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To determine whether dopamine metabolism is abnormal in HIV infected patients and whether dopamine metabolism abnormalities are related to specific neuropsychologic characteristics in HIV-infected patients, we measured cerebrospinal fluid (CSF) levels of homovanilic acid (HVA), the primary dopamine metabolite, in 10 HIV-infected patients and compared it to HVA levels in CSF in a group of 13 healthy control subjects. HIV-infected patients were also assessed with a battery of neuropsychologic tests and HVA levels were then correlated with performance on specific neuropsychologic tests. The mean (+/-SD) HVA level in CSF was 100.9 +/- 29.3 nmol/L in the HIV-infected study group and 230.5 +/- 50.0 nmol/L in the non-HIV-infected control group (p < 0.0001). The decrease in concentrations of HVA in CSF correlated with impairment on performance on neuropsychologic testing (Spearman r = 0.67; p = 0.03). When the relationship between HVA levels and specific cognitive domains was evaluated, we observed trends for positive correlation between HVA levels and tests that measure motor speed (r = 0.59; p = 0.074) and those testing attention, concentration, and executive control (r = 0.54; p = 0.108). There was no relationship between performance on memory tests and CSF HVA levels (r = -0.0061; p = 0.987). These results further support the hypothesis that dopaminergic dysfunction plays an important role in the pathogenesis of AIDS dementia complex (ADC) and suggest that specific motor and cognitive abnormalities may be related to depressed dopaminergic activity. This may have important implications for the development of treatments or preventive strategies for ADC.

The methylation and transsulfuration pathways are intimately linked and have been implicated in the progression of neurologic damage and immune cell depletion caused by human immunodeficiency virus (HIV) infection. We studied the following metabolites related to these pathways: S-adenosylmethionine (SAMe), homocysteine, cysteine, cysteinyl-glycine, and glutathione (GSH) in blood and CSF of 16 HIV-infected patients with neurologic complications and 20 HIV-negative control patients undergoing lumbar punctures for other medical reasons, We confirmed recent studies of decreased CSF SAMe concentrations in HIV infection and demonstrated that diastereomers of SAMe are present in CSF but not in plasma or erythrocytes from both HIV-infected and HIV-negative patients, In HIV-infected patients, CSF GSH and cysteinyl-glycine, but not homocysteine or cysteine, were significantly reduced, This is the first report of decreased CSF GSH induced by HIV infection. GSH has a regulatory effect on the synthesis of SAMe in hepatic tissue, and the same mechanism may also apply in the CNS. Administration of SAMe-butanedisulphonate, 800 mg/d intravenously for 14 days, was associated with significant increases in CSF SAMe and GSH. These findings have potentially important therapeutic implications for the use of SAMe in protecting against SAMe and GSH deficiency in the CNS of HIV-infected patients.

Homocysteine may be involved in the pathogenesis of late onset Alzheimer's disease. It is implicated in the metabolism of several important pathways in the brain. Methylmalonic acid (MMA) is related to the metabolism of branched chained amino acids and fatty acids.To compare cerebrospinal fluid (CSF) total homocysteine and MMA in elderly subjects, patients with Alzheimer's disease, and younger healthy controls.CSF samples were obtained from 33 patients under 20 years of age; 28 patients aged 21 to 60 years; 22 normal elderly subjects aged over 60; and 38 Alzheimer patients aged over 60.CSF total homocysteine increased with age (mean (SD): 57 (35) nmol/l in the youngest group v 123 (89) nmol/l in the elderly group (p0.001)). There was no difference between the elderly group and Alzheimer patients (115 (62) nmol/l). CSF MMA did not differ in the elderly group and the Alzheimer group (38 (13) v 35 (14) ng/ml). In the youngest group, it was significantly higher (60 (15) ng/ml).CSF total homocysteine is not increased in Alzheimer's disease compared with age matched controls. CSF total homocysteine was correlated with age. The decrease in CSF MMA levels with age eliminates a lack of vitamin B-12 at neuronal level.

S-adenosylmethionine (SAM) is a primary methyl donor for the methylation of many molecules including DNA. DNA methylation is believed to play an important role in functions of cells and genes. Dietary, genetic and metabolic factors that influence systematic SAM levels are not fully understood. We conducted cross-sectional analysis to evaluate associations between plasma concentrations of one-carbon metabolism nutrients and metabolites and plasma SAM concentrations using healthy individuals within the Singapore Chinese Health Study. Plasma SAM, betaine, choline, folate, total homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH), vitamin B(6) and vitamin B(12) concentrations were quantified. Genotypes of methionine adenosyltransferases (MAT1A, MAT2A and MAT2B) were also determined. Linear regression and path analysis were performed to depict the directed dependencies in one-carbon metabolism. Age and body mass index were positively associated while cigarette smoking were inversely associated with plasma SAM concentrations. Plasma choline, methionine and SAH were positively and strongly associated with plasma SAM after adjustment for confounders. Plasma betaine and folate were positively associated with plasma SAM only in men. Men carrying the variant MAT1A genotypes had lower plasma SAM concentrations than men carrying the wild type genotype (p for gene x gender interaction = 0.02). This effect modification by gender was restricted to individuals with low plasma methionine. In conclusion, plasma choline, methionine and SAH were strongly associated with plasma SAM concentrations. The MAT1A genetic polymorphism may impact plasma SAM concentrations in men with low plasma methionine concentrations.