Abstract
Individuals with Down syndrome have signs of possible brain damage prior to birth. In addition to slowed and reduced mental development, they are much more
likely to have cognitive deterioration and develop dementia at an earlier age
than individuals without Down syndrome. Some of the cognitive impairments are
likely due to post-natal hydrogen peroxide-mediated oxidative stress caused by
overexpression of the superoxide dismutase (SOD-1) gene, which is located on the
triplicated 21st chromosome and known to be 50% overexpressed. However, some of
this disability may also be due to early accumulation of advanced protein
glycation end-products, which may play an adverse role in prenatal and postnatal
brain development. This paper suggests that essential nutrients such as folate,
vitamin B6, vitamin C, vitamin E, selenium, and zinc, as well as alpha-lipoic
acid and carnosine may possibly be partially preventive. Acetyl-L-carnitine,
aminoguanidine, cysteine, and N-acetylcysteine are also discussed, but have
possible safety concerns for this population. This paper hypothesizes that
nutritional factors begun prenatally, in early infancy, or later may prevent or
delay the onset of dementia in the Down syndrome population. Further examination
of this data may provide insights into nutritional, metabolic and
pharmacological treatments for dementias of many kinds. As the Down syndrome
population may be the largest identifiable group at increased risk for
developing dementia, clinical research to verify the possible validity of the
prophylactic use of anti-glycation nutrients should be performed. Such research
might also help those with glycation complications associated with diabetes or
Alzheimer's.
Introduction
People with Down syndrome (DS) are much more likely to develop dementia than
the general public. While only around 2% of the general public has dementia by
age 40 (1), nearly all of those with DS show signs of an Alzheimer's-like
dementia prior to age 40 (2).
In DS (also known as trisomy 21), there is an extra copy of the 21st
chromosome. Many enzymes that are encoded on the extra 21st chromosome are known
to be actively transcribed, which results in overexpression of these enzymes.
Genetic overexpression of enzymes leads to overconsumption of their enzymatic
substrates and overproduction of their metabolic end-products. One of the best
documented examples of this phenomenon in Down syndrome is the SOD-1 gene, which
is approximately 50% overexpressed (3,4). Elevated levels of cytosolic
superoxide dismutase decrease the levels of superoxide (the enzyme's substrate)
and increase the levels of hydrogen peroxide (the enzyme's metabolite,
end-product or output). These primary consequences of genetic
overexpression may then produce secondary metabolic adaptations as homeostatic
systems attempt to compensate. As an example, increased levels of hydrogen
peroxide might induce the production of glutathione peroxidase, a
selenium-dependent enzyme, and thereby increase selenium requirements (5). Such
genetically driven, enzymatic and metabolic disturbances may help explain why
individuals with DS are more likely than those without it to develop various
forms of dementia (2).
Glycation as a Possible Cause
Glycoxidation damage appears to begin in those before birth who have DS, but
not for those that do not (6). A trial involving human fetuses of between 18-20
weeks of gestation found increased levels of oxidation markers pyrraline and
pentosidine, both of which are well known end-products of nonenzymatic glycation
that tend to accumulate in aging tissues; amyloid beta (Abeta) peptides were
also found (6). "In persons with Down syndrome, soluble Abeta peptides, which
result from the processing of the amyloid precursor protein, appear in the brain
decades before the extracellular deposition of neuritic plaques. These soluble
amyloidogenic peptides accumulate intraneuronally and can be secreted
extracellularly. Their appearance has been reported in the brains of fetuses
with Down syndrome, but not non-DS fetuses. The extra gene dosage effect
associated with trisomy 21 results in abnormalities of the processing of amyloid
precursor protein in persons with Down syndrome" (7). It is possible that this
may account for some (or even much) of the characteristically slowed mental
development for this population. There are multiple causal relationships to
consider. The increased magnitude of amyloid induction may be a direct
manifestation of a genetic overexpression. It is also possible, or even maybe
likely, that the effect of the gene overdose on amyloid metabolism is indirect
and a consequence of mechanisms of prolonged oxidative stress or chronic
inflammation.
