Nancy Presse

Low Vitamin K Intakes in Community-Dwelling Elders at an Early Stage of Alzheimer's Disease

An increasing body of evidence points to a role for vitamin K in brain physiology through its participation in sphingolipid metabolism and biological activation of the vitamin K-dependent protein Gas6. One hypothesis is that vitamin K may also play a role in the pathogenesis of Alzheimers disease. A recent study found that patients with early-stage Alzheimers disease consumed less vitamin K than did cognitively intact control subjects. To learn more about the dietary intakes and food sources of vitamin K in these patients, a detailed analysis was conducted. Dietary vitamin K intakes were assessed from 5 nonconsecutive days of food records collected from 31 community-dwelling patients with early-stage Alzheimers disease and in 31 age- and sex-matched cognitively intact control subjects. Mean vitamin K intake on a person-day basis was 63+/-90 microg/day in patients and 139+/-233 microg/day in control subjects. Vitamin K intakes were significantly less in participants with Alzheimers disease (P<0.0001), even after adjusting for energy intakes (P=0.0003). Vegetables, fats, and fruits contributed more than 70% of total vitamin K intake in both groups. The main source of vitamin K was green vegetables, which contributed 33% and 49% to total intakes in patients and control subjects, respectively. This lower consumption of green vegetables in participants with Alzheimers disease explained their lower vitamin K intakes overall. Despite their limitations, results are in line with the most recent research in both vitamin K and Alzheimers disease and suggest a need to consider vitamin K in future investigations on the role of diet in Alzheimers disease.

Validation of a semi-quantitative food frequency questionnaire measuring dietary vitamin K intake in elderly people.

The study objective was to validate a semi-quantitative food frequency questionnaire (FFQ) specifically designed to measure dietary vitamin K intake. A 50-item FFQ was interviewer-administered and compared with data previously obtained from 5-day food records. Thirty-nine community-dwelling healthy men and women aged 65 to 85 years were recruited from the Montréal metropolitan area. Absolute and relative agreements between methods were assessed. Vitamin K intake measured by the vitamin K FFQ (mean+/-standard deviation; 222+/-186 microg/day) was significantly higher than that obtained by food records (135+/-153 microg/day; P<0.001). Bland-Altman analysis on log(10)-transformed data indicated that vitamin K intake from vitamin K FFQ was 2.26 times (95% confidence interval: 1.90 to 2.67) higher than food records, limits of agreement ranging from 0.80 to 6.35. However, correlation between methods was strong and highly significant (r=0.83; P<0.001). Cross-classification also showed that 72% of participants were correctly classified into thirds and only 8% were grossly miscategorized. Weighted kappa value (kappa=0.60) also indicated a good relative agreement. In light of these results, the vitamin K FFQ is a valid tool for ranking individuals according to their vitamin K intake. The poor absolute agreement likely results from the inability for food records to adequately measure the usual intake of episodically consumed foods, particularly those high in vitamin K. The vitamin K FFQ will be useful in large-scale, population-based research on vitamin K and disease as well as in clinical practice, especially that focusing on anticoagulant therapy.

A Minimum of Six Days of Diet Recording Is Needed to Assess Usual Vitamin K Intake among Older Adults

There is a growing interest in the role of vitamin K in health, especially in aging populations. Knowledge of inter- and intra-individual variability of dietary vitamin K intake could be useful to accurately assess usual intake and rank participants in epidemiological studies. Our objectives were to: 1) estimate the variance components of vitamin K intake; 2) investigate whether day of the week, season, and energy intake are factors related to intra-individual variance; and 3) calculate the requisite number of days to achieve desired degrees of accuracy for estimating individual vitamin K intake, ranking individuals and estimating regression coefficient. Vitamin K intake was assessed in 939 older adults (67-84 y) enrolled in the Québec Longitudinal Study on Nutrition and Successful Aging study using 2 sets of 3 nonconsecutive multiple-pass 24-h dietary recalls (24HR) collected 6 mo apart. Each set included 2 weekdays and one weekend day. Intra- to inter-individual variance ratios for vitamin K intake were 3.2 (95% CI = 2.6-3.9) overall, 2.6 (95% CI = 2.1-3.5) for men, and 3.7 (95% CI = 2.9-5.0) for women. Day of the week (weekdays) and season (May to October) were positively and significantly associated with vitamin K intake but explained a negligible part of intra-individual variation (<1%). Adjusting for energy intake explained <7% of variance and did not affect the variance ratio. Six to 13 24HR are required to properly rank individuals according to their usual vitamin K intake and limit attenuation of the regression coefficient. These results should be considered in studies planning to assess vitamin K intakes in older adults.

