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Low serum and red cell folate concentrations have been reported in up to 42% of elderly healthy subjects in the community or acute geriatric medical admissions, and in 20%–82% of psychogeriatric admissions.1 Although widely attributed to dietary causes, we have long reported a causal link between folate deficiency, depression, or dementia.1-3 Recent community studies have suggested a significant rise in serum total homocysteine and fall in serum folate with age4; and there has been renewed interest in a link between Alzheimer's disease, depression, folate deficiency, and raised serum total homocysteine.5 6 Other studies suggest that high homocysteine and low folate concentrations are independent risk factors for premature occlusive vascular disease, including cerebrovascular disease.4 5
Remarkably, folate in the form of methyl folate is concentrated in CSF by an active transport process at concentrations about three times that in serum.3 We have had the opportunity to study CSF folate in a group of elderly patients undergoing spinal anaesthesia.
Folate in CSF was measured in 41 patients undergoing surgery at Northwick Park Hospital in a study of spinal anaesthesia and postoperative spinal analgesia by the Department of Anaesthetics. The operations were hip replacement (22), knee replacement (four), hernia (eight), haemorrhoids (three), and varicose veins (four). There were 17 men and 24 women, mean age (SD) 74.6 (13.4) years. The patients were otherwise healthy and were not taking medication other than analgesics before surgery.
With informed consent, 2 ml CSF were withdrawn at L3/4 in the fasting recumbent position under local anaesthetic before spinal anaesthesia, and was immediately stored at −70°C. Folate in CSF was measured by microbiological assay using a chloramphenicol resistant strain ofL casei.
The figure shows a highly significant decline in CSF folate with age. The mean CSF folate (28 (SD 7.4) μg/ml) between ages 40 and 59 fell 5% between age 60 and 69 (26.6 (SD 8.1) μg/ml). The greatest fall was after the age of 70, with a 27% fall between 70 and 79 (20.3 (SD 5.8) μg/ml) and a 54% fall between 80 and 99 (13.0 (SD 5.4) μg/ml). (analysis of variance (ANOVA)F=11.73, p<0.001). The correlation between age and CSF folate was−0.72 (p<0.001).
Our findings provide further evidence of a link between folate concentrations and age and, for the first time, directly in the nervous system. Although we did not measure serum folate concentrations, others have already reported a fall in serum folate and rise in plasma homocysteine with age.4 Our subjects were not anaemic or macrocytic and were not known to have medical or psychiatric disorders. It is unlikely, therefore, that the significant decline in CSF folate can be attributable simply to dietary deficiency. Other possibilities include a gradual failure with aging of the active transport mechanism which carries methyl folate into the nervous system.3
Whether due to aging or acquired deficiency, there is evidence causally relating folate status to mental function, especially depression and dementia.1-3 5 6 Controlled and uncontrolled clinical trials suggest a specific effect of folate on mood and cognitive function.1-3 The effects of folate on mental function are mainly mediated through numerous methylation pathways in the nervous system and are similar to the effects of S-adenosylmethionine (SAM), the major methyl donor in the brain which obtains its methyl group mainly from methyl folate.1
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