1. Please check and comment entries here.
Table of Contents

    Topic review

    Vitamins and Neurodegenerative Disease

    Subjects: Clinical Neurology
    View times: 3
    Submitted by:


    Acquiring the recommended daily allowance of vitamins is crucial for maintaining homeostatic balance in humans and other animals. A deficiency in or dysregulation of vitamins adversely affects the neuronal metabolism, which may lead to neurodegenerative diseases. In this article, we discuss how novel vitamin-based approaches aid in attenuating abnormal neuronal functioning in neurodegeneration-based brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, and Prion disease. Vitamins show their therapeutic activity in Parkinson’s disease by antioxidative and anti-inflammatory activity. In addition, different water- and lipid-soluble vitamins have also prevented amyloid beta and tau pathology. On the other hand, some results also show no correlation between vitamin action and the prevention of neurodegenerative diseases. Some vitamins also exhibit toxic activity too. 

    1. Introduction

    In infants and elderly people, vitamin deficiency is common [1]. Prolonged deficiencies in vitamins lead to malnutrition and severe health issues [2][3]. Interestingly, the typical balanced diet of a healthy population has a rich number of vitamins, which prevent several diseases [4][5]. This has prompted researchers to explore the role of different vitamins in the development and progression of diseases. For this review, we focus on vitamins relative to neurodegenerative diseases.
    In general, vitamins are considered organic compounds that are required for the development and normal functioning of the body. The body cannot synthesize vitamins, either at all or not in sufficient quantities. As such, they must be obtained through the diet. Importantly, vitamins commonly function as antioxidants or enzymatic cofactors [6][7]. There are two main categories of vitamins: fat-soluble vitamins, which are stored in the body until your body needs them, and water-soluble vitamins, which are not stored in the body, so a continuous exogenous daily supply is required [8][9].
    Generally, vitamins offer a significant advantage for neurodegenerative diseases. Both water- and lipid-soluble vitamins prevent Parkinson’s and Alzheimer’s disease in a substantial manner. The α-synuclein toxicity has been prevented by vitamin supplementation. In addition, vitamins also exert their protective effects on the dopamine transporter. Amyloid and tau pathologies are also progressively prevented by a higher dose of vitamins. Vitamins also show their therapeutic properties for Huntington’s, Prion, and multiple sclerosis diseases. However, some studies show the contrasting activity of vitamins too for the diseases mentioned above. Some vitamins also show toxicity too.

    2. The Role of Vitamins in Neurodegenerative Disease

    2.1. Vitamins in Parkinson’s Disease

    Parkinson’s disease (PD), characterized by several motor and non-motor symptoms, arises due to the degeneration of dopaminergic neurons in the midbrain region [10][11][12][13][14]. This disease has a high incidence in the aging population [15]. Effective treatments, which can stop the initiation or prevent the progression of PD, are not currently available. Only therapies to alleviate the symptoms are available. However, symptoms become worse following prolonged treatment [16]. Now, research is focused on identifying different compounds that can prevent the progression and initiation of PD [17]. Accordingly, in recent years, a role for several vitamins has been suggested for the treatment of PD [18][19]. These vitamin treatments may offer fewer if any side effects and may improve on currently available therapies for PD.
    One of the major causative factors responsible for the progression of PD is oxidative stress, and vitamin A (VitA), along with its derivatives such as retinoic acid (RA), exhibits strong antioxidative activity [20][21]. VitA is obtained from both animal and plant sources [22]. Fish, meat, and dairy products are animal sources of preformed VitA (retinol and retinyl ester) (Figure 1) [22]. On the other hand, plant sources provide the precursors of VitA in the form of carotenoids (β-carotene, α-carotene, and β-cryptoxanthin) [22][23]. VitA is involved in multiple signaling pathways that regulate gene expression [20][24]. Specifically, in the central nervous system (CNS), VitA regulates several vital processes such as controlling neural cell differentiation and patterning in neural tube formation [25][26].
    Biomedicines 09 01284 g001
    Figure 1. Animal and plant sources of vitamin A (Retinoic acid). Vitamin A shows potent antioxidant activity. Gene regulation and neural differentiation are affected by vitamin A supplementation.

