Serum, Dietary and Supplemental Vitamin D's Association With Cognitive Decline
Condition: Cognitive Decline; Cognitive Impairment
MeSH terms: Cognitive Dysfunction
Study type: Observational

Summary: 
      Serum 25(OH)D, dietary and supplemental vitamin D were shown to influence cognitive outcomes
      in large epidemiological studies. Sex/age-specific and race-specific associations of vitamin
      D status and intake were examined with longitudinal change in various cognitive domains in a
      large sample of ethnically and socio-economically diverse US urban adults. Two prospective
      waves of data from Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS)
      study were used, specifically visit 1: 2004-2009 and visit 2: 2009-2013, mean follow-up
      time±SD: 4.64±0.93y. Cognitive performance was assessed using 11 test scores covering domains
      of global cognition, attention, learning/memory, executive function,
      visuo-spatial/visuo-construction ability, psychomotor speed and language/verbal. Serum
      25(OH)D, vitamin D intake and use of supplements containing vitamin D were the key exposures.
      Multiple mixed-effects linear regression models were conducted, (N=1,231-1,803, k=1.5-2.0
      observation/participant).
    

Detailed description: 
      INTRODUCTION Cognitive impairment, a principal cause for functional disability among the
      elderly, can lead to dementing illness over time mainly in the forms of Alzheimer's Disease
      (AD) and vascular dementia (VaD). In fact, AD prevalence is expected to rise, reaching 100
      million worldwide by 2050, with 1 in 85 persons potentially living with AD.(1) Thus,
      uncovering modifiable risk factors that would prevent or delay cognitive impairment is
      important.

      The neuroprotective effects of antioxidant nutrients (e.g. vitamins E) and B-vitamins (e.g.
      folate) have been at the forefront of cognitive aging and nutritional epidemiology research
      over the past two decades.(2) Vitamin D's role in preserving cognitive function with aging
      has recently gained attention in epidemiological investigations.(3) Its public health
      significance lies in the fact that vitamin D deficiency [25-hydroxyvitamin D3 (25(OH)D)<11
      ng/ml (<27.5 nmol/L)] is a highly prevalent condition, particularly among the poor and among
      African-Americans.(4, 5) Vitamin D is a steroid hormone with its primary function being to
      regulate body levels of calcium, phosphorus and bone mineralization. While sunlight exposure
      is its primary source through skin synthesis from 7-dehydrocholesterol, dietary and
      supplemental intakes of vitamin D play a key role in its overall status. (3) The active form
      of vitamin D3, namely 1,25-dihydroxy vitamin D3 influences many metabolic pathways through
      genomic and nongenomic actions which help maintain and stabilize intracellular signaling
      pathways involved in memory and cognitive function.. (3, 6, 7) The neuroprotective role of
      vitamin D may be mediated through vasculo-protection and preservation of neurons partly
      through the expression of neurotrophins and other neurotransmitters which help protect
      against cognitive dysfunction, through the suppression of inflammatory cytokines.(3, 5, 8)
      Vitamin D can also down-regulate receptors in memory-relevant regions and enhance amyloid
      phagocytosis and clearance. (8) Serum 25(OH)D and dietary vitamin D were shown to influence
      cognitive outcomes in large epidemiological studies. (9-34) This study will examine
      associations between vitamin D status and intake with longitudinal change in various domains
      of cognition among a large sample of ethnically and socio-economically diverse US urban
      adults. It also explores those associations systematically across sex/age groups and race. We
      hypothesize that both vitamin D status and intake are associated with slower decline in
      domain-specific cognitive performance over time, but perhaps differentially by age/sex and
      race.

      MATERIALS AND METHODS Database The Healthy Aging in Neighborhoods of Diversity across the
      Life Span (HANDLS) study is a prospective cohort study initiated in 2004 that focused on the
      cardiovascular and cognitive health of an ethnically and socio-economically diverse urban
      population. Specifically, it used area probability sampling to recruit a socioeconomically
      diverse sample of African American and White urban adults (30-64 years old) residing in
      thirteen neighborhoods of Baltimore, Maryland.(35) Written informed consent was obtained from
      participants who were also provided with a protocol booklet and a video that explains study
      procedures. The study protocol was approved by the National Institute on Environmental Health
      Sciences Institutional Review Board of the National Institutes of Health. Data for the
      present study were derived from baseline visit 1 (2004-2009) and the first follow-up
      examination (visit 2; 2009-2013). Follow-up time ranged from <1y to ~8y, with a mean of
      4.64±0.93y.

