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At a Loss for Words, and for a Single Letter: ‘‘D’’

factor-a and other cytokines that promote inflammation.14 Leptin inhibits food intake, but also, like resistin, can act on macrophages to release cytokines that generate reactive oxygen species in the vascular endothelium.14

Vitamin D can counter the inflammatory effects of adipo-

cytes. Investigations of radiolabeled vitamin D indicate that adipocytes have a larger uptake of the vitamin than other tissues.15,16 The vitamin D receptor interacts with PPARg, which retards adipocyte differentiation.17 Vitamin D can also promote adipocyte apoptosis by inducing calcium to enter the cell and resulting in leakage of hydrogen ions from the inner mitochondrial membrane, triggering apoptotic pathways.18,19 Vitamin D may also influence systemic inflammation by altering adipocyte glucocorticoid release.19

Vitamin D insufficiency is postulated to have other effects on the brain that might influence the pathogenesis of dementia.20 Vitamin D receptors are present throughout the brain, and stimulation of these receptors increases neurotrophins such as glial cell line-derived neurotrophic factor and neurotrophin-3.21 Polymorphisms in vitamin D receptors have been associated with cognitive and depressive symptoms.22 Vitamin D may also protect neurons through the augmentation of anti-inflammatory and antioxidant cellular responses.23 Vitamin D might protect against inflammatory neuronal injury by altering the differentiation of T cells to increase the population of T-suppressor cells.2426


A number of studies have defined a relationship between global cognitive screening tests that include measures of basic cognitive function and vitamin D insufficiency.20,27 Among thirty-two outpatients, aged 6192 years, who attended a university hospital clinic, there was an association between scores on the mini-mental status examination (MMSE) and serum 25-hydroxy vitaminDlevels (p0.006).28 Another in- vestigation in a similar setting and patient population in the Netherlands found again a correlation between MMSE result and vitamin D levels (p0.01).29 The association was clarified in 1766 elderly individuals who took part in the Health Survey for England 2000.30 Individuals had serum vitamin D measured and ranked by quartiles. Persons who had the lowest vitamin D level by quartile (3.212 ng/mL) had a 2.3 greater chance of having cognitive impairment than those in the highest quartile (26.468 ng/mL). In another study, vitamin D dietary intake was associated with MMSE result in 69 healthy elderly individuals (r0.35, pB0.01).31

In a slightly different approach, forty ‘‘mildly demented’’ persons 60 years or older had their vitamin D levels compared with 40 normal persons.32 Subjects took an MMSE, the Short Blessed test, a nine-item cognitive test, and a longer test, the Clinical Dementia Rating. There was an association between vitamin D deficiency and the latter two tests, and between vitamin D deficiency and those who had a mood disorder, but not between vitamin D and the MMSE. 17 A population of 60 persons (mean age 74.99, mean vitamin

D level 21.59 ng/mL) that comprised healthy and ‘‘mild cognitively impaired’’ persons had vitamin D levels and cognitive testing, including the Short Blessed Test and the MMSE.33 Individuals were rated ‘‘vitamin D deficient’’ at serum levels of less than 20 ng/mL. Again, the Short Blessed test was associated with vitamin D deficiency in total subject group, but not the MMSE. African Americans in the population (n30, mean level17.98 ng/mL) had significantly lower vitamin D levels than whites (n30, 25.20 ng/mL, pB0.001), and among the former, MMSE score did correlate with vitamin D deficiency (p0.008).

Finally, in a nested cohort study, vitamin D level was

correlated to cognitive function on another test of cognition, the Short Portable Mental State Questionnaire in women who were at least 57 years old who participated in an osteoporosis study.34 Women with severely reduced serum vitamin D levels of below 10 mg/mL had a greater risk of a poor score on the Pfeiffer Short Portable Mental State Questionnaire (B8).34

In another nested cohort study, an association was found between poorer cognition and greater concentrations of parathyroid hormone (PTH), a counterregulatory hormone to vitamin D in maintaining calcium balance, in the 514 people in the Helsinki Ageing Study who were sampled at ages 75, 80, and 85 years.35,36 Although vitamin D was not measured, higher PTH levels usually correspond to lower vitamin D levels. Those individuals whose initial PTH was 62 ng/L had a 2.4 greater chance of having a lower score on subsequent measurements on the Clinical Dementia Rating and were more likely to have a lower MMSE score on repeated testing after 5 years.

VITAMIN D AND SPECIFIC COGNITIVE FUNCTIONS The potential association between specific cognitive func-

tions specifically and vitamin D has been less well detailed.20 The association has been investigated using tests of basic cognitive functions, such as attention and memory, or executive functions, such as planning, preparing, starting basic cognitive functions, integrating them, reacting emo- tionally, utilizing a working memory, multitasking, and terminating activities.37

Several investigations have incorporated assessment of executive functions in the evaluation of the relationship of vitamin D and cognition. Elderly home care recipients in Boston (n1080, mean age 75 years) had vitamin D levels and measurements of executive and basic cognition.38,39 Low vitamin D levels of B20 ng/mL were found in more than 65% of the participants. A relationship was noted between scores on executive cognitive tests (Trails A and B, block design, digit symbol coding, and matrix reasoning), measures of basic cognitive function (processing speed and attention), and a global cognitive screening test (MMSE). Memory was not associated with vitamin D level. Several tests of cognition and vitamin D levels were obtained on a population of middle-aged and elderly men (n3369, age range 4079

M&B 2011; 2:(1). July 2011

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