    2.2. Vitamins in Alzheimer’s Disease

    Worldwide, Alzheimer’s disease (AD) is ranked first in occurrence among all neurodegenerative diseases [27]. In the aging population, AD is the most common cause of dementia [28]. Clinical symptoms of AD begin with cognitive impairments, which further progress into dementia [29]. AD neuropathology includes the progressive degeneration of neurons, the formation of amyloid (Aβ) plaques, and neurofibrillary tangles (NFT) of the hyperphosphorylated tau protein [30][31]. As such, post-mortem analysis of AD patient brains reveals a reduction in the size of the cerebral cortex and abnormal deposits inside and around neurons [28]. Similar to other neurodegenerative diseases, one of the leading causes responsible for progressive neurodegeneration in AD is oxidative stress [32]. Accumulating evidence has shown that the antioxidative activity of vitamins may be beneficial in the treatment of AD. As such, vitamins have been used as adjuvants in AD therapy [6][33].

    2.3. Vitamins in Huntington’s Disease

    Huntington’s disease (HD) is also an example of a progressive, neurodegenerative disease of the CNS. Similar to PD and AD, motor abnormalities, dementia, and psychiatric problems are the main characteristics of HD [34][35]. HD is caused by a dominantly inherited genetic mutation that elongates a section of the huntingtin gene by the repetition of trinucleotide (CAG) segments (more than 36 repeats), leading to toxic intracellular polyglutamine aggregates and neuronal degradation [36][37] (Figure 2). Alterations in vitamins are involved in the pathogenesis of HD [38]. Oxidative stress is one of the major causative factors responsible for progressive neurodegeneration. Antioxidative therapy targeting the reactive oxygen species shows the potential impact of reducing the stress burden in associated neuronal cells [39]. Similar to AD and PD, vitamins also offer strong antioxidative activity and prevent progressive neurodegeneration in HD [40].
    Biomedicines 09 01284 g004
    Figure 2. Etiology of oxidative stress behind Huntington’s disease (HD). In HD, reduced levels of ascorbate, cysteine, and antioxidants are observed. Excitatory amino acid transporter 3 (EAAT3/EAAC1) is the cysteine transporter, which is dysregulated and responsible for the reduced uptake of cysteine. Uptake of the oxidized form of cysteine is also reduced, which is mediated through the xCT and 4F2hc complex transporter. Sodium-dependent vitamin C transporters 2 (SVCT2)-mediated uptake of ascorbate (vitamin C), which is also reduced in HD, is responsible for the compromised antioxidant defense system in neurons. Cellular components are damaged because of metal deposition such as iron (Fe) and copper (Cu) in both cytoplasms and mitochondria, generating free radicals. Additional oxidative stress generates the mutant form of huntingtin aggregates (mHtt) in both the cytoplasm and nucleus. mHtt aggregates affect vital cellular processes such as mitochondrial dysfunction, proteostasis, and autophagy. In the nucleus, mHtt affects transcription factors involved in the cell’s antioxidant defense system. mHtt also affects DNA repair processes, which are responsible for damage and the error-prone repair system. Ascorbate (vitamin C) supplementation in HD improves the antioxidant defense system and prevents disease progression.

    2.4. Vitamins in Multiple Sclerosis

    Multiple sclerosis (MS) is characterized by progressive neuroinflammation and subsequent neurodegeneration [41]. In the CNS, the body’s immune system attacks the myelin sheaths that coat and protect nerve fibers [42][43]. Movement abnormalities, vision problems, fatigue, and pain are common symptoms associated with MS. The etiology of MS is not clearly defined [44]. However, it is thought that both environmental and genetic factors are equally responsible for MS [45]. While there is no cure for MS, the usefulness of vitamins in MS therapeutics has been explored due to their antioxidant activities.
    VitD has protective activity in MS that usually depends on the patient’s developmental stage. As such, VitD supplementation was more efficacious at ameliorating MS-like neuroinflammation in a juvenile/adolescent rat model of MS compared to adult aged animals [46]. Observational studies and clinical trials have shown that a reduced level of VitD in the blood is a risk factor for developing MS [47][48][49]. Supplementation with VitD shows potent anti-inflammatory activity by increasing the oxidation of white matter. However, overdosing with VitD can lead to hypercalcaemia, a toxic build-up of calcium in the blood [48][50][51][52][53]. In MS patients, supplementation with VitD enhanced blood perfusion, which supports tissue oxygenation and, therefore, reduced neuroinflammation and neurodegeneration [54]. Several studies suggested that the level of apolipoprotein E and two isoforms of VitD binding protein (DBP) in the cerebrospinal fluid could be utilized as potential biomarkers for the diagnosis of MS [55][56]. In contrast, another study found no association between DBP, MS, and VitD in blood samples from MS patients [57]. Therefore, larger controlled clinical trials are needed to evaluate the efficacy of VitD supplementation in MS therapies.

