**4. Multiple sclerosis**

Multiple sclerosis (MS) is a multifactorial, chronic disease of the CNS characterized by demyelination, inflammation, and neurodegeneration.

Epidemiological studies indicate that genetic and environmental factors interact and influence the risk of MS, for example, several SNPs or environmental exposures like an infection with Epstein-Barr virus (EBV), vitamin D status, sunlight exposure, or smoking. There is a high prevalence for MS in areas with low sun/ultraviolet sun exposure [93, 94], and this could be explained by vitamin D [95]. A study from Lucas and colleagues revealed that vitamin D and sun exposure are independent risk factors of CNS demyelination [96]. For an overview over environmental factors and MS, we suggest an article from Ebers GC [97]. Genetic predispositions which are associated with MS are found in genes of the immune system. The strongest correlation was found for genes of the major histocompatibility complex (MHC), especially the HLA genotype HLA-DRB1 [98]. Findings from Ramagopalan and colleagues suggest a direct functional link between known environmental risk factors, for example, vitamin D, and established genetic predispositions. The authors described the localization of a vitamin D response element on the promotor region of *HLA-DRB1* and underlined its functional role by the finding that treatment with calcitriol results in an increased expression [99]. Later on this research group could show that mutations in the *CYP27B1* gene, involved in vitamin D3 metabolism, are causative associated with the risk of MS [100]. Moreover, genetic variations

in the *CYP24A1* gene, involved in catabolism of vitamin D, were found to play a pathogenic role in MS [101]. For detailed information about the results of several genome-wide association studies analyzing the genetic risk of developing MS, we recommend a recent publication from Baranzini and Oksenberg [102].

Clinical studies indicate that vitamin D influences MS development and disease activity including the risk of relapse, gray matter volume loss, and clinical course of MS. A prospective study from Munger et al. included participants from the US military personnel and reported a significantly decreased risk of MS with elevated levels of 25(OH)D3 [103]. Furthermore, a cross-sectional study described a link of serum 25(OH)D3 levels with both relapse rate and disability in MS patients [104]. In line with this, an association of reduced serum 25(OH)D3 levels with a higher risk of relapse in MS was reported in a prospective longitudinal study including 73 individuals with relapsing-remitting MS [105]. Consistent findings are obtained from a retrospective study describing an association of a 10 ng/ml increase in 25(OH)D3 level with a 34% reduced relapse rate in pediatric-onset MS [106] and from a prospective study reporting a 25(OH)D3 elevation of 10 nmol/L to be associated with a 12% decreased risk of relapse in a cohort including 145 participants [107]. A 5-year longitudinal study from Mowry and colleagues using magnetic resonance imaging (MRI) as marker of disease activity provided evidences for a lower risk of developing new T2 lesions and gadolinium-enhancing lesions as well as reduced subsequent disability attended by an 10 ng/ml increase in 25(OH)D3 level [108].

As mentioned before in the context of AD, these clinical studies are not able to rule out the possibility of reverse causality. In this context MR studies are of great interest analyzing this potential causal relationship of vitamin D and MS risk. Mokry et al. identified four 25(OH)D3 level-associated SNPs in a large genome-wide association study for vitamin D, called SUNLIGHT, and performed an MR study to examine the influence of genetically reduced vitamin D3 levels on the odds of MS in a large genetic association study for MS. This leads to the finding that genetically reduced vitamin D3 levels are strongly linked to an elevated MS risk [109]. This thesis is furthermore supported by another novel MR study that described causal effects of decreased vitamin D3 levels on pediatric-onset MS [110]. A very recent study from Graves et al. provides evidence for a causal link between 25(OH)D3 and MS relapses in children. The authors indicate that a vitamin D genetic risk score (vitDGRS) can support the identification of patients at greater relapse risk [111].

The protective role of vitamin D could be exerted on the molecular level mainly due to its several potential immunomodulatory effects. These are summarized in a review from Smolders and colleagues. The authors pointed out that vitamin D causes a shift to an anti-inflammatory immune response and increased regulatory T cells as well as reduced pro-inflammatory helper cells like Th1 and Th17 selectively [112]. In line with this, a study from Munger et al. reported an overlap of genes associated with vitamin D3 and those associated with processes of immune regulation. Furthermore they suggest the sphingosine-1-phosphate receptor-dependent migration of lymphocytes from secondary lymphoid tissue as potential vitamin D3 mediated mechanism [113]. Additional evidences for the MS-underlying molecular mechanisms arise from a recent study using the L-type calcium channel antagonist nimodipine, showing decreased neurodegeneration in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. The authors reported calcium channel-independent, microglia-specific effects: induction of apoptosis, reduced levels of NO and ROS, as well as positive effects on remyelination [114].

