For these reasons, we reckon that a vitamin D deficiency could contribute to the complex relationship between genetics and the environment, the two common poles that many neurological pathologies debate between. It could intervene in the exacerbation of precipitating factors or in demodulating the repair process; therefore, we consider that this topic should be approached from a neurological perspective. Therefore, we have started this review. We searched MEDLINE using the following search terms: “vitamin D central nervous system”, both “vitamin D” and “central nervous system”; “vitamin D immune system/response”, both “vitamin D” and “immune system” or “immune response”; “vitamin D multiple sclerosis risk”, both “vitamin D” and “multiple sclerosis risk”; “vitamin D multiple sclerosis relapse”, both “vitamin D” and “multiple sclerosis relapse”; “vitamin D multiple sclerosis magnetic resonance imaging”, both “vitamin D” and “multiple sclerosis magnetic resonance imaging”; “vitamin D multiple sclerosis disability”, both “vitamin D” and “multiple sclerosis disability”; “vitamin D supplementation/therapy/treatment multiple sclerosis”, both “vitamin D supplementation” or “vitamin D therapy” or “vitamin D treatment” and “multiple sclerosis”; “vascular dementia”, both “vascular” and “dementia”; “subcortical vascular dementia”, both “subcortical” and “dementia”; “Alzheimer’s disease”; “pathogenesis neural-degeneration”; “amyloid”; “cholinergic afferents”; “arteriolosclerosis”; “cerebral flow regulation”; and “stroke”. The publications that were selected were mostly from the past 20 years, but they did not exclude the frequently referenced and highly regarded older publications. The research has been extended, with the same strings, EMBASE, COCHRANE LIBRARY, and LILACS. All of the searches were done from 1 January 1993 up to 31 May 2018. We considered papers published in English, French, German, and Italian. Congress abstracts and isolated case reports (even if the total cases were under 10) were not considered. Review articles and book chapters are cited to provide additional details. The authors carefully read all of the selected articles.

The presence of VDR in the hippocampus, hypothalamus, thalamus, cortex, and substantia nigra [ 15 ] prompted many studies on the possible determinant role of vitamin D in different neurological conditions [ 16 17 ]. It has been evidenced that calcitriol is a fundamental actor in the neuronal differentiation and the neural maturation [ 18 ]. Vitamin D normalizes the trafficking of the septo-hippocampal pathways, mainly via the neural growth factor (NGF); moreover, it is an active controller of the genetic regulation of the synthesis of acetylcholine (Ach), dopamine (DA), serotonin (5HT3), and gamma-aminobutyric (GABA) [ 19 21 ].

The non-genomic actions of vitamin D help to cooperate with the classical genomic pathway, to transactivate VDR, and exert the effects of calcitriol; the signal does not depend on the transcription phases, but it can operate via cross-talk with different signaling pathways, such as rapid membrane response binding proteins (see later). The genomic and the non-genomic pathways support the emerging not calcemic effects of the vitamin D metabolites, trying to define a role in the autoimmune pathologies, infectious diseases, diabetes mellitus, obesity, and cardio-metabolic disorders [ 10 ].

