Vitamin D and Other Diseases

*Vitamin D*

Kocher T. Prospective Study of Serum 25-hydroxy Vitamin D and Tooth Loss. J Dent Res. 2014 Jul; 93(7): 639-644. DOI: [68] Antonoglou G, Knuuttila M, Niemelä O, Hiltunen L, Raunio T, Karttunen R, Vainio O, Ylöstalo P, Tervonen T. Serum 1,25(OH)D Level Increases After Elimination of Periodontal Inflammation in T1DM Subjects. Journal of Clinical Endocrinology and Metabolism. 2013; 98: 3999-4005. DOI: 10.1210/

[69] Zhang X, Meng H, Sun X, Xu L, Zhang L, Shi D, et al. Elevation of vitamin D-binding protein levels in the plasma of patients with generalized aggressive periodontitis. Journal of Periodontal Research. 2013 Feb;48(1):74-9. DOI: 10.1111/j.1600-0765.2012.01505.

[70] Richard R. Kew. The Vitamin D Binding Protein and Inflammatory Injury: A Mediator or Sentinel of Tissue Damage? Frontiers in Endocrinology (Lausanne). 2019 Jul 10;10:470. DOI:

10.3389/fendo.2019.00470

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[71] Speeckaert M, Huang G,

[72] White P, Cooke N. The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol Metab 2000;11:320-327. DOI: 10.1016/ s1043-2760(00)00317-9

[73] Hiremath VP, Rao CB, Naiak V, Prasad KV. Anti-inflammatory effect of vitamin D on gingivitis: a dose response randomised controlled trial. Indian J Public Health. 2013 Jan-Mar;57(1):29-32. DOI: 10.4103/0019-557X.111365

Delanghe JR,Taes YE. Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clinica Chimica Acta 2006;372:33-42. DOI: 10.1016/j.

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[62] Alshouibi EN, Kaye EK, Cabral HJ, Leone CW, Garcia RI. VitaminD and periodontal health in older men. Journal of Dental Research. 2013;92:689-693. DOI: 10.1177/0022034513495239

[63] Wang Y, Sugita N, Yoshihara A, et al. Peroxisome proliferator-activated receptor (PPAR) γ polymorphism, vitamin d, bone mineral density and periodontitis in postmenopausal women. Oral Dis. 2013;19:501-506.DOI:

[64] Dietrich T, Nunn M, Dawson-Hughes B, Heike A, Bischoff-

D and gingival inflammation.

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[65] Garcia MN, Hildebolt CF, Miley DD, Dixon DA, Couture RA, et al. One-year effects of vitamin D and calcium supplementation on chronic periodontitis. Journal of Periodontology.2011; 82: 25-32. DOI:

10.1902/jop.2010.100207

[66] Liu K, Meng H, Lu R, Xu L, Zhang L, Chen Z, Shi D, Feng X, Tang X. Initial periodontal therapy reduced systemic and local 25-hydroxyvitamin D(3) and interleukin-1beta in patients with aggressive periodontitis. Journal of Periodontology. 2010 Feb;81(2):260-6.

DOI: 10.1902/jop.2009.090355

[67] Liu K, Meng H, Tang X, Xu L, Zhang L, et al. Elevated plasma

calcifediol is associated with aggressive periodontitis. Journal of Periodontoogy.l 2009;80: 1114-1120. DOI: 10.1902/

Ferrari H. Association between serum concentrations of 25-hydroxyvitamin

American Journal of Clinical Nutrition.

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10.1111/odi.12032

ajcn.82.3.575

**130**

jop.2009.080675

**133**

**Chapter 9**

**Abstract**

infections

**1. Introduction**

decreased recently [6].

*Antony Macido*

Vitamin D and Diabetic Foot

Approximately 15% of patients with diabetes mellitus (DM) are prone to developing diabetic foot ulcers (DFU) in their lifetime. The term vitamin D status or 25-hydroxyvitamin D [25(OH)D] levels are used interchangeably to represent the status of vitamin D in individuals throughout this paper. Evidence suggests a relationship between 25(OH)D levels and DFU. However, very minimal data is available on the association between DFU and vitamin D deficiency. After a careful review of the literature, it was inferred that vitamin D could be associated with DFU and diabetic foot infections. Available evidence on vitamin D and DFU suggests a negative correlation between 25(OH)D levels and the presence of DFU. Evidence also supports a negative relationship between 25(OH)D levels and diabetic foot infections. Further large-scale randomized controlled studies need to be done to confirm the relationship between 25(OH)D levels and DFU including the use of

vitamin D in the management of DFU and diabetic foot infections.

**Keywords:** Vitamin D, 1,25-dihydroxyvitamin D, diabetic foot ulcers, diabetic foot

The role of serum vitamin D in diabetes mellitus (DM) and in the complications related to DM is an area of interest among researchers in the recent past [1, 2]. Diabetic foot complications including diabetic foot ulcers (DFU) and diabetic foot infections are often common with vitamin D deficiency [3]. The global prevalence of diabetic foot complication is 6.3% [4]. Almost 15% of patients with DM can develop DFU in their lives [1]. Infection of DFU is one of the common causes of hospitalization related to DM and accounts for 20% of admissions to hospitals [5]. Recurrence rates are very high with DFU although the recurrence rates have

DFU accounts for growing economic burden, while increasing the morbidity and mortality globally. It is estimated that the global economic burden of caring for DFU is more than \$1.5 billion per year [7]. Every 30 seconds someone loses a lower extremity from DM in the world [8]. The five-year mortality in patients with DFU

There is growing evidence on the relationship between DFU and vitamin D levels. Nevertheless, data is scarce on the association between vitamin D deficiency and DFU [2]. Evidence suggests a negative correlation between DFU and vitamin D levels. There is growing evidence on a negative relationship between diabetic foot infections and vitamin D levels. Further large-scale randomized controlled studies are needed to solidify the evidence of the correlation between DFU and

is 2.5 times higher than patients with DM but has no DFU [9].

#### **Chapter 9**

## Vitamin D and Diabetic Foot

*Antony Macido*

### **Abstract**

Approximately 15% of patients with diabetes mellitus (DM) are prone to developing diabetic foot ulcers (DFU) in their lifetime. The term vitamin D status or 25-hydroxyvitamin D [25(OH)D] levels are used interchangeably to represent the status of vitamin D in individuals throughout this paper. Evidence suggests a relationship between 25(OH)D levels and DFU. However, very minimal data is available on the association between DFU and vitamin D deficiency. After a careful review of the literature, it was inferred that vitamin D could be associated with DFU and diabetic foot infections. Available evidence on vitamin D and DFU suggests a negative correlation between 25(OH)D levels and the presence of DFU. Evidence also supports a negative relationship between 25(OH)D levels and diabetic foot infections. Further large-scale randomized controlled studies need to be done to confirm the relationship between 25(OH)D levels and DFU including the use of vitamin D in the management of DFU and diabetic foot infections.

**Keywords:** Vitamin D, 1,25-dihydroxyvitamin D, diabetic foot ulcers, diabetic foot infections

#### **1. Introduction**

The role of serum vitamin D in diabetes mellitus (DM) and in the complications related to DM is an area of interest among researchers in the recent past [1, 2]. Diabetic foot complications including diabetic foot ulcers (DFU) and diabetic foot infections are often common with vitamin D deficiency [3]. The global prevalence of diabetic foot complication is 6.3% [4]. Almost 15% of patients with DM can develop DFU in their lives [1]. Infection of DFU is one of the common causes of hospitalization related to DM and accounts for 20% of admissions to hospitals [5]. Recurrence rates are very high with DFU although the recurrence rates have decreased recently [6].

DFU accounts for growing economic burden, while increasing the morbidity and mortality globally. It is estimated that the global economic burden of caring for DFU is more than \$1.5 billion per year [7]. Every 30 seconds someone loses a lower extremity from DM in the world [8]. The five-year mortality in patients with DFU is 2.5 times higher than patients with DM but has no DFU [9].

There is growing evidence on the relationship between DFU and vitamin D levels. Nevertheless, data is scarce on the association between vitamin D deficiency and DFU [2]. Evidence suggests a negative correlation between DFU and vitamin D levels. There is growing evidence on a negative relationship between diabetic foot infections and vitamin D levels. Further large-scale randomized controlled studies are needed to solidify the evidence of the correlation between DFU and

vitamin D levels. Before evaluating the significance of vitamin D in diabetic foot complications it is essential to review the effects of vitamin D in diabetic foot complications including the non-skeletal effects of vitamin D.

#### **2. Non-skeletal effects of vitamin D**

Vitamin D is a fat-soluble vitamin that has effects that are not confined to the skeleton. Vitamin D aids in glucose metabolism, angiogenesis, and migration of inflammatory cells [10]. 1,25-(OH)2D is the active form of vitamin D and it acts as a ligand for an intracellular receptor and transcription factor VDR [11, 12]. Vitamin D in the form of 1,25-(OH)2D exerts prodifferentiative and antiproliferative effects on the cutaneous keratinocytes [13], which in turn helps in defense against toxins and pathogens while helping to prevent water loss from the skin [11]. Vitamin D receptor is essential for differentiation, migration, and self-renewal of epidermal stem cells in wound healing [14].

#### **3. Diabetic foot ulcers**

International Working Group on the Diabetic Foot (IWGDF) defines DFU as a foot ulcer in persons with previously diagnosed or currently diagnosed DM and is usually accompanied by peripheral artery disease (PAD) and/or neuropathy in the lower extremity. Diabetic foot is defined as an ulceration, infection, or destruction of tissues of the foot of an individual with previously or currently diagnosed DM, usually accompanied by PAD and/or neuropathy in the lower extremity. A foot ulcer involves a break of the skin of the foot involving the entire epidermis and the dermis in part [15]. Diabetic foot ulcers can be located in different areas of the foot. Almost 25% of DFU are plantar ulcers that are localized to the forefoot [16].

#### **4. Risk factors for developing DFU**

Peripheral vascular disease and diabetic neuropathy are the important risk factors associated with the development of DFU [17]. Foot deformities and prior history of DFU are also risk factors associated with the development of DFU [18]. Inflammation along with oxidative stress have been postulated in the development of DFU [19]. Vitamin D deficiency is labeled as an independent risk factor in the development of diabetic neuropathy [20].

#### **5. Vitamin D deficiency as a risk factor for diabetic foot ulcers/infections**

Significantly low levels of vitamin D can be seen with diabetic foot complications [3]. Although vitamin D deficiency is common in DM, the magnitude of hypovitaminosis D is noticed to be more significant with infected DFU [21–23]. Vitamin D deficiency can in turn increase inflammatory cytokines and delay wound healing in patients with DFU [23]. An antimicrobial peptide called cathelicidin has an important role in wound healing process [24, 25]. In fact, 1,25-(OH)2D can increase the genes capable of inducing cathelicidin production [26]. The literature on vitamin D deficiency and diabetic foot can be synthesized as follows.

**135**

**8. Conclusion**

*Vitamin D and Diabetic Foot*

**6. Literature review**

*DOI: http://dx.doi.org/10.5772/intechopen.97115*

tion between serum vitamin D levels and DFU.

**7. Vitamin D deficiency and supplementation**

25(OH)D than the control group.

Although there is literature available on the association between vitamin D and diabetic foot, only a few randomized controlled studies and metanalyses are available. A metanalysis by Iannuzzo et al. [27] reported that vitamin D deficiency was associated with PAD and may be an independent risk factor for developing PAD. Adults with diabetes and severe vitamin D deficiency are three times more likely to develop a diabetic foot ulcer than similar patients with sufficient vitamin D levels [28]. The Dai et al. [28] study is the first meta-analysis demonstrating the associa-

A double-blind, randomized controlled clinical trial by Razzaghi et al. [29] showed that vitamin D supplementation can aid in the healing of DFU possibly from its effect of improved glycemic control. The study revealed reasonable decrease in ulcer depth, width, and length in the experiment group with vitamin D therapy [29]. The Tiwari et al. [22] study identified a cutoff value for vitamin D levels (25(OH)D < 25 nmol/l) in diabetic patients that put them at risk to develop diabetic foot infections. The study was a prospective cohort research but not randomized. Another non-randomized prospective cohort hospital-based study by Zubair et al. [2] revealed that patients with DFU had a median lower plasma level of

There is more than a dozen of other non-randomized studies that evaluated the prevalence of vitamin D deficiency and the potential use of vitamin D in diabetic foot complications. Majority of these studies reported low vitamin D levels in patients with DFU when compared to their counterparts with no DFU [3]. This strong association between vitamin D deficiency and DFU may not imply causation or correlation. However, this relationship of vitamin D deficiency and the presence of DFU may have implications in the clinical management of DFU [3]. Surprisingly, a study by Afarideh et al. [30] revealed increased levels of circulating 25 (OH)D with active chronic DFU. The authors claim that this is the only study that showed the conflicting finding of increased vitamin D levels in patients with DFU [30].

According to The Endocrine Society, vitamin D deficiency implies a serum 25(OH)D of less than 20 nanograms per milliliter (ng/ml). The recommended assay for diagnosing vitamin D deficiency is the measurement of serum 25(OH)D. Vitamin D deficiency can be treated with either vitamin D3 or vitamin D2 [31]. Vitamin D supplementation needs to be tailored according to the age, sex, presence of comorbidities, etc. Vitamin D deficiency in adults need to be treated with 50,000 IU of vitamin D2 or D3 once a week for a duration of eight weeks or its equivalent vitamin D2 or vitamin D3 as daily doses to achieve a serum 25 (OH) D level of more than 30 ng/ml, followed by 1500–2000 IU daily for maintenance therapy [31]. There are no current recommendations on vitamin D dosage for individuals with DM or individuals with DFU who also have vitamin D deficiency.

There is insufficient data on the significance of vitamin D in DFU. There are no guidelines or standardized measures available on routine evaluation of vitamin D levels and vitamin D supplementation in DFU or infected DFU. Data available on

#### **6. Literature review**

*Vitamin D*

vitamin D levels. Before evaluating the significance of vitamin D in diabetic foot complications it is essential to review the effects of vitamin D in diabetic foot

Vitamin D is a fat-soluble vitamin that has effects that are not confined to the skeleton. Vitamin D aids in glucose metabolism, angiogenesis, and migration of inflammatory cells [10]. 1,25-(OH)2D is the active form of vitamin D and it acts as a ligand for an intracellular receptor and transcription factor VDR [11, 12]. Vitamin D in the form of 1,25-(OH)2D exerts prodifferentiative and antiproliferative effects on the cutaneous keratinocytes [13], which in turn helps in defense against toxins and pathogens while helping to prevent water loss from the skin [11]. Vitamin D receptor is essential for differentiation, migration, and self-renewal of epidermal stem

International Working Group on the Diabetic Foot (IWGDF) defines DFU as a foot ulcer in persons with previously diagnosed or currently diagnosed DM and is usually accompanied by peripheral artery disease (PAD) and/or neuropathy in the lower extremity. Diabetic foot is defined as an ulceration, infection, or destruction of tissues of the foot of an individual with previously or currently diagnosed DM, usually accompanied by PAD and/or neuropathy in the lower extremity. A foot ulcer involves a break of the skin of the foot involving the entire epidermis and the dermis in part [15]. Diabetic foot ulcers can be located in different areas of the foot.

Almost 25% of DFU are plantar ulcers that are localized to the forefoot [16].

Peripheral vascular disease and diabetic neuropathy are the important risk factors associated with the development of DFU [17]. Foot deformities and prior history of DFU are also risk factors associated with the development of DFU [18]. Inflammation along with oxidative stress have been postulated in the development of DFU [19]. Vitamin D deficiency is labeled as an independent risk factor in the

Significantly low levels of vitamin D can be seen with diabetic foot complications [3]. Although vitamin D deficiency is common in DM, the magnitude of hypovitaminosis D is noticed to be more significant with infected DFU [21–23]. Vitamin D deficiency can in turn increase inflammatory cytokines and delay wound healing in patients with DFU [23]. An antimicrobial peptide called cathelicidin has an important role in wound healing process [24, 25]. In fact, 1,25-(OH)2D can increase the genes capable of inducing cathelicidin production [26]. The literature

complications including the non-skeletal effects of vitamin D.

**2. Non-skeletal effects of vitamin D**

cells in wound healing [14].

**3. Diabetic foot ulcers**

**4. Risk factors for developing DFU**

development of diabetic neuropathy [20].

**ulcers/infections**

**5. Vitamin D deficiency as a risk factor for diabetic foot** 

on vitamin D deficiency and diabetic foot can be synthesized as follows.

**134**

Although there is literature available on the association between vitamin D and diabetic foot, only a few randomized controlled studies and metanalyses are available. A metanalysis by Iannuzzo et al. [27] reported that vitamin D deficiency was associated with PAD and may be an independent risk factor for developing PAD. Adults with diabetes and severe vitamin D deficiency are three times more likely to develop a diabetic foot ulcer than similar patients with sufficient vitamin D levels [28]. The Dai et al. [28] study is the first meta-analysis demonstrating the association between serum vitamin D levels and DFU.

A double-blind, randomized controlled clinical trial by Razzaghi et al. [29] showed that vitamin D supplementation can aid in the healing of DFU possibly from its effect of improved glycemic control. The study revealed reasonable decrease in ulcer depth, width, and length in the experiment group with vitamin D therapy [29]. The Tiwari et al. [22] study identified a cutoff value for vitamin D levels (25(OH)D < 25 nmol/l) in diabetic patients that put them at risk to develop diabetic foot infections. The study was a prospective cohort research but not randomized. Another non-randomized prospective cohort hospital-based study by Zubair et al. [2] revealed that patients with DFU had a median lower plasma level of 25(OH)D than the control group.

There is more than a dozen of other non-randomized studies that evaluated the prevalence of vitamin D deficiency and the potential use of vitamin D in diabetic foot complications. Majority of these studies reported low vitamin D levels in patients with DFU when compared to their counterparts with no DFU [3]. This strong association between vitamin D deficiency and DFU may not imply causation or correlation. However, this relationship of vitamin D deficiency and the presence of DFU may have implications in the clinical management of DFU [3]. Surprisingly, a study by Afarideh et al. [30] revealed increased levels of circulating 25 (OH)D with active chronic DFU. The authors claim that this is the only study that showed the conflicting finding of increased vitamin D levels in patients with DFU [30].

#### **7. Vitamin D deficiency and supplementation**

According to The Endocrine Society, vitamin D deficiency implies a serum 25(OH)D of less than 20 nanograms per milliliter (ng/ml). The recommended assay for diagnosing vitamin D deficiency is the measurement of serum 25(OH)D. Vitamin D deficiency can be treated with either vitamin D3 or vitamin D2 [31]. Vitamin D supplementation needs to be tailored according to the age, sex, presence of comorbidities, etc. Vitamin D deficiency in adults need to be treated with 50,000 IU of vitamin D2 or D3 once a week for a duration of eight weeks or its equivalent vitamin D2 or vitamin D3 as daily doses to achieve a serum 25 (OH) D level of more than 30 ng/ml, followed by 1500–2000 IU daily for maintenance therapy [31]. There are no current recommendations on vitamin D dosage for individuals with DM or individuals with DFU who also have vitamin D deficiency.

#### **8. Conclusion**

There is insufficient data on the significance of vitamin D in DFU. There are no guidelines or standardized measures available on routine evaluation of vitamin D levels and vitamin D supplementation in DFU or infected DFU. Data available on

DM and DFU do not comment on the recommendations on vitamin D use in the prevention and treatment of DFU. Literature does not support the routine use of vitamin D in the treatment and prevention of diabetic foot infections. The literature available on the different types of DM and the role of vitamin D in the development of DFU is scarce. Further research is needed to confirm the relationship between DFU and vitamin D including the use of vitamin D in the management of DFU and diabetic foot infections. Provided the beneficial effects on wound healing, identification and treatment of vitamin D deficiency could improve or prevent diabetic foot complication outcomes [3]. Despite the lack of strong evidence to recommending vitamin D in DM and DFU, routine vitamin D supplements in patients with DM and DFU should be considered for its other benefits.

### **Author details**

Antony Macido Keck Medical Center of USC, University of Southern California, Los Angeles, California, USA

\*Address all correspondence to: amacido@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**137**

*Vitamin D and Diabetic Foot*

**References**

016.1231932

8-13.

*DOI: http://dx.doi.org/10.5772/intechopen.97115*

[1] Leone, S., Pascale, R., & Esposito, S. (2012). Epidemiology of diabetic foot. Infezioni in Medicina*, 20*(Suppl. 1),

[8] Khatib, O., & Tabatabaei-Malazy, O. (2007). Prevention and public approach to diabetic foot. Iranian Journal of Diabetes and Metabolism*, 7*(2), 123-133. Retrieved from http://ijdld.tums.ac.ir/ browse.php?a\_id=276&sid=1&slc\_

[9] Armstrong, D. G., Boulton, A. M., & Bus, S. A. (2017). Diabetic foot ulcers and their recurrence. New England Journal of Medicine, *376*(24), 2367-2375.

[10] McGuire, J., & Sheltzer, A. (2019). A Clinical Approach to Nutrition and Wound Healing: A patient's diet matters. Podiatry Management, *38*(9), 87-94.

[11] Rosen, C. J., Adams, J. S., Bikle, D. D., Black, D. M., Demay, M. B., Manson,

[12] Vanchinathan, V. & Lim, H. W. (2012). A dermatologist's perspective on vitamin D. Mayo Clinic Proceedings*,*

[13] Bikle, D., Chang, S., Crumrine, D., Elalieh, H., Man, M., Choi, E., Elias, P.

J. E., Kovacs, C. S. (2012) The nonskeletal effects of vitamin D: An Endocrine Society scientific statement. Endocrine Reviews, 33(3): 456-492.

doi:10.1210/er.2012-1000

*87*(4), 372-380. doi:10.1016/j.

(2004) 25 Hydroxyvitamin D 1 α-hydroxylase is required for optimal epidermal differentiation and permeability barrier homeostasis. Journal of Investigative Dermatology*,*

122(4): 984-992. doi:10.1111/j. 0022-202X.2004.22424.x

repair. Journal of Investigative

10.1016/j.jid.2018.04.033

C., Zhang,

[14] Oda, Y., Hu, L., Nguyen, T., Fong,

(2018). Vitamin D receptor is required for proliferation, migration, and differentiation of epidermal stem cells and progeny during cutaneous wound

Dermatology*, 138*(11), 2423-2431. doi:

J., Guo, P., & Bikle, D. D.

mayocp.2011.12.010

doi:10.1056/NEJMra1615439

lang=en

[2] Zubair, M., Malik, A., Meerza, D., & Ahmad, J. (2013). 25-Hydroxyvitamin D [25(OH)D] levels and diabetic foot ulcer: Is there any relationship? Diabetes & Metabolic Syndrome*, 7*(3), 148-153.

[3] Yammine, K., Hayek, F., & Assi, C. (2020). Is there an association between vitamin D and diabetic foot disease? A meta-analysis. The International Journal of Tissue Repair and Regeneration*, 28*(1), 90-96. 10.1111/wrr.12762

[4] Zhang, P., Lu, J., Jing, Y., Tang, S., Zhu, D., & Bi, Y. (2017). Global epidemiology of diabetic foot ulceration: A systematic review and meta-analysis. Annals of Medicine, *49*(2), 106-116. doi:10.1080/07853890.2

[5] Frykberg, R. G., Wittmayer, B., & Zgonis, T. (2007). Surgical management

of diabetic foot infections and osteomyelitis. Clinics in Podiatric Medicine and Surgery, *24*(3), 469-482.

doi:10.1016/j.cpm.2007.04.001

and meta-analysis. Diabetes/ Metabolism Research and Reviews, *35*(6), e3160. doi: 10.1002/dmrr.3160

[7] Hicks, C. W., Selvarajah, S., Mathioudakis, N., Perler, B. A., Freischlag, J. A., Black 3rd, J. H., & Abularrage, C. J. (2014). Trends and determinants of costs associated with the inpatient care of diabetic foot ulcers. Journal of Vascular Surgery*,*

*60*(5), 1247-1254. 10.1016/j.

jvs.2014.05.009

[6] Fu, X. L., Ding, H., Miao, W. W., Mao, C. X., Zhan, M. Q., & Chen, H. L. (2019). Global recurrence rates in diabetic foot ulcers: A systematic review

doi:10.1016/j.dsx.2013.06.008

*Vitamin D and Diabetic Foot DOI: http://dx.doi.org/10.5772/intechopen.97115*

#### **References**

*Vitamin D*

**136**

**Author details**

Antony Macido

Los Angeles, California, USA

Keck Medical Center of USC, University of Southern California,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

DM and DFU do not comment on the recommendations on vitamin D use in the prevention and treatment of DFU. Literature does not support the routine use of vitamin D in the treatment and prevention of diabetic foot infections. The literature available on the different types of DM and the role of vitamin D in the development of DFU is scarce. Further research is needed to confirm the relationship between DFU and vitamin D including the use of vitamin D in the management of DFU and diabetic foot infections. Provided the beneficial effects on wound healing, identification and treatment of vitamin D deficiency could improve or prevent diabetic foot complication outcomes [3]. Despite the lack of strong evidence to recommending vitamin D in DM and DFU, routine vitamin D supplements in patients with DM

and DFU should be considered for its other benefits.

\*Address all correspondence to: amacido@gmail.com

provided the original work is properly cited.

[1] Leone, S., Pascale, R., & Esposito, S. (2012). Epidemiology of diabetic foot. Infezioni in Medicina*, 20*(Suppl. 1), 8-13.

