Review: cobalamin deficiency and mental impairment in elderly people

Age and Ageing,  Nov, 1995  by Laura P. van Goor,  Mallory D. Woiski,  A. Margot Lagaay,  A. Edo Meinders,  Paul P. Tak

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Introduction

Little is known about the relationship between cobalamin deficiency and mental impairment in elderly people, but cobalamin deficiency may be an important cause of mental disturbances. Cobalamin deficiency increases with advancing age and is found in 3% to 42% of persons aged 65 and over[1-6]. The large variation in these values may be the result of several factors including differences in the population groups studied, assay techniques, cut-off levels, and exclusion criteria. The increased prevalence of low serum cobalamin with advancing age is generally regarded as a consequence of disease rather than a physiological phenomenon[2, 5, 7].

Ageing is associated with a mild decline of cognitive skills but a severe decline of complex cognitive function may be attributed to extrinsic factors, such as cobalamin deficiency[8]. In elderly people with cobalamin deficiency, mental impairment is more often found than are the so-called classical manifestations, such as megaloblastic anaemia and neuropathy and this is often associated with abnormal serum cobalamin values[2, 9-15]. Improvement of mental impairment as a result of treatment with cobalamin is possible, especially in an early stage of the deficiency, before the symptoms and signs become irreversible[12]. It has been reported, however, that only 34% of patients with low serum levels of cobalamin received appropriate therapy[16]. Diagnosis and treatment of cobalamin deficiency is at present a major problem because of the insensitive diagnostic methods and unfamiliarity with the atypical presentations of cobalamin deficiency in elderly patients.

Causes of cobalamin deficiency

Cobalamin is assimilated in the human body in a complex way. On entering the stomach, protein-bound cobalamin is split by hydrochloric acid and forms a complex with R-binding protein. Cobalamin is then transferred to intrinsic factor by means of pancreatic enzymes. This complex is internalized through specific receptors on the mucosa of the distal ileum and intrinsic factor is removed. Subsequently, cobalamin is bound to transcobalamin II with which it circulates in the plasma until it binds to receptors on cells throughout the body and is absorbed. Several causes of cobalamin deficiency in elderly people have been reported (Table I). The most common is pernicious anaemia, in which intrinsic factor secretion has ceased. This condition is associated with antibodies to gastric parietal cells, gastric mucosal atrophy, hypo- and achlor-hydria[17, 18]. Malabsorption of cobalamin due to intrinsic factor deficiency can be measured by the Schilling test. In elderly people, however, low cobalamin is often found with normal Schilling test results. Several studies have shown that this phenomenon can be the result of protein-bound cobalamin malabsorption, in which the release of cobalamin from its dietary protein bound state is impaired, often owing to achlorhydria[11, 19-21].

Atrophic gastritis is the most common cause of hypo- or achlor-hydria in elderly people[22] and is characterized by a partial loss of fundic glands and a corresponding decrease in parietal cell mass. Gastric atrophy involves the complete loss of fundic glands, and is characteristic of pernicious anaemia[17, 22]. Of persons aged 60 and over, 32% have atrophic gastritis and at ages over 70, the prevalence increases to 50%[22]. Non-invasive methods that have been used as indicators of atrophic gastritis include the presence of circulating parietal-cell antibodies, and elevated gastrin and low pepsinogen (PG) levels in serum. The ratio of PG I to PG II, in combination with the absolute PG I level, can be used to detect mild or moderate atrophic gastritis, which is not detected by other methods[21, 22].

Table I. Main causes of cobalamin deficiency in elderly people

In one study a low serum cobalamin was not only reported in Alzheimer's disease, but also in multi-infarct dementia[63]. Low cobalamin could be a risk factor for cerebrovascular infarction due to homocysteine, which accumulates in cobalamin deficiency and may result in atherosclerotic events, such as heart attack, stroke and multi-infarct dementia[64, 65].

A finding of low serum cobalamin levels in Alzheimer's disease and multi-infarct dementia, but not in other forms of dementia or cognitive impairment, would suggest that cobalamin deficiency may cause specific types of dementia and is not the result of dementia with consequently insufficient dietary intake of cobalamin.

Diagnosing cobalamin deficiency

Establishing the diagnosis of cobalamin deficiency with involvement of the nervous system is difficult because of the lack of correlation between neurological and/or cerebral manifestations on the one hand and haematological variables or serum cobalamin levels on the other. The sensitivity of the measurement of serum cobalamin in order to diagnose cobalamin deficiency is not high, because many elderly patients with serum cobalamin concentrations within the normal limits are metabolically and clinically deficient in cobalamin[3, 9, 18, 36, 40, 66]. Cobalamin deficiency is difficult to define. At present the diagnosis can be made with certainty only in cases of clinical symptoms and laboratory abnormalities compatible with cobalamin deficiency, which resolve after cobalamin therapy.