Increased dietary vitamin K intake is associated with less severe subjective memory complaint among older adults

OBJECTIVES Increased dietary intake of vitamin K, a fat-soluble nutrient involved in brain health and function, has been associated with better cognitive performance in older adults. Our objective was to determine whether the dietary vitamin K intake was associated with the presence and severity of subjective memory complaint among older adults. STUDY DESIGN Observational, cross-sectional cohort study. MAIN OUTCOME MEASURES One hundred sixty older adults taking no vitamin K antagonist were included. The daily dietary vitamin K intake was assessed using a 50-item food frequency questionnaire. The subjective memory complaint was assessed at the same time using the Memory Complaint Questionnaire (MAC-Q; score 0-30, best). Serious subjective memory complaint was defined as MAC-Q score ≤15. Age, gender, body mass index, education level, number of comorbidities, history of stroke, objective cognitive disorders, functional autonomy, mood, serum concentrations of vitamin B12, TSH, albumin, and estimated glomerular filtration rate were used as potential confounders. RESULTS Compared to participants without serious subjective memory complaint, those with serious subjective memory complaint (n=110) had a lower mean dietary vitamin K intake (298.0±191.8μg/day versus 393.8±215.2μg/day, P=0.005). Increased log dietary vitamin K intake was positively associated with the MAC-Q score used as a quantitative variable (fully adjusted β=0.79, P=0.031), and inversely with serious subjective memory complaint (fully adjusted OR=0.34, P=0.017). CONCLUSIONS Increased dietary vitamin K intake was associated with fewer and less severe subjective memory complaint in older adults taking no vitamin K antagonists. These findings provide epidemiological data supporting future vitamin K replacement trials.

Dietary Vitamin K Intake Is Associated with Cognition and Behaviour among Geriatric Patients: The CLIP Study.

Our objective was to determine whether dietary vitamin K intake was associated with cognition and behavior among older adults. 192 consecutive participants ≥65 years, recruited in the cross-sectional CLIP (Cognition and LIPophilic vitamins) study, were separated into two groups according to the tertiles of dietary phylloquinone intake (i.e., lowest third below 207 µg/day versus the other two thirds combined). Daily dietary phylloquinone intake was estimated from 50-item interviewer-administered food frequency questionnaire. Cognition was assessed with Mini-Mental State Examination (MMSE); behaviour with Frontotemporal Behavioral Rating Scale (FBRS). Age, gender, social problems, education, body mass index (BMI), comorbidities, history of stroke, use vitamin K antagonists, inadequate fatty fish intake, serum thyroid-stimulating hormone (TSH), vitamin B12, albumin, and estimated glomerular filtration rate were used as confounders. Compared to participants in the lowest third of dietary phylloquinone intake (n = 64), those with higher intake had higher (i.e., better) mean MMSE score (22.0 ± 5.7 versus 19.9 ± 6.2, p = 0.024) and lower (i.e., better) FBRS score (1.5 ± 1.2 versus 1.9 ± 1.3, p = 0.042). In multivariate linear regressions, log dietary phylloquinone intake was positively associated with MMSE score (adjusted β = 1.66, p = 0.013) and inversely associated with FBRS score (adjusted β = −0.33, p = 0.037). Specifically, log dietary phylloquinone intake correlated negatively with FBRS subscore of physical neglect (r = −0.24, p = 0.001). Higher dietary phylloquinone intake was associated with better cognition and behavior among older adults.

