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Neurology India, Vol. 54, No. 1, January-March, 2006, pp. 51-52 Invited Comments Invited Comments Szolnoki Zoltan Correspondence Address: Code Number: ni06012 Related articles: ni06009, ni06011 A strong association has been suggested between the folic acid level and the occurrence of a congenital neuronal tube defect.[1] Various epidemiological studies have confirmed the presumption that periconceptional folic acid supplementation can reduce the frequency of such a defect.[2] This has led to the introduction of an extensive program of prevention in the United States, in which cereal food productions are fortified with folic acid. There are several other aspects of the daily folic acid intake in adults, which can influence the homocysteine level,[3],[4] a high homocysteine level being a strong predictor of death in patients with coronary artery disease.[5] A paper published in this issue of the journal raises the importance of folic acid intake on the basis of genotype against ischaemic stroke too.[6] I approach the importance of the folic acid supply from the aspect of the disability caused by a cognitive deficiency. In addition to Alzheimer disease, the frequent causes of a cognitive deficiency can be ischaemic stroke and leukoaraiosis. Leukoaraiosis is indicated by bilateral patchy or diffuse areas of hypointensity in CT scans, or hyperintensity in T2-weighted MRI scans. It involves only the white matter. One-quarter of subjects aged 65 years or over are affected by some degree of white matter changes. Leukoaraiosis can cause a mild cognitive impairment or severe subcortical dementia. Ischemic demyelination and small-vessel disease seem to be features of the underlying pathological process of this entity. Age and hypertension have been proved to be the main clinical risk factors. Diabetes mellitus and cardiac diseases, which can be associated with cerebrovascular diseases, have not proved to involve direct significant risks of leukoaraiosis directly. Clinical observations have suggested that vasoregulatory disturbances and chronic cerebral hypoperfusion may be the pathological states which can lead to leukoaraiosis. A number of genetic susceptibility factors for leukoaraiosis have been put forward. With the assumption of polygenic etiological factors, it has been demonstrated that the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-T mutation and angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism play important roles in leukoaraiosis. Both the ACE D and MTHFR 677T alleles are frequent in the normal population, but can be associated with an unfavorable vasoregulatory effect on the circulatory system. The former can lead to an elevated angiotensin II level in the serum and the tissues and the latter to an elevated serum homocysteine level. Leukoaraiosis has been stated to be positively correlated with the serum homocysteine level and inversely correlated with the serum folate level. It has been earlier reported that a clustering of the homozygous MTHFR 677TT and ACE D / D mutations in one person can mean a moderate (approximately 5-fold risk) but highly significant ( P < 0.0005) risk of leukoaraiosis.[7] Alone, however, neither of the mutations proved to be a risk factor for leukoaraiosis. It has also been suggested that low doses of ACE inhibitor drugs can reduce the risk of stroke or a cardiovascular event. The finding of the interaction of two unfavourable mutations that alone are insignificant might open up a new clinical strategy for the prevention or treatment of leukoaraiosis. Although further clinical studies are clearly needed to investigate the clinical and preventive effects of different doses of folic acid supplementation on leukoaraiosis associated with a cognitive disability, I suggest regular folic acid supplementation in the middle aged and elderly if they carry the ACE D/D and homozygous MTHFR 677TT mutations together. It has been demonstrated that this genotype constellation implies a moderate genetic risk for leukoaraiosis.[7] The further question arises of whether co-administration of an ACE inhibitor and folic acid could reduce occurrence of leukoaraiosis. Ischaemic stroke is a very regularly occurring entity underpinned by several genetic factors and clinical risk factors. The MTHFR 677TT genotype and decreased serum folic acid level can be risk factors for ischaemic stroke. The folic acid supplementation can be a preventive measure against ischaemic stroke too.[6] This question is also open and needs further studies. A regular folic acid intake seems to be important health issue in a wide range of nations in general. Its supplementation against general circulatory disorders raises hopes in a broad health issue. The new findings on the roles of folic acid and the genetic background might permit a selective prevention of leukoaraiosis and ischaemic stroke hence the cognitive decline they cause. References
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