**1. Introduction: relationship between vitamin D and neurodegenerative diseases**

The secosteroid vitamin D3 was identified in the year 1928 by Adolf Windaus and colleagues. Its synthesis starts in the skin based on 7-dehydrocholesterol through extraneous cause of ultraviolet B radiation in a spectrum of 290–315 nm wavelengths. Via the vitamin D-binding protein, it is transported in the blood to the liver where the 25-hydroxylase CYP2R1 hydroxylates vitamin D3 to 25-hydroxyvitamin D3 (25(OH)D3). Because of its serum half-life of weeks, this 25-hydroxylated form of vitamin D3 is clinically measured as an indicator for the patients' vitamin D3 level [1, 2]. The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3) or calcitriol, is synthesized in the kidney by the 1α-hydroxylase

CYP27B1. To a limited extent, vitamin D3 can also be taken up with diet as well as vitamin D2 (ergo-calciferol), which is largely found in food.

Calcitriol can perform its genomic actions via vitamin D receptor (VDR) binding. Hence this undergoes a conformational change and forms a complex with the retinoid X receptor (RXR) which interacts with the vitamin D response element (VDRE) to regulate the expression of numerous genes. Because of this ability of transcriptional modulation, vitamin D has influence on various cellular processes, for example, the mitochondrial function by maintaining the mitochondrial respiratory chain activity [3]. Dysfunctional mitochondria will normally be removed by autophagy, a process that is also promoted by vitamin D [4]. Damaged mitochondria could induce inflammation. Vitamin D is able to downregulate the expression of pro-inflammatory cytokines such as the tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6), thereby reducing inflammation [5]. Additionally to these cellular processes, vitamin D antagonizes oxidative stress by enhancing the expression of antioxidants and thereby reduces levels of reactive oxygen species (ROS) [6]. Furthermore the expression of the voltage sensitive L-type Ca2+ channels is suppressed by vitamin D to regulate intraneural calcium [7, 8]. Vitamin D also plays a role in DNA-related cellular processes, for example, epigenetic changes. These are influenced on the one hand by oxidative stress which is regulated by vitamin D, as described before, and on the other hand by histone methylation which is also modulated by vitamin D due to its influence on the transcription of key DNA demethylases [9, 10].

Based on the fact that up to 90% of the elderly population is suffering from a vitamin D hypovitaminosis because of a homebound lifestyle and the reduced ability of their skin to generate vitamin D3, the idea arose to analyze the impact of a vitamin D deficit on the abovementioned cellular processes which are all involved in ageing [11]. Moreover, ageing is a risk factor for neurodegenerative disorders. Michael J. Berridge published a very detailed article 2 years ago reviewing the influence of vitamin D deficiency on ageing and age-related diseases. He figured out that hypovitaminosis D promotes those ageing-related processes, for example, due to a decline of mitochondrial respiration or the electron transport chain. This dysfunction leads to an increase in oxidative stress and inflammation, main drivers of ageing. Furthermore, he describes elevated Ca2+ levels in neurons during ageing which are accompanied by a decline in cognition. This observation can be restored by vitamin D due to its ability to reduce the levels of Ca2+. Additionally, telomere shortening, a DNA-related process that is involved in ageing, is reported to be decreased by vitamin D [12]. Those upregulated ageing processes under vitamin D-deficient conditions in the elderly population could further lead to age-related disorders like dementia or declines in cognition.

A relationship between vitamin D and age-related cognitive disorders was further strengthened by the findings that vitamin D and its metabolites are able to cross the blood-brain barrier. Early research reported the presence of vitamin D metabolism intermediates and products in human cerebrospinal fluid [13]. Furthermore, due to the presence of the metabolizing hydroxylases in the brain, the active form of this hormone-like secosteroid can be synthesized in the human brain. The additive existence of the VDR in neuronal and glial cells suggests that vitamin D might influence functioning of the central nervous system (CNS) [14]. As mentioned earlier, the VDR-mediated nuclear functions of 1,25(OH)2D3 influence cellular processes, for example, immune modulation and cell growth or differentiation. Those biological systems have also an impact on maintaining the function of the brain. Annweiler et al. reported increased risks of cognitive disorders for patients with 25(OH)D3 serum concentrations lower than 10 ng/ml [15]. Vitamin D influences the structure of the brain, like changes in volume and vasculature as

**127**

performance [30].

*The Effects of Vitamin D Deficiency on Neurodegenerative Diseases*

well as its metabolism [16]. Furthermore, in vivo studies using offspring of vitamin D-deficient rats could show that vitamin D plays an important role in the developing brain [17]. Eyles et al. give a detailed overview in their review over all the different animal studies that have been made in this context. One exemplary finding is that rats with a vitamin D deficiency during their development have impairments

