Homocysteine, vitamin B 12 and folate in Alzheimer's and vascular dementias: The paradoxical effect of the superimposed type II diabetes mellitus condition

doi:10.1016/j.cccn.2005.03.049

Clinica Chimica Acta

Volume 359, Issues 1–2, September 2005, Pages 163-170

https://doi.org/10.1016/j.cccn.2005.03.049 Get rights and content

Abstract

Background

Increased concentration of plasmatic homocysteine (tHcy) and decreased vitamin B 12 (B12) and folate (FOL) are associated with Alzheimer's (AD) and vascular (VaD) dementias, with type II diabetes mellitus (DM), and reported as risk factors of these diseases.

Methods

The sample (n = 122; males = 60; mean age = 73 ± 7 years) comprised AD and VaD patients without DM, with a concomitant DM (AD + DM, VaD + DM), DM alone and controls (CTR), resulting in 6 groups. tHcy, B12 and FOL were determined in duplicate.

Results

The one-way ANOVA yielded significant differences between groups for all variables: tHcy p < 10⁻ ¹²; B12 p < 10⁻ ³; FOL p < 10⁻ ⁴. Significance for comparisons between groups was set at α = 0.05, using the Bonferroni's statistic. The comparisons: DM vs. CTR, AD + DM vs. AD, VaD + DM vs. VaD, and DM demented vs. DM non-demented resulted significant for all variables, except for B12 in 2 comparisons.

Conclusions

In demented and control subjects, tHcy and FOL exhibit extreme differences, not so marked between DM and controls. Demented patients with concomitant diabetes are closer to controls than their non-diabetic counterparts. Diabetes affects tHcy and FOL values, which are changed with opposite sign to non-demented. These results suggests a paradoxical phenomenon when diabetes is superimposed to dementias.

Introduction

Increased blood concentrations of plasma homocysteine (tHcy), often associated with low normal folate (FOL) and vitamin B 12 (B12) concentration are common in vascular dementia (VaD) and dementia of the Alzheimer's type (AD). A moderate increase in plasma tHcy constitutes an independent risk factor of VaD, also associated with metabolic disorders in diabetes and with degenerative cognitive deterioration. High concentration of tHcy have been identified as risk factors for vascular disease and potentially for dementia and depression [1], [2], [3], [4], in addition to cardiovascular disease. In association with the non-insulin-dependent type II diabetes (DM) it is a risk factor for vascular disease [5] and might also worsen the neurological course of ischemic cerebral infarctions and silent brain lesions.

The mechanisms behind these relationships are not clear, but enough evidence exists that the increased concentration of tHcy interferes with different coagulation factors and endothelial mechanisms, the individuals becoming prone to vascular lesions.

Methionine from the diet and from the catabolism of proteins in the cells is the only source of homocysteine through 2 metabolic stages: transulfuration and remethylation. The most common cause of increased tHcy is a deficiency of FOL or B12, but low concentration of FOL or B12 do not explain the increased tHcy concentration in Parkinson's disease patients [6], where it was found to be associated with the use of l-dopa [7]. In diabetic patients, hyperinsulinemia has been found to increase tHcy [8]; in the pathogenesis of hyperhomocysteinemia in diabetes, the mutation in the C677T methylene-tetrahydrofolate reductase could contribute to increased concentration of tHcy [9].

The low plasma concentration of vitamins B6, B12 and FOL are normalized when supplemented with vitamins, suggesting that the pathologies related with hyperhomocysteinemia might be prevented with a vitamin-rich diet, a fact yet to be proved in extended trials.

Since many hereditary, mutational, nutritional and pharmacological factors might induce an increase in plasmatic tHcy, the presence of hyperhomocysteinemia is not indicative of a particular condition.

