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Alzheimers I. Kruman, T.S. Kumaravel BACKGROUND: In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. METHODS: A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. RESULTS: Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer's disease nearly doubled. CONCLUSIONS: An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease. Sommer, Hoff, Costa Recent work on high plasma homocysteine levels in patients at risk
for developing Alzheimer's disease has led to the hypothesis that
folic acid supplementation might reduce risk in such patients. The
authors report on the effects of folic acid 10 mg/day versus placebo
on 11 patients (only 7 completers) with dementia and low-normal
folic acid levels. This is the first study evaluating folic acid
or placebo in patients with dementia. Subjects had low-normal baseline
folic acid levels. The magnitude of change between baseline and
second testing was not statistically significant between the 2 groups.
However, there was a trend for the folate group to perform worse
on two specific cognitive measures, suggesting a possible trend
toward worsening of some cognitive abilities after the folic acid.
The folic acid in very high doses was well tolerated. Larger studies
are necessary before empirically administering folic acid to patients
already suffering from dementia. PURPOSE: To study the association between Alzheimer s disease (AD) and plasma total homocysteine (tHcy), dietary folate and vitamin B6. METHODS: 64 AD patients were matched by gender, age, and smoking status to 64 healthy controls. tHcy was determined using an automated immunoassay. Dietary patterns for three age periods (20-39, 40-59, and 60 + yrs) were assessed using a questionnaire adapted from the Block Health Habits and History Questionnaire. Respondents (cases by proxy) reported food frequencies, which were translated into estimated daily nutrient intakes. APOE genotype, cognitive performance (CDR, MMSE), blood lipids, and albumin were obtained for patients and controls. RESULTS: tHcy did not differ significantly between controls (11.5 +/- 3.7 mmol/L) and AD patients (12.3 +/- 4.3 mmol/L)(p=0.25). tHcy levels were not related in AD patients or controls to education, CDR, MMSE, blood lipids, albumin or ApoE genotype (p>0.15). There was a negative correlation between plasma tHcy and triglyceride levels in AD patients (p=0.023), but not in controls. AD patients consumed significantly less dietary vitamin B6 (p=0.05) and folate (p=0.001) after age 60 than controls. CONCLUSIONS: Although plasma tHcy levels were higher in cases than controls, this difference was not significant. tHcy levels were not related to cognitive status. Plasma tHcy was inversely correlated with triglyceride levels in AD patients but not in controls.
Although damage to white matter occurs in the brains of patients
with Alzheimer's disease (AD), the underlying mechanisms are unknown.
Recent findings suggest that individuals with elevated levels of
homocysteine are at increased risk of AD. Here we show that oligodendrocytes
from mice expressing a mutant form of presenilin-1 (PS1) that causes
familial AD exhibit increased sensitivity to death induced by homocysteine
compared to oligodendrocytes from wild-type control mice. Homocysteine
also sensitized oligodendrocytes to the cytotoxicity of amyloid
beta-peptide. Folate deficiency, which is known to result in elevated
levels of homocysteine in vivo, also sensitized oligodendrocytes
to the cell-death-promoting actions of mutant PS1 and amyloid beta-peptide.
Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes
against cell death induced by homocysteine and amyloid beta-peptide,
consistent with a role for a DNA-damage response in the cell death
process. These findings demonstrate an adverse effect of homocysteine
on oligodendrocytes, and suggest roles for homocysteine and folate
deficiency in the white matter damage in AD and related neurodegenerative
disorders. Aisen, Egelko, Andrews, Diaz-Arrastia, Weiner, DeCarli,
Jagust, Miller, Green, Bell, Sano OBJECTIVE: Authors determined the impact of high-dose vitamin supplements on plasma homocysteine levels in patients with Alzheimer disease (AD). METHODS: Authors used an open-label trial of folic acid, vitamin B(12), and vitamin B(6), in combination for 8 weeks, with measurement of plasma homocysteine levels in the fasting state and after methionine-loading. A total of 69 subjects with AD were enrolled, including 33 who were taking standard multivitamin supplements; 66 were available at 8-week follow-up. RESULTS: The high-dose vitamin regimen was associated with a significant reduction in fasting and post-methionine-loading homocysteine. Reductions were greater in the subgroup not using multivitamins, but were also significant in the multivitamin users. CONCLUSION: High-dose vitamin supplementation reduces homocysteine levels in patients with AD. The effect of supplementation on rate of cognitive decline will be assessed later in a randomized, double-blind study.
Homocysteine, a sulfur-containing amino acid, is a metabolite of the essential amino acid methionine, and exists at a critical biochemical intersection in the methionine cycle - between S-adenosylmethionine, the indispensable ubiquitous methyl donor, and vitamins B12 and folic acid. High blood levels of homocysteine signal a breakdown in this vital process, resulting in far-reaching biochemical and life consequences. The link between homocysteine and cardiovascular disease is well established, and decreasing plasma total homocysteine by providing nutritional cofactors for its metabolism has been shown to reduce the risk of cardiovascular events. Information has been emerging regarding a connection between homocysteine metabolism and cognitive function, from mild cognitive decline (age-related memory loss) to vascular dementia and Alzheimer's disease. Significant deficiencies in the homocysteine re-methylation cofactors cobalamin (B12) and folate, as well as the trans-sulfuration cofactor vitamin B6, are commonly seen in the elderly population, with a resultant increase in homocysteine with advancing age. Hyperhomocysteinemia has been shown to be an independent risk factor for cognitive dysfunction. Indirect and direct vascular damage can be caused by homocysteine, which has been implicated in vascular dementia, with an increased risk of multiple brain infarcts and dementia as homocysteine levels rise. A significant correlation has been found between risk of Alzheimer's disease and high plasma levels of homocysteine, as well as low levels of folic acid, and vitamins B6 and B12. All of these disease associations are thought to be interrelated via increased homocysteine and S-adenosylhomocysteine and subsequent hypomethylation of numerous substances, including DNA and proteins, that render vascular structures and neurons more susceptible to damage and apoptosis. Providing the nutritional cofactors for proper functioning of the methionine cycle may improve methylation and protect the brain from damage. Further studies need to be performed to assess whether this will also reduce the risk of cognitive diseases and/or improve cognitive functioning.