For example, it has been reported that both bradykinin B2 receptor
modification and bradykinin mediated tau Ser phosphorylation can be detected in
the fibroblasts of people with DS two decades before the characteristic onset of
Alzheimer's dementia (8). Increased Ser phosphorylation of tau
microtubule-associated protein in the brain is an early feature of Alzheimer's
that tends to precede neuronal disruption (8). It appears that nitrative
(nitrate-mediated) injury is directly linked to the formation of filamentous tau
inclusions and the subsequent neurodegeneration of those with DS and those with
Alzheimer's (9). People with DS over 40 years of age, prematurely and
consistently develop neurofibrillary tangles, intracytoplasmic inclusions of
highly insoluble straight or paired helical 12-16 nm filaments, and senile
plaques composed of abnormal neurites surrounding a core of beta amyloid. These
two lesions occur in distributions similar to those seen in Alzheimer disease
(2).
Deutsch et al reported, "Abeta peptides, especially Abeta1-42, have
been shown to form tight complexes with the alpha7 nicotinic acetylcholine
receptor, interfering with transduction of the acetylcholine signal by this
nicotinic receptor subtype. Furthermore, the selective binding of Abeta peptides
by this nicotinic acetylcholine receptor subtype is associated with
cytotoxicity. The alpha7 nicotinic acetylcholine receptor has unique
electrophysiologic properties and plays a prominent role in normal
psychophysiologic processes (eg, sensory inhibition) and cognition. In persons
with Down syndrome there is a decrease in the ability to perform instrumental
activities of daily living that worsen with aging (7)." While Russo et al reported that "N-terminally truncated amyloid-beta (Abeta) peptides are
present in early and diffuse plaques of individuals with Alzheimer's disease
(AD), are overproduced in early onset familial AD and their amount seems to be
directly correlated to the severity and the progression of the disease in AD and
Down's syndrome (DS)" (10), then in another paper concluded "The
carboxy-terminal fragments (CTFs) of the amyloid precursor protein... constitute in
human brain a molecular species directly involved in AD pathogenesis and in the
development of the AD-like pathology in DS subjects." (11) Thus, it seems
reasonable that Abeta could be a contributor to what we see in Down syndrome. It
may be of interest to note that diabetics also have problems with protein
glycation and related end-products (12).
Nutrition as an Intervention Strategy
Glycoxidation is "a process that occurs with elevated blood glucose levels.
Another pathway that results in the modification of LDL proteins involves the
formation of Amadori products. An adequate amount of antioxidants from the diet
or supplements may help prevent or delay the occurrence of diabetic late
syndrome" (13). Or as Price et al have worded it, "The Maillard or
browning reaction between sugars and proteins leads to the formation of chemical
modifications and cross-links in proteins, known as advanced glycation
end-products (AGEs). These products contribute to the age-dependent chemical
modification of long-lived proteins, and accelerated formation of AGEs during
hyperglycemia is implicated in the development of diabetic complications"
(14).
Various sugars react with amino groups in proteins and nucleic acids to
produce advanced glycation end products (15). As glycation end-products tend to
accumulate as the result of disorders of sugar metabolism such as diabetes, it
is possible that a diet low in refined carbohydrates may be a logical choice for
those with DS (diets naturally high in vitamin C have been shown to result in
reduced protein glycation (16)). Although this would not stop all glycation
end-products from forming and accumulating, it may significantly reduce their
formation and possibly delay the onset of discernable dementia symptoms in the
DS population.
Since glycation of long-half-life proteins, involving carbohydrates, leads to
the formation of intra and intermolecular cross-links and the production of free
radicals (17), it is likely that antioxidants would have potential therapeutic
value.
