Vitamin B₁₂, folate, homocysteine and dementia: are they really related?

Abstract

Dementia is an acquired impairment of intellectual and memory functioning. There are numerous factors affecting neurocognitive functions like vascular factors, Vitamin B₁₂ and folate and homocysteine levels. The aim of this study is to determine whether there is a relationship between the serum levels of these metabolites and diagnosis of dementia and mild cognitive impairment (MCI). A total of 1249 patients admitted to Hacettepe University Hospital Department of Internal Medicine, Division of Geriatric Medicine Outpatient Clinic between 1 February 2002 and 30 June 2003 were included in this study. Vitamin B₁₂, folate and homocysteine levels were measured in all patients, and they were evaluated also for their cognitive abilities. In this study pool, 121 cases were diagnosed as Alzheimer's disease (AD), 60 patients were diagnosed as having non-Alzheimer dementia (NAD), 273 had MCI. When patients with AD, NAD, MCI and patients without dementia were compared according to their median values of folate, Vitamin B₁₂ and homocysteine, there were no significant differences. Results of studies searching for a correlation between Vitamin B₁₂, folate and homocysteine levels and their relation with cognitive status of the elderly are controversial in various studies from different countries. In this study (with 1249 elderly patients) we were unable to find any correlation between homocysteine, Vitamin B₁₂ and folate levels and cognitive functioning in contrast with some literary data. Nevertheless, these metabolites should be measured routinely in the examination of any elderly patient, since they can play important roles in geriatric patients.

Introduction

Dementia is a syndrome of progressive, global decline in cognition that is severe enough to degrade the individuals’ well being and social function (Kennedy, 2003).

AD is the most common form of dementia (50–70%) (Small et al., 1997). The other forms of dementia classified as NAD and vascular dementia (VD) amount to the majority of these cases. Mixed forms of dementia may be common in the elderly and this is associated with poorer cognitive functions (Snowdon et al., 1997). When patients present with MCI followed longitudinally, each year approximately 15% of them develop dementia (Petersen et al., 1999).

There are numerous factors affecting neurocognitive functions like vascular factors, Vitamin B₁₂ and folate and homocysteine levels as mentioned below.

Because low levels of Vitamin B₁₂ can be reversible causes in 1% of dementia cases (Clarfield, 1998), the measurement of Vitamin B₁₂ level is a part of clinical practice in geriatrics.

Homocysteine is closely associated with the metabolism of Vitamin B₁₂ and folate. Methionine synthase requires methyl-tetrahydrofolate and methyl-cobalamin, and catalyzes the conversion of homocysteine to methionine. In turn, methionine is required in the synthesis of S-adenosyl-methionine, which is methyl-donor in numerous methylation reactions taking place in the neural membranes. Homocysteine accumulates in folate- and Vitamin B₁₂-deficient patients. In that case, homocysteine will be rapidly metabolized to S-adenosylhomocysteine, which is a strong inhibitor of methylation reactions (Joosten, 2001). Beside this, plasma homocysteine may be directly toxic to vascular endothelial cells. Increased concentrations of homocysteic acid, an N-methyl-d-aspartate receptor agonist and metabolite of homocysteine, may result in excitotoxic damage to neurons (Lipton et al., 1997). Homocysteine promotes copper mediated and β-amyloidal peptide-mediated toxic effects in neuronal cell cultures (White et al., 2001) and induces apoptosis in hippocampal neurons in rats (Kruman et al., 2000).

It has also been shown that subjects with cardiovascular risk factors and a history of stroke have an increased risk of both VD and AD (Hofman et al., 1997, Breteler, 2000) and hyperhomocysteinemia is an independent major risk factor for atherosclerosis.

It is important to reveal, whether there is a relationship between cognition functions, levels of homocysteine, folate, Vitamin B₁₂ and dementia or not, because they can represent modifiable risk factors for dementia. Vitamin therapy and dietary supplementation can reduce homocysteine levels (Homocysteine Lowering Trialistist’ Collaboration, 1998; Jacques et al., 1999)

To best of our knowledge, routine laboratory assessment includes folate, cyanocobalamine and homocysteine levels in our outpatient clinic, and the aim of this study was to determine whether there is a relationship between the serum levels of these metabolites and diagnosis of dementias and/or MCI.