      Study sample HANDLS initially recruited 3,720 participants (Phase I, visit 1). Given that
      only Phase II had in-depth data including biochemical indices and cognitive performance
      measures, 25(OH)D was available for 1,981 participants at baseline. The corresponding sample
      size for dietary and supplemental vitamin D were N=2,177 and N=2,159, respectively. Complete
      and reliable cognitive tests at each visit varied in sample size as well. Further, the final
      analytic sample was determined based on exposure and covariate non-missingness at baseline
      and outcome non-missingness at either visit. Figure 1 describes sample selection for all
      exposures. The final analytic sizes ranged between N=1,231 and N=1,803 with k=1.5-1.9
      observation/participant.

      Cognitive assessment Cognitive performance was assessed with 7 tests yielding 11 test scores
      and covering 7 domains (Global, attention, learning/memory, executive function,
      visuo-spatial/visuo-construction ability, psychomotor speed, language/verbal): the
      Mini-Mental State Examination (MMSE), the California Verbal Learning Test (CVLT) immediate
      (List A) and Delayed Free Recall (DFR), Digit Span Forward and Backwards tests (DS-F and
      DS-B), the Benton Visual Retention Test (BVRT), Animal Fluency test (AF), Brief Test of
      Attention (BTA), Trails A and B and the Clock Drawing Test (CDT) (Supplemental method 1). All
      participants were judged capable of informed consent and were probed for their understanding
      of the protocol. Although no formal dementia diagnosis was conducted, all participants were
      given mental status tests, which they completed successfully. In every case, low mental
      status performance was due to low literacy level without any sign of dementia.

      Vitamin D status Total 25(OH)D (in ng/ml) was measured using immunoassay at baseline and
      follow-up visits. The collected sample was ~0.8 ml of preferably fasting serum which was
      refrigerated and transported to the lab for analysis. Visit 1 analyses were conducted at the
      Massachusetts General Hospital.(36) Visit 2 analyses were conducted by Quest Diagnostics,
      Chantilly, VA.

      Dietary vitamin D Dietary factors included in our analyses were measured at the baseline
      visit. Baseline 24-hour dietary recalls were obtained using the US Department of Agriculture
      (USDA) Automated Multiple Pass Method, a computerized structured interview.(37) Measurement
      aids used included measuring cups, spoons, ruler and an illustrated Food Model Booklet. Two
      recalls were administered in-person by trained interviewers, 4-10 days apart. Trained
      nutrition professionals used Survey Net, matching foods consumed with 8-digit codes from the
      Food and Nutrient Database for Dietary Studies (FNDDS) version 3.0,(38) and My pyramid
      equivalents database for food groups (MPED 2:
      http://www.ars.usda.gov/SP2UserFiles/Place/80400530/pdf/mped/mped2_doc.pdf). Dietary vitamin
      D was among the nutrients made available by the FNDDS, from which daily values could be
      estimated and expressed in µg/d, using the average from the two 24-hr recalls conducted at
      baseline.

      Supplemental vitamin D The HANDLS dietary supplement questionnaire was adapted from the 2007
      NHANES instrument.(39) HANDLS participants provided supplement bottles during their dietary
      interview at the follow-up visit only (i.e. visit 2). Information on Over-The-Counter (OTC)
      vitamin and mineral supplements, antacids, prescription supplements, and botanicals were
      reported, and supplement users were asked about dose strength, dose amount consumed, length
      of supplement use (converted to days), frequency of use (daily, monthly, seasonally,
      annually), and if each supplement was taken the day prior to interview.

      A HANDLS dietary supplement database was developed by trained nutritionists and registered
      dietitians. This database consisted of 4 files integrated to generate daily intake of each
      nutrient consumed by a dietary supplement user. [See detailed description at the HANDLS study
      website: https://handls.nih.gov/]. Vitamin D supplemental intake was ascertained for visit 1
      if the daily amount (IU/d) was non-zero at visit 2 and the length of time for intake was
      greater or equal than the length of time (days) between the two visits, per individual. Thus,
      HANDLS participant was either 0: non-vitamin D containing supplement user at baseline or
      follow-up, 1: vitamin-D containing supplement user at baseline and during follow-up, 2:
      vitamin-D containing supplement user during follow-up only.

