Homocysteine and Dementia
Homocysteine and Dementia
Abstracts & Commentary
Sources: den Heijer T, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003;126:170-175; Kado DM, et al. Homocysteine levels and decline in physical function: MacArthur studies of successful aging. Am J Med. 2002;113:537-542; Dufouil C, et al. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol (forthcoming article). Available online at http://www.interscience.com.
Three recent studies have provided further evidence linking elevated homocysteine levels to brain atrophy and cognitive dysfunction, as well as a decline in physical function. The first of these studied whether higher homocysteine levels are involved in the early pathogenesis of Alzheimer’s disease. den Heijer and colleagues measured hippocampal, amygdala, and global brain atrophy on brain MRI. The study was part of the Rotterdam study, which is a large population-based study of age-related brain changes. In 1077 nondemented people, aged 60-90, den Heijer et al obtained nonfasting plasma homocysteine levels in 1031 of the participants and in 505 of the participants with hippocampal and amygdalar volumes. There was a linear relationship between higher plasma homocysteine levels and cortical atrophy per standard deviation increase. Similarly, there was more hippocampal atrophy, yet no association was observed between plasma homocysteine levels and amygdalar atrophy.
In the second study, Kado and associates performed a prospective cohort study of 499 highly functioning men and women aged 70-79 who had been enrolled in the MacArthur studies of successful aging. They measured total homocysteine levels and performance of physical function at baseline and then repeated these measures 28 months later. A summary measure of physical performance was obtained from tests of balance, gait, lower body strength and coordination, and manual dexterity. Kado et al found that with each increase and standard deviation of homocysteine there was an increased risk of being in the worst quartile of decline of physical function. This was after adjusting for other parameters such as age, sex, baseline physical performance, smoking status, vitamin B12 levels, and incidence of stroke. It was concluded that older persons with elevated homocysteine levels are at increased risk of decline in physical function.
The third study was part of the epidemiology of vascular aging study, which is a prospective study focusing on determinants of vascular aging and cognitive decline. Dufouil and colleagues examine the relationship between homocysteine levels and cognitive decline in 1241 subjects aged 61-73 followed up over 4 years. Dufouil et al measured plasma homocysteine levels, as well as a number of cardiovascular risk factors and ApoE genotype. Cognitive performance was assessed repeatedly using the Mini-Mental State Examination, Trail Making Test, Digit Symbol Substitution Test, and Finger Tapping Test. At 2 years of follow-up, 841 of the subjects underwent cerebral magnetic resonance imaging, and the number of white matter hyperintensities was rated visually. The major finding was that individuals who had homocysteine levels higher than 15 µmol/L showed significantly worse scores on all 4 cognitive tests. The odds of cognitive decline was 2.8-fold higher in the patients with the elevated homocysteine levels. There, however, was no relationship with numbers of white matter hyperintensities. The number of white matter hyperintensities was equal in the 4 subgroups with varying levels of homocysteine. This study has some limitations since homocysteine levels were measured only once, whereas cognitive performance was measured repeatedly. Nevertheless, none of the patients was initially demented. Also, the prospective nature of the findings are in favor of elevated homocysteine being a contributive factor to cognitive decline.
Commentary
Homocystinuria is an inborn error of methionine metabolism that leads to severely elevated homocysteine levels resulting in mental retardation, lens dislocation, skeletal abnormalities, and early thrombotic events. It was subsequently hypothesized that elevated plasma homocysteine levels may be a cardiovascular risk factor in the general population. This has been confirmed in a number of studies. Of particular note, elevated homocysteine levels have been linked to carotid artery arteriosclerosis. There is a strong association of elevated plasma homocysteine and Alzheimer’s disease. Studies measuring serum levels of homocysteine in patients with senile dementia of Alzheimer’s type have shown significantly elevated homocysteine levels. In one study, the ratio of confirmed Alzheimer’s disease associated with a total homocysteine level in the top third (greater than 14 µmol/L)compared to the bottom third (less than 11 µ mol/L) was 4.6. In the Framingham study, a total 1092 subjects without dementia were followed to establish whether elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. Homocysteine levels were obtained at baseline . They were assessed for dementia 8 years later. Over the period of 8 years, dementia developed in 111 subjects, of whom 83 were given a diagnosis of Alzheimer’s disease. The adjusted relative risk was 1.4 for each increase in 1 standard deviation of the homocysteine level.
In the present studies, den Heijer et al and Dufouil et al provide further evidence that homocysteine may directly contribute to developing Alzheimer’s disease. They documented increased plasma homocysteine levels that were associated with more hippocampal and cortical atrophy in an older and nondemented population. The presumption is that these subjects are at risk of developing Alzheimer’s disease. What is the potential mechanism of this? It has been demonstrated that homocysteine has neurotoxic effects in cortical hippocampal neuronal cultures. It also has been shown to impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer’s disease. Homocysteine has also been directly linked to free radical damage. As such, the recent fortification that diet with more folate in 1996 may have major benefits in public health if it, as expected, lowers plasma homocysteine levels. In the meantime, taking folate supplements as well would make sense for high-risk individuals, particularly those with homocysteine levels greater than 15 µmol/L. — M. Flint Beal
Dr. Beal is Editor of
Neurology Alert and Professor and Chairman, Department of Neurology,
Cornell University Medical College, New York, NY.
Three recent studies have provided further evidence linking elevated homocysteine levels to brain atrophy and cognitive dysfunction, as well as a decline in physical function.
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