[2] Zubair, M., Malik, A., Meerza, D., & Ahmad, J. (2013). 25-Hydroxyvitamin D [25(OH)D] levels and diabetic foot ulcer: Is there any relationship? Diabetes & Metabolic Syndrome*, 7*(3), 148-153. doi:10.1016/j.dsx.2013.06.008

[3] Yammine, K., Hayek, F., & Assi, C. (2020). Is there an association between vitamin D and diabetic foot disease? A meta-analysis. The International Journal of Tissue Repair and Regeneration*, 28*(1), 90-96. 10.1111/wrr.12762

[4] Zhang, P., Lu, J., Jing, Y., Tang, S., Zhu, D., & Bi, Y. (2017). Global epidemiology of diabetic foot ulceration: A systematic review and meta-analysis. Annals of Medicine, *49*(2), 106-116. doi:10.1080/07853890.2 016.1231932

[5] Frykberg, R. G., Wittmayer, B., & Zgonis, T. (2007). Surgical management of diabetic foot infections and osteomyelitis. Clinics in Podiatric Medicine and Surgery, *24*(3), 469-482. doi:10.1016/j.cpm.2007.04.001

[6] Fu, X. L., Ding, H., Miao, W. W., Mao, C. X., Zhan, M. Q., & Chen, H. L. (2019). Global recurrence rates in diabetic foot ulcers: A systematic review and meta-analysis. Diabetes/ Metabolism Research and Reviews, *35*(6), e3160. doi: 10.1002/dmrr.3160

[7] Hicks, C. W., Selvarajah, S., Mathioudakis, N., Perler, B. A., Freischlag, J. A., Black 3rd, J. H., & Abularrage, C. J. (2014). Trends and determinants of costs associated with the inpatient care of diabetic foot ulcers. Journal of Vascular Surgery*, 60*(5), 1247-1254. 10.1016/j. jvs.2014.05.009

[8] Khatib, O., & Tabatabaei-Malazy, O. (2007). Prevention and public approach to diabetic foot. Iranian Journal of Diabetes and Metabolism*, 7*(2), 123-133. Retrieved from http://ijdld.tums.ac.ir/ browse.php?a\_id=276&sid=1&slc\_ lang=en

[9] Armstrong, D. G., Boulton, A. M., & Bus, S. A. (2017). Diabetic foot ulcers and their recurrence. New England Journal of Medicine, *376*(24), 2367-2375. doi:10.1056/NEJMra1615439

[10] McGuire, J., & Sheltzer, A. (2019). A Clinical Approach to Nutrition and Wound Healing: A patient's diet matters. Podiatry Management, *38*(9), 87-94.

[11] Rosen, C. J., Adams, J. S., Bikle, D. D., Black, D. M., Demay, M. B., Manson, J. E., Kovacs, C. S. (2012) The nonskeletal effects of vitamin D: An Endocrine Society scientific statement. Endocrine Reviews, 33(3): 456-492. doi:10.1210/er.2012-1000

[12] Vanchinathan, V. & Lim, H. W. (2012). A dermatologist's perspective on vitamin D. Mayo Clinic Proceedings*, 87*(4), 372-380. doi:10.1016/j. mayocp.2011.12.010

[13] Bikle, D., Chang, S., Crumrine, D., Elalieh, H., Man, M., Choi, E., Elias, P. (2004) 25 Hydroxyvitamin D 1 α-hydroxylase is required for optimal epidermal differentiation and permeability barrier homeostasis. Journal of Investigative Dermatology*,* 122(4): 984-992. doi:10.1111/j. 0022-202X.2004.22424.x

[14] Oda, Y., Hu, L., Nguyen, T., Fong, C., Zhang, J., Guo, P., & Bikle, D. D. (2018). Vitamin D receptor is required for proliferation, migration, and differentiation of epidermal stem cells and progeny during cutaneous wound repair. Journal of Investigative Dermatology*, 138*(11), 2423-2431. doi: 10.1016/j.jid.2018.04.033

[15] van Netten, J. J., Bus, S. A., Apelqvist, J., Lipsky, B. A., Hinchliffe, R. J., Game, F., Rayman, G., Lazzarini, P. A., Forsythe, R. A., Peters, E. J. G., Senneville, E., Vas, P., Monteiro-Soares, M., & Schaper, N. C. (2020). Definitions and criteria for diabetic foot disease. Diabetes/Metabolism Research and Reviews*, 36*(S1), 1-6. doi: 10.1002/ dmrr.3268

[16] Örneholm, H., Apelqvist, J., Larsson, J., & Eneroth, M. (2017). Recurrent and other new foot ulcers after healed plantar forefoot diabetic ulcer. Wound Repair & Regeneration, *25*(2), 309-315. doi:10.1111/wrr.12522

[17] Sinwar, P. D. (2015) The diabetic foot management: Recent advance. International Journal of Surgery*,* 15: 27-30. doi:10.1016/j.ijsu.2015.01.023

[18] Monteiro-Soares, M., Boyko, E., Ribeiro, J., Ribeiro, I., Dinis-Ribeiro, M. (2012) Predictive factors for diabetic foot ulceration: A systematic review. Diabetes/Metabolism Research & Reviews*,* 28(7): 574-600. doi:10.1002/ dmrr.2319

[19] Sytze Van Dam, P., Cotter, M. A., Bravenboer, B., Cameron, N. E. (2013). Pathogenesis of diabetic neuropathy: Focus on neurovascular mechanisms. European Journal of Pharmacology, 5: 180-186. doi: 10.1016/j. ejphar.2013.07.017

[20] He, R., Hu, Y., Zeng, H., Zhao, J., Zhao, J., Chai, Y., Lu, F., Liu, F., & Jia, W. (2017). Vitamin D deficiency increases the risk of peripheral neuropathy in Chinese patients with type 2 diabetes. *Diabetes/Metabolism Research & Reviews*, *33*(2), n/a. doi:10.1002/dmrr.2820

[21] Kota, S. K., Meher, L. K., Jammula, S., & Modi, K. D. (2013). Inflammatory markers in diabetic foot and impact of vitamin D deficiency. Endocrine

Abstracts*, 31*, 198. doi:10.1530/ endoabs.31.P198

[22] Tiwari, S., Pratyush, D. D., Gupta, B., Dwivedi, A., Chaudhary, S., Rayicherla, R. K., & ... Singh, S. K. (2013). Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection. British Journal of Nutrition, *109*(1), 99-102. doi:10.1017/ S0007114512000578

[23] Tiwari, S., Pratyush, D. D., Gupta, S. K., & Singh, S. K. (2014). Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection. The British Journal of Nutrition*, 112*(12), 1938-1943. doi:10.1017/ S0007114514003018

[24] Gonzalez-Curiel, I., Trujillo, V., Montoya-Rosales, A., Rincon, K., Rivas-Calderon, B., deHaro-Acosta, J., &... Rivas-Santiago, B. (2014). 1,25-dihydroxyvitamin D3 induces LL-37 and HBD-2 production in keratinocytes from diabetic foot ulcers promoting wound healing: An in vitro model. Plos One, *9*(10), e111355. doi:10.1371/journal.pone.0111355

[25] Zhang, Y., Wu, S., & Sun, J. (2013). Vitamin D, vitamin D receptor, and tissue barriers. *Tissue Barriers*, *1*(1), e 23118. doi:10.4161/tisb.23118

[26] Schauber, J., Dorschner, R. A., Coda, A. B., Büchau, A. S., Liu, P. T., Kiken, D., & ... Gallo, R. L. (2007). Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. The Journal of Clinical Investigation, *117*(3), 803-811. doi:10.1172/JCI30142

[27] Iannuzzo, G., Forte, F., Lupoli, R., & Di Minno, M. (2018). Association of vitamin D deficiency with peripheral arterial disease: A meta-analysis of literature studies. The Journal of

**139**

*Vitamin D and Diabetic Foot*

jc.2018-00136

*DOI: http://dx.doi.org/10.5772/intechopen.97115*

Clinical Endocrinology & Metabolism*,*

[28] Dai, J., Jiang, C., Che, H., & Chai, Y. (2019). Vitamin D and diabetic foot ulcer: A systematic review and metaanalysis. Nutrition and Diabetes*, 9*(1), 8. doi:10.1038/s41387-019-0078-9

[29] Razzaghi, R., Pourbagheri, H., Momen-Heravi, M., Bahmani, F., Shadi, J., Soleimani, Z., & Asemi, Z. (2017).

supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial.

[30] Afarideh, M., Ghanbari, P., Noshad, S., Ghajar, A., Nakhjavani, M., & Esteghamati, A. (2016). Raised serum 25-hydroxyvitamin D levels in patients with active diabetic foot ulcers. The British Journal of Nutrition*, 115*(11),

The effects of vitamin D

Journal of Diabetes and its Complications*, 31*(4), 766-772. doi:10.1016/j.jdiacomp.2016.06.017

1938-1946. doi:10.1017/ S0007114516001094

[31] Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., Gordon, C. M., Hanley, D. A., Heaney, R. P., & ... Weaver, C. M. (2011). Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. The Journal

of Clinical Endocrinology and Metabolism, *96*(7), 1911-1930. doi:10.1210/jc.2011-0385

*103*(6), 2107-2115. doi:10.1210/

*Vitamin D and Diabetic Foot DOI: http://dx.doi.org/10.5772/intechopen.97115*

*Vitamin D*

dmrr.3268

dmrr.2319

[15] van Netten, J. J., Bus, S. A.,

M., & Schaper, N. C. (2020).

[16] Örneholm, H., Apelqvist, J., Larsson, J., & Eneroth, M. (2017). Recurrent and other new foot ulcers after healed plantar forefoot diabetic ulcer. Wound Repair & Regeneration, *25*(2), 309-315. doi:10.1111/wrr.12522

[17] Sinwar, P. D. (2015) The diabetic foot management: Recent advance. International Journal of Surgery*,* 15: 27-30. doi:10.1016/j.ijsu.2015.01.023

[18] Monteiro-Soares, M., Boyko, E., Ribeiro, J., Ribeiro, I., Dinis-Ribeiro, M. (2012) Predictive factors for diabetic foot ulceration: A systematic review. Diabetes/Metabolism Research & Reviews*,* 28(7): 574-600. doi:10.1002/

[19] Sytze Van Dam, P., Cotter, M. A., Bravenboer, B., Cameron, N. E. (2013). Pathogenesis of diabetic neuropathy: Focus on neurovascular mechanisms. European Journal of Pharmacology, 5:

[20] He, R., Hu, Y., Zeng, H., Zhao, J., Zhao, J., Chai, Y., Lu, F., Liu, F., & Jia, W. (2017). Vitamin D deficiency increases the risk of peripheral neuropathy in Chinese patients with type 2 diabetes. *Diabetes/Metabolism Research & Reviews*, *33*(2), n/a.

[21] Kota, S. K., Meher, L. K., Jammula, S., & Modi, K. D. (2013). Inflammatory markers in diabetic foot and impact of vitamin D deficiency. Endocrine

180-186. doi: 10.1016/j. ejphar.2013.07.017

doi:10.1002/dmrr.2820

Apelqvist, J., Lipsky, B. A., Hinchliffe, R. J., Game, F., Rayman, G., Lazzarini, P. A., Forsythe, R. A., Peters, E. J. G., Senneville, E., Vas, P., Monteiro-Soares, Abstracts*, 31*, 198. doi:10.1530/

[22] Tiwari, S., Pratyush, D. D., Gupta, B., Dwivedi, A., Chaudhary, S., Rayicherla, R. K., & ... Singh, S. K. (2013). Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection. British Journal of Nutrition, *109*(1), 99-102. doi:10.1017/

[23] Tiwari, S., Pratyush, D. D., Gupta, S. K., & Singh, S. K. (2014). Vitamin D

inflammatory cytokine concentrations in patients with diabetic foot infection. The British Journal of Nutrition*, 112*(12), 1938-1943. doi:10.1017/

[24] Gonzalez-Curiel, I., Trujillo, V., Montoya-Rosales, A., Rincon, K., Rivas-Calderon, B., deHaro-Acosta, J.,

[25] Zhang, Y., Wu, S., & Sun, J. (2013). Vitamin D, vitamin D receptor, and tissue barriers. *Tissue Barriers*, *1*(1), e

23118. doi:10.4161/tisb.23118

doi:10.1172/JCI30142

[26] Schauber, J., Dorschner, R. A., Coda, A. B., Büchau, A. S., Liu, P. T., Kiken, D., & ... Gallo, R. L. (2007). Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. The Journal of Clinical Investigation, *117*(3), 803-811.

[27] Iannuzzo, G., Forte, F., Lupoli, R., & Di Minno, M. (2018). Association of vitamin D deficiency with peripheral arterial disease: A meta-analysis of literature studies. The Journal of

&... Rivas-Santiago, B. (2014). 1,25-dihydroxyvitamin D3 induces LL-37 and HBD-2 production in keratinocytes from diabetic foot ulcers promoting wound healing: An in vitro model. Plos One, *9*(10), e111355. doi:10.1371/journal.pone.0111355

deficiency is associated with

endoabs.31.P198

S0007114512000578

S0007114514003018

Definitions and criteria for diabetic foot disease. Diabetes/Metabolism Research and Reviews*, 36*(S1), 1-6. doi: 10.1002/

**138**

Clinical Endocrinology & Metabolism*, 103*(6), 2107-2115. doi:10.1210/ jc.2018-00136

[28] Dai, J., Jiang, C., Che, H., & Chai, Y. (2019). Vitamin D and diabetic foot ulcer: A systematic review and metaanalysis. Nutrition and Diabetes*, 9*(1), 8. doi:10.1038/s41387-019-0078-9

[29] Razzaghi, R., Pourbagheri, H., Momen-Heravi, M., Bahmani, F., Shadi, J., Soleimani, Z., & Asemi, Z. (2017). The effects of vitamin D supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial. Journal of Diabetes and its Complications*, 31*(4), 766-772. doi:10.1016/j.jdiacomp.2016.06.017

[30] Afarideh, M., Ghanbari, P., Noshad, S., Ghajar, A., Nakhjavani, M., & Esteghamati, A. (2016). Raised serum 25-hydroxyvitamin D levels in patients with active diabetic foot ulcers. The British Journal of Nutrition*, 115*(11), 1938-1946. doi:10.1017/ S0007114516001094

[31] Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., Gordon, C. M., Hanley, D. A., Heaney, R. P., & ... Weaver, C. M. (2011). Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism, *96*(7), 1911-1930. doi:10.1210/jc.2011-0385

**141**

**Chapter 10**

**Abstract**

well-founded.

**1. Introduction**

Parkinson's disease, Alzheimer's disease

billion neurons at its disposal.

The Role of Vitamin D in

Central Nervous System

*Carl Nikolaus Homann*

Neurodegeneration and Other

The nervous system is the most complex organ in the human body, and it is the most essential. However nerve cells are particularly precious as, only like muscle cells, once formed, they do not replicate. This means that neural injuries cannot easily be replaced or repaired. Vitamin D seems to play a pivotal role in protecting these vulnerable and most important structures, but exactly how and to what extend is still subject to debate. Systematically reviewing the vast body of research on the influence of Vitamin D in various neuropathological processes, we found that Vitamin D particularly plays a mitigating role in the development of chronic neurodegeneration and the measured response to acutely acquired traumatic and non-traumatic nerve cells incidents. Adequate serum levels of Vitamin D before the initiation of these processes is increasingly viewed as being neuroprotective. However, comprehensive data on using it as a treatment during the ongoing process or after the injury to neurons is completed are much more ambiguous. A recommendation for testing and supplementation of insufficiencies seems to be

**Keywords:** Vitamin D, nervous system, neurodegeneration, nerve cell damage, traumatic brain injury, acquired brain injury, metabolic encephalopathy, toxic encephalopathy, meningitis, stroke, autoimmune processes, neurooncoloy,

The nervous system is the most complex organ in the human body. The brain, as the nervous system's command center, is fundamental to the human experience as it produces our every thought, action, memory, and feeling. In short, it is our apparatus to take in and react to phenomena of the inner and outside world. For this task, the brain has a highly interconnected network of approximately one hundred

These cells, however, are particularly vulnerable. Compared to other cells, neurons have markedly higher energy demands. Also, as they neither have a backup energy source nor adequate energy stores, they depend on a continuous supply of

Pathological Processes of the

#### **Chapter 10**

## The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central Nervous System

*Carl Nikolaus Homann*

#### **Abstract**

The nervous system is the most complex organ in the human body, and it is the most essential. However nerve cells are particularly precious as, only like muscle cells, once formed, they do not replicate. This means that neural injuries cannot easily be replaced or repaired. Vitamin D seems to play a pivotal role in protecting these vulnerable and most important structures, but exactly how and to what extend is still subject to debate. Systematically reviewing the vast body of research on the influence of Vitamin D in various neuropathological processes, we found that Vitamin D particularly plays a mitigating role in the development of chronic neurodegeneration and the measured response to acutely acquired traumatic and non-traumatic nerve cells incidents. Adequate serum levels of Vitamin D before the initiation of these processes is increasingly viewed as being neuroprotective. However, comprehensive data on using it as a treatment during the ongoing process or after the injury to neurons is completed are much more ambiguous. A recommendation for testing and supplementation of insufficiencies seems to be well-founded.

**Keywords:** Vitamin D, nervous system, neurodegeneration, nerve cell damage, traumatic brain injury, acquired brain injury, metabolic encephalopathy, toxic encephalopathy, meningitis, stroke, autoimmune processes, neurooncoloy, Parkinson's disease, Alzheimer's disease

#### **1. Introduction**

The nervous system is the most complex organ in the human body. The brain, as the nervous system's command center, is fundamental to the human experience as it produces our every thought, action, memory, and feeling. In short, it is our apparatus to take in and react to phenomena of the inner and outside world. For this task, the brain has a highly interconnected network of approximately one hundred billion neurons at its disposal.

These cells, however, are particularly vulnerable. Compared to other cells, neurons have markedly higher energy demands. Also, as they neither have a backup energy source nor adequate energy stores, they depend on a continuous supply of

glucose and oxygen by the blood. Any misalignment between demand and supply potentially contributes to permanent damage or cell death. Damage to brain cells can occur through events even before birth, as in congenital disorders caused by genetic abnormalities or perinatal exposure to noxious conditions. Causative conditions after birth can be divided into acquired, traumatic or non-traumatic, and neurodegenerative. Traumatic injuries commonly arise from exposure to external mechanical forces, as in traffic accidents, falls, and assaults [1]. Non-traumatic injuries derive from either an internal or external source and can be classified according to etiology into neurovascular, neoplastic, metabolic, neurotoxic, infectious, or autoimmune inflammatory (**Figure 1**). Only a few epidemiological studies provide proportional figures regarding traumatic and non-traumatic brain injuries. In one population-based survey on annual incidences of acquired brain injuries in Massachusetts [2], the outpatient diagnosis was most frequently related to traumatic causes (97%). Of the 3% of non-traumatic etiologies 39% were infections, in 25% metabolic or toxic conditions, 22% neoplastic, and 14% vascular brain diseases. The most severe cases were admitted to ICU, for which the authors calculated a ratio of 19% traumatic and 81% non-traumatic causes. The latter were predominantly of vascular origin (63%), followed by toxic-metabolic (30%) and infectious conditions (7%).

Whereas traumatic assaults primarily cause tearing and breaking of cells and structural tissue injuries, non-traumatic incidents tend to affect the metabolic functioning on a subcellular basis that either acutely or chronically lead to malfunction and cell destruction.

Neurons are also especially precious as, only like muscle cells, once formed, they do not replicate. This means that abnormalities in the development or injuries later in life cannot easily be replaced or repaired. Vitamin D (VD) appears to play a critical role in safeguarding these delicate and vital structures. VD deficiency affects a broad range of adult brain disorders with various etiologies and causative pathomechanisms, according to emerging evidence [3, 4], but it is also essential for neuronal growth and pruning in neonates and children [5].

This review examines, for each of the primary injury categories (**Figure 1**), the evidence for VD's role in the resilience to neuronal damage. It mainly focuses on

**143**

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central…*

the importance of maintaining adequate VD blood levels before the initiation of these processes, the use of VD as treatment during the ongoing process, and as a remedy after the injury to neurons has been completed. For conciseness, it explicitly

Traumatic brain injury (TBI) may have a wide range of mental and physical consequences. Depending on the gravity, type, and location of impact, symptoms can vary in severity and duration from mild intermittent attention deficits to coma, from discrete transient headaches to permanent and complete incapacity

Traumatic brain injury (TBI) occurs at an incidence rate of 235–556/10 million [6, 7]. Thus, it is one of the most common neurological diseases, and it is also one of the leading causes of morbidity and death among civilians and military personnel worldwide [1]. The mortality rate in severe TBI cases can be as high as 40%. Survivors, on the other hand, have a disability rate of 55–77% [1, 8, 9], resulting in a

TBI is generally divided into two stages: primary and secondary injury. These two stages overlap to some extent [11]. Primary brain injury occurs at the moment of the initial trauma when mechanical forces cause acute and permanent damage to the brain parenchyma. The subsequent secondary brain injury usually starts quickly but may progress slowly over months or years [11]. It is, to a large extend, caused by microparticles released from damaged tissues that trigger hemostatic, ischemic, and inflammatory processes. This eventually leads to lasting secondary biochemical and cellular alterations. Depolarization, excitotoxicity, disruption of calcium homeostasis, free-radical generation, blood–brain barrier disruption, ischemic injury, edema formation, and intracranial hypertension are some of the most frequently cited mechanisms at play [12]. It is widely believed that treatments that can mitigate this cascade of events can considerably improve TBI

VD is thought to have a positive effect on this mechanism at various stages, and inadequate levels are linked to more insufficient recovery. In a comprehensive review, Colon evaluated the current literature regarding the protective properties of VD and its clinical relevance after traumatic brain injury, particularly for military personnel [13]. The included in vivo and in vitro studies support that VD modulates the immune responses to trauma, diminishes oxidative and toxic damage, and

Several observational studies suggested VD deficiency is common in patients after TBI (34–46·5%) [14, 15] and is associated with psychiatric deterioration (cognition, depression) [14] and possibly an unfavorable disease outcome [15]. However, the correlation between VD deficiency and worsening of psychiatric disorders may be an epiphenomenon since they are known to be related to VD

There is no human research examining VD given prophylactically before TBI. Animal data suggests, however, that this strategy might be protective. Itho et al. observed that seven days of oral supplementation decreased the chances of neuronal damage after TBI in rodents [16]. Another animal study, performed by Wei et al., shows similar results, which are thought to be due to reducing the free radical

concentrates on adult diseases and excludes congenital disorders.

decrease in quality of life and high socioeconomic costs [10].

inhibits activation and progression of neuroinflammation.

damage and preventing apoptosis in damaged neurons [17].

deficiency independently of comorbid TBI [4].

**2. Role of Vitamin D in specific neurolopathological processes**

*DOI: http://dx.doi.org/10.5772/intechopen.98390*

**2.1 Vitamin D and traumatic neuronal injury**

or death.

outcomes [11, 12].

**Figure 1.** *Classification of brain injuries in adult life.*

the importance of maintaining adequate VD blood levels before the initiation of these processes, the use of VD as treatment during the ongoing process, and as a remedy after the injury to neurons has been completed. For conciseness, it explicitly concentrates on adult diseases and excludes congenital disorders.

### **2. Role of Vitamin D in specific neurolopathological processes**

#### **2.1 Vitamin D and traumatic neuronal injury**

*Vitamin D*

infectious conditions (7%).

tion and cell destruction.

glucose and oxygen by the blood. Any misalignment between demand and supply potentially contributes to permanent damage or cell death. Damage to brain cells can occur through events even before birth, as in congenital disorders caused by genetic abnormalities or perinatal exposure to noxious conditions. Causative conditions after birth can be divided into acquired, traumatic or non-traumatic, and neurodegenerative. Traumatic injuries commonly arise from exposure to external mechanical forces, as in traffic accidents, falls, and assaults [1]. Non-traumatic injuries derive from either an internal or external source and can be classified according to etiology into neurovascular, neoplastic, metabolic, neurotoxic, infectious, or autoimmune inflammatory (**Figure 1**). Only a few epidemiological studies provide proportional figures regarding traumatic and non-traumatic brain injuries. In one population-based survey on annual incidences of acquired brain injuries in Massachusetts [2], the outpatient diagnosis was most frequently related to traumatic causes (97%). Of the 3% of non-traumatic etiologies 39% were infections, in 25% metabolic or toxic conditions, 22% neoplastic, and 14% vascular brain diseases. The most severe cases were admitted to ICU, for which the authors calculated a ratio of 19% traumatic and 81% non-traumatic causes. The latter were predominantly of vascular origin (63%), followed by toxic-metabolic (30%) and

Whereas traumatic assaults primarily cause tearing and breaking of cells and structural tissue injuries, non-traumatic incidents tend to affect the metabolic functioning on a subcellular basis that either acutely or chronically lead to malfunc-

Neurons are also especially precious as, only like muscle cells, once formed, they do not replicate. This means that abnormalities in the development or injuries later in life cannot easily be replaced or repaired. Vitamin D (VD) appears to play a critical role in safeguarding these delicate and vital structures. VD deficiency affects a broad range of adult brain disorders with various etiologies and causative pathomechanisms, according to emerging evidence [3, 4], but it is also essential for

This review examines, for each of the primary injury categories (**Figure 1**), the evidence for VD's role in the resilience to neuronal damage. It mainly focuses on

neuronal growth and pruning in neonates and children [5].

**142**

**Figure 1.**

*Classification of brain injuries in adult life.*

Traumatic brain injury (TBI) may have a wide range of mental and physical consequences. Depending on the gravity, type, and location of impact, symptoms can vary in severity and duration from mild intermittent attention deficits to coma, from discrete transient headaches to permanent and complete incapacity or death.

Traumatic brain injury (TBI) occurs at an incidence rate of 235–556/10 million [6, 7]. Thus, it is one of the most common neurological diseases, and it is also one of the leading causes of morbidity and death among civilians and military personnel worldwide [1]. The mortality rate in severe TBI cases can be as high as 40%. Survivors, on the other hand, have a disability rate of 55–77% [1, 8, 9], resulting in a decrease in quality of life and high socioeconomic costs [10].

TBI is generally divided into two stages: primary and secondary injury. These two stages overlap to some extent [11]. Primary brain injury occurs at the moment of the initial trauma when mechanical forces cause acute and permanent damage to the brain parenchyma. The subsequent secondary brain injury usually starts quickly but may progress slowly over months or years [11]. It is, to a large extend, caused by microparticles released from damaged tissues that trigger hemostatic, ischemic, and inflammatory processes. This eventually leads to lasting secondary biochemical and cellular alterations. Depolarization, excitotoxicity, disruption of calcium homeostasis, free-radical generation, blood–brain barrier disruption, ischemic injury, edema formation, and intracranial hypertension are some of the most frequently cited mechanisms at play [12]. It is widely believed that treatments that can mitigate this cascade of events can considerably improve TBI outcomes [11, 12].

