Does Down's syndrome support the homocysteine theory of atherogenesis?: Experience in elderly subjects with trisomy 21
Introduction
In England, the life expectancy of a person with DS increased from 9 years in 1929 to 12 in 1949 (Pensrose, 1949). Since then a substantial gain in life expectancy of these patients in Western countries has been observed, and recent estimates indicate mean survival is over 50 years (Janicki et al., 1999, Glasson et al., 2001).
These individuals present several metabolic abnormalities, some involving lipid (Dorner et al., 1984) and tHcy metabolism (Quadri et al., 2004). Therefore, their low prevalence of coronary artery disease presumably cannot be explained by their cholesterol levels. These patients rarely die because of atherosclerosis complications (Pueschel et al., 1992), and pathological studies report no increase in atherosclerosis or even a complete absence of atherosclerotic changes (Murdoch et al., 1977). DS children (Zamorano et al., 1991) and adolescents (Eberhard et al., 1993) may have low levels of high-density lipoprotein (HDL) whose vasoprotective effects are becoming clearer (Soufi et al., 2002). As consequence, DS remains a disease in which atherosclerosis and its clinical manifestations are rare (Baird and Sadovnick, 1988).
The syndrome is associated with several clinical alterations, variable degrees of mental retardation (Franceschi et al., 1981), and accelerated aging of different organs and tissues (Wisniewski et al., 1985). By the fourth decade of life, cognitive status further deteriorates and senile dementia is of frequent observation (Mann and Esiri, 1989). DS brains show many neuropathological features, such as neuritic plaques, neurofibrillary tangles and degeneration of the basal forebrain cholinergic neurons, which are considered the pathological hallmarks of AD (Mann and Esiri, 1989). A strong association has been found with the ɛ4 allele of APO-E and a potentially weak association with tHcy, folate and Vitamin B12.
This study investigated the relations between blood levels of tHcy, related vitamins (folate and Vitamin B12), blood levels of lipid fractions HDL; low density lipoprotein (LDL); apolipoprotein A and apolipoprotein B (Apo-A and Apo-B) and Apo-E in a rare group of healthy elderly DS patients. Genotype assessment of polymorphism in APO-E, MTHFR and CBS genes were also performed.
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Subjects and methods
After informed consent was given, blood samples were drawn from 13-old-DS male patients and 20 healthy male individuals (both male groups, average age 60 years), without dyslipidemia or any family history of coronary heart disease; subjects were non-smokers and non-drinkers. This study was conducted in accordance with the Declaration of Helsinki, 1975, amended in 1983.
Lipid fractions were measured using Konelab (Dasit, Italy): after separation of plasma from blood cells, lipoprotein depletion
Results
Table 1 shows cholesterol fractions, tHcy, folate and Vitamin B12 concentrations of DS patients and healthy controls. DS total cholesterol and HDL did not differ from controls. LDL concentrations were lower in DS patients and Apo-A levels were higher than those of controls; Apo-B levels were decreased. Plasma tHcy was higher in DS patients and folate lower than in controls; blood levels of Vitamin B12 were also lower in DS patients than in controls (Table 1). Genotype assessment for APO-E gene
Discussion
Cardiovascular diseases are less common in the general population than in old DS patients and they have been proposed as “an atheroma-free model” (Murdoch et al., 1977). Serum lipoprotein profiles cannot completely explain the lower prevalence of cardiovascular disease in these individuals. Our findings on lipoprotein levels in DS are in accordance with previous report showing data from young DS subjects (Dorner et al., 1984). High levels of Apo-A and low levels of Apo-B are linked with a low
Acknowledgements
This research was supported by funds from the Italian University Ministry (PRIN, Cofin ex 40 and 60%), Italian CURA, and BPM Foundation Milan, Italy. We are grateful to J.D. Baggott for editing.
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