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Vascular mechanisms in dementia with special reference to folate and fibrinolysis
Örebro University, School of Health and Medical Sciences.ORCID iD: 0000-0002-2869-7239
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2009. , 65 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 33
Keyword [en]
dementia, Alzheimer’s disease, vascular dementia, folate, homocysteine, vitamin B12, CSF/Serum folate ratio, fibrinolysis, tPA, PAI-1
National Category
Geriatrics Medical and Health Sciences
Research subject
Geriatrics; Medicine
Identifiers
URN: urn:nbn:se:oru:diva-7785ISBN: 978-91-7668-682-9 (print)OAI: oai:DiVA.org:oru-7785DiVA: diva2:233536
Public defence
2009-10-06, Bohmanssonsalen, Universitetssjukhuset Örebro, Örebro, 09:00 (English)
Opponent
Supervisors
Available from: 2009-09-02 Created: 2009-09-01 Last updated: 2016-12-06Bibliographically approved
List of papers
1. High homocysteine and methylmalonate among demented and non-demented elderly receiving vitamin-B12 prescription and home help service
Open this publication in new window or tab >>High homocysteine and methylmalonate among demented and non-demented elderly receiving vitamin-B12 prescription and home help service
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background & Aims: Total homocysteine (tHcy) has been suggested as a dementia risk factor. Our aim was to investigate potential differences in tHcy and its determinants (mainly Serum-B12 and Serum-folate) in relation dementia. We examined the effect of vitamin-B12 prescription, whether a family history of dementia, or the need for home help service might have influence on tHcy.

Methods: A cross sectional monocenter study comprising 926 consecutive subjects attending our Memory Care Unit.

Results: Demented subjects being prescribed vitamin-B12 had higher Serum-B12 (p =0.025) but also higher tHcy (p =<0.001) and S-methylmalonate (p =0.032), and lower Serum-folate (p<0.001) than those who did not receive B12 prescriptions. tHcy levels were higher in subjects in need of home help service (non-dementia: p= 0.007), this group also had lower S-albumin (dementia: p<0.001; non-dementia: p=0.004). In multivariate logistic regression analysis with diagnosis of dementia as outcome, both vitamin-B12 prescriptions, family history of dementia, and existent home help service, predicted dementia (p=0.037; 0.044; 0.002 respectively).

Conclusion: Elderly subjects on vitamin-B12 prescription appear to have unmet needs of nutritional support, causing elevated homocysteine levels. The home help service should pay a closer attention to nutritional aspects and drug compliance among geriatric patients.

Keyword
homocysteine, dementia, vitamin-B12, folate, home help service
National Category
Geriatrics Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-7842 (URN)
Available from: 2009-09-09 Created: 2009-09-08 Last updated: 2016-12-08Bibliographically approved
2. Mutations in exons 2 and 3 of the FOLR1 gene in demented and non-demented elderly subjects
Open this publication in new window or tab >>Mutations in exons 2 and 3 of the FOLR1 gene in demented and non-demented elderly subjects
2007 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 20, no 5, 653-662 p.Article in journal (Refereed) Published
Abstract [en]

We have previously reported six novel mutations in the 5'-UTR of the gene for folate receptor-alpha (FOLR1). In our search for additional mutations we screened patients, referred for investigation of suspected dementia (DGM subgroup) by SSCP and DNA sequencing from the end of exon 1 to the first bases of intron 3. We found 4 sequence variations, FOLR1 g.1314G>A, g.1816delC, g.1841G>A, and g.1928C>T. Pyrosequencing genotyping assays were developed for all of them, and 389 active seniors (AS subgroup) and the 202 DGM patients were genotyped for these mutations. The frequency q of the mutated allele was, among the AS subjects, 0.068, 0.0026, 0.0026, and 0.024 respectively, and among the DGM subjects, 0.067, 0.0076, 0.0078, and 0.023. The g.1816delC and g.1841G>A mutations thus were more frequent in the DGM than in the AS subgroup, but the difference did not reach statistical significance. The mutated alleles, FOLR1 1816(-) and 1841A, always occurred together in the same subjects, suggestive of a rare double-mutant haplotype. The two common polymorphisms, FOLR1 g. 1314G>A and g.1928C>T seemed not to raise tHcy plasma levels, whereas the double-mutated g.1816(-)-g.1841A haplotype may possibly have a slight tHcy-raising effect. Thus, so far 8 novel rare FOLR1 mutations with a combined prevalence of approximately 1.3% in Whites as well as two common polymorphisms with 5% and 13%, respectively, have been demonstrated. Only a few of the rare mutations may potentially be associated with raised plasma tHcy concentrations. No association with dementia was found.