    2.5. Vitamins in Amyotrophic Lateral Sclerosis

    Amyotrophic lateral sclerosis (ALS) is a fatal form of motor neuron disease (MND) characterized by progressive degeneration of motor neurons in the brain and spinal cord. The loss of motor neurons leads to the deterioration of whole-body muscle mass [58][59][60]. Similar to MS, very few studies have been performed regarding the role of vitamins in ALS. However, as in MS, there is a strong correlation between ALS and VitD supplementation. The active form of VitD is reduced in ALS patients and animal models of ALS [61][62]. VitD was shown to be protective in motor neurons in vitro, and plasma levels of VitD were directly correlated to the severity of the disease in ALS patients [63]. Genetic studies have shown that VitD is linked to ALS pathology through the regulation of various immune components such as toll-like receptors, major histocompatibility complex (MHC) class II molecules, poly (ADP-ribose) polymerase 1 (PARP1), and heme oxygenase-1 (HO-1) [61]. In addition, VitD influences ALS pathology through cell-signaling mechanisms, including Wnt/β-catenin, mitogen-activated protein kinase (MAPK), glutamate, prostaglandins, reactive oxygen species (ROS), matrix metalloproteinases, and nitric oxidase synthase [61]. In transgenic mouse models of ALS, VitD supplementation reduced symptoms of muscle weakness and improved motor functional capacity but did not prevent the final disease outcome [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][34][35][36][37][38][39][40][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][58][59][60][62][63][135][136][137]. In contrast, a recent study of ALS patients found no reduction in VitD levels, and no benefit for VitD supplementation for improving the prognosis of this disease [138]. Therefore, future studies are needed to determine the role of VitD in ALS pathophysiology.

    2.6. Vitamins in Prion Disease

    Prion disease (PRD), also known as transmissible spongiform encephalopathies, is a rare progressive neurodegenerative disorder caused by abnormal prion protein accumulation, which leads to subsequent brain damage [139]. Structural differences occur between two forms of a prion protein [140]. PrPC is the normal prion protein, while the misfolded PrPSc (scrapie) is the pathogenic form [141]. The difference between the two versions of the prion protein is in the secondary structure [142][143]. Secondary structure α-helix motifs within the normal protein are converted to β-sheet secondary structures, which leads to protein misfolding and toxicity. The molecular mechanisms for this conversion are unclear [144]. Vitamins prevent the transformation of the normal form of the prion protein towards the pathogenic form [145]. Various micronutrients, including copper (Cu) and iron (Fe), are also involved in the vitamin-meditated maintenance of the normal form of the prion protein [146]. In addition, it is thought that oxidative stress and inflammation lead to the formation of the pathogenic form of the prion protein. Therefore, compounds or vitamins with antioxidative and anti-inflammatory characteristics should be beneficial in decreasing the risk of PRD [145].
    Cobalamin (Cbl, Vitamin B12) deficiency plays a major role in the disturbance of the connection between the CNS and the peripheral nervous system (PNS) [147][148]. Cbl deficiency mainly affects glial cells, myelin sheaths, and the interstitium of the nervous system [149][150]. In the rat CNS, Cbl deficiency causes a reduction in the epidermal growth factor (EGF) and an enhancement of the activity of tumor necrosis factor-α (TNF-α), which leads to myelin damage and glial activation in both the CNS and PNS [151]. Interestingly, Cbl inhibits the nuclear localization of the NF-κB pathway, which is responsible for the upregulation of cytokines such as TNF-α and affects the conversion of the normal form of PrPC to the diseased form [152]. Another vitamin relevant to PRD is VitD2, which effectively crossed the BBB and suppressed PrPc oligomerization, a required step before PrPSc formation [153].