Recent epidemiologic studies of different sample populations have suggested that the risk of AD and PD may be increased in individuals with high-calorie diets and in those with increased homocysteine levels. Dietary restriction and supplementation with folic acid can reduce neuronal damage and improve behavioral outcome in mouse models of AD and PD. Animal studies have shown that the beneficial effects of dietary restriction result, in part, from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and can prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although further studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to neurodegenerative disorders. Mattson, Shea Folate is a cofactor in one-carbon metabolism, during which it
promotes the remethylation of homocysteine -- a cytotoxic sulfur-containing
amino acid that can induce DNA strand breakage, oxidative stress
and apoptosis. Dietary folate is required for normal development
of the nervous system, playing important roles regulating neurogenesis
and programmed cell death. Recent epidemiological and experimental
studies have linked folate deficiency and resultant increased homocysteine
levels with several neurodegenerative conditions, including stroke,
Alzheimer's disease and Parkinson's disease. Moreover, genetic and
clinical data suggest roles for folate and homocysteine in the pathogenesis
of psychiatric disorders. A better understanding of the roles of
folate and homocysteine in neuronal homeostasis throughout life
is revealing novel approaches for preventing and treating neurological
disorders. McCaddon, Hudson, Hill, Barber, Lloyd, Davies, Regland BACKGROUND: Plasma homocysteine is elevated in Alzheimer's disease, but little is known regarding levels of related aminothiols in the disease. We therefore determined total plasma homocysteine, cysteine, and glutathione levels in patients and control subjects and investigated their relationship with cognitive scores. METHODS: We performed a prospective, case-controlled survey based in two UK Psychogeriatric Assessment Centres. Fifty patients with features compatible with DSM-IV criteria for primary degenerative dementia of Alzheimer type were recruited together with 57 cognitively intact age- and gender-matched control subjects. Mini-Mental State and Alzheimer's Disease Assessment Scale-Cognitive Subsection (ADAS-Cog) scores were determined for patients and control subjects. Aminothiols were assayed with an automated high-performance liquid chromatography (HPLC) system. RESULTS: Patients had significantly elevated total plasma homocysteine (p <.001) and cysteine (p <.01), but there were no group differences for total plasma glutathione. Glutathione was, however, a highly significant and independent predictor of cognitive scores in patients (p =.002); lower plasma levels were associated with more severe cognitive impairment. CONCLUSIONS: Total plasma homocysteine and cysteine are elevated in Alzheimer's disease, suggesting intact transsulphuration but defective remethylation of homocysteine in the disease. Total plasma glutathione levels in patients correlate with cognitive scores. Taken together, these observations perhaps reflect the differential effects of Alzheimer's disease-related oxidative stress on the two key pathways of homocysteine metabolism.
Nilsson, Gustafson, Hultberg The concentration of blood folates was decreased and the concentration
of plasma homocysteine was increased in a psychogeriatric population,
whereas the concentrations of methylmalonic acid or serum cobalamins
were not changed compared with healthy subjects. The highest frequency
of abnormal values was shown by plasma homocysteine concentration,
which was increased in 88 of 168 patients. In 29 of these 88 patients
increased concentration of plasma homocysteine could possibly be
attributed to tissue cobalamin deficiency. One patient had only
a lowered concentration of blood folate. Thirteen patients had elevated
concentrations of serum creatinine which could explain increased
plasma homocysteine concentration. Even if the remaining patients
(n = 45) had normal vitamin levels in circulation, the increased
plasma homocysteine concentration in most cases must be attributed
to tissue deficiency of cobalamins and/or folates. Thus, many patients
with increased plasma homocysteine concentrations need further vitamin
supplementation despite their normal vitamin levels in serum and
blood. Small, Viitanen, Winblad, Bäckman Longitudinal changes in global cognitive functioning, indexed by the Mini-Mental State Examination (MMSE), in subjects with dementia (Alzheimer's disease and vascular dementia) were examined. The roles of several demographic, psychometric, and biological indices in predicting cognitive deterioration were also examined. The sample consisted of 36 very old (M age at entry = 83.0 years, range = 75-95) adults with dementia from a community-based study. Subjects were tested on two occasions separated by approximately 2.5 years. Results indicated significant longitudinal decline in MMSE scores over the retest interval; the average decline was estimated as 2.43 (SD = 1.81) points per year. Several factors were associated with cognitive deterioration. Higher initial MMSE scores were associated with greater deterioration, whereas superior forward digit span and Block Design at entry were associated with attenuated decline, once differences in baseline severity were accounted for. By contrast, a variety of other putatively important variables exhibited no relationship to decline, including age, gender, education, onset age, dementia type, backward digit span, as well as a number of biological parameters (e.g., vitamin B12, folic acid). The results suggest that although the magnitude of cognitive deterioration in dementia is highly variable, several indicators may be useful predictors of future changes in cognitive functioning.
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