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At a Loss for Words, and for a Single Letter: ‘‘D’’ Vitamin D, Dementia, and Depression in the Elderly

E Paul Cherniack Affiliation: Department of Medicine, Division of Gerontology and Geriatric Medicine, Geriatrics Institute, University of Miami Miller School of Medicine, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA


An increasing number of investigations imply a relationship between lack of vitamin D and two common mental health problems in the elderly, dementia and depression. Vitamin D may have a protective effect on the brain against dementia through its beneficial effect on the systemic vasculature, including the cerebral vasculature, or it may protect or promote the growth of individual neurons. Several large epidemiologic trials and smaller studies have delineated an association between vitamin D and cognitive impairment in assessments using global screening tests and individual tests of specific cognitive function. Similarly, vitamin D levels have been correlated with the presence of depressive symptoms in older persons. A few small trials have used vitamin D to treat depression but have failed to use adequate doses. Larger randomized controlled trials are needed to assess the potential for vitamin D in the treatment of dementia and depression.

Keywords: dementia depression, vitamin D cognition executive function Correspondence: E Paul Cherniack, Department of Medicine, Division of Gerontology and Geriatric Medicine, Geriatrics Institute, University

of Miami Miller School of Medicine, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA. Tel: 1-3055757101; e-mail: evan.

INTRODUCTION Dementia and depression are common mental health

problems in the elderly; at least 35 million older persons worldwide have dementia, and from 8% to 16% or elderly individuals are depressed.1,2 Although these two conditions may not have the same pathology, they both have a relation- ship to a versatile steroid hormone, which is involved in multiple systemic processes: vitamin D. In this manuscript, the possible mechanisms and evidence for the relationship of dementia and depression with vitamin D will be outlined.

THE PATHOPHYSIOLOGY OF VITAMIN D AND DEMENTIA Although the pathophysiology of dementia is a subject too

large for this manuscript, vascular disease of the brain is believed to involve greater than 80% of all cases.3 This includes Alzheimer’s disease, multi-infarct dementia, and dementia that shares features of both (‘‘mixed dementia)’’.3 The etiology of Alzheimer’s disease itself, which has not been entirely elucidated, involves mitochondrial dysfunction, genetic fac- tors, hippocampal synaptic loss, tau protein mutations, and amyloid plaque formation.4 Vascular disease has been found in the brains of 6090% of specimens of Alzheimer’s Disease brains on autopsy.3

Increased systemic inflammation that comprises the meta-

bolic syndrome is associated with vascular disease and dementia. Specific features of the metabolic syndrome, such as hyperlipidemia, diabetes, hypertension, and obesity are

M&B 2011; 2:(1). July 2011 16

also related to the presence of dementia.5,6 One of the characteristic pathologies of Alzheimer’s disease is the abnormal synthesis and metabolism of amyloid precursor protein, which can also act as a cytokine that promotes inflammation.5 Additional inflammatory cytokines, IL-6, IL-8, and IL-1b, have been associated with amyloid precursor protein.5

Adipoctyes are believed to be important in the development

of systemic inflammation. Rather than mostly empty storage places for excess fat, they are active producers of hormones and cytokines and regulate other cell types, such as myocytes and immunocytes. Adipocytes will hypertrophy when exposed to energy by way of a nutrient-sensing gene pathway, the TOR gene pathway.79 TOR genes have been studied for their influence on lifespan in several species.

The TOR pathway acts a receptor in the cell nucleus peroxisome proliferator-activated receptor-g (PPARg), which promotes adipocytes to mature.

Adipocytes release substances that promote vascular growth: angiogenin, vascular endothelial growth factors (VEGF), VEGFC, VEGF-D, soluble VEGF receptor-2 (sVEGFr2), angiopoietin-2, and hepatocyte growth factor (HGF). Increa- sed amounts of angiogenin and VEGF have been observed in vascular disease.10,11 HGF is found in elevated levels in individuals with peripheral vascular disease, coronary artery disease, and diabetes.10,12

Adipocytes regulate insulin and adipocyte-related hormones

including resistin, leptin, and retinal binding protein-4.13 Resistin can induce macrophages to produce tumor necrosis

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