    2.7. Vitamins in Age-Related Macular Degeneration

    Not only influential in PD, AD, and HD, vitamins also exert their therapeutic response against age-related macular degeneration (AMD). Oral supplementation and modifications in diet show significant protection against AMD [154]. The Age-Related Eye Disease Study 2 (AREDS2) research group suggested that lutein/zeaxanthin plays a very vital role in the protection against AMD [155]. In AMD, the cone cell abnormalities caused by oxidative stress were significantly improved by VitD supplementation [156]. A clinical study on the Korean population exhibits that the degeneration of AMD progresses due to a lower level of VitD [157]. In the pathogenesis of AMD, the VitD metabolism plays a very novel role as suggested by a system-biology-based analysis. Therefore, we can say that vitamins are also very effective against AMD. More study will be needed to confirm the applicability and suitability of vitamins in AMD.

    3. Conclusions and Future Prospective

    Oxidative stress and neuroinflammation are the two major factors involved in the progression of neurodegenerative diseases. As such, compounds having antioxidative and anti-inflammatory properties should provide significant neuroprotection. In recent years, accumulating evidence has suggested a beneficial role for vitamins in protecting CNS diseases, as both WSV and FSV can protect neurons from death [158][159]. PD, AD, HD, MS, ALS, and PRD are the major neurodegenerative diseases found in humans. Animal models for these diseases have been utilized to prove the therapeutic efficacy of vitamins. However, the utilization of vitamins in therapies has been delayed due to studies which suggest no correlation between vitamin levels and neurodegenerative diseases. Despite this, several clinical trials support a potential role for vitamins in future therapies of neurodegenerative diseases. Hormesis is an important factor and should be taken into consideration while designing the dose of vitamins. Hormesis differentiates between the beneficial and toxic activity of vitamins at a particular dose. Multivitamin supplementation shows therapeutic solid potential for neurodegenerative diseases as compared to a single vitamin-based option. Multiple signaling pathways are involved in the multivitamin approach that can boost the antioxidative response manifold.
    Here, we discussed both beneficial and controversial studies involving the role of vitamins in neurodegenerative diseases. Future studies involving different drug-dose paradigms, diverse animal models, and various geographical locations are necessary to determine precisely the potential roles for vitamins in therapies to treat neurodegenerative diseases. Moreover, human clinical trials are desirable to prove the efficacy and the protective role of vitamins in neurodegenerative diseases.