VD is thought to have a positive effect on this mechanism at various stages, and inadequate levels are linked to more insufficient recovery. In a comprehensive review, Colon evaluated the current literature regarding the protective properties of VD and its clinical relevance after traumatic brain injury, particularly for military personnel [13]. The included in vivo and in vitro studies support that VD modulates the immune responses to trauma, diminishes oxidative and toxic damage, and inhibits activation and progression of neuroinflammation.

Several observational studies suggested VD deficiency is common in patients after TBI (34–46·5%) [14, 15] and is associated with psychiatric deterioration (cognition, depression) [14] and possibly an unfavorable disease outcome [15]. However, the correlation between VD deficiency and worsening of psychiatric disorders may be an epiphenomenon since they are known to be related to VD deficiency independently of comorbid TBI [4].

There is no human research examining VD given prophylactically before TBI. Animal data suggests, however, that this strategy might be protective. Itho et al. observed that seven days of oral supplementation decreased the chances of neuronal damage after TBI in rodents [16]. Another animal study, performed by Wei et al., shows similar results, which are thought to be due to reducing the free radical damage and preventing apoptosis in damaged neurons [17].

For post-injury interventions, there are also experimental data. They suggest that VD treatment decreases brain edema, attenuates free radical damage, reduces neuronal loss in TBI animal models, reduces the inflammatory cytokines TNFα, IL-6, and nitric oxide (NO), and attenuates neurological abnormalities after ischemia [18–20].

There are also a few human TBI trials. Lee et al. investigated in an open study the acute and long-term effects of VD supplementation on the recovery of patients with TBI [21]. When administering 100,000 IU cholecalciferol intramuscularly to 244 patients with deficiency (VD < 30 ng/mL) they found that 3 months outcomes assessing performance function (Extended Glasgow Outcome Scale: p = 0.002) and cognitive function (Mini Mental Status Examination; p = 0.042, and Clinical Dementia Rating; p = 0.044) were better than those of 64 non-deficient control patients. The initial low VD status measured when patients arrived at the hospital, however, was not found to be a risk factor for mortality. In a randomized placebocontrolled investigation by Sharma et al., 20 patients with moderate to severe TBI received 120,000 IU of VD orally [22]. They had a better overall clinical result than 15 placebo-treated patients, but no improvement in mortality rates (14.3% vs. 14.3%; p = 0.79). The better outcome was depicted by an increase in the level of consciousness from day 2 to day 7 (GCS scores: −3.86 vs. +0.19 points; p 0.0001), a shorter mechanical ventilation time (4.7 vs. 8.2 days, p = 0.0001), and a shorter ICU stay (6.19 vs. 9.07 days, p = 0.003). In addition, relative to the control group, there was a small rise in anti-inflammatory IFN- levels (p = 0.65) and a significant reduction in cytokines, which are key pro-inflammatory biomarkers for brain damage (IL-6: p = 0.08, TNF-: p = 0.02, IL-2: p = 0.36).

Despite promising experimental results, we are unaware of any clinical studies on primary (pre-trauma) or secondary (post-trauma) prophylaxis.

#### **2.2 Vitamin D and neurovascular incidents**

Stroke is the leading cause of disability and the second most common cause of death in the world, causing more than 10% or 5.7 million deaths per year [23]. Although relative stroke mortality has declined in the last decades, stroke prevalence is increasing due to the demographic shift towards a higher life expectancy [23, 24].

Brain tissue injury following stroke results from a complex series of pathophysiological events, including excitotoxicity, oxidative and nitrative stress, inflammation, and apoptosis [25]. VD is thought to have a beneficial impact on several of these factors. In a recently published comprehensive review Yarlagadda et al., based on experimental data, suggest several neuroprotective mechanisms of VD concerning vascular health: First, it can increase the expression of insulin-like growth factor 1 (IGF-1). IGF-1 can mitigate axon and dendrite degeneration, and by activating plasminogen, it also has antithrombotic effects [26]. Second, VD affects the vascular system by inducing vasodilation through nitric oxide synthase potentiation (NOS). As a result, it has the ability to decrease blood pressure, increase blood supply to neurons after an ischemic stroke, and relieve cerebral vasospasm after a subarachnoid hemorrhage. Third, VD stimulates the synthesis of stromal cell-derived factor 1α (SDF1α), vascular endothelial growth factor (VEGF), and endothelial NOS, thereby displaying an anti-inflammatory effect on myeloid and endothelial cells. Finally, VD protects cerebral endothelial cells from post-stroke blood–brain barrier (BBB) dysfunction. Relevant factors for this are its antioxidant properties, which include inhibiting the development of reactive oxygen species (ROS) production, and its ability to prevent tight junction proteins (occludin and claudin-5) expression from decreasing.

**145**

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central…*

It is widely accepted that low plasma concentrations of VD are associated with an increased risk of symptomatic ischemic stroke in the general population. In a large population-based prospective study, Brøndum-Jacobsen et al. observed in 10,170 individuals from the general population a stepwise increasing risk of symptomatic ischemic stroke with decreasing plasma VD concentrations [27]. This finding was substantiated in a meta-analysis on prospective general population studies, including ten studies, 58,384 participants, and 2,644 events [27]. The odds ratio of ischemic stroke was 1.54 (1.43–1.65) when comparing the lowest versus

Low serum VD levels are also thought to be significantly associated with poor prognosis in stroke patients. This has been confirmed by a recent meta-analysis by Liu et al. including ten studies and 6845 stroke patients indicating an increased risk of poor functional outcome (RR = 1.86; 95% CI = 1.16–2.98), all-cause mortality (RR = 3.56; 95% CI = 1.54–8.25), and recurrence of stroke (RR 5.49; 95% CI

While there is a significant body of randomized controlled trials examining vascular changes from VD treatment, there are only two on stroke outcome. In a non-blinded randomized controlled trial on 66 VD-deficient and -insufficient stroke patients, Narasimhan et al. tested the effects of administering single doses of Cholecalciferol (600,000 IU i.m.). The three months improvements of functional outcomes were significantly more prominent in the treatment group than in the control group (Scandinavian Stroke Scale: 6.39 ± 4.56 vs. 2.5 ± 2.20 points, p < 0.001) [29]. The randomized controlled trial by Gupta et al. tested VD-calcium supplementation in 25 out of 53 VD-deficient stroke patients (<75 nmol/L). After six months, patients in the treatment arm had a decreased mortality risk (HR = 0.26) and attained a better functional outcome (modified Rankin Scale score) (OR = 1.90)

There are two recent studies to clarify the effects of oral VD supplementation on the outcomes in post-acute stroke patients in a rehabilitation setting. One randomized, double-blind placebo-controlled study by Sari et al. assessed if VD treatment (300,000 IU i.m.) affects the outcomes of rehabilitation and balance in 72 VD deficient hemiplegic stroke patients. By the end of the third month, activity levels (modified Barthel index scores) had significantly increased, and balance recovery (Berg balance scale) had accelerated in the supplementation group compared to the group of untreated patients [31]. Momosaki et al. conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in 100 patients admitted to a convalescent rehabilitation ward after having an acute stroke [32]. After eight weeks of oral VD supplementation (2,000 IU/day), there were no between-group differences in Barthel Index scores, in Barthel Index efficiency, handgrip strength, and calf circumference. Thus, based on their findings and in contrast to those of the previous study, they cannot report on a positive effect of VD on rehabilitation outcomes.

Glioblastoma multiforme (GBM) is the most commonly occurring malignant primary brain tumor, representing 77–81% of all primary CNS malignancies [33]. The annual incidence rate is 0.59 to 5 per 100,000 persons. GBM is a grade IV diffuse astrocytic and oligodendroglial tumor with a poor prognosis. Despite recently improved standard of care treatment involving surgery, chemo, and radiation therapy, median survival is 14.6 months. Reasons for GBM development are presumably multifactorial, but exact pathomechanisms are not well understood. The inactivation of apoptotic pathways seems to play an essential role in facilitating

*DOI: http://dx.doi.org/10.5772/intechopen.98390*

highest quartile of VD concentrations [27].

compared to those of the untreated group [30].

**2.3 Vitamin D and neurooncologic processes**

tumorigenesis and –progression [34].

2.69–11.23) [28].

#### *The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central… DOI: http://dx.doi.org/10.5772/intechopen.98390*

It is widely accepted that low plasma concentrations of VD are associated with an increased risk of symptomatic ischemic stroke in the general population. In a large population-based prospective study, Brøndum-Jacobsen et al. observed in 10,170 individuals from the general population a stepwise increasing risk of symptomatic ischemic stroke with decreasing plasma VD concentrations [27]. This finding was substantiated in a meta-analysis on prospective general population studies, including ten studies, 58,384 participants, and 2,644 events [27]. The odds ratio of ischemic stroke was 1.54 (1.43–1.65) when comparing the lowest versus highest quartile of VD concentrations [27].

Low serum VD levels are also thought to be significantly associated with poor prognosis in stroke patients. This has been confirmed by a recent meta-analysis by Liu et al. including ten studies and 6845 stroke patients indicating an increased risk of poor functional outcome (RR = 1.86; 95% CI = 1.16–2.98), all-cause mortality (RR = 3.56; 95% CI = 1.54–8.25), and recurrence of stroke (RR 5.49; 95% CI 2.69–11.23) [28].

While there is a significant body of randomized controlled trials examining vascular changes from VD treatment, there are only two on stroke outcome. In a non-blinded randomized controlled trial on 66 VD-deficient and -insufficient stroke patients, Narasimhan et al. tested the effects of administering single doses of Cholecalciferol (600,000 IU i.m.). The three months improvements of functional outcomes were significantly more prominent in the treatment group than in the control group (Scandinavian Stroke Scale: 6.39 ± 4.56 vs. 2.5 ± 2.20 points, p < 0.001) [29]. The randomized controlled trial by Gupta et al. tested VD-calcium supplementation in 25 out of 53 VD-deficient stroke patients (<75 nmol/L). After six months, patients in the treatment arm had a decreased mortality risk (HR = 0.26) and attained a better functional outcome (modified Rankin Scale score) (OR = 1.90) compared to those of the untreated group [30].

There are two recent studies to clarify the effects of oral VD supplementation on the outcomes in post-acute stroke patients in a rehabilitation setting. One randomized, double-blind placebo-controlled study by Sari et al. assessed if VD treatment (300,000 IU i.m.) affects the outcomes of rehabilitation and balance in 72 VD deficient hemiplegic stroke patients. By the end of the third month, activity levels (modified Barthel index scores) had significantly increased, and balance recovery (Berg balance scale) had accelerated in the supplementation group compared to the group of untreated patients [31]. Momosaki et al. conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in 100 patients admitted to a convalescent rehabilitation ward after having an acute stroke [32]. After eight weeks of oral VD supplementation (2,000 IU/day), there were no between-group differences in Barthel Index scores, in Barthel Index efficiency, handgrip strength, and calf circumference. Thus, based on their findings and in contrast to those of the previous study, they cannot report on a positive effect of VD on rehabilitation outcomes.

#### **2.3 Vitamin D and neurooncologic processes**

Glioblastoma multiforme (GBM) is the most commonly occurring malignant primary brain tumor, representing 77–81% of all primary CNS malignancies [33]. The annual incidence rate is 0.59 to 5 per 100,000 persons. GBM is a grade IV diffuse astrocytic and oligodendroglial tumor with a poor prognosis. Despite recently improved standard of care treatment involving surgery, chemo, and radiation therapy, median survival is 14.6 months. Reasons for GBM development are presumably multifactorial, but exact pathomechanisms are not well understood. The inactivation of apoptotic pathways seems to play an essential role in facilitating tumorigenesis and –progression [34].

*Vitamin D*

ischemia [18–20].

(IL-6: p = 0.08, TNF-: p = 0.02, IL-2: p = 0.36).

**2.2 Vitamin D and neurovascular incidents**

claudin-5) expression from decreasing.

For post-injury interventions, there are also experimental data. They suggest that VD treatment decreases brain edema, attenuates free radical damage, reduces neuronal loss in TBI animal models, reduces the inflammatory cytokines TNFα, IL-6, and nitric oxide (NO), and attenuates neurological abnormalities after

There are also a few human TBI trials. Lee et al. investigated in an open study the acute and long-term effects of VD supplementation on the recovery of patients with TBI [21]. When administering 100,000 IU cholecalciferol intramuscularly to 244 patients with deficiency (VD < 30 ng/mL) they found that 3 months outcomes assessing performance function (Extended Glasgow Outcome Scale: p = 0.002) and cognitive function (Mini Mental Status Examination; p = 0.042, and Clinical Dementia Rating; p = 0.044) were better than those of 64 non-deficient control patients. The initial low VD status measured when patients arrived at the hospital, however, was not found to be a risk factor for mortality. In a randomized placebocontrolled investigation by Sharma et al., 20 patients with moderate to severe TBI received 120,000 IU of VD orally [22]. They had a better overall clinical result than 15 placebo-treated patients, but no improvement in mortality rates (14.3% vs. 14.3%; p = 0.79). The better outcome was depicted by an increase in the level of consciousness from day 2 to day 7 (GCS scores: −3.86 vs. +0.19 points; p 0.0001), a shorter mechanical ventilation time (4.7 vs. 8.2 days, p = 0.0001), and a shorter ICU stay (6.19 vs. 9.07 days, p = 0.003). In addition, relative to the control group, there was a small rise in anti-inflammatory IFN- levels (p = 0.65) and a significant reduction in cytokines, which are key pro-inflammatory biomarkers for brain damage

Despite promising experimental results, we are unaware of any clinical studies

Stroke is the leading cause of disability and the second most common cause of death in the world, causing more than 10% or 5.7 million deaths per year [23]. Although relative stroke mortality has declined in the last decades, stroke prevalence is increasing due to the demographic shift towards a higher life expectancy

Brain tissue injury following stroke results from a complex series of pathophysiological events, including excitotoxicity, oxidative and nitrative stress, inflammation, and apoptosis [25]. VD is thought to have a beneficial impact on several of these factors. In a recently published comprehensive review Yarlagadda et al., based on experimental data, suggest several neuroprotective mechanisms of VD concerning vascular health: First, it can increase the expression of insulin-like growth factor 1 (IGF-1). IGF-1 can mitigate axon and dendrite degeneration, and by activating plasminogen, it also has antithrombotic effects [26]. Second, VD affects the vascular system by inducing vasodilation through nitric oxide synthase potentiation (NOS). As a result, it has the ability to decrease blood pressure, increase blood supply to neurons after an ischemic stroke, and relieve cerebral vasospasm after a subarachnoid hemorrhage. Third, VD stimulates the synthesis of stromal cell-derived factor 1α (SDF1α), vascular endothelial growth factor (VEGF), and endothelial NOS, thereby displaying an anti-inflammatory effect on myeloid and endothelial cells. Finally, VD protects cerebral endothelial cells from post-stroke blood–brain barrier (BBB) dysfunction. Relevant factors for this are its antioxidant properties, which include inhibiting the development of reactive oxygen species (ROS) production, and its ability to prevent tight junction proteins (occludin and

on primary (pre-trauma) or secondary (post-trauma) prophylaxis.

**144**

[23, 24].

One of the risk factors to develop GBM is birth in the winter months, suggesting a VD association that goes back decades before disease onset [35]. Also, expression of Vitamin D Receptor (VDR) is associated with a good prognosis in GBM [36]. Zigmont et al. reported an inverse association between VD consumption and GBM risk among men aged 56 years and older. Levels of VD in men >56 were inversely related to the occurrence of high-grade glioma (p = 0.04), i.e., older men with high levels (>66 nmol/L) showing a reduced propensity. This association even existed in samples drawn premorbid i.e. from ≥2 yr. (OR = 0.59; 95% CI = 0.38, 0.91) to ≥15 yr. before diagnosis (OR = 0.61; 95% CI = 0.38,0.96) [37]. This temporal sequence is another piece of evidence for a causative relation.

Mulpur et al. explain possible mechanisms of VD as treatment option: [38]. First, There is direct cancer control by influencing the signaling of macrophages and dendritic cells of the immune system and activating the tumor suppressor p53. It is well known, for example, that in other malignancies like breast cancer, VD down-regulates Akt and MDM2 leading to TGFβ-1-dependent growth inhibition [34]. In GBM, VD can inhibit the hedgehog signaling pathway and disable brain tumor stem cells (BTSCs). Due to their importance in tumor formation, recurrence, and metastasis, BTSCs are considered to be the tumor's driving force. Then, adequate VD availability also has secondary benefits. The immune system's role is bolstered, which indirectly inhibits tumor cell growth. By reducing some of the unintended side effects of standard therapy, sufficient doses can be given, and treatment adherence can be improved [38].

There is but one published prospective open label study in humans that investigated in 470 newly diagnosed GBM-patients VD self-use, among other alternative medications. The sixty patients taking VD as an individual supplement had reduced mortality when compared with non-users (age-adjusted HR = 0.68; p = 0.02) [38].

VD has not yet been studied in a controlled clinical trial as a prophylactic or treatment in late-stage GBM or other primary brain tumors, as far as I am aware.

#### **2.4 Vitamin D and infections**

Meningitis and encephalitis, the infectious diseases of the brain tissue and the covering membranes, are endowed with substantial rates of mortality and with long-term sequelae in survivors. The WHO estimates the global incident cases to be 2.82 million and the death rate to be 318,400. Globally in 2016, 1.48 million YLDs and 21.87 million DALYs were due to meningitis [39]. Incidence, mortality and disability rates vary significantly according to region and pathogen. Bacterial infection is a major cause of meningitis, globally outnumbering other classes of organisms such as viruses, fungi, or parasites [39].

The mechanism of infection-induced brain cell damage is elaborately explained by Chaudhry, Hoffman and Weber [40]: They state that the cascade starts with pathogen invasion, which triggers activation of the immune system, including white blood cells, complement, and immunoglobulins. Immune cells and the damaged endothelial cells start to release cytokines, matrix metalloproteinases (MMPs), and nitric oxide (NO). While cytokines induce capillary wall changes in the blood– brain barrier, the MMPs, and NO, on the other hand, stimulate vasodilation that alters the cerebral blood flow. Cytokine release provokes the expression of more leukocyte receptors, which increases both white blood cell binding, i.e., adherence to capillary endothelium as well as extravasation. This then leads to further damage to the meninges and endothelial cells, thereby stimulating cytotoxic reactive oxygen species production and release of even more cytokines and chemokines. This coordinated assault aims to eliminate the invading pathogen, but it also harms and destroys nearby brain cells. Increased cytotoxic metabolite levels and permeability

**147**

Western Hemisphere [49].

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central…*

may further lead to cerebral edema and elevated intracerebral pressure. Those two factors, together with the altered blood flow, causes reduced perfusion pressure and

As Guevara et al. and Golpour et al. pointed out in their overviews, [41, 42]. VD exerts a wide range of effects on the very pathomechanisms implicated in brain infection. The targets of these actions can be both host cells by enhancing innate immunomodulatory activity as well as pathogen cells by displaying direct antibacterial and antimicrobial properties [41, 42]. The authors elucidate that VD, which is signaling through the VDR, stimulates innate immune cell functions, including phagocytosis, production of antimicrobial peptides (AMPs), and reactive oxygen species (ROS). It is also responsible for upregulation of the pattern recognition receptors (PRR) TLR2 and NOD2 and generation of TIMP-1, which downregulates matrix metalloproteinases (MMPs) [41]. Furthermore, VD inhibits the production of MMPs and proinflammatory cytokines. VD also deranges Th17 programming, which instead leads to the promotion of the regulatory T cell phenotype [41]. But, VD also directly impedes the growth, viability, and biofilm formation of various

Infections with Streptococci and Mycobacteria, both not infrequently causing meningitis, have been shown to be repressed in the presence of adequate VD levels. In an in vitro experiment on isolated human neutrophils, Subramanian et al. found that VD boosts neutrophil killing of *S. pneumoniae* while also lowering inflammatory responses and apoptosis [44]. Rode et al. found in their experiments with naive human CD4+ T cells that in the defense against *M. tuberculosis*, there is an increased expression of VDR and an upregulation of VD-1 hydroxylase genes. VD blocks *M. tuberculosis*-induced cathelicidin downregulation and enables Th1 differentiation and IFN secretion, both of which are protective. These processes promoted *M. tuberculosis* intracellular death in human macrophages and monocytes [45].

While there is plenty of studies on lung, gut, or generalized infections in the form of sepsis [46], there is hardly any data on infections of the CNS. Regarding the effect of VD deficiency and meningitis outcome in adults, there is but one study on tuberculous meningitis (TBM). Dangeti et al. examined prospectively 40 HIV patients with tuberculous meningitis and found that there was but a trend for lower VD levels in patients with a poor compared to those with a good outcome

Contrary to somewhat positive results of a meta-analysis including eight add-on supplementation studies to treat pulmonary tuberculosis, [46] there are no data on supplementing tuberculous meningitis patients. Neither are there any trials in the adult population on encephalitis or meningitis caused by other pathogens. There is also no study investigating prophylactic effects in highly exposed individuals.

Multiple sclerosis (MS) is the most common inflammatory autoimmune disorder of the central nervous system, afflicting worldwide more than 2.8 million people, most of them young and of the female gender [48]. MS is a chronic, incurable condition that causes severe incapacity in one-third of patients after either a relapsing–remitting or gradual, steadily progressing disease path. It is also the most frequent cause of non-traumatic neurological disability among young adults in the

The pathological hallmark, as the name implies, are multifocal demyelinated lesions, or "plaques", followed by gliosis. Perivascular inflammatory infiltration and focal blood–brain barrier breakdown can be seen in these plaques [50]. However, there is diffuse tissue damage even in the normal-appearing white and gray matter.

(28.30 +/− 14.96 vs. 35.92 +/− 17.11 ng/ml, p = 0.141) [47].

**2.5 Vitamin D and neuro-autoimmune processes**

*DOI: http://dx.doi.org/10.5772/intechopen.98390*

possibly neural ischemia.

bacteria [41–43].

#### *The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central… DOI: http://dx.doi.org/10.5772/intechopen.98390*

may further lead to cerebral edema and elevated intracerebral pressure. Those two factors, together with the altered blood flow, causes reduced perfusion pressure and possibly neural ischemia.

As Guevara et al. and Golpour et al. pointed out in their overviews, [41, 42]. VD exerts a wide range of effects on the very pathomechanisms implicated in brain infection. The targets of these actions can be both host cells by enhancing innate immunomodulatory activity as well as pathogen cells by displaying direct antibacterial and antimicrobial properties [41, 42]. The authors elucidate that VD, which is signaling through the VDR, stimulates innate immune cell functions, including phagocytosis, production of antimicrobial peptides (AMPs), and reactive oxygen species (ROS). It is also responsible for upregulation of the pattern recognition receptors (PRR) TLR2 and NOD2 and generation of TIMP-1, which downregulates matrix metalloproteinases (MMPs) [41]. Furthermore, VD inhibits the production of MMPs and proinflammatory cytokines. VD also deranges Th17 programming, which instead leads to the promotion of the regulatory T cell phenotype [41]. But, VD also directly impedes the growth, viability, and biofilm formation of various bacteria [41–43].

Infections with Streptococci and Mycobacteria, both not infrequently causing meningitis, have been shown to be repressed in the presence of adequate VD levels. In an in vitro experiment on isolated human neutrophils, Subramanian et al. found that VD boosts neutrophil killing of *S. pneumoniae* while also lowering inflammatory responses and apoptosis [44]. Rode et al. found in their experiments with naive human CD4+ T cells that in the defense against *M. tuberculosis*, there is an increased expression of VDR and an upregulation of VD-1 hydroxylase genes. VD blocks *M. tuberculosis*-induced cathelicidin downregulation and enables Th1 differentiation and IFN secretion, both of which are protective. These processes promoted *M. tuberculosis* intracellular death in human macrophages and monocytes [45].

While there is plenty of studies on lung, gut, or generalized infections in the form of sepsis [46], there is hardly any data on infections of the CNS. Regarding the effect of VD deficiency and meningitis outcome in adults, there is but one study on tuberculous meningitis (TBM). Dangeti et al. examined prospectively 40 HIV patients with tuberculous meningitis and found that there was but a trend for lower VD levels in patients with a poor compared to those with a good outcome (28.30 +/− 14.96 vs. 35.92 +/− 17.11 ng/ml, p = 0.141) [47].

Contrary to somewhat positive results of a meta-analysis including eight add-on supplementation studies to treat pulmonary tuberculosis, [46] there are no data on supplementing tuberculous meningitis patients. Neither are there any trials in the adult population on encephalitis or meningitis caused by other pathogens. There is also no study investigating prophylactic effects in highly exposed individuals.

#### **2.5 Vitamin D and neuro-autoimmune processes**

Multiple sclerosis (MS) is the most common inflammatory autoimmune disorder of the central nervous system, afflicting worldwide more than 2.8 million people, most of them young and of the female gender [48]. MS is a chronic, incurable condition that causes severe incapacity in one-third of patients after either a relapsing–remitting or gradual, steadily progressing disease path. It is also the most frequent cause of non-traumatic neurological disability among young adults in the Western Hemisphere [49].

The pathological hallmark, as the name implies, are multifocal demyelinated lesions, or "plaques", followed by gliosis. Perivascular inflammatory infiltration and focal blood–brain barrier breakdown can be seen in these plaques [50]. However, there is diffuse tissue damage even in the normal-appearing white and gray matter.

*Vitamin D*

One of the risk factors to develop GBM is birth in the winter months, suggesting a VD association that goes back decades before disease onset [35]. Also, expression of Vitamin D Receptor (VDR) is associated with a good prognosis in GBM [36]. Zigmont et al. reported an inverse association between VD consumption and GBM risk among men aged 56 years and older. Levels of VD in men >56 were inversely related to the occurrence of high-grade glioma (p = 0.04), i.e., older men with high levels (>66 nmol/L) showing a reduced propensity. This association even existed in samples drawn premorbid i.e. from ≥2 yr. (OR = 0.59; 95% CI = 0.38, 0.91) to ≥15 yr. before diagnosis (OR = 0.61; 95% CI = 0.38,0.96) [37]. This temporal

Mulpur et al. explain possible mechanisms of VD as treatment option: [38]. First, There is direct cancer control by influencing the signaling of macrophages and dendritic cells of the immune system and activating the tumor suppressor p53. It is well known, for example, that in other malignancies like breast cancer, VD down-regulates Akt and MDM2 leading to TGFβ-1-dependent growth inhibition [34]. In GBM, VD can inhibit the hedgehog signaling pathway and disable brain tumor stem cells (BTSCs). Due to their importance in tumor formation, recurrence, and metastasis, BTSCs are considered to be the tumor's driving force. Then, adequate VD availability also has secondary benefits. The immune system's role is bolstered, which indirectly inhibits tumor cell growth. By reducing some of the unintended side effects of standard therapy, sufficient doses can be given, and

There is but one published prospective open label study in humans that investigated in 470 newly diagnosed GBM-patients VD self-use, among other alternative medications. The sixty patients taking VD as an individual supplement had reduced mortality when compared with non-users (age-adjusted HR = 0.68; p = 0.02) [38]. VD has not yet been studied in a controlled clinical trial as a prophylactic or treatment in late-stage GBM or other primary brain tumors, as far as I am aware.