Higher vitamin K intake is associated with better INR control and a decreased need for INR tests in long-term warfarin therapy

Warfarin is an oral anticoagulant that still remainswidely prescribed for the prevention of thromboembolic conditions, despite the introduction of new anticoagulant agents. It acts by inhibiting the vitamin K epoxyde reductase, decreasing the activation of vitamin K-dependent clotting factors. Physicians monitor the consequent anticoagulant effect using the International Normalized Ratio (INR), aimingwithin a narrow target range (e.g. 2.0-3.0). However, despite close monitoring, INRs are in the therapeutic range only ≈ 55% (95%CI: 51-58%) of the time [1]. Such poor INR control is associated with an increased risk of bleeding, especially in older adults, and of thromboembolic events [2]. Variations in vitamin K intake are known to influence INR control [3]. However, better INR control has been reported among patients with high vitamin K intakes, regardless of its variations [4–6]. While interesting, these observations were not based on validated indicators of INR control, which limits their interpretation in terms of clinical significance. Rosendaal et al. [7] validated an indicator of INR control where percentage of time in therapeutic range (%TTR) is assessed using linear interpolation between consecutive INRs. In the present study, we investigated the association between usual vitamin K intakes and %TTR in warfarin-treated older adults. We also examined whether high vitamin K intakes were associated with a decreased need for INR tests. From May 2010 through June 2011, 313 patients from the anticoagulation clinic of the Hôpital du Sacré-Coeur de Montréal (HSCM) were invited to participate. Eligibility required age ≥65 years, warfarin therapy for ≥1 year, a target INR range of 2.0-3.0, and ≤3 months between consecutive INR tests in the previous year. Twenty-four percent of eligible patients declined participation, 20% were inapt to participate (e.g. hospitalization, did not speak English or French), and 7% were unreachable. Verbal informed consent was provided by 153 patients. Ethical approval was obtained from the HSCM Ethics Committee. The primary outcome was %TTR over 1 year and the secondary outcome, the annual number of INR tests as ordered by physicians. A semiquantitative food frequency questionnaire (FFQ) specifically designed to assess usual vitamin K intake (μg/d) during the previous yearwas administered by a registered dietitian through a telephone interview. This 50-item FFQ has been proved valid for ranking individuals according to their usual vitamin K intake [8]. Outcomes and vitamin K intake were measured over the same 12-month period. Demographic and clinical data, including duration of warfarin therapy (years), INRs and shortterm warfarin interruptions (e.g. one-day surgery), were obtained from medical charts. Annual mean warfarin dose (mg) was calculated from prescriptions. Patients self-reported their weight (kg), height

Quality-of-Care Processes in Geriatric Assessment Units: Principles, Practice, and Outcomes

OBJECTIVES To assess quality-of-care processes and to examine whether care processes are associated with short-term postdischarge outcomes in older vulnerable hospitalized patients. DESIGN Retrospective study. SETTING Forty-nine Geriatric Assessment Units. PARTICIPANTS Patients aged 65 and older who were admitted to a Geriatric Assessment Unit for a fall with trauma. MEASUREMENTS Three care processes (comprehensiveness, informational continuity, patient-centered care) assessed through chart audit; three-month postdischarge outcomes (emergency department visit, hospital readmission, and death) obtained from national databases. RESULTS A total of 934 hospitalization records were included. Mean comprehensiveness and informational continuity scores were 55% ± 12% and 42% ± 16%, respectively. Items related to geriatric global assessment (eg, functional autonomy) were particularly overlooked. Patient-centered care was poorly provided, with only 24% of hospitalization records showing evidence of advance care directives and at least one patient/family meeting with the physician to discuss clinical evolution. For the three care processes, a large variability among Geriatric Assessment Units was observed. Better comprehensiveness of care was associated with lowered short-term mortality (OR = 0.73, 95% CI = 0.55-0.96, P = .023), whereas higher scores on informational continuity was associated with fewer emergency department visits (OR = 0.91, 95% CI = 0.82-1.00, P = .046), hospital readmissions (OR = 0.84, 95% CI = 0.74-0.94, P = .003), and mortality (OR = 0.72, 95% CI = 0.59-0.88, P = .002). Patient-centered care was not associated with any of the postdischarge outcomes. CONCLUSION A large gap between geriatric care principles and practice in Geriatric Assessment Units has been observed. Our results show that improvement in care processes may be translated to decreased short-term health services use and mortality.