Nutrients
- Folate
- Children with DS often have below-normal levels of
folate (18-20). Erythrocyte macrocytotis is more common in children and adults
with DS and may be due to an alteration of the folate remethylation pathway
(16)—;whether this is due to trisomy or to maternal genetic MTHFR
(methyltetrahydrofolate reductase) status in utero is unclear. As those
with DS age, further declines in folate levels seem to occur (21). An animal
study found that restricting folate, vitamin B6, and vitamin B12 resulted in an
increased formation of methionine related advanced glycation end-products (22).
Methionine is particularly sensitive to oxidation from hydroxyl radicals
(23).
The dietary source and chemical form of folate may also play a role.
Naturally occurring folate, as found in vegetable foods, has been reported to
have less affinity for serum folate-binding proteins than does purified folate
supplied in nutritional supplements (24). However, it is also true that the most
common kind of folate in dietary supplements is folic acid, and only about
266mcg to 400 mcg of folic acid can be converted into methylfolate per day
(24,25). It is possible that accumulation of unconverted folic acid may have
potentially adverse affects on folate metabolism (24,25). However, folate
"trapping," caused by impaired interconversion between the seven biologically
active forms of folate, does causes accumulation of some form(s) of folate and
simultaneous depletion of other form(s), which does adversely affect
folate-dependent metabolic pathways (26,27,28). So there may be unappreciated
advantages to either food-based folate or folate supplements containing other
biologically active folate compounds.
- Vitamin B6
- A three-year double-blind placebo-controlled
longitudinal DS study found that vitamin B6 supplementation helped normalize
brain function by reducing elevated cortical auditory evoked potentials to a
more normal level (29). Vitamin B6 deficiency has been associated with
impairments in gluconeogenesis and abnormal glucose intolerance. It has been
recommended to help deal with glycation (23,29). Furthermore, it or its
derivatives have been shown to have anti-glycation effects (14,15). A compound
containing it and aminoguanidine has been shown to be more effective in reducing
glycation than aminoguanidine alone (30), but the safety of such non-food
compounds needs extensive research. The safety of foods containing vitamin B6
and supplements containing anti-metabolite-free B6 has been well established.
However, ordinary B6 supplements containing food-grade and pharmaceutical-grade
B6 have been historically associated with scattered clinical reports of
peripheral neuropathy and may have contained sufficient levels of B6
antimetabolites to pose a neurological hazard at doses of B6 exceeding 50-500
mg/day. Other clinical reports have noted that extended use if 2000-6000 mg/day
doses of high-purity B6 do not cause peripheral neuropathy.
- Vitamin C
- One study found that many children with DS had a
deficiency of vitamin C according to serum tests (31). A case report found the
same result (32), yet a small study found that institutionalized children with
DS tended to consume more vitamin C than the recommended daily allowance (33),
thus suggesting that perhaps more is needed in the DS population. Vitamin C
appears to be an antiglycation agent (13,34-36).
The type and/or source of vitamin C (or at least associated food factors) may
make a difference. A human study found that a citrus food complex containing
500mg of vitamin C was 216% more effective in reducing sorbitol in diabetics,
42% more effective in reducing protein glycation, and 41% more effective in
decreasing galactiol when cataracts are present than isolated USP ascorbic acid
(34). One study by Vinson and Howard showed an average decrease of 46.8% in
protein glycation after four weeks using 1000mg per day of vitamin C complexed
in citrus food (35), while a study by Davie, Gould, and Yudkin only had a 33%
reduction in three months using 1000mg of isolated ascorbic acid per day (36).
Foods contain both ascorbate and dehydroascorbate forms of vitamin C, and
dehydroascorbate has been found to be a potent antiglycation agent (37).
Furthermore, an in vitro study found that citrus containing vitamin C
has negative ORP (oxidation-reduction potential) while isolated ascorbic acid
has positive ORP (38) (negative ORPs indicate active reducing power, which is
immediately capable of antioxidant activity, whereas items with positive ORPs
are not). The Merck Index also states that isolated ascorbic acid has positive
redox potential (1). However, since ORP is significantly pH dependent and none
of these ORP readings controlled for pH differences, more research in this area
is needed.
