Vitamin D shows associations between low levels of vitamin D, or hypovitaminosis D, and neuropsychiatric disorders,Harms, L. R., Burne, T. H. J., Eyles, D. W., & McGrath, J. J. (2011). Vitamin D and the brain. Best practice & research. Clinical endocrinology & metabolism, 25(4), 657–669. Elsevier Ltd. doi:10.1016/j.beem.2011.05.009 including Alzheimer's disease, autism, epilepsy, multiple sclerosis, Parkinson's disease, and schizophrenia.
Physiology
Vitamin D (the inactive version) is mainly from two forms: vitamin D3 and vitamin D2. Vitamin D3, or cholecalciferol, is formed in the skin after exposure to sunlight or ultra violet radiation or from D3 supplements or fortified food sources. Vitamin D2, or ergocalciferol, is obtained from D2 supplements or fortified food sources.Lips, P. (2006). Vitamin D physiology. Progress in biophysics and molecular biology, 92(1), 4-8. doi:10.1016/j.pbiomolbio.2006.02.016 These two forms of vitamin D are metabolized in the liver and stored as 25-hydroxyvitamin D.Christakos, S., Ajibade, D.V., Dhawan, P., Fechner, A. J., Mady, L.J. (2011). NIH Public Access. Endocrinology And Metabolism, 39(2), 243–253. doi:10.1016/j.ecl.2010.02.002.Vitamin Before biological use, the storage form must be converted into an active form. One common active form is 1,25-dihydroxyvitamin D. The term vitamin D in this article means cholecalciferol, ergocalciferol, 25-hydroxyvitamin D, and the active forms. The role of vitamin D is best characterized as enabling calcium absorption and regulating calcium homeostasis. Vitamin D also play a role in phosphate absorption.Harvey, M. (2012, October 17). Interview by TN Smith [Audio Tape Recording]. Vitamin d and neuropsychiatric disorders
Hypovitaminosis D Hypovitaminosis D is any deficiency of vitamin D. A vitamin D blood-concentration standard for diagnosing hypovitaminosis D does not exist. In the past, hypovitaminosis D was defined by blood concentrations lower than 20 ng/mL.Llewellyn, D. J.; Lang, I. a; Langa, K. M.; Muniz-Terrera, G.; Phillips, C. L.; Cherubini, A.; Ferrucci, L.; et al. (2010). "Vitamin D and Risk of Cognitive Decline in Elderly Persons". Archives of Internal Medicine, 170(13), 1135–1141. doi:10.1001/archinternmed.2010.173 However, in more recent literature many researchers have considered 30 ng/mL to be an insufficient concentration of vitamin D. Subnormal levels of vitamin D are usually caused by poor nutrition or a lack of sun exposure. Risk factors for hypovitaminosis D include premature birth, darker skin pigmentation, obesity, malabsorption, and older age.
Vitamin D and the central nervous system
Location in the central nervous system The brain requires the use of many neurosteroids to develop and function properly. These molecules are often identified as one of many common substances including thyroid hormones, glucocorticoids, and sex hormones. However in recent studies, throughout the brain and spinal fluid, vitamin D has begun to surface as one of these neurosteroids. Metabolites: Several vitamin D metabolites are found in cerebral spinal fluid and have the ability to cross the blood brain barrier. This is similar to many of the previously known neurosteroids. These vitamin D metabolites include 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and 24,25-dihydroxyvitamin D3. Derivatives of these metabolites are highly expressed in the substantia nigra and the hypothalamus. These two brain structures are responsible for motor functions and linking the nervous system to the endocrine system, respectively. The expression of these metabolite derivatives in these areas suggests that these structures have the ability to synthesize these products from vitamin D.
Receptors: In addition to vitamin D metabolites, vitamin D receptor (VDR) proteins are also found in the brain; more specifically, they are found in the cerebellum, thalamus, hypothalamus, basal ganglia, and hippocampus. The highest density of VDR is in substantia nigra, one of the primary areas of dopamine production. Another significant portion of the receptors is located in the hypothalamus (supra optic and paraventricular nuclei) and external granule cell layer of the prefrontal cortex.Evatt, M. L. (2012, October 25). Interview by T.N. Smith [Personal Interview]. Vitamin d deficiency and associated neurological conditions., Atlanta, Ga. VDR are also found in the hippocampus (CA1 and CA2) areas, in slightly lower densities.
Function in the central nervous system The presence of vitamin D, its activating enzyme, and VDR in the brain leads researchers to question what role vitamin D plays in the brain. Research suggests that vitamin D may function as a modulator in brain development and as a neuroprotectant. In recent studies, vitamin D has exhibited an association with the regulation of nerve growth factor (NGF) synthesis. NGF is responsible for the growth and survival of neurons.Garcion, E., Wion-barbot, N., Montero-menei, C. N., Berger, F., & Wion, D. (2002). New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002 13(3):100-105. This relationship has also been studied in embryonic and neonatal rats. Developmental vitamin D deficient (DVD) rats have decreased levels of neurotrophic factors, increased mitosis, and decreased apoptosis. These findings suggest that vitamin D potentially affects the development of neurons as well as their maintenance and survival. Current research is underway investigating whether vitamin D is a factor contributing to normal brain functioning.
