presence of adenosine leads to the resynthesis of SAH and thus the inhibition of SAM-mediated methylation reactions. The rapid removal of homocysteine is accordingly of paramount importance to the maintenance of a normal methylation process (1).
Because it does not possess the betaine methyl transferase system (4), the brain relies on 5-methyltetrahydrofolylpentaglutamate and cobalamin-dependent methionine synthase to remethylate homocysteine; thus, when either folate or cobalamin is deficient, homocysteine accumulates (3). At relatively high concentrations, homocysteine can be catabolized via the transsulfuration pathway to cystathionine and cysteine by vitamin B-6–dependent cystathionine ß-synthase and cystathione ß-lyase, respectively. However, although synthase activity in the brain is 20% of that in the liver, it is doubtful that the lyase enzyme is present at all (5). This suggests that, at best, this pathway is an inefficient means of disposing of homocysteine in the human brain (3).
Although there is as yet no conclusive evidence, many researchers believe that hyperhomocysteinemia is the fundamental link between the observed associations of reduced folate or vitamin B-12 status and the severity of cognitive dysfunction. Postulated mechanisms include a direct toxic effect on vascular endothelial (6) or neuronal cells (7) or an indirect effect on the normal brain methylation process (1). Direct toxic effects of elevated homocysteine could be mediated by damage to vascular endothelial cells, resulting in either major vascular events, such as cerebrovascular accidents, or microvascular disease. This mechanism is supported by results of a study from Oxford showing that elevated serum total homocysteine concentrations are associated with a progressive atrophy of the medial temporal lobe in patients with Alzheimer disease (8). Clarke et al (8) found a significant association of histologically confirmed Alzheimer disease and vascular dementia with moderately elevated blood homocysteine concentrations and with reduced blood concentrations of folate and vitamin B-12. They also found a more rapid atrophy of the medial temporal lobe over a 3-y period in patients who initially had elevated total homocysteine concentrations, leading them to conclude that hyperhomocysteinemia induces microvascular disease affecting specific areas of the brain. This conclusion is supported by the work of Fassbender et al (9), who showed that patients with subcortical vascular encephalopathy, a distinct type of vascular dementia, had marked hyperhomocysteinemia and vitamin B-6 deficiency. Also, patients with Parkinson disease treated with long-term levodopa had hyperhomocysteinemia that was associated with an increased prevalence of vascular disease and endothelial dysfunction of the substantia nigra (10).
In the study by Snowdon et al, serum folate concentrations were significantly lower in subjects with moderate to severe atherosclerosis in the circle of Willis and in those with brain infarcts than in subjects with minimal atherosclerosis and without infarcts. However, the correlation of low folate with the severity of atrophy in Alzheimer disease subjects was present even in those with minimal atherosclerosis and without brain infarcts. No homocysteine measurements were made in this study and the number of subjects was too few to make a conclusive statement as to the relation between folate deficiency and the evolution of cognitive impairment. However, the results mainly agree with those of the other studies mentioned above. The most striking consideration is that the associations of low folate or high homocysteine with brain atrophy go beyond the correlations of hyperhomocysteinemia with macro- or microvascular disease and thus pose further questions as to the mechanisms involved.
Hyperhomocysteinemia could also induce neurotoxicity by activation of N-methyl-d-aspartate receptors, leading to cell death. We can infer from cell culture studies that under pathologic conditions, such as ischemia or head injury when glycine concentrations are elevated, mildly elevated homocysteine concentrations may become neurotoxic possibly because of excessive Ca2+ influx and reactive oxygen generation (7).
Elevated homocysteine may also cause brain damage indirectly via hypomethylation of essential brain metabolites. However, the type of brain lesions caused by such mechanisms in experimental animals varies significantly from that seen in Alzheimer disease and other microvascular-induced dementia, resembling much more the neuropathy associated with vitamin B-12 deficiency and AIDS.
There seems little doubt now that there is an association between the evolution of certain brain diseases associated with cognitive decline in the elderly and vitamin deficiencies associated with hyperhomocysteinemia. The question remains whether these deficiencies are post or propter hoc, whether they play an intrinsic pathogenic role, and whether they exacerbate an existing disease process or are simply bystander phenomena. Whatever the answers to these questions, the potential therapeutic options are exciting.
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