Meningitis and encephalitis, the infectious diseases of the brain tissue and the covering membranes, are endowed with substantial rates of mortality and with long-term sequelae in survivors. The WHO estimates the global incident cases to be 2.82 million and the death rate to be 318,400. Globally in 2016, 1.48 million YLDs and 21.87 million DALYs were due to meningitis [39]. Incidence, mortality and disability rates vary significantly according to region and pathogen. Bacterial infection is a major cause of meningitis, globally outnumbering other classes of organisms

The mechanism of infection-induced brain cell damage is elaborately explained

by Chaudhry, Hoffman and Weber [40]: They state that the cascade starts with pathogen invasion, which triggers activation of the immune system, including white blood cells, complement, and immunoglobulins. Immune cells and the damaged endothelial cells start to release cytokines, matrix metalloproteinases (MMPs), and nitric oxide (NO). While cytokines induce capillary wall changes in the blood– brain barrier, the MMPs, and NO, on the other hand, stimulate vasodilation that alters the cerebral blood flow. Cytokine release provokes the expression of more leukocyte receptors, which increases both white blood cell binding, i.e., adherence to capillary endothelium as well as extravasation. This then leads to further damage to the meninges and endothelial cells, thereby stimulating cytotoxic reactive oxygen species production and release of even more cytokines and chemokines. This coordinated assault aims to eliminate the invading pathogen, but it also harms and destroys nearby brain cells. Increased cytotoxic metabolite levels and permeability

sequence is another piece of evidence for a causative relation.

treatment adherence can be improved [38].

**2.4 Vitamin D and infections**

such as viruses, fungi, or parasites [39].

**146**

Here we find a low-grade diffuse inflammation with perivascular accumulation and parenchymal infiltration of lymphocytes, diffuse microglial activation, diffuse astrocytic gliosis, and diffuse neural or neuroaxonal loss and injury [50]. Different immunological mechanisms seem to be involved in the induction of tissue injury, but microglia activation associated with oxidative injury and mitochondrial damage appears to play a dominant role [50].

Several observational studies have shown that low serum VD levels are associated with an increased risk of developing MS, as well as increased disease activity and progression [51]. Miclea summarizes the various factors on how VD can positively influence MS pathology on a molecular level [51]: The ability of VD to suppress the progression of the experimental disease is attributed to its modulation of T cell trafficking into the CNS, its inhibition of Th1 cells, and its stimulation of IL-10 production. Demyelination is reduced via VD's activation of microglia resulting in the clearance of myelin debris and phagocytosis of pathological proteins such as amyloid-β peptides. Another supportive aspect is VD's ability to reduce the expression of inducible nitric acid synthase, a pro-inflammatory enzyme. Lastly, VD might induce remyelination by stimulating the maturation of oligodendrocytes and the activation of astrocytes.

There is no human study to examine the potential of VD to be used as a preventive therapy to control MS severity. Minura conducted a preclinical study in the MS animal model (EAE). Mice injected with VD but not those with VD analog had better outcomes. VD's down-modulatory potential was demonstrated in the histopathology of VD-treated animals, which showed reduced recruitment of inflammatory cells, mRNA expression of inflammatory parameters, and CNS demyelination.

Optic neuritis is an acute inflammatory and demyelinating disease of the optic nerve, of which at least half of monosymptomatic patients will eventually convert to clinically manifest MS. There is one double-blind, randomized, placebo-controlled pilot clinical trial examining the preventive effect of VD supplementation on conversion to MS [52]. When compared to the 15 patients in the placebo group, the fifteen VD deficient patients who received 50,000 IU of VD weekly for 12 months had a 68.4% lower risk of conversion to MS (relative risk = 0.316, p = 0.007) and a significantly lower incidence rate-ratio of demyelinating plaques in MRI (i.e., less cortical, juxtacortical, and corpus callosal plaques, less new T2 lesions, less new gadolinium-enhancing lesions, and less T1-weighted black holes) (p = 0.001 – 0.005).

Concerning supplementation of VD for patients with clinical manifest MS, there is a large number of studies and several meta-analyses. Overall results, however, were inconclusive. A Cochrane review pointed out that the unresolved nature of the final conclusion rests in great part in the low quality of included studies, but particularly in the heterogeneity of patient cohorts and the small sample size of most studies [53]. Taking this into consideration, Martínez-Lapiscina et al., in a most recent meta-analysis with 13 high-quality studies and 3,498 patients with early relapsing MS, showed that each 25 nmol/L increase in serum VD levels brings with it an average 10% decrease in new relapses and a 14–31% reduction in the risk of new radiological inflammatory activity [54].

The three most recent randomized controlled VD add-on trials published since 2019 that were not included in the previous meta-analyses showed mixed results. The SOLAR trial studied the effect of high-dose VD supplementation (14,007 IU/d) vs. placebo as an add-on therapy to interferon beta-1a. It demonstrated that at week 48 the 113 high-dose VD (14,007 IU/d) treated compared to 116 untreated patients had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI = 0.52–0.89; p = 0.0045) and for change from baseline in total volume of T2 lesions (difference in mean ranks: −0.074; p = 0.035). However, there was no difference regarding the development of the proportion of patients with no

**149**

courses.

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central…*

evidence of disease activity [55]. The CHOLINE trial reported in the VD group after 96 weeks a slower progression of disability (EDSS) (*p* = 0.026), better MRI outcomes with fewer new hypointense T1-weighted lesions (*p* = 0.025), and a lower volume of hypointense T1-weighted lesions (*p* = 0.031). However, there was only a marginal downward trend in the annualized relapse rate [56]. In the EVIDIMS trial, at the 18 months followups, there was no difference between high- (20,400 IU) and low-dose (400 IU) treatment arms regarding clinical outcomes (relapse rates, disability progression) and radiographical markers (T2-weighted lesion, contrastenhancing lesion, brain atrophy) [57]. Unfortunately, only data on intergroup differences, not on intragroup shifts from baseline, were provided in this publication.

The National Institute of Neurological Disorders and Stroke (NINDS) defines encephalopathy as any diffuse disease of the brain that alters brain function or structure … [in a way that it leads to an] altered mental status [58]. Patients can exhibit acute confusion, attention deficits, seizures, and coma, or more insidious

Even though toxic encephalopathy is a condition that can be coded in ICD 10, there is no sound data on its epidemiology, neither regionally nor internationally. Encephalopathies can, according to etiology, be classified into toxic and metabolic and, according to disease course, into acute and chronic. Toxic causes are medications, illicit drugs, or toxic chemicals. Metabolic etiologies include electrolyte imbalance, organ failure (e.g., hepatic, renal), hypoxemia, sepsis, dehydration, hypertension, hereditary enzyme deficiencies, and vitamin deficiency (e.g., Wernicke: thiamine). Chronic encephalopathies are usually slowly progressing and lead to permanent, mostly irreversible, structural changes. Only rarely, depending on early detection and treatment, they may be halted or reversed. In contrast, acute encephalopathies often have a good outcome as soon as underlying abnormalities are corrected. Whereas many metabolic encephalopathies have an acute onset, toxic encephalopathies can have acute (e.g., CO) or chronic (e.g., heavy metals) disease

Encephalopathies are morphologically characterized by cytotoxic cerebral edema (membrane damage), disruption of the membrane enzyme systems, axonal and neuronal injury, focal necrosis, and impairment of neurotransmitters secretion or receptor function [59]. Pathogenetic mechanisms include impairment of oxidative metabolism, protein synthesis, cytoskeletal structure, as well as the injury of

There are but a few hints of an association of environmental toxins and VD, one of which concerns a patient's vulnerability to toxins. Studies using genetic markers of susceptibility suggest that genes can make specific individuals more vulnerable to environmental toxins. One of these candidates is the VDR gene. Recent findings suggest that VDR polymorphism influences, for example, the accumulation of lead in bones and could thus serve as a marker for lead-induced chronic encephalopathy [60]. Air pollutants and other environmental chemicals may trigger VD deficiency, either directly or indirectly. The exact mechanism is still not clear, but for heavy metals, it was suggested that it might be by increasing renal tubular dysfunction and downregulating the transcription of CYPs [61]. Endocrine-disrupting chemicals, on the other hand, may either directly inhibit the activity and expression of CYPs or can do this through indirect pathways [61]. Finally, carbon monoxide (CO) interferes with cytochrome-dependent cellular functions, but how it does this is not fully understood. It is known, however, that CO is released from CO-releasing

*DOI: http://dx.doi.org/10.5772/intechopen.98390*

**2.6 Vitamin D and toxic or metabolic encephalopathy**

chronic symptoms, such as mood disturbances and fatigue.

capillaries and astroglial and microglial reactions [59].

molecules (CORM) and that CORM-2 decreases VD synthesis [62].

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central… DOI: http://dx.doi.org/10.5772/intechopen.98390*

evidence of disease activity [55]. The CHOLINE trial reported in the VD group after 96 weeks a slower progression of disability (EDSS) (*p* = 0.026), better MRI outcomes with fewer new hypointense T1-weighted lesions (*p* = 0.025), and a lower volume of hypointense T1-weighted lesions (*p* = 0.031). However, there was only a marginal downward trend in the annualized relapse rate [56]. In the EVIDIMS trial, at the 18 months followups, there was no difference between high- (20,400 IU) and low-dose (400 IU) treatment arms regarding clinical outcomes (relapse rates, disability progression) and radiographical markers (T2-weighted lesion, contrastenhancing lesion, brain atrophy) [57]. Unfortunately, only data on intergroup differences, not on intragroup shifts from baseline, were provided in this publication.

#### **2.6 Vitamin D and toxic or metabolic encephalopathy**

The National Institute of Neurological Disorders and Stroke (NINDS) defines encephalopathy as any diffuse disease of the brain that alters brain function or structure … [in a way that it leads to an] altered mental status [58]. Patients can exhibit acute confusion, attention deficits, seizures, and coma, or more insidious chronic symptoms, such as mood disturbances and fatigue.

Even though toxic encephalopathy is a condition that can be coded in ICD 10, there is no sound data on its epidemiology, neither regionally nor internationally.

Encephalopathies can, according to etiology, be classified into toxic and metabolic and, according to disease course, into acute and chronic. Toxic causes are medications, illicit drugs, or toxic chemicals. Metabolic etiologies include electrolyte imbalance, organ failure (e.g., hepatic, renal), hypoxemia, sepsis, dehydration, hypertension, hereditary enzyme deficiencies, and vitamin deficiency (e.g., Wernicke: thiamine). Chronic encephalopathies are usually slowly progressing and lead to permanent, mostly irreversible, structural changes. Only rarely, depending on early detection and treatment, they may be halted or reversed. In contrast, acute encephalopathies often have a good outcome as soon as underlying abnormalities are corrected. Whereas many metabolic encephalopathies have an acute onset, toxic encephalopathies can have acute (e.g., CO) or chronic (e.g., heavy metals) disease courses.

Encephalopathies are morphologically characterized by cytotoxic cerebral edema (membrane damage), disruption of the membrane enzyme systems, axonal and neuronal injury, focal necrosis, and impairment of neurotransmitters secretion or receptor function [59]. Pathogenetic mechanisms include impairment of oxidative metabolism, protein synthesis, cytoskeletal structure, as well as the injury of capillaries and astroglial and microglial reactions [59].

There are but a few hints of an association of environmental toxins and VD, one of which concerns a patient's vulnerability to toxins. Studies using genetic markers of susceptibility suggest that genes can make specific individuals more vulnerable to environmental toxins. One of these candidates is the VDR gene. Recent findings suggest that VDR polymorphism influences, for example, the accumulation of lead in bones and could thus serve as a marker for lead-induced chronic encephalopathy [60].

Air pollutants and other environmental chemicals may trigger VD deficiency, either directly or indirectly. The exact mechanism is still not clear, but for heavy metals, it was suggested that it might be by increasing renal tubular dysfunction and downregulating the transcription of CYPs [61]. Endocrine-disrupting chemicals, on the other hand, may either directly inhibit the activity and expression of CYPs or can do this through indirect pathways [61]. Finally, carbon monoxide (CO) interferes with cytochrome-dependent cellular functions, but how it does this is not fully understood. It is known, however, that CO is released from CO-releasing molecules (CORM) and that CORM-2 decreases VD synthesis [62].

*Vitamin D*

appears to play a dominant role [50].

and the activation of astrocytes.

new radiological inflammatory activity [54].

Here we find a low-grade diffuse inflammation with perivascular accumulation and parenchymal infiltration of lymphocytes, diffuse microglial activation, diffuse astrocytic gliosis, and diffuse neural or neuroaxonal loss and injury [50]. Different immunological mechanisms seem to be involved in the induction of tissue injury, but microglia activation associated with oxidative injury and mitochondrial damage

Several observational studies have shown that low serum VD levels are associated with an increased risk of developing MS, as well as increased disease activity and progression [51]. Miclea summarizes the various factors on how VD can positively influence MS pathology on a molecular level [51]: The ability of VD to suppress the progression of the experimental disease is attributed to its modulation of T cell trafficking into the CNS, its inhibition of Th1 cells, and its stimulation of IL-10 production. Demyelination is reduced via VD's activation of microglia resulting in the clearance of myelin debris and phagocytosis of pathological proteins such as amyloid-β peptides. Another supportive aspect is VD's ability to reduce the expression of inducible nitric acid synthase, a pro-inflammatory enzyme. Lastly, VD might induce remyelination by stimulating the maturation of oligodendrocytes

There is no human study to examine the potential of VD to be used as a preventive therapy to control MS severity. Minura conducted a preclinical study in the MS animal model (EAE). Mice injected with VD but not those with VD analog had better outcomes. VD's down-modulatory potential was demonstrated in the histopathology of VD-treated animals, which showed reduced recruitment of inflammatory cells, mRNA expression of inflammatory parameters, and CNS demyelination. Optic neuritis is an acute inflammatory and demyelinating disease of the optic nerve, of which at least half of monosymptomatic patients will eventually convert to clinically manifest MS. There is one double-blind, randomized, placebo-controlled pilot clinical trial examining the preventive effect of VD supplementation on conversion to MS [52]. When compared to the 15 patients in the placebo group, the fifteen VD deficient patients who received 50,000 IU of VD weekly for 12 months had a 68.4% lower risk of conversion to MS (relative risk = 0.316, p = 0.007) and a significantly lower incidence rate-ratio of demyelinating plaques in MRI (i.e., less cortical, juxtacortical, and corpus callosal plaques, less new T2 lesions, less new gadolinium-enhancing lesions, and less T1-weighted black holes) (p = 0.001 – 0.005). Concerning supplementation of VD for patients with clinical manifest MS, there is a large number of studies and several meta-analyses. Overall results, however, were inconclusive. A Cochrane review pointed out that the unresolved nature of the final conclusion rests in great part in the low quality of included studies, but particularly in the heterogeneity of patient cohorts and the small sample size of most studies [53]. Taking this into consideration, Martínez-Lapiscina et al., in a most recent meta-analysis with 13 high-quality studies and 3,498 patients with early relapsing MS, showed that each 25 nmol/L increase in serum VD levels brings with it an average 10% decrease in new relapses and a 14–31% reduction in the risk of

The three most recent randomized controlled VD add-on trials published since 2019 that were not included in the previous meta-analyses showed mixed results. The SOLAR trial studied the effect of high-dose VD supplementation (14,007 IU/d) vs. placebo as an add-on therapy to interferon beta-1a. It demonstrated that at week 48 the 113 high-dose VD (14,007 IU/d) treated compared to 116 untreated patients had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI = 0.52–0.89; p = 0.0045) and for change from baseline in total volume of T2 lesions (difference in mean ranks: −0.074; p = 0.035). However, there was no difference regarding the development of the proportion of patients with no

**148**

#### *Vitamin D*

For metabolic encephalopathy, there is but one study. In this prospective investigation by Yousif et al. on 135 HCV-related liver cirrhosis patients, he detected significantly lower VD levels ((6.81 ± 2.75, vs. 16.28 ± 6.60; p < o.o5) in the 45 patients that developed hepatic encephalopathy (HE) [63]. HE patients with particularly severe deficiency had a significantly higher mortality rate (HR = 2.76, p = 0.001).

There are no retrospective or prospective controlled studies that have looked into the effect of VD as a treatment for encephalopathies.

#### **2.7 Vitamin D and neurodegeneration**

Neurodegeneration is characterized by selective dysfunction and progressive loss of synapses and neurons associated with pathologically altered proteins that deposit primarily in the human central nervous system [64]. Although each neurodegenerative disease is differentiated from the others by distinct protein accumulations and anatomic vulnerability of specific neuronal populations, they all share several fundamental mechanisms that are associated with progressive neuronal loss and death. These pathomechanisms include inflammation, apoptosis, oxidative stress, and proteotoxic stress linked to defects in the ubiquitin–proteasomal and autophagosomal/lysosomal systems [65].

In the following paragraphs, we will discuss the role of VD in Alzheimer's disease (AD) and Parkinson's disease (PD) as typical examples of neurodegenerative disorders.

#### *2.7.1 Alzheimer's dementia*

Dementia is a syndrome in which there is deterioration in memory, thinking, behavior and the ability to perform everyday activities. Globally, around 50 million people, of which 62% are women and 38% are men, have dementia, and there are nearly 10 million new cases every year. It is one of the major causes of disability and dependency among older people worldwide. Dementia, accounting for 2·4 million deaths is the fifth leading cause of death globally [66].

AD is the most common form of dementia, making up 60–70% of cases, [67] and is also the most common neurodegenerative disease. The cardinal pathological features of the disease are senile plaques and neurofibrillary tangles. Senile plaques consist of a central core of beta-amyloid, a 4-kD peptide. They are found outside of neurons and are typically surrounded by neurites that are abnormally configured [68]. Senile plaques are thought to contribute to the damage and death of neurons by interfering with neuron-to-neuron communication at synapses. Neurofibrillary tangles are made up of abnormally phosphorylated tau that accumulates in the perikaryal cytoplasm of specific neurons [68]. They block the intracellular transport of nutrients and other essential molecules [69]. Both senile plaques and neurofibrillary tangles activate microglia, with the aim of clearing toxic proteins and debris from dead and dying cells [69]. Chronic inflammation may set in when the microglia cannot keep up with all that needs to be cleared [69]. Brain function is further compromised by decreases in the brain's ability to metabolize glucose, its primary source of energy [69].

Based on experimental findings of treatment with the VD analog, Maxacalcitol, Saad El-Din suggested that VD may improve the histopathological picture of the brains of AD rats [70]. Also, it might significantly increase expression of Nrf2 and its downstream effectors (HO-1 and GSH), improve serum levels of calcium, decrease neuro-inflammation and Amyloid β load, as well as hyperphosphorylation of MAPK-38, ERK1/2, and tau proteins [70]. Masoumi was able to stimulate AD

**151**

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central…*

patients' macrophages with VD so that Aß phagocytosis and clearance increased

Two trials looked at the effect of VD in patients with established AD. In a retrospective study by Chaves et al. on 202 patients with mild stage AD, the time of progression to severe stage of AD was shorter under VD compared with those without this treatment (5.4 ± 0.4 years vs. 4.4 ± 0.16 years, p = 0.003) [75]. The randomized, double-blind, placebo-controlled trial by Jingya Jia et al. on 210 AD patients suggests that daily oral VD supplementation (800 IU/day) over 12 months may improve cognitive function reflected by information retrieval, arithmetic, digit span, vocabulary, block design, and picture arrange scores (p < 0.05). It also had positive effects on the Aβ-related biomarkers in plasma Aβ42, APP, BACE1,

Parkinson's disease (PD) is a slowly progressing disabling disease characterized by bradykinesia, tremor, rigidity, and eventually postural instability. Furthermore, non-motor symptoms such as autonomic, sensory, or psychiatric symptoms also occur in most patients. PD is the second most common neurodegenerative disorder worldwide, with a prevalence of 1% in populations over 60 years of age in developed countries [77]. Males outnumber women one and a half to one [77]. In 2016 PD was affecting more than 6.1 million people globally and caused 3.2 million

PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, but it also affects a variety of other brain regions. Lewy bodies are the histopathological hallmark of PD and are also held accountable for initiating and maintaining the pathological process [79]. They include several misfolded amyloid proteins such as alpha-synuclein (SNCA), phosphorylated tau (p-tau), and amyloid beta-protein (Aß). Although the exact mechanism of how misfolded proteins accumulate and cause neurodegeneration is unknown, mitochondrial damage, energy failure, oxidative stress, excitotoxicity, impaired protein clearance, and cell-autonomous mechanisms are all thought to play a role [79]. According

Cohort studies, including several meta-analyses, essentially indicate that VD deficiency is associated with a significantly increased risk of AD and all-cause dementia. There are three important prospective studies on the effect of VD to mitigate the risk of developing AD. Littlejohns et al. studied 1,658 older people (mean age 73.6 years), of which 102 developed AD after being observed for 5.6 years. VD deficiency, according to his results, is related to a substantially higher risk of AD. When compared to participants with adequate serum levels, the risk of developing AD was higher in severely (VD 25 nmol/L; HR = 2.22; 95 % CI = 1.02–4.83) and to a lesser extent also in moderately deficient (VD 50 nmol/L; HR = 1.69; 95 % CI = 1.06–2.69) patients [72]. Annweiler et al. investigating the effect of dietary VD intake in 498 older women followed for seven years, also confirmed that higher intake of VD (on average 2336.41 IU weekly) reduced AD risk (OR = 0.23; 95% CI = 0.08–0.67) compared to those with lower intake [73]. SanMartin et al. conducted a study to see whether VD might have properties that could prevent subjects with mild cognitive impairment (MCI) from deteriorating and thus converting to AD. After six months of VD supplementation, they found that correcting low VD levels would protect lymphocytes from oxidative death and increase Aβ1–40 plasma levels in 16 MCI patients. Aβ1–40 was monitored because it served as a marker for Aβ-amyloid clearance from the brain. Additionally, at the 18-month follow-up, cognitive status was assessed, and scores on the Clinical Dementia Rating (CDR), Montreal Cognitive Assessment (MoCA), and Memory

*DOI: http://dx.doi.org/10.5772/intechopen.98390*

Index Score improved [74].

APPmRNA, BACE1mRNA (p < 0.001) [76].

DALYs and 211,296 deaths [78].

*2.7.2 Parkinson's disease and other movement disorders*

while at the same time apoptosis decreased [71].

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central… DOI: http://dx.doi.org/10.5772/intechopen.98390*

patients' macrophages with VD so that Aß phagocytosis and clearance increased while at the same time apoptosis decreased [71].

Cohort studies, including several meta-analyses, essentially indicate that VD deficiency is associated with a significantly increased risk of AD and all-cause dementia. There are three important prospective studies on the effect of VD to mitigate the risk of developing AD. Littlejohns et al. studied 1,658 older people (mean age 73.6 years), of which 102 developed AD after being observed for 5.6 years. VD deficiency, according to his results, is related to a substantially higher risk of AD. When compared to participants with adequate serum levels, the risk of developing AD was higher in severely (VD 25 nmol/L; HR = 2.22; 95 % CI = 1.02–4.83) and to a lesser extent also in moderately deficient (VD 50 nmol/L; HR = 1.69; 95 % CI = 1.06–2.69) patients [72]. Annweiler et al. investigating the effect of dietary VD intake in 498 older women followed for seven years, also confirmed that higher intake of VD (on average 2336.41 IU weekly) reduced AD risk (OR = 0.23; 95% CI = 0.08–0.67) compared to those with lower intake [73]. SanMartin et al. conducted a study to see whether VD might have properties that could prevent subjects with mild cognitive impairment (MCI) from deteriorating and thus converting to AD. After six months of VD supplementation, they found that correcting low VD levels would protect lymphocytes from oxidative death and increase Aβ1–40 plasma levels in 16 MCI patients. Aβ1–40 was monitored because it served as a marker for Aβ-amyloid clearance from the brain. Additionally, at the 18-month follow-up, cognitive status was assessed, and scores on the Clinical Dementia Rating (CDR), Montreal Cognitive Assessment (MoCA), and Memory Index Score improved [74].

Two trials looked at the effect of VD in patients with established AD. In a retrospective study by Chaves et al. on 202 patients with mild stage AD, the time of progression to severe stage of AD was shorter under VD compared with those without this treatment (5.4 ± 0.4 years vs. 4.4 ± 0.16 years, p = 0.003) [75]. The randomized, double-blind, placebo-controlled trial by Jingya Jia et al. on 210 AD patients suggests that daily oral VD supplementation (800 IU/day) over 12 months may improve cognitive function reflected by information retrieval, arithmetic, digit span, vocabulary, block design, and picture arrange scores (p < 0.05). It also had positive effects on the Aβ-related biomarkers in plasma Aβ42, APP, BACE1, APPmRNA, BACE1mRNA (p < 0.001) [76].

#### *2.7.2 Parkinson's disease and other movement disorders*

Parkinson's disease (PD) is a slowly progressing disabling disease characterized by bradykinesia, tremor, rigidity, and eventually postural instability. Furthermore, non-motor symptoms such as autonomic, sensory, or psychiatric symptoms also occur in most patients. PD is the second most common neurodegenerative disorder worldwide, with a prevalence of 1% in populations over 60 years of age in developed countries [77]. Males outnumber women one and a half to one [77]. In 2016 PD was affecting more than 6.1 million people globally and caused 3.2 million DALYs and 211,296 deaths [78].

PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, but it also affects a variety of other brain regions. Lewy bodies are the histopathological hallmark of PD and are also held accountable for initiating and maintaining the pathological process [79]. They include several misfolded amyloid proteins such as alpha-synuclein (SNCA), phosphorylated tau (p-tau), and amyloid beta-protein (Aß). Although the exact mechanism of how misfolded proteins accumulate and cause neurodegeneration is unknown, mitochondrial damage, energy failure, oxidative stress, excitotoxicity, impaired protein clearance, and cell-autonomous mechanisms are all thought to play a role [79]. According

*Vitamin D*

p = 0.001).

tive disorders.

*2.7.1 Alzheimer's dementia*

For metabolic encephalopathy, there is but one study. In this prospective investigation by Yousif et al. on 135 HCV-related liver cirrhosis patients, he detected significantly lower VD levels ((6.81 ± 2.75, vs. 16.28 ± 6.60; p < o.o5) in the 45 patients that developed hepatic encephalopathy (HE) [63]. HE patients with particularly severe deficiency had a significantly higher mortality rate (HR = 2.76,

There are no retrospective or prospective controlled studies that have looked

Neurodegeneration is characterized by selective dysfunction and progressive loss of synapses and neurons associated with pathologically altered proteins that deposit primarily in the human central nervous system [64]. Although each neurodegenerative disease is differentiated from the others by distinct protein accumulations and anatomic vulnerability of specific neuronal populations, they all share several fundamental mechanisms that are associated with progressive neuronal loss and death. These pathomechanisms include inflammation, apoptosis, oxidative stress, and proteotoxic stress linked to defects in the ubiquitin–proteasomal and

In the following paragraphs, we will discuss the role of VD in Alzheimer's disease (AD) and Parkinson's disease (PD) as typical examples of neurodegenera-

Dementia is a syndrome in which there is deterioration in memory, thinking, behavior and the ability to perform everyday activities. Globally, around 50 million people, of which 62% are women and 38% are men, have dementia, and there are nearly 10 million new cases every year. It is one of the major causes of disability and dependency among older people worldwide. Dementia, accounting for 2·4 million

AD is the most common form of dementia, making up 60–70% of cases, [67] and is also the most common neurodegenerative disease. The cardinal pathological features of the disease are senile plaques and neurofibrillary tangles. Senile plaques consist of a central core of beta-amyloid, a 4-kD peptide. They are found outside of neurons and are typically surrounded by neurites that are abnormally configured [68]. Senile plaques are thought to contribute to the damage and death of neurons by interfering with neuron-to-neuron communication at synapses. Neurofibrillary tangles are made up of abnormally phosphorylated tau that accumulates in the perikaryal cytoplasm of specific neurons [68]. They block the intracellular transport of nutrients and other essential molecules [69]. Both senile plaques and neurofibrillary tangles activate microglia, with the aim of clearing toxic proteins and debris from dead and dying cells [69]. Chronic inflammation may set in when the microglia cannot keep up with all that needs to be cleared [69]. Brain function is further compromised by decreases in the brain's ability to metabolize glucose, its primary

Based on experimental findings of treatment with the VD analog, Maxacalcitol, Saad El-Din suggested that VD may improve the histopathological picture of the brains of AD rats [70]. Also, it might significantly increase expression of Nrf2 and its downstream effectors (HO-1 and GSH), improve serum levels of calcium, decrease neuro-inflammation and Amyloid β load, as well as hyperphosphorylation of MAPK-38, ERK1/2, and tau proteins [70]. Masoumi was able to stimulate AD

into the effect of VD as a treatment for encephalopathies.

**2.7 Vitamin D and neurodegeneration**

autophagosomal/lysosomal systems [65].

deaths is the fifth leading cause of death globally [66].

**150**

source of energy [69].

to Braak's widely accepted theory, these processes are triggered by a "prion-like protein infection", starting in the gut or nasal mucosa and is then propagated via olfactory pulp or the vagal nerve to the brainstem. It then spreads to successive parts of the brain in a chronologically predictable rostrocaudal sequence [80].

VD has been linked to PD-pathology through its effects on L-type voltagesensitive calcium channels (L-VSCC), nerve growth factor (NGF), matrix metalloproteinases (MMPs), prostaglandins (PGs), cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), and nitric oxide synthase (NOS) [81]. VD has also been shown to play a role in dopamine synthesis by regulating the tyrosine hydroxylase gene [81].

Seven observational studies and a meta-analysis [82] have looked into the connection between VD and PD and, except for one, have consistently found low serum VD levels in PD patients. Like for other basal ganglia disorders [83], the prevalence of VD deficiency in PD is high (57% - 71%) [82]. However, data to tie this to a causal relationship have been controversial. Using the Finish National Drug-Reimbursement Database, Knekt et al. looked at the connection between VD levels in midlife and the risk of developing PD later in life. Throughout the 29-year follow-up period, 50 of the 3,173 men and women in the sample developed PD. Individuals with higher serum VD concentrations had a 65% lower PD risk than those with insufficient levels. After adjustment for confounding factors, the relative risk highest vs. lowest quartiles was 0.33 (95% CI = 0.14–0.80). Contrary to that, Shrestha et al. in their U.S. population-based prospective cohort study including 15,792 individuals aged 45 to 64 years, discovered no connection between serum VD concentrations and PD risk [84]. A total of 67 participants developed PD after a median of 17 years of follow-up. For those who developed PD and those who did not, the mean serum concentrations of VD were comparable (25.6 ± 8.4 ng/mL vs. 24.2 ± 8.5 ng/mL, p = 0.24).

Several meta-analyses have looked into the connection between VDR polymorphisms and PD risk. The most recent investigation by Wang et al. suggests that the SNP FokI is linked to a lower risk of PD in Asian but not in Caucasian populations [85].

There are three prospective PD supplementation studies and one small metaanalysis, but results are mixed [86]. Suzuki et al. randomized 114 PD patients to receive 1,200 IU of VD a day (n = 58) or a placebo (n = 56) for a period of 12 months [87]. The intervention group's serum VD level doubled, while the placebo group's level remained unchanged. At the same time, the intervention group's motor scores (H&Y stage, UPDRS) remained stable, while the placebo group's scores significantly deteriorated (difference between groups: p = 0.005). They concluded that VD supplementation might help stabilize PD motor aspects, at least for a short period [87]. Habibi et al. randomized 120 PD patients with levodopa-induced dyskinesia to receive either 1,000 IU of VD a day or a placebo [88]. At the 3-month follow-up, there was no difference in scores for levodopa-induced dyskinesia (UPDRS IV sub score) or motor function (UPDRS III motor score) [88]. Hiller et a. looked at balance problems and falls, [89] which are considered to be particularly frequent in PD [90], a major cause of morbidity and mortality, and challenging to treat, even with non-pharmacological therapies specifically designed to alleviate balance deficits [91]. They conducted a pilot (n = 58) randomized, double-blind intervention trial to measure the effects of 16 weeks of high dose VD (10,000 IU/day) on PD symptoms, but mainly on balance. Despite an increase in VD serum concentrations (30.2 ng/ml to 61.1 ng/ml), in the 27 VD treated patients, the Sensory Organization Test did not show a substantial improvement in balance (p = 0.43). A post hoc analysis comparing treatment effects in younger (age < 67 yrs.) and older (age ≥ 67 yrs.) participants, however, found a significant improvement in the SOT

**153**

**Brain injury classification**

Aquired

Traumatic

vascular Neoplastic Infectious Autoimmune Toxic-Metabolic

Alzheimer's D.

Parkinson's D. *Study-outcome: Favorable +, very favorable ++, unfavorable - (\*same study for two aspects).*

**Table 1.**

*Characteristics of studies on vitamin D and neuropathological processes.*

A ++/−

B +/− *Study quality: D: observational studies only, C: one randomized controlled trial (RCT) or one representative cohort study (RCS), B: more than one RCT or RCS, A: one or more meta-Analysis.*

Degenerative

C + \*

C + \*

C + B +

D +

C +

B (+)/−

C +

A +/−

D + \* A + \*

D +

A + \*

D \*

C + C +

**VitD** ≈ **Risk**

**VitD** ≈ **outcome**

**experimental**

**prophylaxis**

**treatment early**

B + C + D + D -

B +/−

**treatment late**

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central…*

*DOI: http://dx.doi.org/10.5772/intechopen.98390*



*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central… DOI: http://dx.doi.org/10.5772/intechopen.98390*

*Vitamin D*

gene [81].

24.2 ± 8.5 ng/mL, p = 0.24).

populations [85].

to Braak's widely accepted theory, these processes are triggered by a "prion-like protein infection", starting in the gut or nasal mucosa and is then propagated via olfactory pulp or the vagal nerve to the brainstem. It then spreads to successive parts

VD has been linked to PD-pathology through its effects on L-type voltagesensitive calcium channels (L-VSCC), nerve growth factor (NGF), matrix metalloproteinases (MMPs), prostaglandins (PGs), cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), and nitric oxide synthase (NOS) [81]. VD has also been shown to play a role in dopamine synthesis by regulating the tyrosine hydroxylase

Seven observational studies and a meta-analysis [82] have looked into the connection between VD and PD and, except for one, have consistently found low serum VD levels in PD patients. Like for other basal ganglia disorders [83], the prevalence of VD deficiency in PD is high (57% - 71%) [82]. However, data to tie this to a causal relationship have been controversial. Using the Finish National Drug-Reimbursement Database, Knekt et al. looked at the connection between VD levels in midlife and the risk of developing PD later in life. Throughout the 29-year follow-up period, 50 of the 3,173 men and women in the sample developed PD. Individuals with higher serum VD concentrations had a 65% lower PD risk than those with insufficient levels. After adjustment for confounding factors, the relative risk highest vs. lowest quartiles was 0.33 (95% CI = 0.14–0.80). Contrary to that, Shrestha et al. in their U.S. population-based prospective cohort study including 15,792 individuals aged 45 to 64 years, discovered no connection between serum VD concentrations and PD risk [84]. A total of 67 participants developed PD after a median of 17 years of follow-up. For those who developed PD and those who did not, the mean serum concentrations of VD were comparable (25.6 ± 8.4 ng/mL vs.

Several meta-analyses have looked into the connection between VDR polymorphisms and PD risk. The most recent investigation by Wang et al. suggests that the SNP FokI is linked to a lower risk of PD in Asian but not in Caucasian

There are three prospective PD supplementation studies and one small metaanalysis, but results are mixed [86]. Suzuki et al. randomized 114 PD patients to receive 1,200 IU of VD a day (n = 58) or a placebo (n = 56) for a period of 12 months [87]. The intervention group's serum VD level doubled, while the placebo group's level remained unchanged. At the same time, the intervention group's motor scores (H&Y stage, UPDRS) remained stable, while the placebo group's scores significantly deteriorated (difference between groups: p = 0.005). They concluded that VD supplementation might help stabilize PD motor aspects, at least for a short period [87]. Habibi et al. randomized 120 PD patients with levodopa-induced dyskinesia to receive either 1,000 IU of VD a day or a placebo [88]. At the 3-month follow-up, there was no difference in scores for levodopa-induced dyskinesia (UPDRS IV sub score) or motor function (UPDRS III motor score) [88]. Hiller et a. looked at balance problems and falls, [89] which are considered to be particularly frequent in PD [90], a major cause of morbidity and mortality, and challenging to treat, even with non-pharmacological therapies specifically designed to alleviate balance deficits [91]. They conducted a pilot (n = 58) randomized, double-blind intervention trial to measure the effects of 16 weeks of high dose VD (10,000 IU/day) on PD symptoms, but mainly on balance. Despite an increase in VD serum concentrations (30.2 ng/ml to 61.1 ng/ml), in the 27 VD treated patients, the Sensory Organization Test did not show a substantial improvement in balance (p = 0.43). A post hoc analysis comparing treatment effects in younger (age < 67 yrs.) and older (age ≥ 67 yrs.) participants, however, found a significant improvement in the SOT

of the brain in a chronologically predictable rostrocaudal sequence [80].

**152**

of 10.6 points in the group of younger PD patients (p = 0.012) [89]. There was, however, no effect on other PD symptoms.

In summary, there exist a large number of studies on VD and neurological diseases, but there is a broad variety of levels of evidence for individual neuropathological processes, and the result is not always favorable (**Table 1**). On epidemiological trials, the most widespread agreement is that VD deficiency is a risk factor for acquired and neurodegenerative nerve cell injury (Vit D ≈ risk) and a poor outcome (Vit D ≈ outcome) once the injury has occurred. Epidemiological studies with the highest degree of evidence (A) exist for stroke and AD, but there are none for brain infections and toxic-metabolic encephalopathy. VD as medication, particularly when used early in the process, has been extensively investigated in all categories with high-quality research for autoimmune diseases of the brain (A), neuro-trauma (B), and PD (B). VD was only studied as a late-stage treatment for stroke, with high-quality evidence (A) but mixed results, and as a prophylaxis for autoimmune diseases and AD, with medium to low-quality evidence (C and D) and positive results.

#### **3. Conclusion**

Going through the meanwhile numerous studies on the influence of VD in the various neuropathological processes, there is strong support that VD particularly plays a mitigating role in the development of chronic neurodegeneration and the measured response to acutely acquired nerve cell injuries and potential secondary damages. The mechanisms of cell afflictions and recovery are complex and not fully understood. However, despite the differences depending on the type of insult, there appear to be some common pathways in which VD is relevant. Adequate serum levels of VD prior to the initiation of these processes are now be thought to be neuroprotective. However, comprehensive data on using it as a treatment during the ongoing process or after the injury to neurons has been completed are much vaguer. (**Table 1**) There appears to be no evidence to support its use in patients who already have adequate levels in their system. Extremely high doses seem not to provide any added benefit but may increase the risk of VD intoxication [92].

There are a few other reviews on the link between VD and diseases of the brain. This work differs from these as it is currently the most up-to-date survey. But, more importantly, while most of them covered either specific subsections, for example, neurodegenerative [93] and psychiatric diseases [4], or disease groups like dementias [72] and movement disorders [83], this is one of the few articles that addresses the full spectrum of neurological conditions. Furthermore, it is the first to focus on the neuropathological process. This is significant because it refocuses attention on the basic science track, where there are still so many uncharted regions and where scientific advances can possibly have therapeutic implications.

Due to a vast body of evidence of recorded benefits, a consistent safety record, and low costs, VD deficiency should be assessed and corrected on a routine basis in all neurological disorders, regardless of the underlying neuropathological mechanism.

**155**

**Author details**

Carl Nikolaus Homann1,2

1 Department of Neurology, Medical University Graz, Austria

\*Address all correspondence to: nik.homann@medunigraz.at

provided the original work is properly cited.

2 St. Elizabeth University of Health and Social Work, Bratislava, Slovakia

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central…*

*DOI: http://dx.doi.org/10.5772/intechopen.98390*

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central… DOI: http://dx.doi.org/10.5772/intechopen.98390*

### **Author details**

*Vitamin D*

and positive results.

**3. Conclusion**

of 10.6 points in the group of younger PD patients (p = 0.012) [89]. There was,

In summary, there exist a large number of studies on VD and neurological diseases, but there is a broad variety of levels of evidence for individual neuropathological processes, and the result is not always favorable (**Table 1**). On epidemiological trials, the most widespread agreement is that VD deficiency is a risk factor for acquired and neurodegenerative nerve cell injury (Vit D ≈ risk) and a poor outcome (Vit D ≈ outcome) once the injury has occurred. Epidemiological studies with the highest degree of evidence (A) exist for stroke and AD, but there are none for brain infections and toxic-metabolic encephalopathy. VD as medication, particularly when used early in the process, has been extensively investigated in all categories with high-quality research for autoimmune diseases of the brain (A), neuro-trauma (B), and PD (B). VD was only studied as a late-stage treatment for stroke, with high-quality evidence (A) but mixed results, and as a prophylaxis for autoimmune diseases and AD, with medium to low-quality evidence (C and D)

Going through the meanwhile numerous studies on the influence of VD in the various neuropathological processes, there is strong support that VD particularly plays a mitigating role in the development of chronic neurodegeneration and the measured response to acutely acquired nerve cell injuries and potential secondary damages. The mechanisms of cell afflictions and recovery are complex and not fully understood. However, despite the differences depending on the type of insult, there appear to be some common pathways in which VD is relevant. Adequate serum levels of VD prior to the initiation of these processes are now be thought to be neuroprotective. However, comprehensive data on using it as a treatment during the ongoing process or after the injury to neurons has been completed are much vaguer. (**Table 1**) There appears to be no evidence to support its use in patients who already have adequate levels in their system. Extremely high doses seem not to provide any

There are a few other reviews on the link between VD and diseases of the brain. This work differs from these as it is currently the most up-to-date survey. But, more importantly, while most of them covered either specific subsections, for example, neurodegenerative [93] and psychiatric diseases [4], or disease groups like dementias [72] and movement disorders [83], this is one of the few articles that addresses the full spectrum of neurological conditions. Furthermore, it is the first to focus on the neuropathological process. This is significant because it refocuses attention on the basic science track, where there are still so many uncharted regions and where

Due to a vast body of evidence of recorded benefits, a consistent safety record, and low costs, VD deficiency should be assessed and corrected on a routine basis in all neurological disorders, regardless of the underlying neuropathological

added benefit but may increase the risk of VD intoxication [92].

scientific advances can possibly have therapeutic implications.

however, no effect on other PD symptoms.

**154**

mechanism.

Carl Nikolaus Homann1,2

1 Department of Neurology, Medical University Graz, Austria

2 St. Elizabeth University of Health and Social Work, Bratislava, Slovakia

\*Address all correspondence to: nik.homann@medunigraz.at

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[71] Masoumi, A., et al., *1alpha,25 dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by macrophages of Alzheimer's disease patients.* J Alzheimers Dis, 2009. **17**(3): p. 703-17.

[72] Littlejohns, T.J., et al., *Vitamin D and the risk of dementia and Alzheimer disease.* Neurology, 2014. **83**(10): p. 920-928.

[73] Annweiler, C., et al., *Higher vitamin D dietary intake is associated with lower risk of alzheimer's disease: a 7-year follow-up.* J Gerontol A Biol Sci Med Sci, 2012. **67**(11): p. 1205-11.

[74] Sanmartin, C., et al., *Vitamin D Increases A*β*140 Plasma Levels and Protects Lymphocytes from Oxidative Death in Mild Cognitive Impairment Patients.* Current Alzheimer Research, 2017. **15**.

[75] Chaves, M., et al., *[Treatment with vitamin D and slowing of progression to severe stage of Alzheimer's disease].* Vertex, 2014. **25**(114): p. 85-91.

[76] Jia, J., et al., *Effects of vitamin D supplementation on cognitive function and blood Abeta-related biomarkers in older adults with Alzheimer's disease: a randomised, double-blind, placebocontrolled trial.* J Neurol Neurosurg Psychiatry, 2019. **90**(12): p. 1347-1352.

[77] Portillo, M.C., A. Haahr, and M.V. Navarta-Sánchez, *Management, Levels of Support, Quality of Life, and Social Inclusion in Parkinson's Disease: Interventions, Innovation, and Practice Development.* Parkinson's Disease, 2021. **2021**: p. 4681251.

[78] *Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.* Lancet Neurol, 2018. **17**(11): p. 939-953.

[79] Maiti, P., J. Manna, and G.L. Dunbar, *Current understanding of the*  *molecular mechanisms in Parkinson's disease: Targets for potential treatments.* Translational neurodegeneration, 2017. **6**: p. 28-28.

[80] Braak, H., et al., *Staging of brain pathology related to sporadic Parkinson's disease.* Neurobiol Aging, 2003. **24**(2): p. 197-211.

[81] K, L.N. and L. Nguyễn, *Role of vitamin d in Parkinson's disease.* ISRN Neurol, 2012. **2012**: p. 134289.

[82] Rimmelzwaan, L.M., et al., *Systematic Review of the Relationship between Vitamin D and Parkinson's Disease.* J Parkinsons Dis, 2016. **6**(1): p. 29-37.

[83] Homann, C.N., et al., *Vitamin D and Hyperkinetic Movement Disorders: A Systematic Review.* Tremor and other hyperkinetic movements (New York, N.Y.), 2020. **10**: p. 32-32.

[84] Shrestha, S., et al., *Serum 25-hydroxyvitamin D concentrations in Mid-adulthood and Parkinson's disease risk.* Movement disorders : official journal of the Movement Disorder Society, 2016. **31**(7): p. 972-978.

[85] Wang, X., et al., *Vitamin D receptor polymorphisms and the susceptibility of Parkinson's disease.* Neurosci Lett, 2019. **699**: p. 206-211.

[86] Zhou, Z., et al., *The Association Between Vitamin D Status, Vitamin D Supplementation, Sunlight Exposure, and Parkinson's Disease: A Systematic Review and Meta-Analysis.* Medical science monitor : international medical journal of experimental and clinical research, 2019. **25**: p. 666-674.

[87] Suzuki, M., et al., *Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease.* Am J Clin Nutr, 2013. **97**(5): p. 1004-13.

**161**

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central…*

*DOI: http://dx.doi.org/10.5772/intechopen.98390*

[88] Habibi, A.H., et al., *Treatment of Levodopainduced dyskinesia with Vitamin D: A Randomized, double-blind, placebocontrolled trial.* Neurol Int, 2018. **10**(3):

[89] Hiller, A.L., et al., *A randomized, controlled pilot study of the effects of vitamin D supplementation on balance in Parkinson's disease: Does age matter?* PLOS ONE, 2018. **13**(9): p. e0203637.

[90] Homann, B., et al., *The impact of neurological disorders on the risk for falls in the community dwelling elderly: a case-controlled study.* BMJ Open, 2013.

[91] Steiger, L. and C.N. Homann, *Exercise therapy in Parkinson`s disease – An overview of current interventional studies.* Physiotherapy Research and

p. 7737.

**3**(11): p. e003367.

Reports, 2019. **1**: p. 1-10.

2017. **8**(4): p. 313-325.

[92] Feige, J., et al., *Vitamin D* 

*Supplementation in Multiple Sclerosis: A Critical Analysis of Potentials and Threats.* Nutrients, 2020. **12**(3).

[93] Koduah, P., F. Paul, and J.M. Dorr, *Vitamin D in the prevention, prediction and treatment of neurodegenerative and neuroinflammatory diseases.* EPMA J,

*The Role of Vitamin D in Neurodegeneration and Other Pathological Processes of the Central… DOI: http://dx.doi.org/10.5772/intechopen.98390*

[88] Habibi, A.H., et al., *Treatment of Levodopainduced dyskinesia with Vitamin D: A Randomized, double-blind, placebocontrolled trial.* Neurol Int, 2018. **10**(3): p. 7737.

*Vitamin D*

**17**(3): p. 703-17.

920-928.

[71] Masoumi, A., et al., *1alpha,25 dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by macrophages of Alzheimer's disease patients.* J Alzheimers Dis, 2009. *molecular mechanisms in Parkinson's disease: Targets for potential treatments.* Translational neurodegeneration, 2017.

[80] Braak, H., et al., *Staging of brain pathology related to sporadic Parkinson's disease.* Neurobiol Aging, 2003. **24**(2):

[81] K, L.N. and L. Nguyễn, *Role of vitamin d in Parkinson's disease.* ISRN Neurol, 2012. **2012**: p. 134289.

[82] Rimmelzwaan, L.M., et al., *Systematic Review of the Relationship between Vitamin D and Parkinson's Disease.* J Parkinsons Dis, 2016. **6**(1):

N.Y.), 2020. **10**: p. 32-32.

**699**: p. 206-211.

2019. **25**: p. 666-674.

p. 1004-13.

[84] Shrestha, S., et al., *Serum* 

*25-hydroxyvitamin D concentrations in Mid-adulthood and Parkinson's disease risk.* Movement disorders : official journal of the Movement Disorder Society, 2016. **31**(7): p. 972-978.

[85] Wang, X., et al., *Vitamin D receptor polymorphisms and the susceptibility of Parkinson's disease.* Neurosci Lett, 2019.

[86] Zhou, Z., et al., *The Association Between Vitamin D Status, Vitamin D Supplementation, Sunlight Exposure, and Parkinson's Disease: A Systematic Review and Meta-Analysis.* Medical science monitor : international medical journal of experimental and clinical research,

[87] Suzuki, M., et al., *Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease.* Am J Clin Nutr, 2013. **97**(5):

[83] Homann, C.N., et al., *Vitamin D and Hyperkinetic Movement Disorders: A Systematic Review.* Tremor and other hyperkinetic movements (New York,

**6**: p. 28-28.

p. 197-211.

p. 29-37.

[72] Littlejohns, T.J., et al., *Vitamin D and the risk of dementia and Alzheimer disease.* Neurology, 2014. **83**(10): p.

[73] Annweiler, C., et al., *Higher vitamin D dietary intake is associated with lower risk of alzheimer's disease: a 7-year follow-up.* J Gerontol A Biol Sci Med Sci,

[74] Sanmartin, C., et al., *Vitamin D Increases A*β*140 Plasma Levels and Protects Lymphocytes from Oxidative Death in Mild Cognitive Impairment Patients.* Current

[75] Chaves, M., et al., *[Treatment with vitamin D and slowing of progression to severe stage of Alzheimer's disease].* Vertex, 2014. **25**(114): p. 85-91.

[76] Jia, J., et al., *Effects of vitamin D supplementation on cognitive function and blood Abeta-related biomarkers in older adults with Alzheimer's disease: a randomised, double-blind, placebocontrolled trial.* J Neurol Neurosurg Psychiatry, 2019. **90**(12): p. 1347-1352.

[77] Portillo, M.C., A. Haahr, and M.V. Navarta-Sánchez, *Management, Levels of Support, Quality of Life, and Social Inclusion in Parkinson's Disease: Interventions, Innovation, and Practice Development.* Parkinson's Disease, 2021. **2021**: p. 4681251.

[78] *Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.* Lancet Neurol,

2018. **17**(11): p. 939-953.

[79] Maiti, P., J. Manna, and G.L. Dunbar, *Current understanding of the* 

Alzheimer Research, 2017. **15**.

2012. **67**(11): p. 1205-11.

**160**

[89] Hiller, A.L., et al., *A randomized, controlled pilot study of the effects of vitamin D supplementation on balance in Parkinson's disease: Does age matter?* PLOS ONE, 2018. **13**(9): p. e0203637.

[90] Homann, B., et al., *The impact of neurological disorders on the risk for falls in the community dwelling elderly: a case-controlled study.* BMJ Open, 2013. **3**(11): p. e003367.

[91] Steiger, L. and C.N. Homann, *Exercise therapy in Parkinson`s disease – An overview of current interventional studies.* Physiotherapy Research and Reports, 2019. **1**: p. 1-10.