In a retrospective study from 2007, Przybelski and colleagues reported that serum 25(OH)D3 can be positively associated with increased cognitive function [19]. Consistent finding results from a prospective cohort study in older adults that showed a vitamin D hypovitaminosis (levels <30 ng/mL) in 68% of the participants and moreover that these ones have lower baseline cognitive function and increased decline over the 4 years of follow-up [20]. In the same year, another prospective study including 1185 women also pointed out an association of higher plasma 25(OH)D3 levels and better cognitive performance [21]. A meta-analysis showed that participants with insufficient vitamin D levels have a 2.4-fold increased risk of cognitive impairments than those with sufficient levels [22]. In line with this, further systematic reviews and meta-analysis support an association between hypovitaminosis D and declined cognitive functions [23, 24]. Additionally, some longitudinal studies suggest a link between low serum 25(OH)D3 levels and cognitive performance. Toffanello et al. reported decreasing scores at Mini-Mental State Examination (MMSE) in participants having serum 25(OH)D3 levels below 75 nmol/L in their 4.4-year follow-up study including 1927 elderly subjects [25]. One year later, Miller et al. published a vitamin D-associated accelerated decline in cognitive performance in their study of a multiethnic cohort of older adults [26]. In line with these data, a more recent clinical study in the elderly US population (3325 participants) reported that low serum levels of vitamin D3 are linked to an

Due to the suggested role of vitamin D in brain function, several studies examining the effect of dietary supplemented vitamin D exist. Animal studies and epidemiological studies generate biological evidences for a relationship between vitamin D levels and brain health. Latimer et al. could show that a 6-month supplementation of vitamin D improves cognitive function in a rat model of aging [28]. One study from Annweiler and colleagues in the year 2010, including 5596 women with a mean age of 80.5 years, concluded that higher weekly dietary vitamin D intake is associated with better cognitive performance in older adults [29]. In line with this, a current cross-sectional and longitudinal study describes a significant association between serum vitamin D levels below 30 nmol/L and reduced general cognitive

Unlike those animal and epidemiological findings, clinical studies using randomized controls examining the role of vitamin D in individuals without any form of dementia show heterogeneous data [31–34]. In general, it should not be disregarded that differences in clinical intervention studies might be because included participants who already had sufficient vitamin D levels at baseline could mask the benefit of supplementation on cognitive function. To prevent this, it would be beneficial including exclusively participants affected by a hypovitaminosis D at the baseline measurement. These inconclusive data also support the idea of individually adjusted supplementation protocols for each patient. Furthermore, methodological differences between the studies, for example, duration, form, and dose of vitamin D supplementation, have to be considered. A current study from Pettersen et al. [35] considered these abovementioned methodological pitfalls by administering 4000 IU/day of vitamin D3 for 18 weeks to healthy adults and by baseline as well as endpoint measurements of serum 25(OH)D3 levels. Furthermore, they were able to distinguish between the two cognitive domains, verbal and visual memory, with

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

enhanced risk of cognitive impairment [27].

in their adult behavior [18].

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

*Vitamin D Deficiency*

demethylases [9, 10].

disorders like dementia or declines in cognition.

CYP27B1. To a limited extent, vitamin D3 can also be taken up with diet as well as

Based on the fact that up to 90% of the elderly population is suffering from a vitamin D hypovitaminosis because of a homebound lifestyle and the reduced ability of their skin to generate vitamin D3, the idea arose to analyze the impact of a vitamin D deficit on the abovementioned cellular processes which are all involved in ageing [11]. Moreover, ageing is a risk factor for neurodegenerative disorders. Michael J. Berridge published a very detailed article 2 years ago reviewing the influence of vitamin D deficiency on ageing and age-related diseases. He figured out that hypovitaminosis D promotes those ageing-related processes, for example, due to a decline of mitochondrial respiration or the electron transport chain. This dysfunction leads to an increase in oxidative stress and inflammation, main drivers of ageing. Furthermore, he describes elevated Ca2+ levels in neurons during ageing which are accompanied by a decline in cognition. This observation can be restored by vitamin D due to its ability to reduce the levels of Ca2+. Additionally, telomere shortening, a DNA-related process that is involved in ageing, is reported to be decreased by vitamin D [12]. Those upregulated ageing processes under vitamin D-deficient conditions in the elderly population could further lead to age-related

A relationship between vitamin D and age-related cognitive disorders was further strengthened by the findings that vitamin D and its metabolites are able to cross the blood-brain barrier. Early research reported the presence of vitamin D metabolism intermediates and products in human cerebrospinal fluid [13]. Furthermore, due to the presence of the metabolizing hydroxylases in the brain, the active form of this hormone-like secosteroid can be synthesized in the human brain. The additive existence of the VDR in neuronal and glial cells suggests that vitamin D might influence functioning of the central nervous system (CNS) [14]. As mentioned earlier, the VDR-mediated nuclear functions of 1,25(OH)2D3 influence cellular processes, for example, immune modulation and cell growth or differentiation. Those biological systems have also an impact on maintaining the function of the brain. Annweiler et al. reported increased risks of cognitive disorders for patients with 25(OH)D3 serum concentrations lower than 10 ng/ml [15]. Vitamin D influences the structure of the brain, like changes in volume and vasculature as

