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Warfarin Treatment is Associated With Lower Postmortem Brain Vitamin K Concentrations in Older Adults
M Kyla Shea1, Erica A Israel1, Xueyan Fu1
1USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, United States.
Background:
Menaquinone 4 (MK-4) is the primary form of vitamin K found in the brain. In rodent studies, treatment with the vitamin K-antagonist warfarin lowered brain MK-4 concentrations.
Objectives:
It is not known whether brain MK-4 levels are influenced by warfarin treatment in humans. To address this, we compared postmortem brain MK-4 concentrations in older adults treated with warfarin prior to death to older adults not treated with warfarin. We also determined the likelihood of having mild cognitive impairment (MCI) or dementia in warfarin users, compared to nonusers.
Methods:
We used data from 381 autopsied participants, 76% female, mean (SD) age at death 92(6) y, in the Rush Memory and Aging Project (MAP) in whom MK-4 was measured in 4 brain regions: the mid-frontal and temporal cortices, anterior watershed (AWS), and cerebellum. Brain MK-4 concentrations were compared between those treated with warfarin and those not treated, using linear regression adjusted for age, sex, and cognitive diagnosis at death. The association of warfarin use prior to death with cognitive diagnosis at death was evaluated using logistic regression, adjusted for age, sex, education, and apolipoprotein E4 status.
Results:
Warfarin users [n = 73, median (IQR) duration of warfarin use = 585 (479-656) d] had 68%-79% lower brain MK-4 concentrations in all measured regions, and the mean across all regions, compared with nonwarfarin users (unstandardized β -1.538 to -1.140; all P < 0.001, fully adjusted). The likelihood of having MCI or dementia, compared with no cognitive impairment, at death did not significantly differ between those treated with warfarin prior to death and those not [OR (95% confidence interval) for MCI: 0.82 (0.41, 1.62), dementia: 1.04 (0.57, 1.93), fully adjusted].
Conclusions:
These findings suggest that warfarin treatment influences MK-4 concentrations in the human brain. Future studies are needed to elucidate the mechanisms underlying this effect and its clinical implications.
Insights
Warfarin treatment significantly reduces menaquinone 4 (MK-4) levels in the human brain, but does not appear to affect the risk of mild cognitive impairment or dementia. Further research is needed to understand the implications of these vitamin K findings.
Area of Science:
- Neuroscience
- Biochemistry
- Gerontology
Background:
- Menaquinone 4 (MK-4) is the predominant form of vitamin K in the brain.
- Previous rodent studies indicated warfarin, a vitamin K antagonist, lowers brain MK-4 concentrations.
Purpose of the Study:
- To investigate if warfarin treatment impacts MK-4 levels in the human brain.
- To examine the association between warfarin use and the likelihood of mild cognitive impairment (MCI) or dementia in older adults.
Main Methods:
- Analysis of postmortem brain tissue from 381 older adults (Rush Memory and Aging Project).
- Measurement of MK-4 concentrations in four brain regions (mid-frontal cortex, temporal cortex, anterior watershed, cerebellum).
- Comparison of MK-4 levels and cognitive diagnoses between warfarin users and non-users, with statistical adjustments.
Main Results:
- Warfarin users exhibited significantly lower MK-4 concentrations (68%-79% reduction) across all measured brain regions compared to non-users.
- No significant difference was observed in the likelihood of MCI or dementia between warfarin users and non-users.
Conclusions:
- Warfarin treatment demonstrably influences MK-4 concentrations in the human brain.
- The clinical implications and underlying mechanisms of warfarin's effect on brain MK-4 require further investigation.
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