[92] Feige, J., et al., *Vitamin D Supplementation in Multiple Sclerosis: A Critical Analysis of Potentials and Threats.* Nutrients, 2020. **12**(3).

[93] Koduah, P., F. Paul, and J.M. Dorr, *Vitamin D in the prevention, prediction and treatment of neurodegenerative and neuroinflammatory diseases.* EPMA J, 2017. **8**(4): p. 313-325.

**163**

**Chapter 11**

**Abstract**

Disorder

Vitamin D and Autism Spectrum

*Maud Vegelin, Gosia Teodorowicz and Huub F.J. Savelkoul*

1,25(OH)2D is the hormonally active form of vitamin D known for its pleiotropic immunomodulatory effects. Via altering gene transcription, 1,25(OH) D exerts immunosuppressive effects and stimulates immune regulation. Recently, the interest in vitamin D in association with autism spectrum disorder (ASD) has been triggered. The prevalence of ASD has increased excessively over the last few decades, emphasizing the need for a better understanding of the etiology of the disorder as well as to find better treatments. Vitamin D levels in ASD patients are observed to be lower compared to healthy individuals and maternal vitamin D deficiency has been associated with an increased risk of ASD. Moreover, vitamin D supplementation improves ASD symptoms. These recent clinical findings strongly suggest that vitamin D is a factor in ASD onset and progression. Yet, possible mechanisms behind this association remain unknown. This review summarizes immunomodulatory properties of vitamin D and peripheral immune dysregulation in ASD, after which possible mechanisms via which vitamin D could rebalance the immune system in ASD are discussed. Although promising clinical results have been found, further research is necessary to draw conclusions about the effect and

mechanisms behind the effect of vitamin D on ASD development.

vitamin D responsive element, immune system

**1. Introduction**

**Keywords:** autism spectrum disorder, vitamin D, vitamin D receptor,

For many decades vitamin D has been known for its immunomodulatory effects.

When metabolized into the active hormone calcitriol, it can bind to vitamin D receptors (VDRs). These VDRs are expressed by most cells in the human body, allowing vitamin D to have a broad range of functions. Upon binding of vitamin D to a VDR, gene transcription is altered. All types of immune cells in the human body express the vitamin D receptor, enabling vitamin D to alter immune responses [1]. In general, vitamin D has immunosuppressive properties and can therefore be beneficial in diseases characterized by inflammation and autoimmunity such as multiple sclerosis and inflammatory bowel disease [2]. Vitamin D deficiency is an increasing global problem with an estimated 30% of the population suffering from vitamin D deficiency and 60% being vitamin D insufficient [3]. Inadequate levels of vitamin D can have many adverse effects throughout the body due to the abundant expression of VDRs. Furthermore, maternal vitamin D deficiency has been suggested to affect development of the offspring. To date, the World Health

#### **Chapter 11**

## Vitamin D and Autism Spectrum Disorder

*Maud Vegelin, Gosia Teodorowicz and Huub F.J. Savelkoul*

#### **Abstract**

1,25(OH)2D is the hormonally active form of vitamin D known for its pleiotropic immunomodulatory effects. Via altering gene transcription, 1,25(OH) D exerts immunosuppressive effects and stimulates immune regulation. Recently, the interest in vitamin D in association with autism spectrum disorder (ASD) has been triggered. The prevalence of ASD has increased excessively over the last few decades, emphasizing the need for a better understanding of the etiology of the disorder as well as to find better treatments. Vitamin D levels in ASD patients are observed to be lower compared to healthy individuals and maternal vitamin D deficiency has been associated with an increased risk of ASD. Moreover, vitamin D supplementation improves ASD symptoms. These recent clinical findings strongly suggest that vitamin D is a factor in ASD onset and progression. Yet, possible mechanisms behind this association remain unknown. This review summarizes immunomodulatory properties of vitamin D and peripheral immune dysregulation in ASD, after which possible mechanisms via which vitamin D could rebalance the immune system in ASD are discussed. Although promising clinical results have been found, further research is necessary to draw conclusions about the effect and mechanisms behind the effect of vitamin D on ASD development.

**Keywords:** autism spectrum disorder, vitamin D, vitamin D receptor, vitamin D responsive element, immune system

#### **1. Introduction**

For many decades vitamin D has been known for its immunomodulatory effects. When metabolized into the active hormone calcitriol, it can bind to vitamin D receptors (VDRs). These VDRs are expressed by most cells in the human body, allowing vitamin D to have a broad range of functions. Upon binding of vitamin D to a VDR, gene transcription is altered. All types of immune cells in the human body express the vitamin D receptor, enabling vitamin D to alter immune responses [1]. In general, vitamin D has immunosuppressive properties and can therefore be beneficial in diseases characterized by inflammation and autoimmunity such as multiple sclerosis and inflammatory bowel disease [2]. Vitamin D deficiency is an increasing global problem with an estimated 30% of the population suffering from vitamin D deficiency and 60% being vitamin D insufficient [3]. Inadequate levels of vitamin D can have many adverse effects throughout the body due to the abundant expression of VDRs. Furthermore, maternal vitamin D deficiency has been suggested to affect development of the offspring. To date, the World Health

Organization does not recommend vitamin D supplementation to pregnant women. This illustrates the lack of awareness on the importance of vitamin D in health.

A disorder that recently received increased attention is autism spectrum disorder (ASD). ASD is a heterogeneous neurodevelopmental disorder, collectively describing autistic disorder, Asperger's syndrome and Pervasive Developmental Disorders Not Otherwise Specified (PDD-NOS). It is characterized by behavioral deficits, impaired communicative functioning and restricted and repetitive patterns of behavior [4]. ASD onset usually occurs in the first few years of life and proceeds into childhood and adulthood [5]. Genetics are of importance in the disorder – several studies show monozygotic twins share 60–90% of ASD symptoms [5, 6]. Additionally, ASD is four times more prevalent in boys, which is suggested to be due to the protective effects of estrogens in women [5, 7].

Despite the role of genetics, the prevalence of ASD has increased tremendously over the past few decades [8]. In the Netherlands, the prevalence of ASD increased from 90.000 to 190.000 cases between 2001 and 2009 [9]. More recently, the prevalence of ASD in the US was estimated at one in every 59 children aged eight years in 2014, which increased to one in every 54 children in 2016 [10]. Across all ages, the prevalence of ASD is estimated to be 1% of the worldwide population [11, 12]. Partially, this increase can be explained by improved diagnostics and increased awareness. However, the sudden and rapid increase also suggests the role of environmental factors in ASD onset. Research indicates that genetic predisposition predominates, requiring additional environmental triggers to develop ASD. Multiple environmental factors have been suggested, including antibiotic use, maternal infections during pregnancy and sun exposure. The strong increase in prevalence highlights the importance of understanding the role of environmental factors in the etiology of ASD [6].

The association between vitamin D and ASD was suggested in 2008 when it was observed that the increase in ASD prevalence coincides with the medical advice to avoid sun exposure [7]. Since then, clinical trials have been performed, trying to prove the association between vitamin D and ASD. UV-B is the most important source of vitamin D in humans, illustrating the requirement for sunlight. Research shows ASD prevalence is higher in countries at higher latitudes, coinciding with reduced UV-B intensity. Moreover, ASD patients consistently exhibit lower vitamin D levels than healthy individuals and studies have shown maternal vitamin D deficiency increases the risk of ASD. These findings encouraged scientists to study the effect of vitamin D supplementation on improving ASD symptoms, and thus far promising results have been found [7, 13]. Yet, the mechanisms behind the possible association between vitamin D and ASD remain unknown. Neuroinflammation, oxidative stress, autoimmunity and immune dysregulation are all observed in individuals with ASD [14]. Of these phenomena, immune dysregulation is the least well-described in literature. ASD patients suffer from chronic systemic inflammation, which is illustrated by a disbalance in cytokine expression and the presence of comorbidities such as gastrointestinal problems in a large fraction of ASD patients [15]. Increased immune activation is observed in ASD patients and is associated with more severe symptoms [16]. Taking into consideration the immunosuppressive properties of vitamin D, this suggests that perhaps vitamin D could play a role in rebalancing the dysregulated immune system in ASD patients and thereby reduce systemic inflammation. However, to date there is no recommendation for vitamin D supplementation in ASD patients.

Therefore, in this review the role of vitamin D in immune dysregulation in ASD patients is examined. First, immunomodulatory properties of vitamin D in general and peripheral immune dysregulation in ASD are described, with a focus on CD4+ T cell activity. Next, possible mechanisms behind this effect of vitamin D on

**165**

**2.2 Vitamin D: mode of action**

*Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

vitamin D might slow ASD development.

**2.1 Vitamin D: production and metabolism**

**2. The immunomodulatory properties of vitamin D**

immune dysregulation in ASD are discussed. This review is summarizing current knowledge on vitamin D and ASD and to examine possible mechanisms via which

Vitamin D is a steroid hormone with varying functions in the human body. Vitamin D precursors are extracted both from food and through the exposure to sunlight. Around 10% of the total amount of vitamin D in the body is provided by dietary sources and supplements [17]. There are two forms of vitamin D precursors: D2 (ergocalciferol) and D3 (cholecalciferol). Some plant products are rich in vitamin D2, whereas vitamin D3 is present in animal products, including fish and egg yolk [18]. Sunlight exposure accounts for about 90% of vitamin D and is thus the most important source of this vitamin [17]. When the human skin is exposed to UV-B, 7-dehydrocholesterol is converted into pre-vitamin D [19]. This process depends on factors such as UV-B intensity, skin color and coverage of the skin. After the production of vitamin D3 in the body, it is first metabolized into the precursor 25-hydroxyvitamin D (25(OH)D). This reaction is performed in the liver by hydroxylases, of which CYP2R1 has the highest affinity for pre-vitamin D [20]. Vitamin D binding protein functions as a transporter of 25(OH)D to the kidney. Consequently, 1,25-dihydroxyvitamin D (1,25(OH)2D) is formed in the kidney by the enzyme CYP27B1. The activity of this enzyme is essential to produce bioactive vitamin D. 1,25(OH)2D is the hormonally active form of vitamin D [21]. In this review 1,25 (OH)2D reflects bioactive vitamin D. Besides renal CYP27B1, other cells in the human body can also express this enzyme. In this way, vitamin D can be directly synthesized not solely in the kidney but also in other tissues [20]. 1,25(OH)2D can be absorbed and then bind to the intracellular vitamin D receptor (VDR). Due to the lack of 1,25(OH)2D in its free form in the blood, vitamin D levels are based on 25(OH)D. This precursor is bound to vitamin D binding protein (DBP) in the circulation, allowing measurements to determine vitamin D levels [22, 23]. 1,25(OH)2D can influence its own serum levels and binding to VDR. When serum 1,25(OH)2D levels are high, this enhances VDR expression. Moreover, 1,25(OH)2D has a negative feedback on CYP27B1, the enzyme involved in 1,25(OH)2D synthesis. Besides self-regulation, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are important regulators of vitamin D metabolism. To sustain normal systemic vitamin D levels, CYP24A1 is stimulated by 1,25(OH)2D and degrades vitamin D. The CYP24A1 enzyme is present in all vitamin D target cells, resulting in the ability to regulate intracellular vitamin D levels [20].

By binding to VDR, which has a DNA-binding domain, 1,25(OH)2D can exert effects on the body through gene transcription. VDRs are located intracellularly in a wide range of cells. Due to this, vitamin D can exert effects on many different biological processes in the body [21, 24]. The regulation of genes by VDR is cell specific. After the binding of vitamin D to VDR, VDR interacts with the retinoic X receptor (RXR). The VDR/RXR heterodimer binds to vitamin D responsive elements (VDRE) in the promoter region of vitamin D responsive genes, influencing gene transcription [21, 25]. These VDREs are upstream of many genes and thereby exert an effect on different functions of the body. The most well-known activity

*Vitamin D*

Organization does not recommend vitamin D supplementation to pregnant women. This illustrates the lack of awareness on the importance of vitamin D in health. A disorder that recently received increased attention is autism spectrum disorder (ASD). ASD is a heterogeneous neurodevelopmental disorder, collectively describing autistic disorder, Asperger's syndrome and Pervasive Developmental Disorders Not Otherwise Specified (PDD-NOS). It is characterized by behavioral deficits, impaired communicative functioning and restricted and repetitive patterns of behavior [4]. ASD onset usually occurs in the first few years of life and proceeds into childhood and adulthood [5]. Genetics are of importance in the disorder – several studies show monozygotic twins share 60–90% of ASD symptoms [5, 6]. Additionally, ASD is four times more prevalent in boys, which is suggested to be due

Despite the role of genetics, the prevalence of ASD has increased tremendously over the past few decades [8]. In the Netherlands, the prevalence of ASD increased from 90.000 to 190.000 cases between 2001 and 2009 [9]. More recently, the prevalence of ASD in the US was estimated at one in every 59 children aged eight years in 2014, which increased to one in every 54 children in 2016 [10]. Across all ages, the prevalence of ASD is estimated to be 1% of the worldwide population [11, 12]. Partially, this increase can be explained by improved diagnostics and increased awareness. However, the sudden and rapid increase also suggests the role of environmental factors in ASD onset. Research indicates that genetic predisposition predominates, requiring additional environmental triggers to develop ASD. Multiple environmental factors have been suggested, including antibiotic use, maternal infections during pregnancy and sun exposure. The strong increase in prevalence highlights the importance of understanding the role of environmental

The association between vitamin D and ASD was suggested in 2008 when it was observed that the increase in ASD prevalence coincides with the medical advice to avoid sun exposure [7]. Since then, clinical trials have been performed, trying to prove the association between vitamin D and ASD. UV-B is the most important source of vitamin D in humans, illustrating the requirement for sunlight. Research shows ASD prevalence is higher in countries at higher latitudes, coinciding with reduced UV-B intensity. Moreover, ASD patients consistently exhibit lower vitamin D levels than healthy individuals and studies have shown maternal vitamin D deficiency increases the risk of ASD. These findings encouraged scientists to study the effect of vitamin D supplementation on improving ASD symptoms, and thus far promising results have been found [7, 13]. Yet, the mechanisms behind the possible association between vitamin D and ASD remain unknown. Neuroinflammation, oxidative stress, autoimmunity and immune dysregulation are all observed in individuals with ASD [14]. Of these phenomena, immune dysregulation is the least well-described in literature. ASD patients suffer from chronic systemic inflammation, which is illustrated by a disbalance in cytokine expression and the presence of comorbidities such as gastrointestinal problems in a large fraction of ASD patients [15]. Increased immune activation is observed in ASD patients and is associated with more severe symptoms [16]. Taking into consideration the immunosuppressive properties of vitamin D, this suggests that perhaps vitamin D could play a role in rebalancing the dysregulated immune system in ASD patients and thereby reduce systemic inflammation. However, to date there is no recommendation for vitamin D

Therefore, in this review the role of vitamin D in immune dysregulation in ASD patients is examined. First, immunomodulatory properties of vitamin D in general and peripheral immune dysregulation in ASD are described, with a focus on CD4+ T cell activity. Next, possible mechanisms behind this effect of vitamin D on

to the protective effects of estrogens in women [5, 7].

factors in the etiology of ASD [6].

supplementation in ASD patients.

**164**

immune dysregulation in ASD are discussed. This review is summarizing current knowledge on vitamin D and ASD and to examine possible mechanisms via which vitamin D might slow ASD development.

### **2. The immunomodulatory properties of vitamin D**

#### **2.1 Vitamin D: production and metabolism**

Vitamin D is a steroid hormone with varying functions in the human body. Vitamin D precursors are extracted both from food and through the exposure to sunlight. Around 10% of the total amount of vitamin D in the body is provided by dietary sources and supplements [17]. There are two forms of vitamin D precursors: D2 (ergocalciferol) and D3 (cholecalciferol). Some plant products are rich in vitamin D2, whereas vitamin D3 is present in animal products, including fish and egg yolk [18]. Sunlight exposure accounts for about 90% of vitamin D and is thus the most important source of this vitamin [17]. When the human skin is exposed to UV-B, 7-dehydrocholesterol is converted into pre-vitamin D [19]. This process depends on factors such as UV-B intensity, skin color and coverage of the skin.

After the production of vitamin D3 in the body, it is first metabolized into the precursor 25-hydroxyvitamin D (25(OH)D). This reaction is performed in the liver by hydroxylases, of which CYP2R1 has the highest affinity for pre-vitamin D [20]. Vitamin D binding protein functions as a transporter of 25(OH)D to the kidney. Consequently, 1,25-dihydroxyvitamin D (1,25(OH)2D) is formed in the kidney by the enzyme CYP27B1. The activity of this enzyme is essential to produce bioactive vitamin D. 1,25(OH)2D is the hormonally active form of vitamin D [21]. In this review 1,25 (OH)2D reflects bioactive vitamin D. Besides renal CYP27B1, other cells in the human body can also express this enzyme. In this way, vitamin D can be directly synthesized not solely in the kidney but also in other tissues [20]. 1,25(OH)2D can be absorbed and then bind to the intracellular vitamin D receptor (VDR). Due to the lack of 1,25(OH)2D in its free form in the blood, vitamin D levels are based on 25(OH)D. This precursor is bound to vitamin D binding protein (DBP) in the circulation, allowing measurements to determine vitamin D levels [22, 23].

1,25(OH)2D can influence its own serum levels and binding to VDR. When serum 1,25(OH)2D levels are high, this enhances VDR expression. Moreover, 1,25(OH)2D has a negative feedback on CYP27B1, the enzyme involved in 1,25(OH)2D synthesis. Besides self-regulation, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are important regulators of vitamin D metabolism. To sustain normal systemic vitamin D levels, CYP24A1 is stimulated by 1,25(OH)2D and degrades vitamin D. The CYP24A1 enzyme is present in all vitamin D target cells, resulting in the ability to regulate intracellular vitamin D levels [20].

#### **2.2 Vitamin D: mode of action**

By binding to VDR, which has a DNA-binding domain, 1,25(OH)2D can exert effects on the body through gene transcription. VDRs are located intracellularly in a wide range of cells. Due to this, vitamin D can exert effects on many different biological processes in the body [21, 24]. The regulation of genes by VDR is cell specific. After the binding of vitamin D to VDR, VDR interacts with the retinoic X receptor (RXR). The VDR/RXR heterodimer binds to vitamin D responsive elements (VDRE) in the promoter region of vitamin D responsive genes, influencing gene transcription [21, 25]. These VDREs are upstream of many genes and thereby exert an effect on different functions of the body. The most well-known activity

of vitamin D in the body is its role in calcium homeostasis. By stimulating calcium absorption, vitamin D enhances bone density. However, vitamin D also plays a role in many other biological processes, including the control of cancer cell proliferation, skin function, cardiovascular disease and regulation of the immune system [20]. It has vasculo-protective roles, especially in blood vessels that are sensitive to inflammation [26]. Moreover, vitamin D is important in neurocognitive development through its stimulation of nerve growth factor production [27].

#### **2.3 Vitamin D: modulating immune responses**

Vitamin D has also been described to affect both innate and adaptive immunity and is therefore considered to be immunomodulatory, including control of effector functions, increasing barrier function and stimulating regulatory T cells [28]. 1,25(OH)2D binds to a VDR which is located intracellularly. Consequently, the VDR/RXR complex translocates to the nucleus and binds to a VDRE, thereby altering gene transcription [29]. Studies show that the required 1,25(OH)2D levels are likely to be higher than the average serum vitamin D levels to facilitate immunomodulation. To maintain bone health, 1,25(OH)2D serum levels should be around 20 ng/mL or higher [30]. In contrast, 1,25(OH)2D levels should approximately be 40–80 ng/mL to reach sufficient amounts necessary for immunomodulation. These high 1,25(OH)2D levels can be achieved by the autocrine and paracrine functions of immune cells regarding vitamin D [31]. As stated before, vitamin D exerts its effects through VDRs. These receptors are expressed in all immune cells, although in ranging amounts [31]. By binding of 1,25(OH)2D to VDRs, vitamin D can activate or suppress gene transcription. Additionally, 1,25(OH)2D can exert rapid nongenomic responses. In contrast to genomic responses which require hours to days to become apparent, these rapid responses take 1 to 45 minutes [32]. Unfortunately, the exact mechanism of how this works has yet to be discovered.

Interestingly, immune cells can also affect 1,25(OH)2D levels. Most immune cells, including macrophages and dendritic cells, express CYP27B1 and CYP24A1, the enzymes needed for active vitamin D synthesis and degradation respectively. This allows immune cells to directly control 1,25(OH)2D levels in their direct local microenvironment, exerting autocrine and paracrine effects [33, 34]. This contrasts with systemic 1,25(OH)2D levels, which are regulated by CYP27B1, PTH and FGF23. Previous studies show that the negative feedback loop present in renal CYP24A1 and 1,25(OH)2D does not apply to immune cell hydroxylases. Due to this, CYP24A1 is not activated by high levels of 1,25(OH)2D, resulting in increased vitamin D levels [35].

#### **3. Peripheral immune dysregulation in ASD**

ASD is characterized not only by behavioral deficits, but also by comorbidities, including gastrointestinal problems. In addition, there is an involvement of the immune system based on the increased inflammation, autoimmunity and oxidative stress in ASD patients compared to healthy individuals [36]. Additionally, the prevalence of allergies and infections among ASD patients is higher compared to healthy individuals [37, 38]. A recent study states that approximately 60% of all ASD patients suffers from immune dysregulation [39, 40].

#### **3.1 Antigen presenting cells**

Studies indicate that innate immune activation with activated antigen presenting cells and associated cytokine production is observed in ASD patients [41]. Increased

**167**

*Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

responses to a more anti-inflammatory state [50, 51].

study reported no change in IL-1ß levels in ASD patients [57].

Altered cytokine expression has been observed in ASD patients with increased levels of pro-inflammatory cytokines IFN-y, IL-6, TNF-alpha, IL-8, IL-12, IL-17, IL-1ß, GM-CSF and MCP-1. IL-2 and IL-23. A meta-analysis described the strongest elevations were seen for IFN-y and thus Th1 cells stimulating inflammation and inhibiting Th2 proliferation in ASD patients compared to healthy individuals [52]. Besides, IL-6 is increased which as an important B cell activator enhances antibody production. In addition, IL-6 induces innate immune responses via the production of acute phase proteins [53]. Besides, IL-6 is important in signaling pathways in the central nervous system (CNS) by impairing synaptic plasticity and mediating behavioral deficits seen in ASD patients [54, 55]. IL-1ß has been shown to play a role in depression and anxiety through the hypothalamus-pituitary–adrenal (HPA) axis. Moreover, the role of IL-1ß has been suggested in training of the immune system. Upon excessive IL-1ß production, the immune system is characterized by less tolerance induction and increased prevalence of chronic inflammation [56]. However, a

**3.2 Pro-inflammatory cytokines**

numbers of monocytes with increased amounts of cytokines, with a shift towards pro-inflammatory cytokines are found in ASD patients compared to healthy individuals. IL-1β is one of these cytokines and is associated with more severe ASD symptoms. Upon TLR signaling, monocytes in ASD patients show increased activation and pro-inflammatory cytokine production [42, 43]. Macrophage or microglial activity associated with increased production of macrophage migration inhibitory factor (MIF) neuroinflammation in the brain is also altered in ASD patients [44]. MIF is a mediator of innate immunity by enhancing pro-inflammatory cytokine release and higher MIF levels result in less suppression of macrophage activity. Moreover, MIF levels are positively correlated with increased macrophage activity and thus ASD severity [45, 46]. Individuals with ASD show an increased number of dendritic cells, which is associated with more severe ASD symptoms [47]. These different findings thus illustrate increased innate immune activation in ASD patients. Monocyte and macrophage activity are increased in ASD patients, both due to increased cell numbers and increased pro-inflammatory cytokine production. Contradictory, vitamin D suppresses pro-inflammatory cytokine release by M1 macrophages, while antimicrobial activities and differentiation into M2 macrophages are stimulated. Like a balance between Th1 and Th2 cells, a balance between M1 and M2 macrophages is required for immune homeostasis. An increase in both types of macrophages could thus be beneficial, if a balance is maintained [48, 49]. Altogether, vitamin D balances macrophage function and is thereby likely to positively affect macrophage function in ASD patients. The number of dendritic cells is also increased in individuals with ASD, resulting in increased T cell activation and, indirectly, development of more severe symptoms [47]. In contrast, vitamin D can induce a tolerogenic state in dendritic cells. The expression of surface molecules required for antigen presentation and T cell activation is inhibited and a shift from pro-inflammatory to anti-inflammatory cytokine secretion arises. Via these pathways, vitamin D could affect dendritic cells in ASD patients in such a way that it facilitates immunosuppression. Besides altered cytokine profiles that illustrate changes in CD4+ T cell differentiation, this shift in subsets is also shown by absolute cell numbers. Increased Th1 and Th17 populations are observed in ASD patients, combined with a decreased Treg population. Moreover, Tregs exhibit a reduced expression of Foxp3, CD25 and CTLA-4, which are all required for regulation of immune responses. Opposingly, vitamin D positively influences Th2 and Treg populations and hereby shifts immune

#### *Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

*Vitamin D*

of vitamin D in the body is its role in calcium homeostasis. By stimulating calcium absorption, vitamin D enhances bone density. However, vitamin D also plays a role in many other biological processes, including the control of cancer cell proliferation, skin function, cardiovascular disease and regulation of the immune system [20]. It has vasculo-protective roles, especially in blood vessels that are sensitive to inflammation [26]. Moreover, vitamin D is important in neurocognitive develop-

Vitamin D has also been described to affect both innate and adaptive immunity and is therefore considered to be immunomodulatory, including control of effector functions, increasing barrier function and stimulating regulatory T cells [28]. 1,25(OH)2D binds to a VDR which is located intracellularly. Consequently, the VDR/RXR complex translocates to the nucleus and binds to a VDRE, thereby altering gene transcription [29]. Studies show that the required 1,25(OH)2D levels are likely to be higher than the average serum vitamin D levels to facilitate immunomodulation. To maintain bone health, 1,25(OH)2D serum levels should be around 20 ng/mL or higher [30]. In contrast, 1,25(OH)2D levels should approximately be 40–80 ng/mL to reach sufficient amounts necessary for immunomodulation. These high 1,25(OH)2D levels can be achieved by the autocrine and paracrine functions of immune cells regarding vitamin D [31]. As stated before, vitamin D exerts its effects through VDRs. These receptors are expressed in all immune cells, although in ranging amounts [31]. By binding of 1,25(OH)2D to VDRs, vitamin D can activate or suppress gene transcription. Additionally, 1,25(OH)2D can exert rapid nongenomic responses. In contrast to genomic responses which require hours to days to become apparent, these rapid responses take 1 to 45 minutes [32]. Unfortunately,

ment through its stimulation of nerve growth factor production [27].

the exact mechanism of how this works has yet to be discovered.