Calcitriol can perform its genomic actions via vitamin D receptor (VDR) binding. Hence this undergoes a conformational change and forms a complex with the retinoid X receptor (RXR) which interacts with the vitamin D response element (VDRE) to regulate the expression of numerous genes. Because of this ability of transcriptional modulation, vitamin D has influence on various cellular processes, for example, the mitochondrial function by maintaining the mitochondrial respiratory chain activity [3]. Dysfunctional mitochondria will normally be removed by autophagy, a process that is also promoted by vitamin D [4]. Damaged mitochondria could induce inflammation. Vitamin D is able to downregulate the expression of pro-inflammatory cytokines such as the tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6), thereby reducing inflammation [5]. Additionally to these cellular processes, vitamin D antagonizes oxidative stress by enhancing the expression of antioxidants and thereby reduces levels of reactive oxygen species (ROS) [6]. Furthermore the expression of the voltage sensitive L-type Ca2+ channels is suppressed by vitamin D to regulate intraneural calcium [7, 8]. Vitamin D also plays a role in DNA-related cellular processes, for example, epigenetic changes. These are influenced on the one hand by oxidative stress which is regulated by vitamin D, as described before, and on the other hand by histone methylation which is also modulated by vitamin D due to its influence on the transcription of key DNA

vitamin D2 (ergo-calciferol), which is largely found in food.

**126**

well as its metabolism [16]. Furthermore, in vivo studies using offspring of vitamin D-deficient rats could show that vitamin D plays an important role in the developing brain [17]. Eyles et al. give a detailed overview in their review over all the different animal studies that have been made in this context. One exemplary finding is that rats with a vitamin D deficiency during their development have impairments in their adult behavior [18].

In a retrospective study from 2007, Przybelski and colleagues reported that serum 25(OH)D3 can be positively associated with increased cognitive function [19]. Consistent finding results from a prospective cohort study in older adults that showed a vitamin D hypovitaminosis (levels <30 ng/mL) in 68% of the participants and moreover that these ones have lower baseline cognitive function and increased decline over the 4 years of follow-up [20]. In the same year, another prospective study including 1185 women also pointed out an association of higher plasma 25(OH)D3 levels and better cognitive performance [21]. A meta-analysis showed that participants with insufficient vitamin D levels have a 2.4-fold increased risk of cognitive impairments than those with sufficient levels [22]. In line with this, further systematic reviews and meta-analysis support an association between hypovitaminosis D and declined cognitive functions [23, 24]. Additionally, some longitudinal studies suggest a link between low serum 25(OH)D3 levels and cognitive performance. Toffanello et al. reported decreasing scores at Mini-Mental State Examination (MMSE) in participants having serum 25(OH)D3 levels below 75 nmol/L in their 4.4-year follow-up study including 1927 elderly subjects [25]. One year later, Miller et al. published a vitamin D-associated accelerated decline in cognitive performance in their study of a multiethnic cohort of older adults [26]. In line with these data, a more recent clinical study in the elderly US population (3325 participants) reported that low serum levels of vitamin D3 are linked to an enhanced risk of cognitive impairment [27].

Due to the suggested role of vitamin D in brain function, several studies examining the effect of dietary supplemented vitamin D exist. Animal studies and epidemiological studies generate biological evidences for a relationship between vitamin D levels and brain health. Latimer et al. could show that a 6-month supplementation of vitamin D improves cognitive function in a rat model of aging [28]. One study from Annweiler and colleagues in the year 2010, including 5596 women with a mean age of 80.5 years, concluded that higher weekly dietary vitamin D intake is associated with better cognitive performance in older adults [29]. In line with this, a current cross-sectional and longitudinal study describes a significant association between serum vitamin D levels below 30 nmol/L and reduced general cognitive performance [30].

Unlike those animal and epidemiological findings, clinical studies using randomized controls examining the role of vitamin D in individuals without any form of dementia show heterogeneous data [31–34]. In general, it should not be disregarded that differences in clinical intervention studies might be because included participants who already had sufficient vitamin D levels at baseline could mask the benefit of supplementation on cognitive function. To prevent this, it would be beneficial including exclusively participants affected by a hypovitaminosis D at the baseline measurement. These inconclusive data also support the idea of individually adjusted supplementation protocols for each patient. Furthermore, methodological differences between the studies, for example, duration, form, and dose of vitamin D supplementation, have to be considered. A current study from Pettersen et al. [35] considered these abovementioned methodological pitfalls by administering 4000 IU/day of vitamin D3 for 18 weeks to healthy adults and by baseline as well as endpoint measurements of serum 25(OH)D3 levels. Furthermore, they were able to distinguish between the two cognitive domains, verbal and visual memory, with

several cognitive tests. High doses of vitamin D enhanced visual memory, while low doses (400 IU/day) improved verbal memory. As summarized by the authors, there seems to be a small positive effect of vitamin D3 supplementation on executive functioning, despite the outlined limitations (modest sample size with wide range of ages, no true placebo group) [35]. Recently, Aspell et al. give a well elaborated overview over a possible supporting role of vitamin D in cognitive function in age [36]. In the following chapter, we will present the results of current available studies examining the impact of vitamin D supplementation on brain-related disorders for each neurodegenerative disease itself. Up to this date, also the nutrition research field examines the influence of dietary components on brain health. In a recent review from Moore et al., the authors describe a potential protective role for vitamin D among others [37].
