From MedscapeCME Clinical Briefs

Low Vitamin D Levels Associated With Increased Risk for Cognitive Impairment CME

News Author: Susan Jeffrey
CME Author: Laurie Barclay, MD

Authors and Disclosures

CME Released: 07/19/2010; Valid for credit through 07/19/2011

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July 19, 2010 — Results of a new analysis using data from the Third National Health and Nutrition Survey (NHANES III) show that vitamin D deficiency is associated with an increased risk for cognitive impairment in older Americans.

The findings echo those from a second report from the same group in a different cohort showing that low levels of vitamin D were associated with subsequent cognitive decline during 6 years of follow-up.

Taken together, it appears that, "low levels of vitamin D are just genuinely bad for the brain," lead author David J. Llewellyn, PhD, from the University of Exeter Peninsula Medical School in the United Kingdom, told Medscape Medical News. "That's why we're so excited, because vitamin D supplements are such an obvious thing that we can do something about now."

Dr. David J. Llewellyn

The expected epidemic of dementia with the aging population is already starting to appear, he said, and although long-term strategies are needed, trials that may have a short- to medium-term payoff are urgently required immediately. In that setting, trials of vitamin D for prevention may be a promising strategy, he said.

The results from NHANES III were presented here at the Alzheimer's Association International Conference on Alzheimer's Disease 2010. The results from the Invecchiare in Chianti (InCHIANTI) study appear in the July 12 issue of the Archives of Internal Medicine.

NHANES Findings

Vitamin D was once just of interest in bone health, but recent work has suggested low vitamin D levels may be a risk factor for a wide range of age-associated diseases, Dr. Llewellyn said, including cancer, hypertension, stroke, and more recently, cognitive decline.

It is known that vitamin D crosses the blood–brain barrier and that receptors for vitamin D are found across the brain, but its precise role is still not known, Dr. Llewellyn noted. It does seem to play a role in processes that may be important for dementia risk, including vascular health and amyloid clearance from the brain. Given these associations, he noted, it seems "biologically plausible" that there might be an association of low vitamin D levels with dementia risk and cognitive performance in the general population.

It is estimated that about a billion people worldwide have vitamin D levels considered insufficient (<75>

A previous paper using data from NHANES III did not find an association between vitamin D levels and cognitive performance (McGrath J, et al. Neuroepidemiol. 2007;29:49-54), but the researchers speculated this may have related to methodology — specifically, the choice of cognitive tests included.

The previous paper used only delayed verbal memory from the Mini-Mental State Examination (MMSE) and the East Boston Memory Test, Dr. Llewellyn said. "I threw everything in, because I was interested in whether this would be a more stable representation of these individuals' cognitive status."

The researchers also adjusted for a wide range of variables, including vitamin E levels, family income, more extensive measures of physical activity, and obesity.

A total of 3325 adults aged 65 years or older had complete cognitive assessments and blood samples available; cognitive impairment was defined as the worst 10% of the distribution of combined scores. Vitamin D levels were divided by cut points previously established for bone health, from severely deficient (<25>

Compared with those patients with sufficient levels of vitamin D, those participants who were very vitamin D deficient had a 6-fold higher risk for cognitive impairment, with a doubling of risk still for those who were considered deficient (≥25 to <50>

"We see some attenuation in the fully adjusted model, but this is still a relatively large effect size, I think it's fair to say," Dr. Llewellyn noted. "People [with severe vitamin D deficiency] have about 4 times higher odds of cognitive impairment, and again the trend across groups remains significant."

NHANES III: Risk for Cognitive Impairment With Severe Vitamin D Deficiency vs Sufficient Levels

Model	Hazard Ratio	95% Confidence Interval	P for Trend
Unadjusted model	5.97	2.82 - 12.6	<.001
Fully adjusted model	3.94	1.49 - 10.43	.017

When they restricted the analysis to only the memory items, there was still a trend across groups, although it was no longer significant (P = .18), which may explain the previous null finding, Dr. Llewellyn noted.

Further prospective data on this link are needed, he told the meeting here, "and we also need to consider whether the enormous expense of a trial is now justified."

At a press conference here, Dr. Llewellyn noted that they are now in the early stages of designing the protocol for a vitamin D trial, probably a dose-comparison trial, to see whether supplementation might have an effect in preventing progression among those with early cognitive impairment. Of course, "it will be funding-dependent," he added wryly.

Dr. William Thies

William Thies, PhD, who moderated a press conference here featuring this paper among others, pointed out that since 2 previous trials treating cognitive impairment with vitamin D have been negative, "I think prevention is the logical place to go, but typically you're dealing with 5 to 10 times as many people and you're following them for a much longer period of time, so the cost-escalation is often 10 to 20 times what it is for treatment."

InCHIANTI Findings

In a separate analysis published in the Archives of Internal Medicine, Dr. Llewellyn and colleagues looked prospectively at the relationship between vitamin D and cognitive decline in the InCHIANTI study, a population-based study conducted in Italy between 1998 and 2006.

"To our knowledge," the researchers write, "no prospective study has examined the association between vitamin D and cognitive decline or dementia."

The InCHIANTI study included 858 adults aged 65 years or older who completed interviews, cognitive assessments, and medical examinations, as well as providing blood samples. Cognitive examination was done using the MMSE, with substantial decline defined as 3 or more points. Trail-Making Tests A and B were also used, with substantial decline defined as the worst 10% of the distribution of decline or as discontinued testing. Assessments were done at baseline and then at 3 and 6 years.

