Homocysteine vs. brain function

[Guest guest]

Hi All,

It seems that homocysteine (tHcy) levels in our blood are harbingers of poor

brain

health, as reviewed and updated in the below editorial.

Fortification of foods with B vitamin supplements containing folic acid, vitamin

B12, and vitamin B6 in most developed countries may have been the reason that

previous experiments had not found that the B vitamin levels in our diets

predispose

the population to increase risk of Alzheimer disease (AD), Parkinson disease

(PD)

and dementia.

Are CRers who eat less or none of the foods that are supplemented with B

vitamins in

our eating less or no processed breakfast cereals, etcetera at a greater risk?

The two latest articles editorialized in the below are pdf-available.

Editorial:

Teodoro Bottiglieri and Ramon -Arrastia

Hyperhomocysteinemia and cognitive function: more than just a casual link?

Am J Clin Nutr 2005 82: 493-494.

See corresponding [below] articles on pages 627 and 636.

Over the past 2 decades, numerous epidemiologic studies have confirmed that

elevated

plasma total homocysteine (tHcy) is associated with an increased risk of

vascular

diseases, including cardiovascular, peripheral vascular, and cerebral vascular

disease (1, 2). Because elevated plasma tHcy is effectively treated with B

vitamin

supplements (folic acid, vitamin B-12, and vitamin B-6), therapy that is

inexpensive

and well tolerated, an explosion of clinical and basic research on the vascular

effects of hyperhomocysteinemia has occurred over the past decade. Vascular

disease

has deleterious effects on various organs of the body, and the brain is

particularly

susceptible. Elevated tHcy is now a recognized risk factor for vascular

dementia.

More surprising have been a series of observations from cross-sectional and

prospective epidemiologic studies that elevated tHcy is associated with an

increased

risk of Alzheimer disease (AD) and with cognitive problems in the elderly that

fall

short of dementia.

In this issue of the Journal, Ravaglia et al (3) present the latest data on this

issue, which led them to conclude that elevated plasma tHcy and low serum folate

concentrations are independent predictors of AD development. The prospective and

longitudinal nature of this study provides an important measure of confidence to

their conclusions. The authors point out that several case-control and

cross-sectional studies have reported an association between AD and elevated

plasma

tHcy. However, only 2 prospective longitudinal studies, which have conflicting

results, have appeared in the literature. The findings of the current study by

Ravaglia et al confirm previous findings from the Framingham Study (4), which

indicate that hyperhomocysteinemia is associated with a 2-fold increase in the

relative risk of developing AD. The negative findings from the Washington

Heights–Inwood Columbia Ageing Project (WHICAP) (5) were dismissed on the basis

of

insufficient statistical power and other methodologic issues. There are other

important findings of the study by Ravaglia et al. The increased risk of

developing

AD in hyperhomocysteinemic persons remained unchanged even after subjects with

brain

imaging evidence of vascular disease were excluded. Although elevated tHcy may

promote vascular disease that contributes to AD pathology, it may also have

other

direct neurotoxic effects. Another interesting aspect of this study, which was

conducted in Italy (where food fortification is not mandated), was the

observation

that low folate status is independently associated with an increased risk of

developing AD—a finding not evident in the Framingham Study or WHICAP.

Another article in this issue, by Tucker et al (6), presents data on the

relation

between tHcy, B vitamins, and cognitive decline that falls short of dementia.

Study

subjects from the VA Normative Aging Study were assessed over a 3-y period

before

the fortification of food sources with folate. On the basis of both plasma

concentrations and dietary intake assessments, this longitudinal study showed

that

tHcy, folate, vitamin B-12, and vitamin B-6 are independently associated with

various measures of cognitive decline. Although elevated plasma tHcy was shown

to be

associated with memory recall, low plasma folate was shown to be associated with

constructural praxis after adjustment for tHcy and other B vitamins. These

independent associations highlight a central argument in this field of research:

whether elevated plasma tHcy is merely a marker for deficiencies in folate and

other

B vitamins or whether it is more directly involved in cognitive function and

dementia. Recent data from studies in Parkinson disease (PD) argue for a more

direct

neurotoxic role for Hcy in central nervous system function. In the setting of

L-dopa

therapy for PD, hyperhomocysteinemia results from an excessive methylation

burden

rather than from a vitamin deficiency, and PD patients with elevated plasma tHcy

and

normal B vitamin status are more likely to be cognitively impaired and depressed

(7).

Epidemiologic studies, even when elegantly designed and rigorously conducted,

cannot

address the issue of causality. The available data are consistent with the

hypothesis that elevated tHcy is toxic to the nervous system; however, the

possibility that elevated plasma tHcy is simply a marker of an underlying

neurodegenerative process cannot be excluded. In the latter case, therapy aimed

at

correcting hyperhomocysteinemia will not be effective at correcting

neurodegeneration. Studies to address this important issue will have to focus in

2

directions. First, molecular and animal model studies are needed to identify as

precisely as possible the neuropathogenic mechanisms associated with tHcy

elevations. The metabolic relations between homocysteine, folate, and B vitamins

are

intimate and complex. The consequences of hyperhomocysteinemia or B vitamin

deficiency and the potentially associated neurotoxic mechanisms involved are

equally

complex. These consequences have been discussed in various reviews (8-11) and

include the following: Hcy-induced atherosclerosis; neurotoxicity from the

activation of N-methyl-D-aspartate receptors; hypomethylation of DNA, proteins,

lipids, and neurotransmitters; increased oxidative stress; and increased

ß-amyloid

toxicity. It is probable that multiple mechanisms, perhaps acting

synergistically,

may be responsible for the pathophysiologic consequences of hyperhomocysteinemia

and

B vitamin deficiency. Fortunately, animal models are now available to test these

possibilities. Second, clinical studies are needed to determine whether the

correction of tHcy concentrations results in cognitive improvement or, at a

minimum,

protection from cognitive deterioration. Several secondary treatment trials are

currently underway. Although we eagerly await their results, we must realize

that

the epidemiologic literature indicates that the toxic effects of elevated plasma

tHcy may occur over years or decades, which raises the possibility that the

ongoing

secondary therapy trials may fail to identify a beneficial effect of

tHcy-lowering

therapy. Primary treatment trials are expensive and lengthy, and, although such

trials are ultimately necessary, clinical scientists must first take advantage

of

insights from preclinical studies to design more feasible studies that use

biomarkers or neuroimaging as surrogate endpoints.

The direction pointed to by excellent epidemiologic studies, such as those

conducted

by Ravaglia et al and Tucker et al and published in this issue of the Journal,

should stimulate exciting studies over the next decade. Although it is unlikely

that

the answers will be simple, the potential to ameliorate one of the major public

health burdens facing developed nations today is substantial.

REFERENCES

.... 3. Ravaglia G, Forti P, Maioli, F, et al.

Homocysteine and folate as risk factors for dementia and Alzheimer disease.

Am J Clin Nutr 2005;82:636-43.

.... 6. Tucker KL, Qiao N, T, Irwin T, Rosenberg I, Spiro A III.

High homocysteine and low B vitamins predict cognitive decline in aging men: the

VA

Normative Aging Study.

Am J Clin Nutr 2005;82:627-35.

Al Pater, PhD; email: old542000@...

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