Vitamin D yields both genomic and non-genomic actions; the Vitamin D Receptors (VDR) mediates the former, one of the representative of the steroid hormone superfamily, which are evident in more than 30 human tissues, therefore regulating 3% of the human genome (approximately 700 genes) [ 5 ]. Nuclear VDRs are found in most cells, and support the role for the extra-skeletal benefits of vitamin D. The VDR are found in almost all human tissues, participating in the classic actions of vitamin D in the bone, gut, and kidney, but are also involved in immune functions, hormone secretion, and cellular proliferation and differentiation [ 6 ]. To be biologically active, vitamin D undergoes hydroxylations in the liver, mediated by the 25-hydroxylase, and in the kidney, mediated by 1α-hydroxylase. The 1,25(OH)D is recognized by VDR, in various cells, mainly in the intestine. As vitamin D plays a significant role in modulating the immune system in the intestine, it is possible that its deficiency could deteriorate the gut barrier function, favoring the translocation of endotoxins. Vitamin D deficiency has been associated with intestinal dysbiosis and increased susceptibility to intestinal diseases; moreover, vitamin D could be contributing to disturbances of the glucose metabolism by modulating the composition of the gut microbiota. The changed intestinal microbiome has become epidemic, in parallel with the epidemic of vitamin D deficiency, suggesting that they might be linked. Proper supplemental doses of vitamin D plus all of the B vitamins appears to return the intestinal microbiome back to normal after few months [ 7 8 ]. Moreover, there are more and more evidence that links the microbiome to neurologic disorders [ 9 ], which can share a common auto-immune involvement; the potential link between the three actors (VDR, neurological disorders, and vitamin D) is quite fascinating and many studies should be done to gain knowledge on them.

2. Vitamin D Deficiency and Multiple Sclerosis: Role in the Susceptibility, Activity, and Treatment of the Disease

Multiple Sclerosis (MS) is a multifactorial demyelinating pathology affecting the brain and the spinal cord, firmly relying on an altered immune response. Activated autoreactive T cells invade the blood–brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, the mechanisms associated with its onset, the unpredictable clinical course, and the different rates of progression leading to disability over time, remain unresolved questions [ 28 ].

Immunological research makes two significant observations to explain the link between vitamin D and the immune system.

2 vitamin D induces monocytes proliferation and differentiation into macrophages [ Firstly, most immune cells, of both the innate and the adaptive immune system, express the VDR [ 29 30 ]. Secondly, the immune cells exhibit an active vitamin D metabolism, with the expression of the rate-limiting enzyme for vitamin D synthesis, 1α-hydroxylase (CYP27B1) [ 31 ]. Immune cells are, therefore, able to synthesize and secrete vitamin D in an autocrine and paracrine condition [ 32 ]. The immune cell types, targeted by vitamin D, include monocytes and macrophages, dendritic cells (DCs), and T and B cells [ 33 ]. 1,25(OH)vitamin D induces monocytes proliferation and differentiation into macrophages [ 34 ], the potentiate the expression of interleukin-1 (IL-1), and the antimicrobial peptides (cathelicidin, β-defensin-2, and hepcidin) [ 35 ]. Vitamin D inhibits DC differentiation and maturation, their major histocompatibility complex (class II) expression (MHC), CD40, CD80, CD86, and IL-12 (while inducing the production of IL-10), leading to reduced T cell stimulatory capacity [ 36 37 ]. Vitamin D decreases the production of nitric oxide (NO), mediating the downregulation of the inducible nitric oxide synthase (iNOS) expression [ 38 ]. Moreover, it stimulates the development of natural killer T (NKT) cells, and it increases IL-4 and interferon (IFN)-γ production [ 39 ]; vitamin D attenuates the proliferation of CD8+ T cells and reduces their cytotoxic activity by decreasing the production of IL-2, IL-17, and IFN-γ.

Vitamin D exerts its immunomodulatory effects on T lymphocytes, by inhibiting the production of pro-inflammatory Th1 cytokines (IL-1, IL-2, IL-6, IL-12, IFN-γ, TNF-α, and TNF-β), and stimulating the production of anti-inflammatory regulatory Th2 cytokines (IL-4, IL-5, and IL-10) [ 40 41 ].

Thus, vitamin D potentiates the innate immune system and regulates the adaptive immune system, mainly by inducing the split to Th2 and regulatory T cells (Tregs), over the Th1 and Th17 lymphocytes differentiation [ 42 ], via direct and indirect actions on naive CD4+ cells. The general result is an evident effect of switching capacity, from a pro-inflammatory autoimmune to an anti-inflammatory tolerogenic immunological response.