Place, publisher, year, edition, pages
Athens, Greece: D.A. Spandidos, 2007
National Category
Medical and Health Sciences Geriatrics
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-3036 (URN)17912458 (PubMedID)
Available from: 2008-11-15 Created: 2008-11-15 Last updated: 2016-12-06Bibliographically approved
3. CSF/serum folate gradient: physiology and determinants with special reference to dementia
Open this publication in new window or tab >>CSF/serum folate gradient: physiology and determinants with special reference to dementia
2008 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 25, no 6, 516-523 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Folate depletion has been implicated as a risk factor for neurodegenerative disorders. We hypothesized that transport of folate to the cerebrospinal fluid (CSF) compartment could be involved in the pathophysiology of these disorders.

METHODS: The CSF/serum folate gradient (R(CSF/S)) was studied in 205 subjects with suspected cognitive disorder. Its relation to clinical and biochemical indices, including the integrity of the blood-CSF barrier, were characterized.

RESULTS: In subjects who were diagnosed as nondemented (ND) the mean R(CSF/S )+/- SD was 2.46 +/- 0.62 versus 2.09 +/- 0.67 (p = 0.008) in the dementia subgroup with a vascular component (VaD + mixed). The ND subgroup had higher CSF folate (p = 0.001) and lower serum homocysteine values (p = 0.001) than the VaD + mixed subgroup. The folate gradient R(CSF/S) was negatively correlated with serum folate (p < 0.001, R(2) = 0.518) and to the albumin ratio, a blood-CSF barrier biomarker (beta = -0.235). The Alzheimer patients had R(CSF/S) and albumin ratios similar to the ND subjects.

CONCLUSION: The R(CSF/S) was significantly lower in the VaD + mixed dementia subgroup, suggestive of a defect in the transport of folate over the choroid plexus that seems to be characteristic of, and limited to, the VaD + mixed dementia subgroup.

Keyword
Aged, Aged; 80 and over, Alzheimer Disease/blood/cerebrospinal fluid/epidemiology, Blood-Brain Barrier/*physiology, Case-Control Studies, Choroid Plexus/metabolism, Dementia; Vascular/blood/cerebrospinal fluid/epidemiology, Female, Folic Acid/*blood/*cerebrospinal fluid, Homocysteine/blood, Humans, Linear Models, Male, Middle Aged, Multivariate Analysis, Risk Factors, Serum Albumin/metabolism, Vitamin B 12/blood
National Category
Medical and Health Sciences Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:oru:diva-3509 (URN)10.1159/000129696 (DOI)18463447 (PubMedID)
Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2016-12-06Bibliographically approved
4. Fibrinolysis and von Willebrand factor in Alzheimer's disease and vascular dementia: a case-referent study
Open this publication in new window or tab >>Fibrinolysis and von Willebrand factor in Alzheimer's disease and vascular dementia: a case-referent study
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: The importance of vascular risk factors for Alzheimer’s disease (AD) is not settled. Our aim was to compare patients with AD or vascular dementia (VaD) with non-demented subjects with regard to endothelial derived fibrinolytic and hemostatic factors.

Materials and methods: In a cross-sectional mono-center case-referent study in Örebro, Sweden, we consecutively included 95 patients with AD and 55 with VaD and 154 non-demented active seniors (AS). Plasma biomarkers including the endothelial derived fibrinolytic factors: mass concentrations of tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), tPA/PAI-1 complex and von Willebrand factor (vWF), as well as clinical data were analyzed.

Results: None of the endothelial derived fibrinolytic markers or vWF differed between AD vs. VaD. In comparison with the AS group, tPA was higher in AD (p=0.001) and VaD (p=0.023) but its inhibitor, PAI-1 mass concentration did not differ significantly; tPA/PAI-1 complex was higher in both VaD (p=0.038) and AD (p=0.005). vWF concentration was lower in the AS group (p<0.001) than in both dementia groups.

Conclusion: Thus, endothelial derived fibrinolytic factors, tPA/PAI-1 complex and vWF, discriminated between the reference group of non-demented elderly and the AD and VaD groups, but not between AD and VaD. This suggests similar disturbances for endothelial derived fibrinolytic and hemostatic factors among AD and VaD patients and may reflect shared vascular pathophysiological mechanisms in the dementias.

Keyword
vascular dementia, Alzheimer’s disease, fibrinolysis, hemostasis, von Willebrand factor
National Category
Geriatrics Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-7845 (URN)
Available from: 2009-09-09 Created: 2009-09-08 Last updated: 2016-12-08Bibliographically approved

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