- Vitamin E
- One study found that children with Down syndrome
have significantly less vitamin E levels than those without it (39). Down
syndrome patients with dementia have lower plasma levels of vitamin E than those
that do not (40). It is reported that vitamin E appears to be an anti-glycation
agent (13,41).
Chemical form and source may play a role as "chemically synthesized
alpha-tocopherol is not identical to the naturally occurring form"(42). By weight, vitamin E as natural RRR-alpha-tocopherol has 1.7 - 4.0 times the
peroxyl-radical-scavenging-activity of the other tocopherols, RRR-alpha
tocopherol has 3 times the biological activity of the alpha-tocotrienol form,
and vitamin E acetate (a synthetic form) simply does not have the same biologic
activity of natural vitamin E (some synthetic forms have only 2% of the
biological activity of RRR-alpha-tocopherol) (42). It should be pointed
out, however, that mixtures of different forms of vitamin E have a broader range
of free-radical-scavenging abilities than any purified or single form of vitamin
E. Vitamin E in food seems to be retained 7.02 times better than isolated
alpha-tocopherol acetates (43), thus it may be the preferred way to help prevent
glycation. High-vitamin-E food has also been shown to prevent glycation (44).
- Selenium
- DS patients may have below-normal plasma levels of
selenium (45,46). This may be a direct consequence of increased incorporation of
selenium into glutathione peroxidase, which is induced to higher-than-normal
levels by excessive SOD-mediated hydrogen peroxide production. Selenium may be
beneficial in DS by protecting the biosynthesis of thyroxine from free radical
attack (47). Selenoenzymes also catalyze the iodination of tyrosine residues in
the manufacture of T4 and T3, and regulate the tissue conversion of T4 into
T3.
Selenium has not generally been considered much of an anti-glycation agent,
but this may be because most common selenium forms in supplements are not in the
biologically active form (i.e., "Factor 3," as naturally occurs in liver) and
have little proven anti-glycation effects. However, yeast grown in high-selenium
media has been found to produce significant anti-glycation effects as a dietary
supplement. One study found that high-selenium yeast was 123 times more
effective than selenomethionine in preventing nonenzymatic glycation in
diabetics (44). This same study found that high-selenium yeast was more
effective in glycation prevention than ascorbic acid, niacinamide, carnosine,
tocopherol, and pyridoxal (44).
Another study using 247 mcg/day of high-selenium yeast found that plasma
selenium levels were 2-fold higher than baseline values after 3 and 9 months and
returned to 136% of baseline after 12 months, whereas there was a 32% increase
in blood glutathione levels also seen after 9 months. This change coincided with
a 26% decrease in protein-bound glutathione and a 44% decrease in the ratio of
protein-bound glutathione to blood glutathione. The changes in glutathione and
protein-bound glutathione were highly correlated with changes in plasma selenium
levels and were believed to reflect a reduction in oxidative stress (48).
However, cellular selenium levels were not determined, nor were any
seleno-enzyme activities measured. So further research is needed to clarify the
advantages of high-selenium yeast.
- Zinc
- Reports suggest that DS patients have below-normal
plasma levels of zinc (49,50). While diabetics often also have zinc deficiency,
this deficiency may be refractory to mineral salt zinc supplements (12). Even
though high-zinc yeast has been shown to be 6.46 times more absorbed into the
blood than zinc gluconate (51), zinc helps with diabetic complications (52), and
zinc is highly recommended to assist with oxidative stress (53). It is not clear
that zinc has any significant effect on preventing accumulation of advanced
protein glycation end-products. However, since zinc can reduce copper in some
tissues (54), individuals with DS have frequently been found to be high in
copper in various measurements (40), and zinc and copper compete with each other
for enzyme binding, zinc should not be overlooked in DS. Future research into
copper-zinc dynamics is warranted.