2 D has been linked with the suppressive activity of Tregs [ 2 D. The Tregs are increased in the MS patients that have supplemented with vitamin D [ In multiple sclerosis (MS) patients, the blood level of 25(OH)D or 1,25(OH)D has been linked with the suppressive activity of Tregs [ 43 ], and the number of Tregs has been correlated with the serum levels of 25(OH)D or 1,25(OH)D. The Tregs are increased in the MS patients that have supplemented with vitamin D [ 44 45 ].

48, 2 D, which seems to promote the NCS proliferation and differentiation into neurons and oligodendrocytes, and to reduce astrogliosis [ According to many studies, vitamin D may have an impact on the balance between the inflammatory and anti-inflammatory mechanisms, which might help/regulate the remyelination process. Vitamin D increases the microglial activation, promoting the clearance of myelin debris, and consequently activating the remyelination process [ 46 ]. In the oligodendrocyte precursor cells (OPC) cultures, vitamin D up-regulates the transcription of VDR and NGF mRNA, but not of myelin basic protein (MBP) [ 47 49 ]. The remyelination of demyelinated lesions has been observed in the early stages of MS [ 50 51 ], and it has been supported by neuroimaging findings [ 52 53 ]. However, remyelination might be incomplete [ 54 ], and eventually, it might cease [ 55 ], because of the OPC inability to migrate and reach the site of demyelination [ 56 ], or for the OPC differentiation inability [ 57 ]. In fact, an inflammatory microenvironment prevents OPC maturation and the differentiation into oligodendrocytes, and subsequently prevents axon remyelination. This is relevant for MS treatment, as current treatments are only useful for controlling immune mechanisms (i.e., in the early stages of the disease), but do not affect remyelination. In vitro studies show that when blocking VDR, there is a reduction of OPC differentiation, with a consequent blockage of myelination and remyelination; on the other hand, by activating VDR, via vitamin D, there is an increase in the differentiation of OPC and the consequent remyelination [ 58 ]. Likewise, neural stem cells (NSC) express VDR and 1,25(OH)D, which seems to promote the NCS proliferation and differentiation into neurons and oligodendrocytes, and to reduce astrogliosis [ 59 60 ].

63,64, As vitamin D deficiency has been proposed as a significant risk factor in MS development, most epidemiologic observational studies have suggested that adequate vitamin D levels may reduce the risk of MS onset and modify the course of the disease. MS is a disease that is virtually unknown at the equator, and the prevalence of the disease increases in populations that live farther away from the equator [ 61 ]. The prevalence of MS is higher at higher latitudes, and tends to peak in the areas with the lowest exposure to ultraviolet (UV) light [ 62 63 ]; however, in these areas, diets rich in vitamin D-containing oily fish may offset this risk to some degree [ 62 65 ]. Moreover, the risk of MS has been found to decrease among people who migrate from higher to lower latitudes [ 66 ]. This latitudinal finding has been declining in recent decades, instead of an associated increasing trend towards avoiding sun exposure by staying indoors for more extended periods of the day, even in warmer climates [ 67 68 ]. In fact, higher levels of sun exposure (past, recent, and cumulative) were independently associated with higher levels of vitamin D and with a significantly reduced risk of developing demyelinating events [ 69 ]. Sunlight seems to have an immunosuppressive effect and, therefore, the effects of sunlight on MS risk could be related to the sunlight itself, or to an increase of vitamin D [ 70 ]. The association between the calculated vitamin D intake from diet or supplements, and the risk of developing MS has been prospectively evaluated in two large cohorts involving more than 187,000 women [ 71 ]. Women who had a higher intake of dietary vitamin D (approximately 700 IU/day) had a 33% lower incidence of MS compared with those with a lower intake. Moreover, the women who used vitamin D supplements (more than 400 UI/day) had a 41% reduced risk of developing MS compared with non-users. Higher levels of 25(OH)D (independently, from dietary vitamin D intake) also seem to predict a lower risk of MS onset. A more recent prospective study confirmed these findings and reported that the levels of vitamin D over 30 ng/mL were associated with a decreased MS risk [ 72 ]. Adiposity has been associated with lower vitamin D levels [ 73 74 ], and a higher body mass index (BMI) has been associated with higher incidence of MS in adolescent women, but not in adult women [ 75 ].

