Review: cobalamin deficiency and mental impairment in elderly people.
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. 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. It has been reported, however, that only 34% of patients with low serum levels of cobalamin received appropriate therapy. 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 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%. 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
1. Dietary insufficiency 2. Intrinsic factor deficiency: Gastric atrophy Gastrectomy Congenital deficiency 3. Achlorhydria Atrophic gastritis Medication 4. Protein-bound malabsorption 5. Competition for cobalamin: Bacterial proliferation Parasites
Cobalamin deficiency due to protein-bound cobalamin malabsorption has been noted particularly in patients with neuropsychiatric abnormalities [9, 11, 23, 24]. There is a positive correlation between levels of cobalamin and PG I in serum in demented patients, indicating that atrophic gastritis could be a cause of their low serum cobalamin values.
Protein-bound cobalamin malabsorption is not always a consequence of gastric dysfunction. It has been shown that nearly 50% of patients with low serum cobalamin and a normal Schilling test are unable to absorb protein-bound cobalamin as opposed to the free cobalamin used in the Schilling test[11, 16, 21, 25]. In half of these cases there was no evidence of gastric abnormalities[19, 21]. It is conceivable that salivary abnormalities or, more likely, upper intestinal or pancreatic abnormalities may sometimes be responsible for the defective transfer of cobalamin from protein to intrinsic factor. A normal Schilling test does not exclude cobalamin malabsorption.
The clinical features of cobalamin deficiency are varied. Impaired DNA synthesis secondary to cobalamin deficiency causes changes in the peripheral blood and bone marrow cells; retarded cell division results in macrocytosis, hypersegmented granulocytes and megaloblastic anaemia.
Other feature of cobalamin deficiency are neuropathy and myelopathy, which manifest as symmetrical paresthesiae in feet and fingers with associated disturbance of vibratory and position sense, symmetrical limb weakness and diminished cutaneous sensation. There may also be spinal cord involvement with spastic ataxia[10, 26-28]. The paresthesiae are the most common initial complaints, and occur in more than 70% of the patients with neurological symptoms.
Another manifestation of cobalamin deficiency is altered mental status, which consists of impairment of attention span, memory abstraction, or other intellectual functions with or without abnormalities of behaviour, mood, affect, or logical thought[10, 26, 29, 30]. Neuropsychiatric symptoms may be the initial, or the only, manifestations of cobalamin deficiency[9, 10, 31]. In a study of 141 consecutive patients in whom various neuropsychiatric abnormalities were attributed to cobalamin deficiency, 40 patients (28%) had no anaemia or macrocytosis, and results of both tests were norma in 13%. In other studies this finding was confirmed[9, 11, 15, 31-37]. These data add to accumulating evidence that the haematological status and neuropsychiatric phenomena due to cobalamin deficiency are not coupled in any predictable manner [9, 11, 16, 33, 38, 39].
Cobalamin deficiency may result in a variety of mental symptoms, such as organic psychosis, dementia paranoia, memory impairment, mania, slow mentation hallucinations, and depression[10, 12, 14, 26, 29-31, 39-48]. A relation between serum cobalamin levels and cognitive status as indicated by various neuropsychological tests, such as IQ-tests, MMSE, verbal and visual memory tests, has been reported in healthy elderly subjects[14, 49]. Several aspects of cognitive functioning appear to be impaired by cobalamin deficiency and may respond to cobalamin therapy (Table II)[ 10, 38, 49-52]. Memory of deficits and slowing of mental processes are the most commonly reported cognitive disturbances in cobalamin deficiency.
Table II. Cognitive disturbances reported to respond to cobalamin therapy
Slowing of mental processes Memory deficits Confusion Disorientation Difficulties with conceptualization Impaired ability of construction Visuospatial problem-solving abilities Decrease of initiation Fatigue
A causal relation between cobalamin deficiency and organic mental changes resulting in paranoia, hallucinations, and delirium has also been described [10, 14, 29, 31, 41, 46, 53-55]. In two patients with organic psychosis, who showed diffuse slowing of cerebral activity on electroencephalographic examination, and mild cognitive dysfunction on neuropsychological testing, a complete recovery was demonstrated after cobalamin therapy.