Based on the results of all these studies demonstrating a causal link between vitamin D hypovitaminosis and the risk of MS, the role of vitamin D3 supplementation in MS therapy was investigated. A study from Munger et al. reported an approximately 41% reduced relative risk of MS due to the supplementation of

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*The Effects of Vitamin D Deficiency on Neurodegenerative Diseases*

400 IU vitamin D/day in two large cohorts of women [115]. Several following studies also describe beneficial effects of vitamin D3 supplementation on gadoliniumenhancing lesions, relapses, and T-cell proliferation without unrequested calcemic side effects [116–118]. Inconsistent with these results, another study revealed no positive effect of high-dose vitamin D3 supplementation (20,000 IU/week) on course and activity of the disease, for example, the relapse risk. A possible explanation for this finding could be individuals with high vitamin D3 levels in the placebo group. Furthermore the authors could not preclude that the used vitamin D dose was too low or that the sample size was too small [119]. In this context it should be mentioned that the individual vitamin D metabolism, which could be influenced by genetically mutations in the enzymes required for the anabolism and catabolism of vitamin D3 as discussed before, has to be analyzed since this would influence the response to identical supplemented doses of vitamin D in different individuals [120]. Subsequent studies were able to show a reduction in relapse rate after supplementation of vitamin D3 [121] and an improved cognitive performance [122]. Oral supplementation of 20,000 IU vitamin D3/week in a 96-week randomized double-blind placebo-controlled study in 68 MS patients results in reduced levels of anti-EBV nuclear antigen 1 (EBNA1) protein and fragment antibody [123]. A previous study could show a remarkable overlap of EBNA2 with VDR binding sites and thereby demonstrates a genetic argument for an interaction between genetic and environmental risk factors of MS [124]. A current study reports that long-term supplementation for several months with high doses of cholecalciferol results in a significantly promoted aggravation of clinical and histological EAE, but simultaneously they find a direct, anti-inflammatory, beneficial effect of vitamin D on

Prion diseases are a group of neurodegenerative disorders whose pathology is caused by the conversion of the cellular prion protein (PrPC) into a misfolded form of the protein, called prion or "scrapie prion protein" (PrPSc), a proteinaceous, insoluble, infectious particle which is resistant to proteases and seems to act as template for exponential transformation and further accumulation of prion proteins. One characteristic of prion diseases is their appearance by sporadic (spontaneously conversion, Jakob-Creutzfeldt disease), genetic (familial mutations in the prion protein gene, PRNP), or acquired (accidentally transmission or infection) mecha-

A study on transgenic mice was able to identify a naturally occurring polymorphism in the human PRNP which is very rare but seems to completely prevent prion disease [127]. Up to this date, no clinical trial on human prion disease was successful, and most of the analyzed chemical compounds failed as potential therapeutics because of their toxicity. A study from Suenaga and colleagues intended to identify compounds that interfere with the direct PrPC-PrPSc interaction by screening hydrophobic vitamins. The authors reported for the first time that vitamin D2 was able to interact with a truncated form of human recombinant PrPC leading to a reduced oligomerization in vitro. The absence of such an effect mediated by vitamin D3 could be due to structural differences between these two vitamin D forms. This study suggests vitamin D2 as suitable therapeutic candidate to target PrPC in the brain of patients with prion disease because of its direct inhibition of PrPC oligomerization, its blood–brain barrier permeability, and its safety compared to other synthetic compounds [128]. But apart from that, more studies, especially clinical trials, are essential to elucidate the relationship of vitamin D and prion diseases.

*DOI: http://dx.doi.org/10.5772/intechopen.89160*

lymphocytes of human and murine origin [125].

**5. Prion diseases**

nisms [126].

#### *The Effects of Vitamin D Deficiency on Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.89160*

400 IU vitamin D/day in two large cohorts of women [115]. Several following studies also describe beneficial effects of vitamin D3 supplementation on gadoliniumenhancing lesions, relapses, and T-cell proliferation without unrequested calcemic side effects [116–118]. Inconsistent with these results, another study revealed no positive effect of high-dose vitamin D3 supplementation (20,000 IU/week) on course and activity of the disease, for example, the relapse risk. A possible explanation for this finding could be individuals with high vitamin D3 levels in the placebo group. Furthermore the authors could not preclude that the used vitamin D dose was too low or that the sample size was too small [119]. In this context it should be mentioned that the individual vitamin D metabolism, which could be influenced by genetically mutations in the enzymes required for the anabolism and catabolism of vitamin D3 as discussed before, has to be analyzed since this would influence the response to identical supplemented doses of vitamin D in different individuals [120]. Subsequent studies were able to show a reduction in relapse rate after supplementation of vitamin D3 [121] and an improved cognitive performance [122]. Oral supplementation of 20,000 IU vitamin D3/week in a 96-week randomized double-blind placebo-controlled study in 68 MS patients results in reduced levels of anti-EBV nuclear antigen 1 (EBNA1) protein and fragment antibody [123]. A previous study could show a remarkable overlap of EBNA2 with VDR binding sites and thereby demonstrates a genetic argument for an interaction between genetic and environmental risk factors of MS [124]. A current study reports that long-term supplementation for several months with high doses of cholecalciferol results in a significantly promoted aggravation of clinical and histological EAE, but simultaneously they find a direct, anti-inflammatory, beneficial effect of vitamin D on lymphocytes of human and murine origin [125].
