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CSF/serum folate gradient: physiology and determinants with special reference to dementia
Örebro University, School of Health and Medical Sciences.
2008 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 25, no 6, p. 516-523Article 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.

Place, publisher, year, edition, pages
2008. Vol. 25, no 6, p. 516-523
Keywords [en]
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: urn:nbn:se:oru:diva-3509DOI: 10.1159/000129696PubMedID: 18463447OAI: oai:DiVA.org:oru-3509DiVA, id: diva2:137806
Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2018-01-13Bibliographically approved
In thesis
1. Vascular mechanisms in dementia with special reference to folate and fibrinolysis
Open this publication in new window or tab >>Vascular mechanisms in dementia with special reference to folate and fibrinolysis
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. p. 65
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 33
Keywords
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:nbn:se:oru:diva-7785 (URN)978-91-7668-682-9 (ISBN)
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: 2017-10-18Bibliographically approved

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Hagnelius, Nils-OlofNilsson, Torbjörn K.

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