2 and vitamin D occurred through the VDR-mediated enhancement of E 2 synthesis, as well as through the E 2 -mediated enhancement of VDR expression due to the inflammation of central nervous system (CNS). In males, E 2 did not enable vitamin D to inhibit EAE [ A crucial question related to a primary prevention trial or from vitamin D supplementation in MS is the relevant age of exposure, which can range from in utero to adolescence and adulthood [ 76 ]. Mirzaei et al. studied a large cohort and analyzed the association between maternal dietary vitamin D intake and the predicted maternal serum 25(OH)D during pregnancy, and their daughters’ risk of developing MS [ 77 ]. The study showed that the relative risk of MS was significantly lower in the women whose mothers had high vitamin D intake during pregnancy compared with the women born to low-intake mothers. A diminished in utero exposure to vitamin D, coupled with the solar cycle and latitudinal differences, may be an environmental risk factor for the development of MS. Similarly, albeit not statistically significant, a reduced MS risk was reported among the women reporting an increased vitamin D intake from supplements in adolescence [ 78 ]. These results suggest that MS risk is related not only to new vitamin D levels, but it might also be related to its levels during childhood or even in utero. Several studies, including a meta-analysis, demonstrated that spring-born have a significantly higher lifetime MS risk than autumn-born, which has been attributed, at least in part, to insufficient in utero vitamin D levels, because of low maternal serum vitamin D levels during winter [ 79 80 ]. In a large population-based case-control study [ 81 ], children born with 25(OH)D levels <10 ng/mL seemed to be at a high risk of developing MS. Likewise, the level of sun exposure in childhood and adolescence (e.g., by outdoor leisure activities), which may serve as a proxy for vitamin D supply in early life, has been inversely linked to the risk of MS in adulthood [ 82 83 ]. In a recent longitudinal Canadian study of 302 children with the acute demyelinating syndrome, low vitamin D levels were significantly associated with MS risk in the subsequent three years [ 84 ]. One report showed that children with higher serum 25(OH)D concentrations at presentation, with an acquired demyelinating syndrome, had a lower risk of early MS diagnosis [ 85 ]. Gender- and sex-related immunological differences may influence the association between vitamin D and MS. The disproportional increase in the incidence of MS in women is likely to be caused by sex-specific exposure or susceptibility to environmental factors [ 86 ]. The data supporting an interaction between female sex, possibly mediated by estrogen, and vitamin D for MS risk is accumulating. A protective effect of sun exposure was only observed in female monozygotic twins [ 87 ], and the association of sun-sensitive skin types with a disability was only found in untreated female MS patients [ 88 ]. In vitro studies of MBP-specific T cell proliferation have shown sex differences in the metabolism of vitamin D, which were confirmed by treating male MBP-specific T cells with 17β-estradiol in the assay [ 89 ]. In one animal study, vitamin D resulted in fewer clinical, histopathologic, and immunologic signs of Experimental Autoimmune Encephalomyelitis (EAE) in female mice compared with ovariectomized females and intact or castrated males [ 90 ]. A synergy between Eand vitamin D occurred through the VDR-mediated enhancement of Esynthesis, as well as through the E-mediated enhancement of VDR expression due to the inflammation of central nervous system (CNS). In males, Edid not enable vitamin D to inhibit EAE [ 91 ], possibly suggesting that vitamin D-mediated protection in EAE is female-specific, and that MS tends to have a more aggressive course in men than in women.