    This entry is adapted from 10.3390/biomedicines9101284


    1. Darnton-Hill, I. Public health aspects in the prevention and control of vitamin deficiencies. Curr. Dev. Nutr. 2019, 3, nzz075.
    2. Shenkin, A. Micronutrients in health and disease. Postgrad. Med. J. 2006, 82, 559–567.
    3. Woteki, C.E.; Thomas, P.R. In eat for life: The food and nutrition board’s guide to reducing your risk of chronic disease. Clin. Nutr. Insight 1993, 19, 7.
    4. Heaney, R.P. The nutrient problem. Nutr. Rev. 2012, 70, 165–169.
    5. Shao, A.; Drewnowski, A.; Willcox, D.C.; Kramer, L.; Lausted, C.; Eggersdorfer, M.; Mathers, J.; Bell, J.D.; Randolph, R.K.; Witkamp, R.; et al. Optimal nutrition and the ever- changing dietary landscape: A conference report. Eur. J. Nutr. 2017, 56, 1–21.
    6. Kurutas, E.B. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: Current state. Nutr. J. 2015, 15, 71.
    7. Sies, H.; Stahl, W.; Sundquist, A.R. Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids. Ann. N. Y. Acad. Sci. 1992, 669, 7–20.
    8. Albahrani, A.A.; Greaves, R.F. Fat-soluble vitamins: Clinical indications and current challenges for chromatographic measurement. Clin. Biochem. Rev. 2016, 37, 27.
    9. Bruno, E.J.; Ziegenfuss, T.N. Water-soluble vitamins: Research update. Curr. Sports Med. Rep. 2005, 4, 207–213.
    10. Rai, S.N.; Birla, H.; Singh, S.S.; Zahra, W.; Patil, R.R.; Jadhav, J.P.; Gedda, M.R.; Singh, S.P. Mucuna pruriens protects against MPTP Intoxicated neuroinflammation in Parkinson’s disease through NF-κB/pAKT signaling pathways. Front. Aging Neurosci. 2017, 9, 421.
    11. Rai, S.N.; Birla, H.; Zahra, W.; Singh, S.S.; Singh, S.P. Immunomodulation of Parkinson’s disease using Mucuna pruriens (Mp). J. Chem. Neuroanat. 2017, 85, 27–35.
    12. Rai, S.N.; Zahra, W.; Singh, S.S.; Birla, H.; Keswani, C.; Dilnashin, H.; Rathore, A.S.; Singh, R.; Singh, R.K.; Singh, S.P. Anti-inflammatory activity of ursolic acid in MPTP-induced parkinsonian mouse model. Neurotox. Res. 2019, 36, 452–462.
    13. Rai, S.N.; Chaturvedi, V.K.; Singh, P.; Singh, B.K.; Singh, M.P. Mucuna pruriens in Parkinson’s and in some other diseases: Recent advancement and future prospective. 3 Biotech 2020, 10, 522.
    14. Rai, S.N.; Singh, P.; Varshney, R.; Chaturvedi, V.K.; Vamanu, E.; Singh, M.P.; Singh, B.K. Promising drug targets and associated therapeutic interventions in Parkinson’s disease. Neural Regen. Res. 2021, 16, 1730–1739.
    15. Rodriguez, M.; Rodriguez-Sabate, C.; Morales, I.; Sanchez, A.; Sabate, M. Parkinson’s disease as a result of aging. Aging Cell 2015, 14, 293–308.
    16. Goldenberg, M.M. Medical management of Parkinson’s disease. Pharm. Ther. 2008, 33, 590.
    17. Elkouzi, A.; Vedam-Mai, V.; Eisinger, R.S.; Okun, M.S. Emerging therapies in Parkinson disease—Repurposed drugs and new approaches. Nat. Rev. Neurol. 2019, 15, 204–223.
    18. Mischley, L.K.; Lau, R.C.; Bennett, R.D. Role of diet and nutritional supplements in Parkinson’s disease progression. Oxid. Med. Cell. Longev. 2017, 2017, 1–9.
    19. Ciulla, M.; Marinelli, L.; Cacciatore, I.; Stefano, A.D. Role of dietary supplements in the management of Parkinson’s disease. Biomolecules 2019, 9, 271.
    20. Huang, Z.; Liu, Y.; Qi, G.; Brand, D.; Zheng, S.G. Role of vitamin A in the immune system. J. Clin. Med. 2018, 7, 258.
    21. Dias, V.; Junn, E.; Mouradian, M. The role of oxidative stress in Parkinson’s disease. J. Park. Dis. 2013, 3, 461–491.
    22. Gilbert, C. What is vitamin A and why do we need it? Community Eye Health 2013, 26, 65.
    23. Burri, B.J.; Chang, J.S.; Neidlinger, T.R. beta-Cryptoxanthin- and alpha-carotene-rich foods have greater apparent bioavailability than beta-carotene-rich foods in Western diets. Br. J. Nutr. 2011, 105, 212–219.
    24. Al Tanoury, Z.; Piskunov, A.; Rochette-Egly, C. Vitamin A and retinoid signaling: Genomic and nongenomic effects. J. Lipid Res. 2013, 54, 1761–1775.