      Covariates Covariates included age, sex, race (White vs. African American), marital status,
      educational attainment (<High School (HS); HS, >HS), poverty income ratio (PIR<125% for
      "poor"), measured body mass index (BMI, kg/m2), opiate, marijuana or cocaine use ("current"
      vs. "never or former"), smoking status ("current" vs. "never or former") and the Wide Range
      Achievement Test (WRAT) letter and word reading subtotal scores to measure literacy. (See
      Supplemental Method 1) To assess depressive symptoms with focus on affective, depressed mood,
      the 20-item CES-D was used. Baseline CES-D total score was included in the analysis as a
      potential confounder in the association between vitamin D exposures and cognitive change or
      baseline performance. (See Supplemental Method 1) The Healthy Eating Index (HEI-2010) total
      score, based on two 24-hr recalls administered at baseline, was used as a measure of overall
      dietary quality. See steps for calculating HEI-2010 at
      http://appliedresearch.cancer.gov/tools/hei/tools.html and
      http://handls.nih.gov/06Coll-dataDoc.html. Further, season of baseline MRV exam was used as
      proxy for sunshine exposure and was included as covariate in all models. Finally,
      self-reported history of type 2 diabetes, hypertension, cardiovascular disease (stroke,
      congestive heart failure, non-fatal myocardial infarction or atrial fibrillation) and
      dyslipidemia at first-visit were considered as covariates.(40) Statistical analysis Using
      Stata 15.0 (41) and accounting for sampling weights, population estimates of means and
      proportions were obtained. Means across stratifying variables (e.g. age/sex or race) were
      compared using svy:reg, relationship between categorical variables using svy:tab and
      design-based F-tests. Further, mixed-effects regression models with 11 continuous cognitive
      test score(s) as alternative outcomes were conducted. In these models the time variable was
      interacted with several covariates including the main exposure variables, namely VITDserum,
      VITDdiet and VITDsuppl. The models assume missingness at random with time points ranging
      between ~1.5-2.0 visits/person. (42) Predictive margins were estimated and plotted across
      TIME, stratifying by exposure group, from selected mixed-effects regression models,
      particularly those showing significant associations in the total population.

      Moderating effect of sex and age groups was tested by adding interaction terms to separate
      multivariable mixed-effects regressions (3-way and 4-way interaction terms between Time,
      exposure, Age group and sex) and stratifying by sex and age group to examine relationships
      among the following groups: (1) Younger men, (2) Older men, (3) Younger women, (4) Older
      women, whenever at least one 4-way interaction was deemed statistically significant. Further,
      moderating effects by race were also examined using a similar approach [(1) Whites, (2)
      African-Americans] (Supplemental method 2), given the well-known higher prevalence of vitamin
      D deficiency among African-Americans compared with Whites and the differential rates of
      increases in vitamin D status recently shown by age, sex and race groups.(43) Variable time
      of follow-up is accounted for in the mixed-effects regression model as annual rate of change
      in the outcome was of primary interest.

      Moreover, selection bias may occur due to non-random selection of participants with complete
      data from the target study population. Thus, in each mixed-effect regression model, a 2-stage
      Heckman selection process was conducted, by running a probit model to compute an inverse
      mills ratio at the first stage (derived from the predicted probability of being selected,
      conditional on the covariates in the probit model, mainly baseline age, sex, race, poverty
      status and education). At the second stage, this inverse mills ratio was then entered as a
      covariate in the final mixed-effects regression model, as was done in a previous study.(44)
      In all analyses, a type I error of 0.05 was considered for main effects whereas a p<0.10 was
      deemed significant for interaction terms,(45), prior to correcting for multiple testing. A
      familywise Bonferroni procedure was used to correct for multiple testing by accounting only
      for cognitive tests and assuming that exposures related to separate substantive
      hypotheses.(46) Therefore, for main effects, p<0.004 (0.05/11) was considered significant.
      Due to their lower statistical power compared to main effects, 2-way interaction terms had
      their critical p-values reduced to (0.10/11=0.009), while 3-way and 4-way interaction terms
      had their critical p-value reduced to 0.05. A similar approach was adopted in two other
      studies. (47, 48)
    

Intervention name(s): Vitamin D
Intervention type(s): Other
Other intervention name(s): Serum 25(OH)D status and dietarysupplemental vitamin D
Intervention MeSH terms: Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Serum 25(OH)D was lower among African-Americans who had a higher prevalence of vitamin D
        deficiency compared with Whites, in addition to consuming a smaller amount of vitamin D in
        the diet. Older participants tended to have a significant increase in serum 25(OH)D over
        time compared with younger men. Finally, older participants were more likely than younger
        men to be vitamin D-containing supplement users.