Several genome-wide association studies (GWAS) and gene-candidate studies have investigated the influence of the specific genetic polymorphisms of vitamin D metabolites on the 25(OH)D levels, and their susceptibility to MS; one study found [ 92 ] an association between the short variant of the VDR protein (F allele) and a genetic predisposition to lower 25(OH)D levels, but not to a higher risk of MS; in a GWAS of 4501 European patients [ 93 ], single-nucleotide polymorphisms (SNPs) of the gene encoding components of the vitamin D binding protein were associated with 25(OH)D concentrations, or with the genes involved in vitamin D synthesis or activation; moreover, a genetically lowered 25(OH)D level was strongly associated with increased MS risk and progression in two studies [ 94 95 ].

113, The role of vitamin D in MS disease progression has also been assessed: it has been hypothesized that 25(OH)D levels can predict a later development of MS in acute optic neuritis (ON) [ 96 ], but the result is inconclusive. A discrete quantity of studies demonstrated that vitamin D levels affect clinical relapses and MS disease activity. In a retrospective study of 110 patients with pediatric-onset MS, the authors found that each increase of 10 ng/mL in the 25(OH)D level was associated with a 34% decrease in the relapse risk [ 97 ]. Similar findings were seen in a prospective cohort study, whose authors concluded that raising 25(OH)D by 20 ng/mL could decrease the hazard of relapse by up to 50% [ 98 ]. In a prospective longitudinal study, the relapse risk was significantly reduced in those patients with medium (20–40 ng/mL) and high (>40 ng/mL) serum vitamin D levels, compared with those with low levels (<20 ng/mL) [ 99 ]. Moreover, the same authors found that for each doubling of the serum vitamin D concentration from a baseline of 10, 20, and 30 ng/mL, MS relapse risk decreased by 27%. In another study, lower vitamin D levels predicted a conversion from Clinically Isolated Syndrome (CIS) to clinically definite MS [ 100 101 ]. In the study by Embry et al., low serum 25(OH)D levels predicted an increased likelihood of gadolinium-enhancing lesions (Gd+) in the Magnetic Resonance Imaging (MRI) scans performed in the subsequent two months period [ 102 ]. In the EPIC study [ 103 ], a five-year MS cohort study in which subjects had clinical and MRI evaluations and gave a blood sample annually. The authors concluded that individuals with CIS/relapsing-remitting multiple sclerosis (RRMS) with higher vitamin D levels have a lower risk of the subsequent development of new T2 lesions and Gd+ lesions on a brain MRI, even after accounting for potential confounding factors. Moreover, an increment of 10 ng/mL of 25(OH)D was associated with a 15% lower risk of new T2 lesions and a 32% lower risk of Gd+ lesions [ 103 ]. In a post hoc analysis, including up to two years of follow-up of participants treated with interferon beta (IFNB)-1b in the BENEFIT trial [ 104 ], Gd+ lesions development was inversely associated with 25(OH)D levels, those patients whose 25(OH)D levels were >20 ng/mL had a 39% lower risk of new Gd+ lesions. Unfortunately, across all of the analyses, associations with lower vitamin D were generally stronger for MRI than for the clinical outcomes. Moreover, the participants of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study (BEYOND study) [ 105 ], treated with IFNB-1b, with higher serum 25(OH)D levels, had lower numbers of new T2 and Gd+ lesions during the first 12 months of follow-up. Moreover, a 20 ng/mL higher serum 25(OH)D level was associated with a 31% lower rate of new lesions, and the patients with 25(OH)D ≥ 40 ng/mL showed 47% lower rate of new T2 lesions and new Gd+ lesions, when compared with the patients who had serum levels of 20–32 ng/mL. Vitamin D and disease-modifying therapies (DMTs) may positively influence each other and produce an additive, or even synergistic, effect on MS disease activity. In an observational cohort study, which included 178 patients with MS [ 106 ], the patients who were treated by IFN had significantly higher 25(OH)D levels than those who were not. Interestingly, the IFN treatment was protective only against relapses among the patients with higher vitamin D levels. The authors hypothesized that treatment with IFNB might increase the serum vitamin D levels through an enhanced responsiveness to sun exposure [ 106 ]. The same authors did not find similar associations for glatiramer acetate (GA) therapy and vitamin D. More recently, Laursen et al. [ 107 ] found that higher vitamin D levels in CIS may slow neurodegeneration evaluated by brain volume measures. In fact, they found that each 10 ng/mL increase in 25(OH)D was significantly associated with a 7.8 mL higher gray matter volume [ 108 ]. Variations in the relapse rate and the number of MRI brain lesions have shown a seasonal pattern that can be related to a variation in Ultra Violet Radiation (UVR) exposure and vitamin D status [ 109 110 ], with some exceptions [ 111 112 ]. Most cross-sectional studies have concluded a negative correlation between the 25(OH) D level and disability [ 103 114 ], and, interestingly, even a direct correlation between the 25(OH) D level and poorer memory performance [ 115 ]. However, the causality is considered uncertain, at the moment.

