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- Hagnelius, Nils-Olof, 1953-
(författare)
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Vascular mechanisms in dementia with special reference to folate and fibrinolysis
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to study the biomarker homocysteine and other novel potential vascular risk factors for dementia. In an out-patient based study of a cohort of 926 consecutive subjects referred to our Memory Unit during 1996―2000, serum-folate was lower and total plasma homocysteine (tHcy) and serum methyl malonate were higher in subjects being prescribed with B12. In the subgroup diagnosed with dementia and with a positive family history of dementia, tHcy was higher than in the subgroup diagnosed as non-demented. It is necessary to supplement subjects with vitamin B12 deficiency with B12, but our results indicate that it is not sufficient with B12 alone because this gives rise to intracellular folate deficiency. We also found indications of a genetic component in dementia because tHcy was higher in the group with a positive family history of dementia. These findings prompted further studies of homocysteine metabolism. The frequency of mutations in the gene for folate receptor-α (FOLR-1), and the fibrinolytic pattern in dementia and non-dementia were studied in the two cohorts DGM (n=300) and AS (n=389). The DGM cohort is a consecutive series of subjects attending our Memory Care Unit for investigation of suspected cognitive problems or dementia between 2003 - 2007. The AS (= active seniors) cohort comprises retired, apparently healthy subjects from central Sweden, actively participating in study circles. A rare haplotype in the FOLR-1, with mutations in two nearby loci, was discovered, possibly associated with lower serum-folate and higher tHcy concentrations and was more frequent in the DGM group. The transport of folate to the CSF was studied in the DGM-cohort. Dementia with a vascular component was associated with a lower CSF to serum folate ratio indicative of reduced transport of folate to the CSF and further to the brain. The vascular endothelial derived fibrinolytic markers tPA, tPA/PAI-1-complex, and vWF were not only higher in vascular dementia (VaD) but also in Alzheimer’s Disease (AD) when compared to the AS group. The impaired fibrinolytic activity in both vascular dementia and in AD is a novel finding, signifying a vascular component in the development of dementia. In conclusion we found that both hereditary and nutritional background factors were linked to dementia and furthermore that a dysregulated fibrinolysis was linked to both VaD and AD.
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| 2. |
- Söderström, Elisabet, 1975-
(författare)
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Homocysteine and its determinants in relation to cardiovascular risk factors and myocardial infarction
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Globally, cardiovascular diseases (CVD), including myocardial infarction (MI) and stroke, are the leading cause of illness and death and constitute a significant part of the disease burden in Sweden and Western Europe. Age, hypertension, smoking, obesity, dyslipoproteinemia, diabetes, and impaired renal function are considered established risk factors for CVD. However, these factors do not explain all MI cases, and much is still unknown. Homocysteine is a sulfur-containing amino acid used in clinical practice as a biomarker of functional vitamin B12 and folate status. Earlier observational studies have shown associations with higher plasma homocysteine concentrations (tHcy) and CVD. The causal relationship between tHcy and MI has been debated as homocysteine-lowering prevention studies have not shown a protective effect on MI, although there may be a protective effect on ischemic stroke. Still, tHcy is a prognostic biomarker or risk determinant of MI. There is a need for more knowledge on the pathophysiologic mechanisms of how homocysteine interacts with its determinants, and other risk factors, on the risk of MI.Aims: The overall aim of the thesis was to expand knowledge about how homocysteine, as a risk determinant, can have an impact on cardiovascular disease. Specifically, the purposes were to explore the associations between tHcy, determinants of homocysteine and risk factors of CVD, and the associated risk of prospectively developing a first-ever MI.Material and methods: In papers I, III, and IV, a prospective incident nested case-referent study design was used with 545 cases of MI and 1054 matched referents. In paper II the design was cross-sectional, comparing strictly defined smokers and snus users. All study subjects emanated from the Northern Sweden Health and Disease Study (NSHDS). Blood samples stored frozen at -80ºC were later thawed, and analyses of biomarkers for renal function, lipids, B-vitamins, tHcy, cotinine, and genetic polymorphisms related to homocysteine metabolism were performed. Results: In a prospective setting, folate, but not tHcy, was positively associated with apolipoprotein A1 (Apo A1). The association was seen among referents and not among those later developing an MI. Among strictly defined smokers and snus users, cotinine was positively associated with tHcy among smokers but not among snus users, despite higher cotinine concentrations in snus users. No association was observed between tHcy and the number of cigarettes/day.The CTH G1208T and MTHFR A1298C polymorphisms were, among women, associated with a higher risk of developing a first-ever MI with a fatal outcome. No such associations were seen among men or all MI patients. Further, no associations were seen between the MTHFR C677T polymorphism and the risk of having an MI, fatal or non-fatal. Mild impairment of renal glomerular function defined by eGFRcystatin C /eGFRcreatinine ratio and the associated risk of MI is previously not studied prospectively. In the present study, a lower eGFRcystatin C/eGFRcreatinine ratio was associated with a higher risk of later developing a first-ever MI among women, both when analyzed as a continuous variable and across the quartiles of the ratio. These associations did not appear among men.Conclusions: The independent association of folate but not tHcy with Apo A1 emphasizes the need to adjust for possible confounding effects in studies on homocysteine and endpoints or biomarkers. The results suggest a possible link between one-carbon metabolism and lipid metabolism. The independent association between cotinine and tHcy in smokers and not among snus users indicate that nicotine per se may not mediate higher tHcy concentrations. Cotinine concentrations in plasma appeared as a better predictor of tHcy than self-reported smoking data. Thus, whenever possible, self-reported smoking should be supplemented by biomarkers, such as cotinine, in epidemiological studies. After outcome stratification, fatal or non-fatal MI, the associated higher risk among women of a fatal MI and CTH G1208T and MTHFR A1298C polymorphisms, respectively, may indicate that women with the minor alleles risk having a more serious MI leading to death than women with the wild-type alleles. In a prospective setting, the eGFRcystatin C/eGFR creatinine ratio was associated with an increased risk of later developing a first-ever MI among women. The eGFRcystatin C/eGFRcreatinine ratio may be a tool, easily implemented at clinical laboratories, for evaluating the risk of having a future first-ever MI.
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