Vitamin D and neurological disorders Hypovitaminosis D is associated with several neuropsychiatric disorders including dementia, Parkinson's disease, multiple sclerosis, epilepsy, and schizophrenia. There are several proposed mechanisms by which hypovitaminosis D may impact these disorders. One of these mechanisms is through neuronal apoptosis. Neuronal apoptosis is the programmed death of the neurons. Hypovitaminosis D causes this specific apoptosis by decreasing the expression of cytochrome C and decreasing the cell cycle of neurons. Cytochrome C is a protein that promotes the activation of pro-apoptotic factors.Goodsell, D.S. (2004). The molecular perspective: cytochrome c and apoptosis. The Oncologist Fundamentals of Cancer Medicine. 2004(9),226-227 A second mechanism is through the association of neurotrophic factors like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF). These neurotrophic factors are proteins that are involved in the growth and survival of developing neurons and they are involved in the maintenance of mature neurons.Deister, C. and C.E. Schmidt, Optimizing neurotrophic factor combinations for neurite outgrowth. Journal of Neural Engineering, 2006. 3: p. 172-179.
Dementia: Alzheimer's disease "Dementia" is a term referring to neurodegenerative disorders characterized by a loss of memory and such brain functions as executive functioning. Included under this umbrella term is Alzheimer's disease. Alzheimer's disease is characterized by the loss of cortical functions like language and motor skills. Patients with Alzheimer's disease exhibit an extreme shrinkage of the cerebral cortex and hippocampus with an enlargement of the ventricles. In several recent studies, higher vitamin D levels have been associated with lower risks of developing Alzheimer's disease.Annweiler, C., Rolland, Y., Schott, A. M., Blain, H., Vellas, B., Herrmann, F. R., & Beauchet, O. (2012). Higher vitamin D dietary intake is associated with lower risk of alzheimer's disease: a 7-year follow-up . Journals of Gerontology Alzheimer's disease is associated with a decrease in vitamin D receptors in the Cornu Ammonius areas (CA 1& 2) of the hippocampus. The hippocampus is a portion of the limbic system responsible for memory and spatial navigation. Additionally, certain VDR haplotypes were detected with increased frequency in patients with Alzheimer's disease while other VDR haplotypes were detected with decreased frequency, suggesting that specific haplotypes may increase or decrease risk of developing Alzheimer's.Gezen-ak, D., Dursun, E., Bilgiç, B., Hanağasi, H., Ertan, T., Gürvit, H., Emre, M., et al. (2012). Vitamin D Receptor Gene Haplotype Is Associated with Late-Onset Alzheimer ’ s Disease. October, 189-196. doi:10.1620/tjem.228.189.CorrespondenceValdivielso, J. M., & Fernandez, E. (2006). Vitamin D receptor polymorphisms and diseases. Clinica Chimica Acta, 371(1-2), 1-12. doi:10.1016/j.cca.2006.02.016 It is hypothesized that this lack of VDRs in the hippocampus prevents the proper functioning (ie. memory) of this structure.
Parkinson's disease Parkinson's disease is characterized by progressive deterioration of movement and coordination. Patients with Parkinson's disease lose dopaminergic (DA) neurons in the substantia nigra,Vinh Quôc Luong, K., & Thi Hoàng Nguyên, L. (2012). Vitamin D and Parkinson’s disease. Journal of Neuroscience Research, 90(12), 2227-36. doi:10.1002/jnr.23115 a part of the brain that plays a central role in such brain functions as reward, addiction, and coordination of movement. Studies suggest that low vitamin D levels could play a role in PD, and in one case report, vitamin D supplements lessened parkinsonian symptoms. In a study of vitamin D receptor knockout mice, mice without VDR exhibited motor impairments similar to impairments seen in patients with Parkinson's disease. One proposed mechanism linking vitamin D to Parkinson's disease involves the Nurr 1 gene. Vitamin D deficiency is associated with decreased expression of the Nurr1 gene, a gene responsible for development of DA neurons. It is therefore plausible that a lack of Nurr1 expression leads to impaired DA neuronal development. Failure to form DA neurons would lead to lower dopamine concentrations in the basal ganglia. Additionally, rats lacking Nurr1 exhibited hypoactivity followed by death shortly after birth.Non-motor symptoms may be influenced by vitamin D deficiency; for example, orthostatic hypotension has been inversely associated with decreased vitamin D levels.
Multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease causing demyelination within the central nervous system.Pierrot-Deseilligny, C., & Souberbielle, J.-C. (2010). Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis? Brain: A Journal of Neurology, 133(Pt 7), 1869-88. doi:10.1093/brain/awq147 In the central nervous system, there are many cells encased in a fatty coating called the myelin sheath. This sheath allows for informational signals to be transmitted at greater speeds down through the cell. In multiple sclerosis, this sheath deterioration causes a slower transmission of nerve signals. This ultimately results in severe motor deficits.