**3. Peripheral immune dysregulation in ASD**

ASD patients suffers from immune dysregulation [39, 40].

**3.1 Antigen presenting cells**

Interestingly, immune cells can also affect 1,25(OH)2D levels. Most immune cells, including macrophages and dendritic cells, express CYP27B1 and CYP24A1, the enzymes needed for active vitamin D synthesis and degradation respectively. This allows immune cells to directly control 1,25(OH)2D levels in their direct local microenvironment, exerting autocrine and paracrine effects [33, 34]. This contrasts with systemic 1,25(OH)2D levels, which are regulated by CYP27B1, PTH and FGF23. Previous studies show that the negative feedback loop present in renal CYP24A1 and 1,25(OH)2D does not apply to immune cell hydroxylases. Due to this, CYP24A1 is not activated by high levels of 1,25(OH)2D, resulting in increased vitamin D levels [35].

ASD is characterized not only by behavioral deficits, but also by comorbidities, including gastrointestinal problems. In addition, there is an involvement of the immune system based on the increased inflammation, autoimmunity and oxidative stress in ASD patients compared to healthy individuals [36]. Additionally, the prevalence of allergies and infections among ASD patients is higher compared to healthy individuals [37, 38]. A recent study states that approximately 60% of all

Studies indicate that innate immune activation with activated antigen presenting cells and associated cytokine production is observed in ASD patients [41]. Increased

**2.3 Vitamin D: modulating immune responses**

**166**

numbers of monocytes with increased amounts of cytokines, with a shift towards pro-inflammatory cytokines are found in ASD patients compared to healthy individuals. IL-1β is one of these cytokines and is associated with more severe ASD symptoms. Upon TLR signaling, monocytes in ASD patients show increased activation and pro-inflammatory cytokine production [42, 43]. Macrophage or microglial activity associated with increased production of macrophage migration inhibitory factor (MIF) neuroinflammation in the brain is also altered in ASD patients [44]. MIF is a mediator of innate immunity by enhancing pro-inflammatory cytokine release and higher MIF levels result in less suppression of macrophage activity. Moreover, MIF levels are positively correlated with increased macrophage activity and thus ASD severity [45, 46]. Individuals with ASD show an increased number of dendritic cells, which is associated with more severe ASD symptoms [47]. These different findings thus illustrate increased innate immune activation in ASD patients.

Monocyte and macrophage activity are increased in ASD patients, both due to increased cell numbers and increased pro-inflammatory cytokine production. Contradictory, vitamin D suppresses pro-inflammatory cytokine release by M1 macrophages, while antimicrobial activities and differentiation into M2 macrophages are stimulated. Like a balance between Th1 and Th2 cells, a balance between M1 and M2 macrophages is required for immune homeostasis. An increase in both types of macrophages could thus be beneficial, if a balance is maintained [48, 49]. Altogether, vitamin D balances macrophage function and is thereby likely to positively affect macrophage function in ASD patients. The number of dendritic cells is also increased in individuals with ASD, resulting in increased T cell activation and, indirectly, development of more severe symptoms [47]. In contrast, vitamin D can induce a tolerogenic state in dendritic cells. The expression of surface molecules required for antigen presentation and T cell activation is inhibited and a shift from pro-inflammatory to anti-inflammatory cytokine secretion arises. Via these pathways, vitamin D could affect dendritic cells in ASD patients in such a way that it facilitates immunosuppression. Besides altered cytokine profiles that illustrate changes in CD4+ T cell differentiation, this shift in subsets is also shown by absolute cell numbers. Increased Th1 and Th17 populations are observed in ASD patients, combined with a decreased Treg population. Moreover, Tregs exhibit a reduced expression of Foxp3, CD25 and CTLA-4, which are all required for regulation of immune responses. Opposingly, vitamin D positively influences Th2 and Treg populations and hereby shifts immune responses to a more anti-inflammatory state [50, 51].

#### **3.2 Pro-inflammatory cytokines**

Altered cytokine expression has been observed in ASD patients with increased levels of pro-inflammatory cytokines IFN-y, IL-6, TNF-alpha, IL-8, IL-12, IL-17, IL-1ß, GM-CSF and MCP-1. IL-2 and IL-23. A meta-analysis described the strongest elevations were seen for IFN-y and thus Th1 cells stimulating inflammation and inhibiting Th2 proliferation in ASD patients compared to healthy individuals [52]. Besides, IL-6 is increased which as an important B cell activator enhances antibody production. In addition, IL-6 induces innate immune responses via the production of acute phase proteins [53]. Besides, IL-6 is important in signaling pathways in the central nervous system (CNS) by impairing synaptic plasticity and mediating behavioral deficits seen in ASD patients [54, 55]. IL-1ß has been shown to play a role in depression and anxiety through the hypothalamus-pituitary–adrenal (HPA) axis. Moreover, the role of IL-1ß has been suggested in training of the immune system. Upon excessive IL-1ß production, the immune system is characterized by less tolerance induction and increased prevalence of chronic inflammation [56]. However, a study reported no change in IL-1ß levels in ASD patients [57].

A study described significantly increased TNF-alpha, IL-6 and IL-17 levels and a decrease in IL-2 by peripheral blood samples of thirty ASD individuals compared to healthy controls [58]. Another study did not find significant alterations in IL-2 levels of ASD patients compared to healthy individuals [59]. TNF-alpha and IL-12 expression are consistently proven to be elevated in ASD patients [57, 60]. IL-17 expression is shown either to be increased [61–63] or similar in ASD patients compared to healthy individuals [64, 65]. Besides IL-17, IL-21 and IL-22 are two other important Th17 cytokines. These are both shown to be increasingly expressed in ASD patients [66]. Contradicting findings exist on the expression of IL-23, a cytokine important in Th17 differentiation [64, 65, 67]. GM-CSF is shown to be elevated in ASD patients. This cytokine is important in the activation of Th17 cells and hereby plays a role in autoimmunity [68]. Contradictory, GM-CSF is also suggested to have beneficial effects on ASD symptoms. For example, GM-CSF can cross the blood brain barrier and can act as neuronal growth factor [68]. GM-CSF was associated with improved development and behavior in ASD patients. Several chemokines, including IL-8 and MCP-1, are also elevated in ASD patients. These chemokines have the capacity to attract T cells to tissue inflammation sites [69].

#### **3.3 Anti-inflammatory cytokines**

Several studies observe alterations in anti-inflammatory cytokines in ASD patients, like reductions in TGF-ß expression [70, 71]. TGF-ß being involved in immune regulation and is associated with severity of ASD symptoms; the lower the TGF-ß status, the more severe ASD symptoms are [72]. The levels of IL-10 in ASD patients remain debatable. Some studies observed increased IL-10 levels [69], while others found similar IL-10 levels [73] or even lower IL-10 levels [71, 74] in ASD patients compared to healthy individuals. IL-10 modulates inflammatory response and thus the observed increased inflammation in ASD patients could be expected to be increased. Lack of this compensatory activity of IL-10 suggests immune dysregulation. Lastly, IL-35 is also connected to regulatory T cells and was found to be reduced in ASD patients [75]. Meta-analysis findings suggest that the changes in IL-4, IL-5 and IL-13 levels in ASD patients are insignificant [70]. On the other hand, multiple studies observe increased concentrations of IL-4, IL-5 and IL-13 in ASD patients [76]. In general, a decreased level of anti-inflammatory cytokines is found in ASD patients. This can result in chronic inflammation in ASD patients [6].

In summary, pro-inflammatory cytokines and chemokines are all increasingly expressed in ASD patients while anti-inflammatory cytokines are downregulated. Nevertheless, other studies showed an increased expression of anti-inflammatory cytokines combined with a decreased expression of pro-inflammatory cytokines upon vitamin D treatment. Upon exposure to vitamin D, immune cells secrete increased amounts of the anti-inflammatory cytokines IL-10 and TGF-ß. At the same time vitamin D suppresses the production of pro-inflammatory cytokines and chemokines. This cytokine expression profile indicates that vitamin D might have protective effects against ASD development.

#### **3.4 CD4+ T cell populations**

In general, an increase in inflammatory Th1 and Th17 cells can be observed in individuals with ASD and were directly correlated with severity of symptoms [71, 77]. In contrast, increased Th2 responses are associated with improved behavior in children with ASD [72]. This suggests also beneficial effects of a Th2-skewed immune system in ASD patients. While mostly an increased Th1/Th2 ratio is observed in ASD patients compared to healthy individuals [78], others describe

**169**

*Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

decreased ratio [79].

ment should be acknowledged.

**3.5 Inflammation in ASD**

in ASD patients [13].

increased Th2 relative to Th1 [72]. This contrast illustrates immune dysregulation in ASD patients [70]. In addition, a decreased Foxp3 expression positive Treg population is observed [] as well as decreased CTLA-4 expression [72]. Also, CD25 expression in activated CD4+ and CD8+ T cells is decreased [66, 71], while others showed a

The observed dysregulation of the immune system in individuals with ASD is important not only for developing symptoms, but also affects the severity of the symptoms. In general, it can be concluded that ASD patients have increased Th1 and Th17-mediated immune responses and decreased Th2 and Tregs cytokines. Due to the increased immune activation, chronic inflammation can occur and worsen ASD symptoms. Children with genetic heritability have a higher chance of developing ASD, and the role of a disbalanced immune system in ASD develop-

In addition to peripheral immune dysregulation in ASD, other immunological dysfunctions in ASD are also of importance. The role of neuroinflammation, autoimmunity and oxidative stress have been investigated more widely in ASD patients and the importance of these processes should be noted. The difference between systemic inflammation and neuroinflammation is reflected by the fact that some cytokines are differentially expressed in the brain versus systemically. Increased TGF-ß levels are measured in the cerebellum of ASD patients, in contrast to decreased levels in the cerebrospinal fluid or the periphery [80]. Upon cell death, cells often secrete TGF-ß to reduce local inflammation. Neurons that showed degeneration were high in TGF-ß, suggesting the increased TGF-ß levels found in the brain of ASD patients are targeted at controlling neuroinflammation. Increased microglial activation, combined with increased pro-inflammatory cytokines and i-NOS activation results in neuroinflammation [41]. This is observed in a large fraction of all ASD cases and could lead to impaired connectivity in the CNS, resulting in the pathophysiology observed in ASD patients. Moreover, oxidative stress is increased in ASD patients, which is among others shown by increased i-NOS activation and the presence of reactive oxygen species. Oxidative stress can affect both immune cells and neurons, thereby causing neuroinflammation and neuron degeneration [36]. Vitamin D has been shown to increase glutamine, an antioxidant capable of counteracting the negative activities of free oxygen radicals, and to decrease nitric oxide. Via these ways, vitamin D could reduce oxidative stress

Lastly, improving ASD symptoms is touched upon most in this review by discussing immune dysregulation in ASD, prevention of ASD is another topic that requires attention. While vitamin D is presumed to play a role in immune dysregulation, and thereby systemic inflammation in ASD patients, this is thought to be limited to the progression of ASD symptoms. ASD is a neurodevelopmental disorder, indicating the importance of the CNS in the etiology and pathophysiology of ASD. Considering the onset of ASD, neuroinflammation, rather than systemic inflammation, should be focused on. Vitamin D is proven to play an important role in neuronal development, which is also illustrated by the abundance of VDRs in the CNS [81]. Maternal vitamin D deficiency and risk of ASD have been commonly shown to be associated. When maternal vitamin D deficiency occurs, insufficient vitamin D impairs neurodevelopment in the infant [82] This illustrates the importance of adequate vitamin D levels during gestation. A recent study tested the efficacy of vitamin D supplementation in pregnant mothers of children with autism on reducing the risk of autism in the newborn sibling [83]. After maternal vitamin D

#### *Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

*Vitamin D*

A study described significantly increased TNF-alpha, IL-6 and IL-17 levels and a decrease in IL-2 by peripheral blood samples of thirty ASD individuals compared to healthy controls [58]. Another study did not find significant alterations in IL-2 levels of ASD patients compared to healthy individuals [59]. TNF-alpha and IL-12 expression are consistently proven to be elevated in ASD patients [57, 60]. IL-17 expression is shown either to be increased [61–63] or similar in ASD patients compared to healthy individuals [64, 65]. Besides IL-17, IL-21 and IL-22 are two other important Th17 cytokines. These are both shown to be increasingly expressed in ASD patients [66]. Contradicting findings exist on the expression of IL-23, a cytokine important in Th17 differentiation [64, 65, 67]. GM-CSF is shown to be elevated in ASD patients. This cytokine is important in the activation of Th17 cells and hereby plays a role in autoimmunity [68]. Contradictory, GM-CSF is also suggested to have beneficial effects on ASD symptoms. For example, GM-CSF can cross the blood brain barrier and can act as neuronal growth factor [68]. GM-CSF was associated with improved development and behavior in ASD patients. Several chemokines, including IL-8 and MCP-1, are also elevated in ASD patients. These chemokines have the

capacity to attract T cells to tissue inflammation sites [69].

Several studies observe alterations in anti-inflammatory cytokines in ASD patients, like reductions in TGF-ß expression [70, 71]. TGF-ß being involved in immune regulation and is associated with severity of ASD symptoms; the lower the TGF-ß status, the more severe ASD symptoms are [72]. The levels of IL-10 in ASD patients remain debatable. Some studies observed increased IL-10 levels [69], while others found similar IL-10 levels [73] or even lower IL-10 levels [71, 74] in ASD patients compared to healthy individuals. IL-10 modulates inflammatory response and thus the observed increased inflammation in ASD patients could be expected to be increased. Lack of this compensatory activity of IL-10 suggests immune dysregulation. Lastly, IL-35 is also connected to regulatory T cells and was found to be reduced in ASD patients [75]. Meta-analysis findings suggest that the changes in IL-4, IL-5 and IL-13 levels in ASD patients are insignificant [70]. On the other hand, multiple studies observe increased concentrations of IL-4, IL-5 and IL-13 in ASD patients [76]. In general, a decreased level of anti-inflammatory cytokines is found in ASD patients. This can result in chronic inflammation in ASD patients [6]. In summary, pro-inflammatory cytokines and chemokines are all increasingly expressed in ASD patients while anti-inflammatory cytokines are downregulated. Nevertheless, other studies showed an increased expression of anti-inflammatory cytokines combined with a decreased expression of pro-inflammatory cytokines upon vitamin D treatment. Upon exposure to vitamin D, immune cells secrete increased amounts of the anti-inflammatory cytokines IL-10 and TGF-ß. At the same time vitamin D suppresses the production of pro-inflammatory cytokines and chemokines. This cytokine expression profile indicates that vitamin D might have

In general, an increase in inflammatory Th1 and Th17 cells can be observed in individuals with ASD and were directly correlated with severity of symptoms [71, 77]. In contrast, increased Th2 responses are associated with improved behavior in children with ASD [72]. This suggests also beneficial effects of a Th2-skewed immune system in ASD patients. While mostly an increased Th1/Th2 ratio is observed in ASD patients compared to healthy individuals [78], others describe

**3.3 Anti-inflammatory cytokines**

protective effects against ASD development.

**3.4 CD4+ T cell populations**

**168**

increased Th2 relative to Th1 [72]. This contrast illustrates immune dysregulation in ASD patients [70]. In addition, a decreased Foxp3 expression positive Treg population is observed [] as well as decreased CTLA-4 expression [72]. Also, CD25 expression in activated CD4+ and CD8+ T cells is decreased [66, 71], while others showed a decreased ratio [79].

The observed dysregulation of the immune system in individuals with ASD is important not only for developing symptoms, but also affects the severity of the symptoms. In general, it can be concluded that ASD patients have increased Th1 and Th17-mediated immune responses and decreased Th2 and Tregs cytokines. Due to the increased immune activation, chronic inflammation can occur and worsen ASD symptoms. Children with genetic heritability have a higher chance of developing ASD, and the role of a disbalanced immune system in ASD development should be acknowledged.

#### **3.5 Inflammation in ASD**

In addition to peripheral immune dysregulation in ASD, other immunological dysfunctions in ASD are also of importance. The role of neuroinflammation, autoimmunity and oxidative stress have been investigated more widely in ASD patients and the importance of these processes should be noted. The difference between systemic inflammation and neuroinflammation is reflected by the fact that some cytokines are differentially expressed in the brain versus systemically. Increased TGF-ß levels are measured in the cerebellum of ASD patients, in contrast to decreased levels in the cerebrospinal fluid or the periphery [80]. Upon cell death, cells often secrete TGF-ß to reduce local inflammation. Neurons that showed degeneration were high in TGF-ß, suggesting the increased TGF-ß levels found in the brain of ASD patients are targeted at controlling neuroinflammation. Increased microglial activation, combined with increased pro-inflammatory cytokines and i-NOS activation results in neuroinflammation [41]. This is observed in a large fraction of all ASD cases and could lead to impaired connectivity in the CNS, resulting in the pathophysiology observed in ASD patients. Moreover, oxidative stress is increased in ASD patients, which is among others shown by increased i-NOS activation and the presence of reactive oxygen species. Oxidative stress can affect both immune cells and neurons, thereby causing neuroinflammation and neuron degeneration [36]. Vitamin D has been shown to increase glutamine, an antioxidant capable of counteracting the negative activities of free oxygen radicals, and to decrease nitric oxide. Via these ways, vitamin D could reduce oxidative stress in ASD patients [13].

Lastly, improving ASD symptoms is touched upon most in this review by discussing immune dysregulation in ASD, prevention of ASD is another topic that requires attention. While vitamin D is presumed to play a role in immune dysregulation, and thereby systemic inflammation in ASD patients, this is thought to be limited to the progression of ASD symptoms. ASD is a neurodevelopmental disorder, indicating the importance of the CNS in the etiology and pathophysiology of ASD. Considering the onset of ASD, neuroinflammation, rather than systemic inflammation, should be focused on. Vitamin D is proven to play an important role in neuronal development, which is also illustrated by the abundance of VDRs in the CNS [81]. Maternal vitamin D deficiency and risk of ASD have been commonly shown to be associated. When maternal vitamin D deficiency occurs, insufficient vitamin D impairs neurodevelopment in the infant [82] This illustrates the importance of adequate vitamin D levels during gestation. A recent study tested the efficacy of vitamin D supplementation in pregnant mothers of children with autism on reducing the risk of autism in the newborn sibling [83]. After maternal vitamin D

supplementation and supplementation during the first three years of the newborn's lives, the risk of autism was shown to be reduced from 20% to 5%. This illustrates the importance of adequate maternal vitamin D status and the influence on ASD risk. Vitamin D supplementation is likely to be effective at reducing inflammation in ASD patients and improve symptoms of ASD. However, to prevent ASD it is more relevant to look at maternal vitamin D supplementation and the role of vitamin D in neurodevelopment. Therefore, further research should be performed to examine the possible mechanisms of vitamin D during gestation and the association with ASD development in the infant.

#### **4. Vitamin D and ASD: clinical results**

The possibility of an association between vitamin D and ASD was found when studies concluded that ASD prevalence is increased in high-latitude countries and with more cloud coverage, resulting in reduced UV-B intensity. Many studies observe the connection between low sun exposure and risk of ASD [84]. UV-B exposure is required for the conversion of 7-dehydrocholesterol into previtamin D underscoring the link between UV exposure, vitamin D generation and ASD development [85]. However, it was shown that vitamin D insufficiency in ASD patients is independent of sun exposure, ruling out the environmental factor causing vitamin D deficiency later in life. Moreover, ASD prevalence is suggested to be higher in dark skin-colored people compared to light skin-colored people [86]. It is suggested that increased skin pigmentation lowers the production of previtamin D, due to UV-B radiation that is absorbed by melanin and thereby less available for vitamin D synthesis [11]. For example, a study showed only 4.1% of the dark skin-colored pregnant women had sufficient vitamin D levels, compared to 37.3% in light skincolored pregnant women [87]. However, other studies state skin pigmentation does not influence vitamin D synthesis and that a different lifestyle, i.e. less exposure to sunlight, could explain lower vitamin D levels in dark skin-colored people [88, 89]. Thus, common vitamin D deficiency in dark skin-colored people might explain the higher ASD prevalence among this group, however results are contradictory regarding the cause of lower vitamin D status.

#### **4.1 Maternal vitamin D deficiency**

ASD prevalence is increased in children of whom the mother was vitamin D deficient during gestation [87] and thus it is suggested that maternal vitamin D deficiency increases the risk of ASD in the infant [84, 90].

The possible role of maternal vitamin D deficiency is also illustrated by the influence of season of birth on ASD risk. Maternal vitamin D levels are often lowest in winter and spring months [91], which could be explained by differences in sun exposure and UV-B intensity [85, 91]. However, studies observe conflicting results regarding seasons most positively associated with ASD risk, questioning whether birth season is indeed a cofactor influencing the risk of ASD. Multiple studies observe highest ASD prevalence in children born in March [92]. These children have a higher risk of maternal vitamin D deficiency in the second half of gestation, since maternal 25(OH)D levels are lowest in winter and spring months. On the other hand, studies observing highest ASD prevalence among children born in May, July or August also exist [93–95]. Autumn months coincided with highest ASD prevalence, while birth in spring months reduced the risk of ASD [96]. Studies show that the first six months of gestation are most important for neurocognitive development in the infant, a process which is influenced by vitamin D [97, 98]. Therefore,

**171**

factors [105, 106].

*Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

birth season and ASD risk hinder a definite conclusion.

the plausible association between vitamin D and ASD [103].

that reduced vitamin D levels are observed in ASD patients.

**4.3 Vitamin D treatment in ASD patients**

In addition to the above-mentioned environmental factors that could cause vitamin D deficiency in ASD patients and are associated with progression of the disorder, genetics also play a role. In a study that compared vitamin D levels in ASD children and their healthy siblings, lower 25(OH)D levels were found in ASD children, suggesting genetics are upstream of vitamin D deficiency in ASD patients, rather than environmental factors [104]. Moreover, most studies on neonatal vitamin D levels and the association with ASD risk have found a negative correlation, illustrating that vitamin D deficiency presumably develops during gestation and is dependent on either or both genetics and maternal environmental

Furthermore, genetic polymorphisms are shown to be associated with impaired vitamin D metabolism and binding to VDR and can therefore predispose ASD. VDR gene polymorphisms were studied of which two were significantly associated with ASD [86]. Measured 25(OH)D serum levels did not significantly correlate with gene polymorphisms, suggesting vitamin D deficiency itself is not the cause of increased ASD risk, but rather genetic mutations. However, not all ASD patients suffer from these gene mutations and thus gene polymorphisms cannot explain all ASD cases [107]. To conclude, it is uncertain whether genetic or environmental factors alone predispose vitamin D deficiency in ASD patients. Nonetheless, clinical trials agree

Due to the suggested association between vitamin D levels and ASD symptom severity, it is being investigated whether vitamin D supplementation could work as treatment to reduce ASD symptoms. The effect of vitamin D, n-3 fatty acids and the combination of the two were tested on ASD symptoms [108]. In the study,

**4.2 Vitamin D deficiency in ASD children**

it is suggested that maternal vitamin D deficiency increases the risk of ASD most when occurring in the first six months of gestation. As vitamin D levels are lowest in winter and spring, this would result in highest ASD prevalence among children who are born in summer. However, contradicting results on the association between

Studies show that children with ASD have lower vitamin D levels than healthy

children. Since 2011, vitamin D insufficiency is classified as a 25(OH)D level between 20–30 ng/mL, whereas levels below 20 ng/mL are considered vitamin D deficient [3]. Individuals with ASD on average show 25(OH)D levels below 30 ng/mL [99–101]. In a recent study, 48% of the ASD cases was vitamin D insufficient and 40% vitamin D deficient, whereas none of the healthy children were deficient and only 20% was insufficient [101]. This study used different cut-off values, resulting in the fact that when using the standard cut-off of 20 ng/ mL for vitamin D deficiency, the percentage of deficient children would even be higher than 40%. An average vitamin D level of 28.5 ng/mL was measured in ASD children, compared to 40.1 ng/mL in healthy children [102]. A significant negative correlation between vitamin D levels and severity of ASD symptoms was found, indicating low vitamin D levels can increase the severity of ASD [100]. When combining this finding with the previously mentioned association between season and vitamin D levels, this suggests the effect of season on ASD symptoms. Several case studies indeed observe that children with ASD experience less symptoms during summer compared to other seasons, which supports

*Vitamin D*

ASD development in the infant.

**4. Vitamin D and ASD: clinical results**

ing the cause of lower vitamin D status.

deficiency increases the risk of ASD in the infant [84, 90].

