low vitamin B12 concentrations are associated with cognitive impairment and missing ankle tendon jerks in older people in the absence of anaemia. Large-scale trials of vitamin B12 supplementation are required to assess the clinical significance of these associations.
Concerns about risks for older people with vitamin B 12 deficiency have delayed the introduction of mandatory folic acid fortification in the UK. We examined the risks of anaemia and cognitive impairment in older people with low B 12 and high folate status in the setting of voluntary fortification in the UK. Data were obtained from two cross-sectional studies (n 2403) conducted in Oxford city and Banbury in 1995 and 2003, respectively. Associations (OR and 95 % CI) of cognitive impairment and of anaemia with low B 12 status (holotranscobalamin ,45 pmol/l) with or without high folate status (defined either as serum folate . 30 nmol/l or . 60 nmol/l) were estimated after adjustment for age, sex, smoking and study. Mean serum folate levels increased from 15·8 (SD 14·7) nmol/l in 1995 to 31·1 (SD 26·2) nmol/l in 2003. Serum folate levels were greater than 30 nmol/l in 9 % and greater than 60 nmol/l in 5 %. The association of cognitive impairment with low B 12 status was unaffected by high v. low folate status (.30 nmol/l) (OR 1·50 (95 % CI 0·91, 2·46) v. 1·45 (95 % CI 1·19, 1·76)), respectively. The associations of cognitive impairment with low B 12 status were also similar using the higher cut-off point of 60 nmol/l for folate status ((OR 2·46; 95 % CI 0·90, 6·71) v. (1·56; 95 % CI 1·30, 1·88)). There was no evidence of modification by high folate status of the associations of low B 12 with anaemia or cognitive impairment in the setting of voluntary fortification, but periodic surveys are needed to monitor fortification. Reports of adverse effects from treating individuals with pernicious anaemia with a high-dose folic acid have suggested that high-level folic acid fortification might delay the diagnosis or exacerbate the effects of vitamin B 12 deficiency in older people. Low B 12 status affects about 10 -25 % of older people and has been associated with a higher prevalence of anaemia and cognitive impairment (1 -4) . Using direct measurements of holotranscobalamin (holoTC), the active fraction of B 12 (5) , it has been estimated that almost 25 % of older people have low B 12 status (holoTC , 45 pmol/l) (4) . Concerns that highlevel folic acid fortification might delay the diagnosis of B 12 deficiency (6,7) or exacerbate the neurological complications of B 12 deficiency (and cause colon cancer) have delayed the introduction of mandatory fortification in the UK (1) . In North America, mandatory folic acid fortification does not appear to increase the risk of anaemia (6,7) , but it has been suggested that it may increase the rate of cognitive decline (8,9) and risk of cognitive impairment (10) in people with low vitamin B 12 status. In the UK, folic acid was added to most breakfast cereals in 1987 and the amount of added folic acid was subsequently increased in 1994. In addition, folic acid was added to 'spreads' in 2000. Voluntary folic acid fortification has resulted in a substantial increase in blood folate levels in the population (1) . Data collected on vitamin status in older people in the Oxford Healthy Ag...
A commercially available holotranscobalamin (holo-TC) radioimmunoassay (RIA) (Axis-Shield, Dundee, Scotland) was evaluated in four laboratories and compared with a holoTC ELISA run in one laboratory. The performance of the holoTC RIA assay was comparable in three of the four participating laboratories. The results from these three laboratories, involving at least 20 initial runs of "low", "medium" and "high" serum-based controls (mean holoTC concentrations 34, 60 and 110 pmol/L, respectively) yielded an intra-laboratory imprecision of 6-10%. No systematic inter-laboratory deviations were observed on runs involving 72 patient samples (holoTC concentration range 10-160 pmol/L). A fourth laboratory demonstrated higher assay imprecision for control samples and systematic deviation of results for the patient samples. Measurement of holoTC by ELISA showed an imprecision of 4-5%, and slightly higher mean values for the controls (mean holoTC concentrations 40, 70 and 114 pmol/L, respectively). Comparable results were obtained for the patient samples. The long-term intra-laboratory imprecision was 12% for the holoTC RIA and 6% for the ELISA. In conclusion, it would be prudent to check the calibration and precision prior to starting to use these holoTC assays in research or clinical practice. The results obtained using the holoTC RIA were similar to those obtained using the holoTC ELISA assay.
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