In this study, the profile studied comprises measurements of tHcy, B12, and FOL in plasma. We studied demented patients using diabetes as a second criterion, testing the following hypotheses: (a) increased concentration of tHcy and decreased concentration of B12 and FOL are linked with diabetes; (b) when associated with AD and VaD diseases the variations due to the diabetes condition are added to the pathological concentration observed in AD and VaD patients, rendering them more abnormal; (c) the profiles of demented plus diabetes patients could be distinguished.

Section snippets

Patients and controls

The initial population of 130 subjects consisted of healthy controls (CTR), DM patients, and demented patients of the AD and VaD types with and without associated DM. CTR subjects were selected by age and sex to reflect the general gender and age distribution of the diseased groups. Outpatients and controls were from Caucasian origin, recruited from the Neurology Service and the Diabetes Unit of the Hospital Sirio-Libanés, the Hospital General de Agudos Juan A. Fernández and the FACENE.

Patients

Results

The basic statistics of the 6 experimental groups are presented in Table 1, together with the mean and S.D. obtained for tHcy, B12 and FOL. Table 2 shows the ANOVA results for each variable, and the Bonferroni statistics calculated for the planned comparisons: DM vs. CTR, AD + DM vs. AD, VaD + DM vs. VaD, and diabetes effect on non-demented vs. diabetes effect on demented subjects. The ratios of males/females in each comparison were almost similar (0.55 vs. 0.63, 0.36 vs. 0.21, 0.72 vs. 0.58, and

Discussion

It has been suggested that an increase in tHcy concentration precedes the development of dementia [23]. The mechanism underlining this interpretation is unknown; meanwhile the hyperhomocysteinemia has been related with brain microangiopathy, endothelial dysfunction, impairment of the nitric oxide activity, increase in oxidative stress and neuronal apoptosis, all mechanisms implied in brain aging.

It has been found that those individuals with cardiovascular risk factors and ictus antecedents have

Acknowledgements

This study has been partially supported by a grant from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and the Fundación Argentina Contra las Enfermedades Neurológicas del Envejecimiento (FACENE) of Argentina. We express our gratitude to Prof. Alberto A. Boveris for critically reading the manuscript.

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¹: Collaborative Group for the Study of the Oxidative Stress and Related Abnormalities (CGSOSRA) —Integrated by the following medical degrees (MD) and psychologists (Ps) from the Neurology Service and the Diabetes Unit of the Hospital General de Agudos Juan A. Fernández, Hospital Sirio-Libanés and the FACENE: Eduardo L. Bartolomé MD, Silvia González MD, Graciela D'Abraccio MD, Marcela Arata Ps, Liliana Oudkerk Ps, Laura Garau MD, Fernando Krinsky MD, Edith Labos Ps, Cecilia Ruiz Ps, Gustavo Frechtel MD, Alejandra Arana MD, and Silvia Lovecchio MD.

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Homocysteine, vitamin B 12 and folate in Alzheimer's and vascular dementias: The paradoxical effect of the superimposed type II diabetes mellitus condition

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Patients and controls

Results

Discussion

Acknowledgements

Am J Clin Nutr

Diabetes Metab

Lancet

Neurobiol Aging

Plasma homocysteine as a risk factor for dementia and Alzheimer's disease

N Engl J Med

Vitamin B(12) and folate in relation to the development of Alzheimer's disease

Neurology

Plasma homocysteine concentration and risk of Alzheimer disease

Neurology

Homocisteína y enfermedad vascular en diabetes mellitus tipo 2

Rev Endocrinol Nutr

Elevated plasma homocysteine concentration in patients treated with levodopa: association with vascular disease

Arch Neurol

Homocysteine and levodopa: should Parkinson disease patients receive preventive therapy?

Neurology

Insulin in methionine and homocysteine kinetics in healthy humans: plasma vs. intracellular models

Am J Physiol Endocrinol Metab

Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force of Alzheimer's disease

Neurology

Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop

Neurology

Report of the expert committee on the diagnosis and classification of diabetes mellitus

Diabetes Care

Diagnostic and statistical manual of mental disorders (DSM IV)