Again, the researchers found that those severely deficient in vitamin D (<25>

Severe deficiency was also associated with the risk for substantial decline on the Trail-Making Test B, but no significant association was seen with the Trail-Making Test A.

Fully Adjusted Risk for Substantial Cognitive Decline for Severe Vitamin D Insufficiency vs Sufficient Levels, by Cognitive Test

Test	Hazard Ratio	95% Confidence Interval	P for Trend
MMSE	1.60	1.19 - 2.00	.02
Trail-Making Test A	1.16	0.65 - 1.84	.44
Trail-Making Test B	1.31	1.03 - 1.51	.04

"If future prospective studies and randomized controlled trials confirm that vitamin D deficiency is causally related to cognitive decline, then this would open up important new possibilities for treatment and prevention," Dr. Llewellyn and colleagues conclude.

Just a Marker of Poor Health?

In an editorial accompanying the Archives of Internal Medicine article, Andrew Grey, MD, and Mark Bolland, MBChB, PhD, from the Department of Medicine at the University of Auckland, New Zealand, are cautious in their assessment of the vitamin D link with cognitive decline and other health problems.

Results from recent observational studies, they write, "have prompted calls for widespread treatment of individuals with low levels of vitamin D and the establishment of public health programs aimed at raising the population levels of vitamin D to 'healthy' values."

Despite the preliminary evidence that components of vitamin D may have a favorable effect in certain diseases, "it seems intuitively unlikely that a single hormone could play a substantial role in preventing or ameliorating the diverse range of diseases that have been linked to low levels of vitamin D."

Instead, a more likely explanation is that low vitamin D is a marker of overall poor health — low sunlight exposure, low physical activity, high adiposity — not the cause of it, they speculate, a possibility supported by the findings of this study as well.

We should therefore treat the data from observational studies of vitamin D with caution.

Positive observational data have been proven wrong before after randomized trials in settings such as postmenopausal hormone therapy, they add. "We should therefore treat the data from observational studies of vitamin D with caution."

"It is now time to test the various hypotheses generated by observational studies of vitamin D, including that of Llewellyn et al, in adequately designed and conducted randomized controlled trials," they conclude. "Very importantly, such trials will also provide an opportunity to systematically assess potential harms of vitamin D supplementation, an issue that has been largely overlooked or dismissed.

"We should invest in trials that provide the best possible evidence on the benefits and risks of vitamin D before we invest in costly, difficult and potentially unrewarding interventional strategies."

NHANES III is funded by the Kaiser Permanente Division of Research. The InCHIANTI study is supported in part by the Italian Ministry of Health and by the United States National Institute on Aging. The authors have disclosed no relevant financial relationships.

Alzheimer's Association International Conference on Alzheimer's Disease 2010: Abstract 01-06-03. Presented July 11, 2010.

Arch Intern Med. 2010;170:1135-1141, 1099-1100.

Clinical Context

Study Highlights

• The goal of the study was to examine whether low levels of serum 25-hydroxyvitamin D (25[OH]D) were associated with an increased risk for significant cognitive decline in an elderly population.
• The InCHIANTI population–based study took place in Italy between 1998 and 2006.
• The study cohort consisted of 858 adults at least 65 years old, of white European origin, who completed interviews, cognitive evaluations, physical examinations, and blood testing.
• Severe serum 25(OH)D deficiency was defined as levels of less than 25 nmol/L, and sufficient levels of 25(OH)D were defined as 75 nmol/L or more.
• Every 3 years, participants underwent follow-up evaluations.
• Substantial cognitive decline was defined as a decrease of 3 points or more on the MMSE.
• On Trail-Making Tests A and B, substantial decline was defined as the worst 10% of the distribution of decline or as discontinued testing.
• Multivariate adjusted relative risk (RR) of substantial cognitive decline on the MMSE in participants with severe serum 25 (OH)D deficiency vs those with sufficient levels of 25(OH)D was 1.60 (95% CI, 1.19 - 2.00; P for trend = .02).
• Compared with participants who had sufficient 25(OH)D levels, those who were severely 25(OH)D deficient had an additional decrease of 0.3 MMSE points per year, based on multivariate adjusted random-effects models.
• The association remained significant when analyses were restricted to elderly subjects with no dementia at baseline.
• Compared with participants who had sufficient 25(OH)D levels, those who were severely 25(OH)D deficient had an RR for substantial decline on the Trail-Making Test B of 1.31 (95% CI, 1.03 - 1.51; P for trend = .04).
• There was no significant association of 25(OH)D levels with decline on Trail-Making Test A (RR, 1.16; 95% CI, 0.65 - 1.84; P for trend = .44).
• On the basis of these findings, the investigators concluded that low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied during a 6-year period.
• They also suggest that this finding has important implications for treatment and prevention.
• They note that low levels of 25(OH)D may be especially harmful to executive functions, whereas memory and other cognitive domains may be relatively preserved.
• In future trials of vitamin D supplementation in the elderly population, it may be useful to include tests of cognitive function.
• Limitations of this study include inability to determine whether these findings generalize to other regions or races, possible effect of attrition, and inability to determine the underlying cause of the observed cognitive changes.

Clinical Implications

• In the InCHIANTI Italian population–based study, low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied during a 6-year period.
• This finding may have important implications for treatment and prevention. Low levels of 25(OH)D may be especially harmful to executive functions, whereas memory and other cognitive domains may be relatively preserved. Future trials of vitamin D supplementation in the elderly should include cognitive evaluation.

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