Avoidance of Vitamin K−Rich Foods Is Common among Warfarin Users and Translates into Lower Usual Vitamin K Intakes

BACKGROUND Warfarin users should aim for stable daily vitamin K intakes. However, some studies report that patients are often advised to avoid eating green vegetables. Whether this advice impacts vitamin K intakes is unknown. OBJECTIVE Our aim was to describe the nature and sources of vitamin K-related dietary recommendations that patients received at the initiation of warfarin therapy, assess their adherence to these recommendations, and examine whether usual vitamin K intakes vary according to these recommendations. DESIGN We conducted a retrospective cohort study with patients enrolled in the Québec Warfarin Cohort Study. Patients were asked to report dietary recommendations they had received at warfarin initiation and their adherence to these recommendations. Usual vitamin K intakes were assessed using a validated semi-quantitative food frequency questionnaire. PARTICIPANTS/SETTING Three hundred seventeen patients aged 36 to 97 years who initiated warfarin between 2011 and 2012 and were treated for 12 months or longer with a target international normalized ratio range of 2.0 to 3.0 or 2.5 to 3.5. STATISTICAL ANALYSES PERFORMED Patients were classified according to vitamin K-related recommendations reported: limit or avoid vitamin K-rich foods; aim for stable consumption of vitamin K-rich foods; or no vitamin K-related advice. A one-way analysis of covariance was used to compare mean usual vitamin K intakes between patients after adjustment for covariates. RESULTS Most patients (68%) reported being advised to limit or avoid vitamin K-rich foods, particularly green vegetables, 10% reported being advised to aim for stable consumption of vitamin K-rich foods, and 22% did not recall receiving any vitamin K-related recommendation. Mean usual vitamin K intakes of patients adhering to the recommendation to limit or avoid vitamin K-rich foods was 35% to 46% lower than those of other patients (P<0.001), a difference resulting almost entirely (82%) from a lower consumption of green vegetables. CONCLUSIONS In contrast with current dietary recommendation, most warfarin users reported avoiding vitamin K-rich foods, which translated into lower usual vitamin K intakes.

High usual dietary vitamin K intake is associated with low relative variability in vitamin K intake: implications for anticoagulant therapy.