Similar studies were performed in groups of depressive patients, in whom a stronger relation was found between low serum cobalamin levels and poor cognitive functioning than in patients who were not depressive[46, 48]. In other studies the relation between low serum cobalamin levels and cognitive status was investigated in older subjects with psychotic depression, in a comparison with subjects with non-psychotic depression. A stronger relation was found between low cobalamin levels and poor cognitive functioning in the older subjects with psychotic depression [30, 46, 48]. These data implicate a possible relation between low serum cobalamin and depression [10, 14, 30, 44, 46, 48], and suggest that low cobalamin may result more often in psychotic depression than in non-psychotic depression.
Much controversy exists on the subject of the association of dementia with cobalamin deficiency. In several studies dementia has been related to low serum cobalamin levels and cobalamin deficiency. The prevalence of low serum cobalamin[33, 37, 56-59] and cobalamin deficiency[23, 58, 60, 61] was reported to be markedly increased in the Alzheimer type of dementia in comparison with other types of dementia or with healthy elderly subjects. Patients with dementia, especially of the Alzheimer type, also had low levels of cobalamin in the cerebrospinal fluid (CSF) compared with normal individuals[59, 62]. These data suggest that cobalamin deficiency may be an aetiological factor of dementia, especially in dementia of the Alzheimer type. In other studies, however, a relation between serum cobalamin levels and Alzheimer's disease or other types of dementia could not be demonstrated[4, 58].
In one study a low serum cobalamin was not only reported in Alzheimer's disease, but also in multi-infarct dementia. 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.
Neuropsychiatric symptoms in the absence of macrocytosis or anaemia are often found in association with serum cobalamin levels that are nearly normal or only mildly decreased[9, 10, 31] and, as already noted subnormal cobalamin levels are common in elderly populations[3, 11, 14, 15, 32, 46, 67, 68]. Cobalamin deficiency with only subnormal cobalamin levels was found in 9% of elderly outpatients. This was established by measuring methylmalonic acid (MMA) and homocysteine in serum which indicates tissue cobalamin deficiency in combination with a positive reaction to therapy. This method will be discussed below.) A possible explanation for the finding of subnormal cobalamin levels in combination with cobalamin deficiency is the presence of cobalamin analogues in human plasma[35, 69]. This can result in falsely high cobalamin values measured with the current assays using R-binders. Patients with primarily neurological symptoms had significantly higher analogue levels than patients with primarily haematological abnormalities. Conversely, low serum cobalamin levels in healthy individuals have also been reported.
From these data we suggest that there may be a higher prevalence of atypical cobalamin deficiency than previously recognized. Therefore, there is a need for better diagnostic tests to distinguish patients who are cobalamin deficient and who will benefit from treatment from patients who are not deficient and should not be treated.
The measurement of elevated levels of unmetabolized substrates of two enzymes dependent on the cofactors methylcobalamin (Figure 1) and adenosylcobalamin (Figure 2) can be used to detect cobalamin deficiency. These metabolites, MMA and homocysteine, have been shown to be elevated in most patients with cobalamin deficiency[10, 66, 70]. Studies ave shown a serum concentration of one or both metabolites more than 3 SD above the mean of normal control subjects in 99.8% of patients with clinical symptoms compatible with cobalamin deficiency and responsive to cobalamin therapy[3, 70, 71]. This test is more sensitive than the measurement of serum cobalamin levels; in 5% to 9% of patients with clear-cut haematological or neurological disorders or both caused by a lack of cobalamin, serum cobalamin values are in the lower to normal range, even though circulating metabolite concentrations are unequivocally elevated [13, 66, 72]. Serum levels of both MMA and homocyteine fall to the normal range when cobalamin-deficient patients are treated with cobalamin [3, 10, 70, 71, 73-75]. They rise further if such patients are treated erroneously with folic acid, which can cause a deterioration the cobalamin deficiency .
A positive correlation was found between serum MMA and homocysteine and the degree of neurological involvement in cobalamin deficiency [73, 76]. Increased CSF MMA was demonstrated in patients with cobalamin deficiency. Measurement of CSF levels of this metabolite might be informative in patients with borderline serum cobalamin or MMA values  but the disadvantage of this method is the requirement for lumbar puncture.