Other Substances
- Acetyl-L-carnitine
- At least in eyes, it appears that
acetyl-L-carnitine may have antiglycation abilities (55). Hendlor and Rorvik
report, "Acetyl-L-carnitine has recently demonstrated some efficacy as a
possible neuroprotective agent for strokes, Alzheimer's disease, Down's syndrome
and for the management of various neuropathies... recent studies show beneficial
effects in Alzheimer's disease. Younger patients seem to benefit most" (55).
However, some few with seizure disorders have reported increases in seizure
frequency or severity on acetyl-L-carnitine (54). As the DS population is much
more inclined towards seizure disorders than the general public (56), caution
would seem to be advisable regarding using acetyl-L-carnitine to attempt to
prevent glycation.
- Alpha-Lipoic Acid
- Alpha-lipoic acid, also known as thioctic
acid, appears to have anti-glycation abilities (57,58). Alpha-lipoic acid may
act to limiting cofactors in the product of advanced protein glycation end
products (58). Animal research suggests that it may have anti-aging effects
(53).
- Aminoguanidine
- Aminoguanidine may be one of the most
powerful substances with anti-glycation abilities (14,30). However, since it has
the effect of greatly reducing the vitamin B6 from the body, it may not be safe
enough for use in the DS population—which tends to be deficient in vitamin B6
(56). A pyridoxal-containing form is being tested (30).
- Carnosine
- Serum carnosine deficiency is a rare condition,
which is not often clinically assessed. Symptoms of serum carnosine deficiency
are similar to some often associated with DS such as mental retardation, absence
seizures, and childhood dementia (59). Carnosine and related compounds (such as
homocarnosine) have been found to have protective effects against hydrogen
peroxide-mediated Cu,Zn-superoxide dismutase fragmentation (60) and SOD-1mutants
(61) which may cause problems for those with DS. Carnosine is also an
antiglycation agent that may prevent or at least reduce this brain damage (62).
A recent study concluded "that carnosine and such related compounds as Gly-His
and Ala-His are effective anti-glycating agents for human Cu,Zn-SOD and that the
effectiveness is based not only on high reactivity with carbonyl compounds but
also on hydroxyl radical-scavenging activity" (63). Furthermore involving heat,
carnosinylation tags glycated proteins for cell removal (64); it also appears to
have anti-inflammatory properties, which may be due to its anti-glycation
abilities (65). Carnosine has even been proposed as a possible "anti-dementia
drug" (66).
- Cysteine
- People with DS have been found to have abnormally
high levels of cysteine (67). This is likely due to the overexpression of
cystathionine-beta-synthase, which diverts homocysteine into cysteine, thus
preventing it from being recycled (remethylated) into methionine within the
S-adenosylmethionine (SAM) cycle. This may be why abnormally high levels of
cathepsin S (a lysosomal cysteine protease) have been found, postmortem, in
those with DS and Alzheimer's (68). Despite this, a study of mice with trisomy
16 (a mouse model for human Down syndrome) found that N-acetyl-cysteine reduced
toxicity believed similar to that caused by the oxidative stress of triplication
of superoxide dismutase (69). Since N-acetyl-cysteine is an anti-glycation agent
(70), it may be of interest for use in the DS population. However, since
L-cysteine can induce seizures (71,72), and there is also a case report of
status epilepticus being induced by the injection of N-acetylcysteine (73) , it
may have only limited possible use.
Discussion
It is speculated that the presence of advanced glycation end-products in the
fetal brain are not significant enough to stop, but may slow down, brain
differentiation and development. It is logical to conclude that increases in
brain size during growth may partially explain why those with DS do tend to make
developmental progress, though at a much slower pace than the non-trisomy
population. Although glycation accumulation in DS appears be markedly slower
than that which occurs with Alzheimer's disease, the accumulation appears to
begin at the earliest stages of life, which is in distinct contrast to the
accumulation seen in Alzheimer's disease. The early accumulation of advanced
glycation end-products appears to finally result in dementia in much of the DS
population.
