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The frequency of Alzheimer's disease increases with age. Despite numerous studies, the pathogenesis remains poorly understood. Anatomically, it is characterised by the coexistence of two different types of abnormality: senile plaques, which are extracellular formations with a central compound primarily composed of protein amyloid; and neurofibrillary tangles, which are formed of intracellular paired helical filaments. During Alzheimer's disease, the brain is the seat of considerable oxidative stress. Recent studies have suggested that cardiovascular risk factors such as hypertension, diabetes, and plasma homocysteine could be involved in the pathogenesis of late onset Alzheimer's disease. 1
Homocysteine is formed by demethylation of the essential amino acid methionine. This free methyl group is implicated in the synthesis of numerous brain substrates. 2 Homocysteine is catabolised by two possible pathways: in the first, homocysteine and serine are condensed to form cystathionine; in the second, the remethylation of homocysteine to methionine is dependent on methionine synthase. Vitamin B-12 and folate are the cofactors of this enzyme.
Methylmalonic acid (MMA) is a dicarboxylic acid related to the metabolism of several amino acids. 3 Vitamin B-12 is required as a cofactor in the conversion of methylmalonyl coA to succinyl coA. In vitamin B-12 deficiency, MMA coA is converted to MMA 3 and results in an intracellular increase in MMA followed by increased concentrations in the serum. Homocysteine and MMA are known to be the most sensitive serum markers of early intracellular vitamin B-12 and folate deficiency. 4, 5 Folate deficiency results in increased total homocysteine levels. 2 In cobalamin deficiency, cerebrospinal fluid (CSF) levels of homocysteine and MMA are raised but the increase of CSF MMA concentration is more important than that of homocysteine. 6
Several studies have also suggest a direct correlation between Alzheimer's disease and serum total homocysteine levels. 1 Decreased brain and CSF vitamin B-12 and decreased CSF folate have been described in Alzheimer's disease. 5, 7- 9 These abnormalities could be responsible for modifications to brain metabolism. The diagnosis of mild vitamin B-12 deficiency is often difficult. CSF total homocysteine and CSF MMA could be considered as markers of early folate or B-12 functional deficiency at neuronal level.
Our aims in this study were to determine CSF levels of total homocysteine and MMA during aging and in Alzheimer's...