These serum metabolites have also been used to measure the prevalence of cobalamin deficiency in the elderly population. Significantly higher serum metabolite concentrations have been found in elderly patients with clinical cobalamin deficiency than in healthy elderly subjects. The lowest levels were found in a healthy young control group . This indicates that a higher prevalence of metabolic cobalamin deficiency is found by measuring serum MMA and homocysteine than by using seru cobalamin. However, the clinical importance of these findings has yet to be clarified.
The sensitivity of measurements of MMA and homocysteine in cobalamin deficiency can be influenced by various factors such as chronic renal failure and intravascular volume depletion in which serum MMA and homocysteine are falsely elevated. Metabolic activities of the anaerobic gut flora which can produce propionic acid, a precursor of MMA, can also influence the serum levels of MMA. Folic acid deficiency leads to accumulation of homocysteine and thus to higher serum homocysteine values [3, 66, 78]. This can be overcome, however, by measuring both metabolites. The sensitivity of cobalamin deficiency detection is higher when both MMA and homocysteine are measured .
In conclusion, the measurement of both MMA and homocysteine serum concentrations is a sensitive and non-invasive test to establish cobalamin deficiency. Normal levels of both MMA and total homocysteine seem to rule out clinically significant cobalamin deficiency. However, since the assays are more expensive than the conventional tests and are beyond the scope of routine laboratories, their place in diagnosis remains to be determined.
Not all symptoms of cobalamin deficiency respond to administration of cobalamin in the same way. In megaloblastic anaemia the morphological changes of megaloblastic maturation in the bone marrow revert to normal within 24-48 hours after cobalamin therapy [15, 18]. The haematological abnormalities return to normal within two months of therapy.
The neurological and neuropsychiatric symptoms respond differently to cobalamin therapy. Most patients with neurological abnormalities have a complete or partial reversion of their symptoms after cobalamin treatment . However, the extent of the neurological features remaining after therapy is related to the severity and the duration of neurological abnormalities before treatment .
Several cases have been described in which there was complete reversion of neuropsychiatric abnormalities secondary to cobalamin deficiency after treatment with cobalamin [26, 31, 38, 40]. A complete recovery has been observed in 61% of patients with mental impairment associated with cobalamin deficiency . In other studies improvement of mental symptoms without complete reversion to normal was found after cobalamin therapy [10, 12, 13, 26, 50, 79]. In a recent study 18 subjects with low serum cobalamin and evidence of cognitive dysfunction were investigated . Only-patients who had symptoms for less than 1 year showed improvement after therapy. The best clinical responders had been symptomatic for less than 6 months. This finding has been confirmed by others [79, 801. In disease of longer duration there may be widespread myelinolysis with a loss of ability for neuronal repair. These investigations indicate that the duration of the cobalamin deficiency plays an essential role in the degree of improvement of neuropsychiatric symptoms after treatment.
The prevalence of cobalamin deficiency in elderly people increases with age, and may become a major problem because of the ageing of the population. Diagnosing cobalamin deficiency with primarily neuropsychiatric manifestations can be difficult in the elderly population, mainly because of the great variety of the symptoms and signs. In addition, haematological abnormalities may be absent. Moreover, the measurement of serum cobalamin levels is not a sensitive method to diagnose cobalamin deficiency. The advent of new and more sensitive techniques makes it possible to diagnose atypical cobalamin deficiency, which was previously often unrecognized, in an early stage of the disease.
Studies of serum levels of MMA and homocysteine in relation to clinical symptoms and the effect of cobalamin therapy may expand our knowledge of the prevalence of cobalamin deficiency, the associated clinical syndromes, and the therapeutic options. This is important, because cobalamin deficiency may have to be acknowledged as a significant cause of neuropsychiatric disorders in elderly people. Early treatment may prevent irreversibility of the neuropsychological features and organic lesions of the brain related to the deficiency.
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|Author:||van Goor, Laura P.; Woiski, Mallory D.; Lagaay, A. Margot; Meinders, A. Edo; Tak, Paul P.|
|Publication:||Age and Ageing|
|Date:||Nov 1, 1995|
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