Similarly, Deutsch et al observed, "The progressive worsening of
adaptive functions and cognition in persons with Down syndrome may be, at least
in part, mediated by interference with [the alpha7 nicotinic acetylcholine]
receptor by soluble Abeta peptides...Ideally, selective cholinergic
interventions would slow the progression of the worsening of adaptive function
and emergence of dementia in persons with Down syndrome" (7). Anti-glycation
agents may be a way to accomplish that.
Stadtman and Levine noted that, "the accumulation of oxidized protein is a
complex function of the rates of ROS [reactive oxygen species] formation,
antioxidant levels, and the ability to proteolytically eliminate oxidized forms
of proteins. Thus, the accumulation of oxidized proteins is also dependent upon
genetic factors and individual life styles" (23). Although it is unclear how
anti-glycation agents precisely work, heat (65) and antioxidant properties
(17,23), anti-inflammatory properties (66) and other pathways have been
proposed. Price et al "conclude that both carbonyl trapping and
chelation activity of AGE inhibitors and AGE-breakers may be involved in their
therapeutic mechanism of action (14). Price et al also concluded "All
AGE inhibitors studied were chelators of copper... AGE inhibitors have significant
copper chelating activity" (14). As those with DS have often been found to have
excesses of copper in certain metabolic compartments (40,45,48), it appears
quite plausible that anti-glycation agents could be either reducing copper
toxicity or counteracting copper sequestration mechanisms as a mechanism of
action. Either way, anti-AGE therapies could prove to be a legitimate treatment
for those with DS.
The efficacy of multi-nutrients in DS alone, though advocated by some (i.e.
74-76), has been discounted by others (i.e.77-79)—but none have looked into
anti-glycation therapies, nor into the use of high-nutrient foods for enhancing
nutritional status. High-nutrient foods may have significantly higher
antioxidant properties in vivo compared with isolated or synthetic
anti-oxidant nutrients (35,38), which may be, in key instances, not even in the
same biochemical form as those found in food (80).
Irrespective of these controversies, a review of the nutrients and metabolic
end-products shown above suggests that it is logical that certain nutrients may
be preventive for key pathological processes involved in dementias, such as DS
and Alzheimer's. Furthermore, considering the relative safety and theoretical
benefits of the above-mentioned nutrients, as well as the inevitability of
accumulations of advanced protein glycation end-products in the untreated DS
population, it seems wise to seriously consider such supplementation. It seems
equally wise to undertake additional research to verify the safety and efficacy
of such substances as acetyl-L-carnitine, aminoguanidine, cysteine, and
N-acetylcysteine in the DS population. Other substances mentioned and not
mentioned in this paper may also be of value.
Glycation end-products also tend to accumulate in the brains of those who
develop Alzheimer's or similar forms of dementia (81). It is possible that these
accumulations play only a small role in cognitive decline, but it appears
reasonable to conclude that any "sticky plaque on the brain" is not mentally
helpful (especially as this does not tend to occur in the non-DS,
non-Alzheimer's populations).
The predictable and consistent appearance of the Alzheimer's-like
neuropathologic changes in DS provides an unusual opportunity to examine the
sequential development of advanced protein glycation end-products and their
consequences (1). As the DS population is probably the largest identifiable
group for developing dementia, clinical research to verify the possible validity
of the prophylactic food-born nutrients, use of anti-glycation agents for this
population should be performed—specifically including food-bound nutrients,
folate, vitamin B6, vitamin C, vitamin E, selenium and zinc, along with
alpha-lipoic acid and carnosine. Such research may not only benefit those with
DS, but would also be expected to have benefit for others at risk for
Alzheimer's and other forms of dementia (63,81). It may also be of benefit to
those with certain complications associated with diabetes.
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