**4.1 Maternal vitamin D deficiency**

supplementation and supplementation during the first three years of the newborn's lives, the risk of autism was shown to be reduced from 20% to 5%. This illustrates the importance of adequate maternal vitamin D status and the influence on ASD risk. Vitamin D supplementation is likely to be effective at reducing inflammation in ASD patients and improve symptoms of ASD. However, to prevent ASD it is more relevant to look at maternal vitamin D supplementation and the role of vitamin D in neurodevelopment. Therefore, further research should be performed to examine the possible mechanisms of vitamin D during gestation and the association with

The possibility of an association between vitamin D and ASD was found when

ASD prevalence is increased in children of whom the mother was vitamin D deficient during gestation [87] and thus it is suggested that maternal vitamin D

The possible role of maternal vitamin D deficiency is also illustrated by the influence of season of birth on ASD risk. Maternal vitamin D levels are often lowest in winter and spring months [91], which could be explained by differences in sun exposure and UV-B intensity [85, 91]. However, studies observe conflicting results regarding seasons most positively associated with ASD risk, questioning whether birth season is indeed a cofactor influencing the risk of ASD. Multiple studies observe highest ASD prevalence in children born in March [92]. These children have a higher risk of maternal vitamin D deficiency in the second half of gestation, since maternal 25(OH)D levels are lowest in winter and spring months. On the other hand, studies observing highest ASD prevalence among children born in May, July or August also exist [93–95]. Autumn months coincided with highest ASD prevalence, while birth in spring months reduced the risk of ASD [96]. Studies show that the first six months of gestation are most important for neurocognitive development in the infant, a process which is influenced by vitamin D [97, 98]. Therefore,

studies concluded that ASD prevalence is increased in high-latitude countries and with more cloud coverage, resulting in reduced UV-B intensity. Many studies observe the connection between low sun exposure and risk of ASD [84]. UV-B exposure is required for the conversion of 7-dehydrocholesterol into previtamin D underscoring the link between UV exposure, vitamin D generation and ASD development [85]. However, it was shown that vitamin D insufficiency in ASD patients is independent of sun exposure, ruling out the environmental factor causing vitamin D deficiency later in life. Moreover, ASD prevalence is suggested to be higher in dark skin-colored people compared to light skin-colored people [86]. It is suggested that increased skin pigmentation lowers the production of previtamin D, due to UV-B radiation that is absorbed by melanin and thereby less available for vitamin D synthesis [11]. For example, a study showed only 4.1% of the dark skin-colored pregnant women had sufficient vitamin D levels, compared to 37.3% in light skincolored pregnant women [87]. However, other studies state skin pigmentation does not influence vitamin D synthesis and that a different lifestyle, i.e. less exposure to sunlight, could explain lower vitamin D levels in dark skin-colored people [88, 89]. Thus, common vitamin D deficiency in dark skin-colored people might explain the higher ASD prevalence among this group, however results are contradictory regard-

**170**

it is suggested that maternal vitamin D deficiency increases the risk of ASD most when occurring in the first six months of gestation. As vitamin D levels are lowest in winter and spring, this would result in highest ASD prevalence among children who are born in summer. However, contradicting results on the association between birth season and ASD risk hinder a definite conclusion.

#### **4.2 Vitamin D deficiency in ASD children**

Studies show that children with ASD have lower vitamin D levels than healthy children. Since 2011, vitamin D insufficiency is classified as a 25(OH)D level between 20–30 ng/mL, whereas levels below 20 ng/mL are considered vitamin D deficient [3]. Individuals with ASD on average show 25(OH)D levels below 30 ng/mL [99–101]. In a recent study, 48% of the ASD cases was vitamin D insufficient and 40% vitamin D deficient, whereas none of the healthy children were deficient and only 20% was insufficient [101]. This study used different cut-off values, resulting in the fact that when using the standard cut-off of 20 ng/ mL for vitamin D deficiency, the percentage of deficient children would even be higher than 40%. An average vitamin D level of 28.5 ng/mL was measured in ASD children, compared to 40.1 ng/mL in healthy children [102]. A significant negative correlation between vitamin D levels and severity of ASD symptoms was found, indicating low vitamin D levels can increase the severity of ASD [100]. When combining this finding with the previously mentioned association between season and vitamin D levels, this suggests the effect of season on ASD symptoms. Several case studies indeed observe that children with ASD experience less symptoms during summer compared to other seasons, which supports the plausible association between vitamin D and ASD [103].

In addition to the above-mentioned environmental factors that could cause vitamin D deficiency in ASD patients and are associated with progression of the disorder, genetics also play a role. In a study that compared vitamin D levels in ASD children and their healthy siblings, lower 25(OH)D levels were found in ASD children, suggesting genetics are upstream of vitamin D deficiency in ASD patients, rather than environmental factors [104]. Moreover, most studies on neonatal vitamin D levels and the association with ASD risk have found a negative correlation, illustrating that vitamin D deficiency presumably develops during gestation and is dependent on either or both genetics and maternal environmental factors [105, 106].

Furthermore, genetic polymorphisms are shown to be associated with impaired vitamin D metabolism and binding to VDR and can therefore predispose ASD. VDR gene polymorphisms were studied of which two were significantly associated with ASD [86]. Measured 25(OH)D serum levels did not significantly correlate with gene polymorphisms, suggesting vitamin D deficiency itself is not the cause of increased ASD risk, but rather genetic mutations. However, not all ASD patients suffer from these gene mutations and thus gene polymorphisms cannot explain all ASD cases [107]. To conclude, it is uncertain whether genetic or environmental factors alone predispose vitamin D deficiency in ASD patients. Nonetheless, clinical trials agree that reduced vitamin D levels are observed in ASD patients.

#### **4.3 Vitamin D treatment in ASD patients**

Due to the suggested association between vitamin D levels and ASD symptom severity, it is being investigated whether vitamin D supplementation could work as treatment to reduce ASD symptoms. The effect of vitamin D, n-3 fatty acids and the combination of the two were tested on ASD symptoms [108]. In the study, children with ASD received a daily dose of 2000 IU vitamin D3 for twelve months. This study did not find a positive effect of only vitamin D supplementation on reducing ASD symptoms. However, treatment with n-3 fatty acids only or the combined treatment with vitamin D and n-3 fatty acids did improve social awareness scores in children with ASD. In contrast, a positive effect of vitamin D treatment was observed on ASD symptoms [109]. Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) scores were used, two methods commonly used for scoring ASD symptoms. Children with ASD received one monthly dose of 150,000 IU vitamin D intramuscularly and daily doses of 400 IU vitamin D orally. After three months, both total ABC and total CARS scored were decreased significantly. These reductions were prominent in ASD children under the age of three compared to ASD children above the age of three, suggesting vitamin D treatment possibly is more effective at a younger age. Similarly, vitamin D treatment can be effective at reducing ASD symptoms. Upon receiving daily doses of 300 IU vitamin D3 per kg bodyweight orally, 67 out of 83 children with ASD experienced improved symptoms [110]. The positive effect of vitamin D was most prominent in the group with 25(OH)D levels above 40 ng/mL at the end of the study, suggesting higher vitamin D levels correlate with increased improvement of behavior. Although research is limited, recent studies on the effect of vitamin D treatment in ASD children show promising results.

A review supported the need of a high vitamin D dose for its efficacy [31]. Whereas the recommended daily intake of vitamin D is 30 ng/mL, a minimum dose of 40–80 ng/mL is suggested for vitamin D to exert its immunomodulatory effects in general. In ASD, most improved ASD symptoms upon vitamin D administration above 40 ng/mL. Worldwide it is estimated that 30% of all children and adults are vitamin D deficient, and around 60% has insufficient vitamin D levels [110]. This high percentage of insufficiency cases illustrates the need for vitamin D supplementation and/or increased sun exposure when the effect of vitamin D on the immune system is wished upon. Presumably, this would not cause adverse effects as studies on the toxicity of vitamin D have found little disease outcomes, except possibly hypercalcemia [111]. However, findings on hypercalcemia are inconsistent and it is thus not known whether hypercalcemia will indeed occur in the case of vitamin D levels above 40–80 ng/mL and most likely at a dose of 150 ng/mL [3, 91].

All in all, many clinical trials have been performed on the association between vitamin D and ASD. Low vitamin D levels are observed more often in ASD children compared to healthy children. Moreover, research indicates the role of maternal vitamin D deficiency in ASD is plausible and recent studies have illustrated the effectiveness of vitamin D treatment on improving ASD symptoms. Thus, clinical trials show promising results on the association between vitamin D and ASD and the effectiveness of vitamin D treatment in ASD patients. Lastly, rather than in ASD children there is still little research performed on immune functioning and vitamin D levels in adults with ASD as lower 25(OH)D levels were observed in adults with autistic disorder compared to healthy individuals [112]. The lack of research in this target group complicates extrapolation of the discussed results to adults. It is therefore uncertain whether vitamin D supplementation could improve ASD symptoms in adults.

#### **5. Association vitamin D and ASD**

The association between vitamin D and ASD is proven through clinical research. Clinical trials show promising results on vitamin D supplementation and the improvement of ASD symptoms. Characteristics of ASD, including behavioral deficits and impaired communicative functioning, impair the lifestyle of both

**173**

dysregulation in ASD patients with confidence.

**6. Conclusion**

*Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

patients and their close relatives – improvement of symptoms therefore would be highly beneficial [113]. Insights into the mechanisms would support a better understanding of the etiology of the disorder. Consequently, this can enhance the finding of better preventive measures and treatments. Besides the lack of research into the mechanisms behind the effect of vitamin D on ASD, further research is also required to better understand immunomodulatory properties of vitamin D in general, as well as immune dysfunction in individuals with ASD [31]. Similarly, there is a lack of research on several important cytokines in ASD patients, like IL-21, IL-22 and IL-35. Additionally, IL-10 expression in ASD patients remains debatable. Different studies have found either reduced, similar or increased IL-10 levels compared to healthy individuals. This suggests the high interpersonal variability between ASD patients and the heterogeneous etiology of the disorder, emphasizing the need for further research to determine possible subgroups on which tailored treatment design could be based [114]. In addition, the role of IL-2 in regulating immune responses in ASD remains elusive. IL-2 is a Th1 cytokine, important for T cell proliferation of effector T cells but also for regulatory T cells. Vitamin D is shown to reduce IL-2 levels. This implies a reduction in Th1 cytokines, but as IL-2 is required for TGF-ß-mediated induction of CTLA-4 and Foxp3 expression on Tregs this suggests that increased

IL-2 expression would enhance immunosuppression [115–117].

Although research on the association between vitamin D and ASD is receiving increased attention, no causality has been proven. As discussed, it is unknown whether vitamin D deficiency is caused by genetic or environmental factors. The possibility of reduced endogenous vitamin D production in ASD patients raises the question whether vitamin D insufficiency is a cause or consequence of ASD. To date, it is uncertain whether vitamin D deficiency predisposes ASD onset or is developed because of ASD. Effectiveness of vitamin D supplementation is irrespective of the outcome of causality, as clinical trials have shown promising results on the positive effect of vitamin D on ASD symptoms. However, increasing sun exposure could be less effective in the case of impaired endogenous vitamin D production in ASD patients. Research on the mechanisms behind the role of vitamin D in ASD could support a better understanding of a possible causal relationship.

Vitamin D can have immunosuppressive effects on the immune system that could be of interest in ASD. By shifting immune responses away from Th1- and Th17-mediated towards Th2- and Treg-mediated, vitamin D promotes a tolerogenic state in the immune system. This could rebalance immune dysregulation in ASD, consequently reducing systemic inflammation among others. Clinical trials on the effect of vitamin D supplementation on improving ASD symptoms and reducing ASD risk are promising, highlighting the relevance of investigating vitamin D when studying ASD. This relevance is best illustrated by the finding that increased immune activity is positively correlated with severity of ASD symptoms, a process which could be counteracted by vitamin D. However, studies on the direct mechanisms of vitamin D on the immune system in ASD patients are absent. Therefore, further research is necessary to draw conclusions about a possible causal relationship. Moreover, further research into the mechanisms behind maternal vitamin deficiency and neuroinflammation are advised to investigate possible preventive actions of vitamin D in relation to ASD. Since vitamin D toxicity is rare, it is advised to increase vitamin D levels in pregnant women and ASD patients. However, insufficient research exists to state the effectiveness of vitamin D in regulating immune

#### *Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

*Vitamin D*

children show promising results.

**5. Association vitamin D and ASD**

children with ASD received a daily dose of 2000 IU vitamin D3 for twelve months. This study did not find a positive effect of only vitamin D supplementation on reducing ASD symptoms. However, treatment with n-3 fatty acids only or the combined treatment with vitamin D and n-3 fatty acids did improve social awareness scores in children with ASD. In contrast, a positive effect of vitamin D treatment was observed on ASD symptoms [109]. Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) scores were used, two methods commonly used for scoring ASD symptoms. Children with ASD received one monthly dose of 150,000 IU vitamin D intramuscularly and daily doses of 400 IU vitamin D orally. After three months, both total ABC and total CARS scored were decreased significantly. These reductions were prominent in ASD children under the age of three compared to ASD children above the age of three, suggesting vitamin D treatment possibly is more effective at a younger age. Similarly, vitamin D treatment can be effective at reducing ASD symptoms. Upon receiving daily doses of 300 IU vitamin D3 per kg bodyweight orally, 67 out of 83 children with ASD experienced improved symptoms [110]. The positive effect of vitamin D was most prominent in the group with 25(OH)D levels above 40 ng/mL at the end of the study, suggesting higher vitamin D levels correlate with increased improvement of behavior. Although research is limited, recent studies on the effect of vitamin D treatment in ASD

A review supported the need of a high vitamin D dose for its efficacy [31]. Whereas the recommended daily intake of vitamin D is 30 ng/mL, a minimum dose of 40–80 ng/mL is suggested for vitamin D to exert its immunomodulatory effects in general. In ASD, most improved ASD symptoms upon vitamin D administration above 40 ng/mL. Worldwide it is estimated that 30% of all children and adults are vitamin D deficient, and around 60% has insufficient vitamin D levels [110]. This high percentage of insufficiency cases illustrates the need for vitamin D supplementation and/or increased sun exposure when the effect of vitamin D on the immune system is wished upon. Presumably, this would not cause adverse effects as studies on the toxicity of vitamin D have found little disease outcomes, except possibly hypercalcemia [111]. However, findings on hypercalcemia are inconsistent and it is thus not known whether hypercalcemia will indeed occur in the case of vitamin D

levels above 40–80 ng/mL and most likely at a dose of 150 ng/mL [3, 91].

All in all, many clinical trials have been performed on the association between vitamin D and ASD. Low vitamin D levels are observed more often in ASD children compared to healthy children. Moreover, research indicates the role of maternal vitamin D deficiency in ASD is plausible and recent studies have illustrated the effectiveness of vitamin D treatment on improving ASD symptoms. Thus, clinical trials show promising results on the association between vitamin D and ASD and the effectiveness of vitamin D treatment in ASD patients. Lastly, rather than in ASD children there is still little research performed on immune functioning and vitamin D levels in adults with ASD as lower 25(OH)D levels were observed in adults with autistic disorder compared to healthy individuals [112]. The lack of research in this target group complicates extrapolation of the discussed results to adults. It is therefore uncertain whether vitamin D supplementation could improve ASD symptoms in adults.

The association between vitamin D and ASD is proven through clinical research.

Clinical trials show promising results on vitamin D supplementation and the improvement of ASD symptoms. Characteristics of ASD, including behavioral deficits and impaired communicative functioning, impair the lifestyle of both

**172**

patients and their close relatives – improvement of symptoms therefore would be highly beneficial [113]. Insights into the mechanisms would support a better understanding of the etiology of the disorder. Consequently, this can enhance the finding of better preventive measures and treatments. Besides the lack of research into the mechanisms behind the effect of vitamin D on ASD, further research is also required to better understand immunomodulatory properties of vitamin D in general, as well as immune dysfunction in individuals with ASD [31]. Similarly, there is a lack of research on several important cytokines in ASD patients, like IL-21, IL-22 and IL-35. Additionally, IL-10 expression in ASD patients remains debatable. Different studies have found either reduced, similar or increased IL-10 levels compared to healthy individuals. This suggests the high interpersonal variability between ASD patients and the heterogeneous etiology of the disorder, emphasizing the need for further research to determine possible subgroups on which tailored treatment design could be based [114]. In addition, the role of IL-2 in regulating immune responses in ASD remains elusive. IL-2 is a Th1 cytokine, important for T cell proliferation of effector T cells but also for regulatory T cells. Vitamin D is shown to reduce IL-2 levels. This implies a reduction in Th1 cytokines, but as IL-2 is required for TGF-ß-mediated induction of CTLA-4 and Foxp3 expression on Tregs this suggests that increased IL-2 expression would enhance immunosuppression [115–117].

Although research on the association between vitamin D and ASD is receiving increased attention, no causality has been proven. As discussed, it is unknown whether vitamin D deficiency is caused by genetic or environmental factors. The possibility of reduced endogenous vitamin D production in ASD patients raises the question whether vitamin D insufficiency is a cause or consequence of ASD. To date, it is uncertain whether vitamin D deficiency predisposes ASD onset or is developed because of ASD. Effectiveness of vitamin D supplementation is irrespective of the outcome of causality, as clinical trials have shown promising results on the positive effect of vitamin D on ASD symptoms. However, increasing sun exposure could be less effective in the case of impaired endogenous vitamin D production in ASD patients. Research on the mechanisms behind the role of vitamin D in ASD could support a better understanding of a possible causal relationship.

#### **6. Conclusion**

Vitamin D can have immunosuppressive effects on the immune system that could be of interest in ASD. By shifting immune responses away from Th1- and Th17-mediated towards Th2- and Treg-mediated, vitamin D promotes a tolerogenic state in the immune system. This could rebalance immune dysregulation in ASD, consequently reducing systemic inflammation among others. Clinical trials on the effect of vitamin D supplementation on improving ASD symptoms and reducing ASD risk are promising, highlighting the relevance of investigating vitamin D when studying ASD. This relevance is best illustrated by the finding that increased immune activity is positively correlated with severity of ASD symptoms, a process which could be counteracted by vitamin D. However, studies on the direct mechanisms of vitamin D on the immune system in ASD patients are absent. Therefore, further research is necessary to draw conclusions about a possible causal relationship. Moreover, further research into the mechanisms behind maternal vitamin deficiency and neuroinflammation are advised to investigate possible preventive actions of vitamin D in relation to ASD. Since vitamin D toxicity is rare, it is advised to increase vitamin D levels in pregnant women and ASD patients. However, insufficient research exists to state the effectiveness of vitamin D in regulating immune dysregulation in ASD patients with confidence.

*Vitamin D*

#### **Author details**

Maud Vegelin, Gosia Teodorowicz and Huub F.J. Savelkoul\* Cell Biology and Immunology Group, Wageningen University and Research, Wageningen, The Netherlands

\*Address all correspondence to: huub.savelkoul@wur.nl

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**175**

*Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

[1] Mora, J. R., Iwata, M., & Von Andrian, U. H. (2008). Vitamin effects on the immune system: vitamins A and D take centre stage. Nature Reviews, Immunology, 8(9), 685-698. https://doi. British Medical Bulletin, 127, 91-100. https://doi.org/10.1093/bmb/ldy026

Autismespectrumstoornissen: een leven

[10] Maenner, M. J., Shaw, K. A., Baio, J., Washington, A., Patrick, M., DiRienzo, M., Christensen, D. L., Wiggins, L. D., Pettygrove, S., Andrews, J. G., Lopez, M., Hudson, A., Baroud, T., Schwenk, Y., White, T., Rosenberg, C. R., Lee, L.-C., Harrington, R. A., Huston, M., … Dietz, P. M. (2020). Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2016. MMWR. Surveillance Summaries, 69(4), 1-12. https://doi.org/10.15585/

[9] Gezondheidsraad. (2009).

lang anders. Gezondheidsraad.

mmwr.ss6904a1

ajp.2011.10101532

IJNS.2019.81436.1004

[11] El-Ansary, A., Cannell, J. J., Bjørklund, G., Bhat, R. S., Al Dbass, A. M., Alfawaz, H. A., Chirumbolo, S., & Al-Ayadhi, L. (2018). In the search for reliable biomarkers for the early diagnosis of autism spectrum disorder: the role of vitamin D. Metabolic Brain Disease, 33(3), 917-931. https://doi. org/10.1007/s11011-018-0199-1

[12] Kim, Y. S., Leventhal, B. L., Koh, Y. J., Fombonne, E., Laska, E., Lim, E. C., Cheon, K. A., Kim, S. J., Kim, Y. K., Lee, H. K., Song, D. H., & Grinker, R. R. (2011). Prevalence of autism spectrum disorders in a total population sample. American Journal of Psychiatry, 168(9), 904-912. https://doi.org/10.1176/appi.

[13] Khamoushi, A., Aalipanah, E., Sohrabi, Z., & Akbarzadeh, M. (2019). Vitamin D and Autism Spectrum Disorder: A Review. International Journal of Nutrition Sciences, 4(1), 9-13. https://doi.org/10.30476/

[2] Cantorna, M. T., Snyder, L., Lin, Y. D., & Yang, L. (2015). Vitamin D and 1,25(OH)2D regulation of T cells. In Nutrients (Vol. 7, Issue 4, pp. 3011-3021). MDPI AG. https://doi.

[3] Holick, M. F. (2017). The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. In Reviews in Endocrine and Metabolic Disorders (Vol. 18, Issue 2, pp. 153-165). Springer New York LLC. https://doi. org/10.1007/s11154-017-9424-1

[4] Kodak, T., & Bergmann, S. (2020). Autism Spectrum Disorder Characteristics, Associated Behaviors, and Early Intervention. Pediatr Clin N Am, 67, 525-535. https://doi. org/10.1016/j.pcl.2020.02.007

[5] Tchaconas, A., & Adesman, A. (2013). Autism spectrum disorders. Current Opinion in Pediatrics, 25(1), 130-144. https://doi.org/10.1097/

[6] Briceno Noriega, D., Savelkoul, H. F. J. (2014). Immune dysregulation in autism spectrum disorder. In European Journal of Pediatrics (Vol. 173, Issue 1, pp. 33-43). Springer. https://doi. org/10.1007/s00431-013-2183-4

[7] Cannell, J. J. (2008). Autism and vitamin D. Medical Hypotheses, 70(4), 750-759. https://doi.org/10.1016/j.

[8] Campisi, L., Imran, N., Nazeer, A., Skokauskas, N., & Azeem, M. W. (2018). Autism spectrum disorder.

MOP.0b013e32835c2b70

mehy.2007.08.016

**References**

org/10.1038/nri2378

org/10.3390/nu7043011

*Vitamin D and Autism Spectrum Disorder DOI: http://dx.doi.org/10.5772/intechopen.96928*

#### **References**

*Vitamin D*

**174**

**Author details**

Wageningen, The Netherlands

provided the original work is properly cited.

Maud Vegelin, Gosia Teodorowicz and Huub F.J. Savelkoul\*

\*Address all correspondence to: huub.savelkoul@wur.nl

Cell Biology and Immunology Group, Wageningen University and Research,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, [1] Mora, J. R., Iwata, M., & Von Andrian, U. H. (2008). Vitamin effects on the immune system: vitamins A and D take centre stage. Nature Reviews, Immunology, 8(9), 685-698. https://doi. org/10.1038/nri2378

[2] Cantorna, M. T., Snyder, L., Lin, Y. D., & Yang, L. (2015). Vitamin D and 1,25(OH)2D regulation of T cells. In Nutrients (Vol. 7, Issue 4, pp. 3011-3021). MDPI AG. https://doi. org/10.3390/nu7043011

[3] Holick, M. F. (2017). The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. In Reviews in Endocrine and Metabolic Disorders (Vol. 18, Issue 2, pp. 153-165). Springer New York LLC. https://doi. org/10.1007/s11154-017-9424-1

[4] Kodak, T., & Bergmann, S. (2020). Autism Spectrum Disorder Characteristics, Associated Behaviors, and Early Intervention. Pediatr Clin N Am, 67, 525-535. https://doi. org/10.1016/j.pcl.2020.02.007

[5] Tchaconas, A., & Adesman, A. (2013). Autism spectrum disorders. Current Opinion in Pediatrics, 25(1), 130-144. https://doi.org/10.1097/ MOP.0b013e32835c2b70

[6] Briceno Noriega, D., Savelkoul, H. F. J. (2014). Immune dysregulation in autism spectrum disorder. In European Journal of Pediatrics (Vol. 173, Issue 1, pp. 33-43). Springer. https://doi. org/10.1007/s00431-013-2183-4

[7] Cannell, J. J. (2008). Autism and vitamin D. Medical Hypotheses, 70(4), 750-759. https://doi.org/10.1016/j. mehy.2007.08.016

[8] Campisi, L., Imran, N., Nazeer, A., Skokauskas, N., & Azeem, M. W. (2018). Autism spectrum disorder.

British Medical Bulletin, 127, 91-100. https://doi.org/10.1093/bmb/ldy026

[9] Gezondheidsraad. (2009). Autismespectrumstoornissen: een leven lang anders. Gezondheidsraad.

[10] Maenner, M. J., Shaw, K. A., Baio, J., Washington, A., Patrick, M., DiRienzo, M., Christensen, D. L., Wiggins, L. D., Pettygrove, S., Andrews, J. G., Lopez, M., Hudson, A., Baroud, T., Schwenk, Y., White, T., Rosenberg, C. R., Lee, L.-C., Harrington, R. A., Huston, M., … Dietz, P. M. (2020). Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2016. MMWR. Surveillance Summaries, 69(4), 1-12. https://doi.org/10.15585/ mmwr.ss6904a1

[11] El-Ansary, A., Cannell, J. J., Bjørklund, G., Bhat, R. S., Al Dbass, A. M., Alfawaz, H. A., Chirumbolo, S., & Al-Ayadhi, L. (2018). In the search for reliable biomarkers for the early diagnosis of autism spectrum disorder: the role of vitamin D. Metabolic Brain Disease, 33(3), 917-931. https://doi. org/10.1007/s11011-018-0199-1

[12] Kim, Y. S., Leventhal, B. L., Koh, Y. J., Fombonne, E., Laska, E., Lim, E. C., Cheon, K. A., Kim, S. J., Kim, Y. K., Lee, H. K., Song, D. H., & Grinker, R. R. (2011). Prevalence of autism spectrum disorders in a total population sample. American Journal of Psychiatry, 168(9), 904-912. https://doi.org/10.1176/appi. ajp.2011.10101532

[13] Khamoushi, A., Aalipanah, E., Sohrabi, Z., & Akbarzadeh, M. (2019). Vitamin D and Autism Spectrum Disorder: A Review. International Journal of Nutrition Sciences, 4(1), 9-13. https://doi.org/10.30476/ IJNS.2019.81436.1004

[14] Gładysz, D., Krzywdzińska, A., & Hozyasz, K. K. (2018). Immune Abnormalities in Autism Spectrum Disorder-Could They Hold Promise for Causative Treatment? Molecular Neurobiology, 55, 6387-6435. https:// doi.org/10.1007/s12035-017-0822-x

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**184**

## *Edited by Öner Özdemir*

This book examines the sometimes controversial role of vitamin D in various health problems. Divided into four sections, chapters cover such topics as vitamin D deficiency in women, newborns, and the elderly, as well as the role of vitamin D in COVID-19, autism spectrum disorder, diabetes, dental diseases, and central nervous system pathological processes.

Published in London, UK © 2021 IntechOpen © Andrey Shevchuk / iStock

Vitamin D

Vitamin D

*Edited by Öner Özdemir*