Author: Katarina Nägga, MD, PhD Dept. of Geriatric Medicine Linköping University Hospital SE-581 85 Linköping, Sweden Phone: +46-13-224093 Fax: +46-13-224141 E-Mail: katarina.nagga@lio.se

Several classification systems exist for diagnosing dementia and determining its subtypes. In clinical practice, the two most frequently used are the DSM IV [1] and the ICD-10 [2] criteria. There is no specification of the characteristics of dementia supposedly caused by cobalamin deficiency in these criteria, even though such diagnostic codes exist in both.

Potentially reversible causes of dementia are seen in 9 % of cases [3]. Examples of reversible conditions are drug-related disorders, depression and space-occupying lesions [4]. However, such conditions should be considered as associates to dementia rather than causes. True reversibility is, however, an extremely uncommon characteristic [3]. Nevertheless, the search for these conditions is an important part of the diagnostic procedure.

Several studies have reported that cobalamin deficiency is common in dementia disorders [5-7]. However, the mechanism of neurological damage induced by a quantitative or functional cobalamin deficiency is still unclear.

Homocysteine (Hcy), cobalamin and folate are closely linked together in the so-called one-carbon cycle and Hcy levels are elevated in the case of cobalamin or folate deficiency [8, 9]. A disturbance in the one-carbon cycle may be the cause of elevated plasma Hcy. A defective remethylation has been posited to occur in Alzheimer's disease (AD) [10]. Furthermore, Hcy may have a direct neurotoxic effect through its action on the N-Methyl-D-Aspartate glutamate receptor [11-13]. In the case of hyperhomocysteinaemia, the brain has been proposed to suffer from both cerebrovascular damage that triggers or potentiates the effect of Alzheimer pathology and a direct neurotoxic effect of Hcy [14].

It has been established that Hcy levels in serum correlate negatively with cognitive performance [15-17]. Elevated Hcy levels have been found to be a strong, independent risk factor for the development of dementia disorders [18] and AD [19], as well as for the presence of white-matter changes in AD [20, 21] and in vascular dementia (VaD) [21].

In a recent study performed at the Clinic of Geriatric Medicine at the University Hospital, Linköping, we found that mean plasma Hcy levels were significantly higher in all patients with different dementia diagnoses compared with controls. Although the highest levels were found in patients with VaD, there were no statistically significant differences between the dementia subtypes [22]. We also showed positive correlations between serum levels of Hcy and creatinine [22], replicating previous findings [23-25]. A recent hypothesis suggests that reduced renal function in the elderly, due to hypertension and atherosclerosis, is an important cause of elevated Hcy in patients with vascular disease and that hyperhomocysteinaemia might be an effect rather than a cause of atherosclerotic disease [26].

Recent European guidelines concluded that laboratory testing is rarely aimed to identify the cause of dementia, but rather to identify comorbidity and reveal potential risk factors. The guidelines recommend that analysis of cobalamin is optional [27].

There seem to be little doubt that there is an association between dementia of different origin and hyperhomocysteinaemia. However, the clinical significance of this association is still unclear. Plasma levels of Hcy does not contribute to the diagnostic considerations in dementia patients but can be used as a marker of cobalamin and/or folate deficiency, keeping the renal function in mind.

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Published August 24, 2005