Regular articleVitamin K status and cognitive function in healthy older adults
Introduction
Vitamin K is a fat-soluble compound found predominantly in green leafy vegetables and, to lesser extent, other vegetables, fruits, and some vegetable oils. It was originally discovered for its role in blood coagulation, activating the vitamin K–dependent clotting factors through its function as a cofactor of the γ-glutamyl-carboxylase. The discovery of additional vitamin K-dependent proteins (e.g. osteocalcin) and functions independent of the γ-carboxylation has expanded the role of vitamin K beyond coagulation (Suttie, 2009). A role in the human brain was first suspected after cases of central nervous system abnormalities in newborns exposed in utero to vitamin K antagonists (Hall et al., 1980). In rat and human brain tissues, high vitamin K levels in the form of menaquinone-4 (MK-4) have been reported (Carrie et al., 2004, Thijssen and Drittij-Reijnders, 1994, Thijssen and Drittij-Reijnders, 1996). In rodents, brain MK-4 was shown to respond, in a dose-dependent manner, to intakes of vitamin K, whether provided in a natural dietary form (phylloquinone) or a synthetic form (Carrie et al., 2004, Okano et al., 2008, Thijssen and Drittij-Reijnders, 1994).
Our understanding of the vitamin K functions in brain is growing (Ferland, 2012). The vitamin K-dependent proteins Gas6 (growth arrest-specific gene 6) and protein S are expressed in the central nervous system (He et al., 1995, Prieto et al., 1999). Protein S is notably known to possess neuroprotective effects during hypoxic/ischemic injury, whereas Gas6 is now recognized as an important regulator of cell survival, cell growth, and myelination processes (Ferland, 2012). Furthermore, vitamin K participates in the metabolism of sphingolipids, a major constituent of the myelin sheath and neuronal membranes, also involved in important molecular events such as cell signaling (Denisova and Booth, 2005, Ferland, 2012). Finally, the K vitamers were also shown to possess neuroprotective effects against oxidative-induced death of primary cultures of rat oligodendrocytes, rat neurons, and human neuroblastoma cells by preventing the accumulation of reactive oxygen species (Isaev et al., 2004, Li et al., 2003, Li et al., 2009, Sakaue et al., 2011).
Consistent with mechanistic studies, in vivo rodent models have provided evidence that vitamin K status can modulate brain sphingolipids, behavior, and cognitive performances (Carrie et al., 2011, Carrie et al., 2004, Cocchetto et al., 1985, Crivello et al., 2010, Sundaram et al., 1996). Interestingly, current research suggests that vitamin K exerts its actions in aging. Notably, higher concentrations of MK-4 in the hippocampus and cortex were shown to be correlated with higher myelin sulfatides in adult and aged rats, but not in younger animals (Crivello et al., 2010). Similarly, 20-month-old rats fed a vitamin K–rich or –adequate diet throughout their lives had better spatial learning performances in the Morris Water Maze task than those fed a low–vitamin K diet, a result not observed in 6-month-old rats (Carrie et al., 2011). A vulnerability of the aging brain to vitamin K status is also strengthened by studies reporting a marked age-dependent loss of Gas6 in rat brain (Tsaioun et al., 2000) and sphingolipid alterations in brain tissues of aged mice and older adults with Alzheimer's disease (Cutler et al., 2004).
The potential role of vitamin K in cognitive function of older adults has not yet been examined. Thus far, two cross-sectional studies reported a lower vitamin K status in subjects in the early and late stages of Alzheimer's disease in comparison with controls (Presse et al., 2008, Sato et al., 2005). In the present study, we examined the associations between serum phylloquinone concentration and performances in verbal and non-verbal episodic memory, executive functions, and speed of processing in 320 healthy older adults selected from the Québec Longitudinal Study on Nutrition and Successful Aging (NuAge). To our knowledge, this is the first study to investigate the potential role of vitamin K in specific cognitive domains.
Section snippets
Methods
The NuAge Study is a prospective cohort study of nutritional factors of successful aging. The methodology has been detailed elsewhere (Gaudreau et al., 2007). Briefly, community-dwelling men and women aged 67 to 84 years were randomly selected from the Québec Medicare Database. To be include in the NuAge Study, participants had to be in good general health, free of disabilities in activities of daily living, free of cognitive impairment as established by a Modified Mini-Mental State Examination
Results
The 320 selected participants from the NuAge cohort were younger, more educated, had greater household income, had higher global cognitive scores, had fewer depressive symptoms, were more likely to consume alcohol, and tended to be more physically active than those not selected (Supplemental Table 1). However, they did not differ by sex, race, health and smoking status, use of vitamin/mineral supplements, or diet quality.
At the time of the cognitive evaluation, participants were aged 70.0 to
Discussion
The present study is important, because it provides support for an emerging role of vitamin K in the aging brain. Specifically, we showed that serum phylloquinone was positively associated with performance in verbal episodic memory, while being unrelated to non-verbal episodic memory, executive functions, and speed of processing.
Episodic memory refers to the memory of events within their spatio-temporal context. For example, remembering where one's keys were last left relies on episodic memory.
Disclosure statement
None of the authors has a conflict of interest.
Acknowledgements
We thank Doriane Kwong Hoi Fung for assistance with the serum phylloquinone analysis and Mélanie Drisdelle for coordinating the cognitive evaluation. The NuAge Study was supported by the research grant MOP-62842 from the Canadian Institutes of Health Research (CIHR) and by the Quebec Network for Research on Aging funded by the Fonds de Recherche du Québec- Santé (FRQS; formerly Fonds de la Recherche en Santé du Québec). Access to NuAge databases and measurement of serum phylloquinone
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