a dozen deficiency, is an independent vascular risk factor associated with cerebral microvascular disease. 31 Cerebral microangiopathy is considered to be the basis for vascular dementia. High homocysteine (HY) levels may also lead to an excessive production of homocysteic acid and cysteine sulphinic acid, which act as endogenous agonists of N-methyl- d – aspartatate receptors and may impair cognitive functions by excitotoxic mechanisms (see review 32 ).
Factors
Vitamin B12 is contained in a wide variety of animal proteins. After intestinal absorption it enters enterohepatic circulation. The reported body half-life exceeds 1,300 days. With normal absorption, the recommended daily intake ranges from 2 ?g to 5 ?g. 10,33 Malnutrition as a sole cause is rare and occurs in cases of chronic alcoholism, extreme vegetarianism, and other forms of insufficient dietary supply. 33 Intestinal absorption of vitamin B12 depends on a series of steps including the liberation of protein-bound vitamin B12 from proteins by gastric acid 34 and its transfer to intrinsic factor produced by gastric parietal cells.
The most common cause of impaired vitamin B12 absorption is the lack of intrinsic factor, which can be measured by the Schilling test. 11 A cause of vitamin B12 malabsorption in spite of a normal Schilling test, which is frequently encountered in the elderly population, is an insufficient amount of gastric acid to proteolyze vitamin B12 from other nutritional proteins. 35,36 This hypo- or achlorhydria is often due to the reduction of fundus glands and parietal cell mass found in atrophic gastritis, which is reported to be present in more than 30% of patients above 60 years of age. 37 Other rare causes of cobalamin deficiency 33 are summarized in Table 2.
Symptomatic Factors
Numerous studies report an age-related in B12 levels. Depending on the population studied and the criteria and methods used, the prevalence of vitamin B12 deficiency varies from 3% to 40% in elderly patients. 38–40 The minimum serum level of vitamin B12 is usually recommended to be above 200 pg/ml. 33 However, metabolic evidence of cobalamin deficiency has been observed in patients with serum levels between 200 and 300 pg/ml with a frequency similar to that in patients with levels below 200 pg/ml. 39 Van Goor et al. 11 therefore suggest the diagnostic measurement of serum levels of methylmalonyl acid (MMA) and homocysteine (HY). Elevated serum levels of these metabolites have been shown to be more reliable and sensitive indicators of cobalamin deficiency than serum cobalamin levels alone. 3,29,41
With this procedure, a functional lack of vitamin B12 was demonstrated in 5% to 9% of symptomatic elderly patients with normal to only borderline subnormal vitamin B12 levels, 39,41 and a positive correlation between serum MMA and HY and the degree of neurological deficit has been observed. 42,43 Serum HY levels were also found to be significantly higher, and serum folate and vitamin B12 levels lower, in patients with senile dementia of Alzheimer type than in control subjects. 44,45 Elevated serum levels of MMA and HY have been shown to fall to normal when vitamin B12 is substituted, 3,39,43,46 whereas MMA rises under the substitution of folic acid. 21
One possible explanation for vitamin B12 deficiency with only borderline subnormal vitamin B12 serum levels is the presence of cobalamin analogues that cause high vitamin B12 values in presently used assays with R-binders. Patients with neurological deficits have been shown to have higher analogue levels than patients with hematological disorders. 47
Falsely high serum levels of MMA and HY can occur in chronic renal failure or intravascular volume depletion. 48 Certain anaerobic intestinal flora can cause MMA elevation due to the production of propionic acid, a precursor of MMA. Folic acid deficiency, on the other hand, can result in elevated HY levels. 49 Van Goor et al. 11 therefore suggest the measurement of both MMA and HY. Normal levels of MMA and HY seem to rule out clinically significant vitamin B12 deficiency. 41