It was with great interest that we read the recent article by Rombouts et al (2010). In this study, high usual dietary vitamin K intake was associated with a lower risk of subtherapeutic International Normalized Ratio (INR) in patients treated with vitamin K antagonists (VKA). These findings are in line with previous work by Sconce et al (2005) and a recent study by Kim et al (2010) where high dietary vitamin K intake was associated with more stable anticoagulant therapy. The rationale behind the beneficial effect of high dietary vitamin K intake in relation to the stability of anticoagulant therapy is still not well understood. In individuals treated with VKA, the bioactivation of vitamin K-dependent clotting factors is sensitive to variations in dietary vitamin K intake (Franco et al, 2004; Khan et al, 2004; Couris et al, 2006). However, data reported by Rombouts et al (2010) suggest that an increase of vitamin K intake has a lesser impact on INR when the usual dietary vitamin K intake is high. Similar results were also observed by Kurnik et al (2004). In this latter study, a daily supplement containing 25 lg of vitamin K resulted in subtherapeutic INRs in all nine patients with low vitamin K status, but in only one of the seven patients with normal vitamin K status. Together, these studies suggest that the impact of a given variation in vitamin K intakes on INR decreases as the individual’s vitamin K status increases. In other words, it is not so much the absolute variation in vitamin K intakes that is associated with INR instability, but rather the relative variation (expressed as a percentage of usual intake). In light of these results, we hypothesised that the higher the individual’s usual vitamin K intake, the lower the relative variability, and that this association could partly explain the beneficial effect of high dietary vitamin K intake on anticoagulant therapy. Our group recently examined the intraindividual variance of vitamin K intake in 939 healthy older adults and its implications on research involving assessment of vitamin K intake (Presse et al, in press). Using this database, we conducted a second set of analyses to examine whether absolute and relative variability in dietary vitamin K intakes, expressed as the standard deviation (SD) and coefficient of variation (CV) respectively, is associated with usual dietary vitamin K intakes. Data collection is detailed elsewhere (Presse et al, in press). Briefly, the study sample included 939 healthy free-living elderly aged 67–84 years enrolled in the Québec NuAge study (Gaudreau et al, 2007). Following recruitment, dietary intake was estimated using two sets of three non-consecutive 24-h dietary recalls collected 6 months apart. Vitamin K intake was assessed using an extensive food composition database for phylloquinone. None of the participants consumed over-thecounter or prescribed vitamin K supplements. Phylloquinone data were natural log-transformed prior to analyses to improve the distribution symmetry. The 6-day average phylloquinone intake, SD and CV (100 · SD/mean) was calculated for each participant. Mean vitamin K intake in our sample was 70Æ0 lg/day (geometric mean). A non-significant Spearman correlation was observed between the SD and the 6-day average vitamin K intake (r = 0Æ06; P = 0Æ09), indicating that the variation around the mean did not vary across individuals as a function of their usual vitamin K intake. Conversely, the intraindividual relative variation in vitamin K intakes was significantly larger in people with low usual vitamin K intakes (r = )0Æ21; P < 0Æ001). As illustrated in Fig 1, the proportion of participants with high relative variability (defined as CV ‡ 20%) dropped as individuals’ usual vitamin K intake (expressed as geometric mean) increased. Our results strongly support the hypothesis that individuals with high dietary vitamin K intake show a lower relative variability in vitamin K intakes, which could, in part, explain the beneficial effect of high dietary vitamin K intake on anticoagulant therapy. From a physiological point of view, high vitamin K intakes could foster more stable plasma phylloquinone levels. In fact, plasma phylloquinone concentrations have been shown to plateau when phylloquinone intake exceeds 200 lg/day (McKeown et al, 2002), suggesting a saturation effect in the absorption mechanisms. Furthermore, high vitamin K intakes could promote maintenance of high vitamin K levels in the liver, which could help buffer shortterm variations in plasma phylloquinone. Currently, the main nutritional advice for patients treated with VKA is to aim for stable daily vitamin K intake, a recommendation which many acknowledge is not easily translated to patients and implemented in daily life (Khan et al, 2004; Kurnik et al, 2004; Rombouts et al, 2010). In fact, our study sample included 48 (5%) participants who reported *Québec equivalent to registered dietitian. correspondence

Vitamin K Antagonists and Cognitive Function in Older Adults: The Three-City Cohort Study

BACKGROUND A growing body of evidence supports a beneficial role for vitamin K in brain and cognition, notably in studies where animals are rendered vitamin K deficient by warfarin, a potent vitamin K antagonist (VKA). Given VKAs are commonly used oral anticoagulants in older persons, we investigated the relationship between VKA therapy and cognitive performances over 10 years in participants of the Three-City study. METHODS The Three-City cohort included 7,133 nondemented community dwellers, aged 65 years or older at baseline. Exposures to VKAs and platelet aggregation inhibitors, another antithrombotic agent, were determined at baseline. Participants underwent cognitive assessment at baseline and every 2 years over 10 years. Associations were analyzed with mixed linear models adjusting for many covariates including VKA and platelet aggregation inhibitor indications. RESULTS About 239 (3.4%) and 1,192 (16.7%) of the participants were treated with VKAs and platelet aggregation inhibitors at baseline, respectively. VKA treatment was significantly associated with worse performances on Benton Visual Retention Test assessing visual memory (adjusted mean difference -0.29; p = .02 in multivariate models) and Isaacs Set Test assessing verbal fluency (adjusted mean difference -1.37; p = .0009) at baseline. Treatment with VKAs was not associated with global cognitive functioning on the Mini Mental State Examination, neither with rate of subsequent decline in scores on all three cognitive tests. No associations were found between platelet aggregation inhibitors and cognitive performances or rate of decline. CONCLUSION These findings do not indicate a long-term detrimental effect of VKAs on cognition, but the risk-benefit balance of VKA treatment still deserves further research.