Given the previous reviewed findings, the assessment of vitamin D supplementation for a possible disease-modifying course of MS is obviously of crucial interest. Unfortunately, the current evidence does not offer a definite consensus for supplementation. Kimball et al. [ 115 ] performed a six-month safety study with escalating doses of vitamin D, and they found a significant reduction in the mean number of Gd+ lesions at the end of the study. In an open-label randomized trial, patients randomized to a vitamin D supplementation had an annualized relapse rate (ARR) significantly lower in the treatment, with a prolonged relapse-free time and with a persistent reduction in the T cell proliferation [ 44 ]. In a one year double-blind, randomized placebo-controlled trial with vitamin D3 as an add-on treatment to IFNB-1b, the MRI T2 lesion burden and the new/enlarging T2 lesions, tended to increase more in the placebo group than in the vitamin D group, however, without statistical significance [ 116 ]. A preliminary Iranian study assessed the safety and efficacy of high-dose vitamin D supplementation during pregnancy in women with MS [ 117 ]. The women in the vitamin D group had significantly fewer relapses during pregnancy, a tendency for fewer relapses up six months after delivery, and a more stable Expanded Disability Status Scale (EDSS) than those without supplementation [ 107 ]. In a longitudinal study [ 118 ], in which 170 natalizumab-treated patients were followed for one year between two winter seasons, patients with insufficient serum 25(OH)D levels at baseline (<20 ng/mL) were advised to take vitamin D supplements, and a significant inverse relationship with the ARR was found, as, for each nmol/L increase in 25(OH)D, a 0.014 decrease in ARR was observed. The double-blind, multicentre, 48-week study, named SOLAR, of supplementation of high-dose oral vitamin D has been the most extensive study to date [ 119 ]. An insignificant trend toward lower ARR in the treatment group was found in vitamin D groupersus placebo, and no statistically significant differences in the disease activity were found between the two groups. Vitamin D3 was associated with a statistically significant reduction in the combined unique lesions (secondary endpoint). The effect of the addition of vitamin D3 to IFNB-1a over 96 weeks was investigated with appropriate cognitive tests [ 120 ]. It did not show a significant trend toward a lower ARR (primary endpoint) among those patients receiving vitamin D treatment, which became statistically significant when the analysis was restricted to those who completed the study. Among the completers, there were also significantly fewer new T2 lesions in the vitamin D group. It is unclear whether the findings of these trials are related to insufficient power or other issues leading to an inability to detect a treatment effect for all outcomes [ 120 ].

Larger randomized controlled trails (RCTs) are currently underway to reveal the role of vitamin D supplementation as an add-on to IFNB therapy in the treatment of RRMS, and even CIS, patients, namely, the VITADEM study in Spain, EVIDIMS study in Germany, PrevANZ study in Australia, D-Lay-MS study in France, and the VIDAMS trial in the United States. One study investigated the cognitive effects of vitamin D supplementation on patients with MS who were treated with IFNB [ 121 ], and after the follow-up period they scored better on the Brief Visuospatial Memory test (BVMT) for delayed recall.