    25. Janesick, A.; Wu, S.C.; Blumberg, B. Retinoic acid signaling and neuronal differentiation. Cell. Mol. Life Sci. 2015, 72, 1559–1576.
    26. Tafti, M.; Ghyselinck, N.B. Functional implication of the vitamin A signaling pathway in the brain. Arch. Neurol. 2007, 64, 1706–1711.
    27. Dong, R.; Wang, H.; Ye, J.; Wang, M.; Bi, Y. Publication trends for Alzheimer’s disease worldwide and in China: A 30-year bibliometric analysis. Front. Human Neurosci. 2019, 13, 259.
    28. Serrano-Pozo, A.; Frosch, M.P.; Masliah, E.; Hyman, B.T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2011, 1, a006189.
    29. DeTure, M.A.; Dickson, D.W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegen. 2019, 14, 1–18.
    30. Lacosta, A.-M.; Insua, D.; Badi, H.; Pesini, P.; Sarasa, M. Neurofibrillary tangles of Aβ x- 40 in Alzheimer’s disease brains. J. Alzheimers Dis. 2017, 58, 661–667.
    31. Castellani, R.J.; Lee, H.-G.; Zhu, X.; Nunomura, A.; Perry, G.; Smith, M.A. Neuropathology of Alzheimer disease: Pathognomonic but not pathogenic. Acta Neuropathol. 2006, 111, 503–509.
    32. Tönnies, E.; Trushina, E. Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J. Alz. Dis. 2017, 57, 1105–1121.
    33. Tan, B.L.; Norhaizan, M.E.; Liew, W.P.; Sulaiman Rahman, H. Antioxidant and oxidative stress: A mutual interplay in age-related diseases. Front. Pharmacol. 2018, 9, 1162.
    34. Caron, N.S.; Wright, G.E.B.; Hayden, M.R. Huntington Disease; Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Stephens, K., Amemiya, A., Eds.; GeneReviews: Seattle, DC, USA, 1993. Available online: http://www.ncbi.nlm.nih.gov/books/nbk1305/ (accessed on 17 September 2021).
    35. Dayalu, P.; Albin, R.L. Huntington disease: Pathogenesis and treatment. Neurol. Clin. 2015, 33, 101–114.
    36. Chel, V.G.; Ooms, M.E.; van der Bent, J.; Veldkamp, F.; Roos, R.A.; Achterberg, W.P.; Lips, P. High prevalence of vitamin D deficiency and insufficiency in patients with manifest Huntington disease: An explorative study. Dermato Endocrinol. 2013, 5, 348–351.
    37. Roos, R. Huntington’s disease: A clinical review. Orphanet J. Rare Dis. 2010, 5, 40.
    38. Patassini, S.; Begley, P.; Xu, J.; Church, S.J.; Kureishy, N.; Reid, S.J.; Waldvogel, H.J.; Faull, R.L.; Snell, R.G.; Unwin, R.D. Cerebral vitamin B5 (D-Pantothenic Acid) deficiency as a potential cause of metabolic perturbation and neurodegeneration in Huntington’s disease. Metabolites 2019, 9, 113.
    39. Uttara, B.; Singh, A.V.; Zamboni, P.; Mahajan, R.T. Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Curr. Neuropharmacol. 2009, 7, 65–74.
    40. Johri, A.; Beal, M.F. Antioxidants in Huntington’s disease. Biochim. Biophys. Acta 2012, 1822, 664–674.
    41. Fitzner, D.; Simons, M. Chronic progressive multiple sclerosis-pathogenesis of neurodegeneration and therapeutic strategies. Curr. Neuropharmacol. 2010, 8, 305–315.
    42. Correale, J.; Marrodan, M.; Ysrraelit, M.C. Mechanisms of neurodegeneration and axonal dysfunction in progressive multiple sclerosis. Biomedicines 2019, 7, 14.
    43. Miljković, D.; Spasojević, I. Multiple sclerosis: Molecular mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 2013, 19, 2286–2334.
    44. Serra, A.; Chisari, C.G.; Matta, M. Eye movement abnormalities in multiple sclerosis: Pathogenesis, modeling, and treatment. Front. Neurol. 2018, 9, 31.
    45. Dobson, R.; Giovannoni, G. Multiple sclerosis—A review. Eur. J. Neurol. 2019, 26, 27–40.
    46. Adzemovic, M.Z.; Zeitelhofer, M.; Hochmeister, S.; Gustafsson, S.A.; Jagodic, M. Efficacy of vitamin D in treating multiple sclerosis-like neuroinflammation depends on developmental stage. Exp. Neurol. 2013, 249, 39–48.
    47. Munger, K.L.; Åivo, J.; Hongell, K.; Soilu-Hänninen, M.; Surcel, H.-M.; Ascherio, A. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish maternity cohort. JAMA Neurol. 2016, 73, 515–519.
    48. Smolders, J.; Damoiseaux, J.; Menheere, P.; Hupperts, R. Vitamin D as an immune modulator in multiple sclerosis, a review. J. Neuroimmun. 2008, 194, 7–17.
    49. Sintzel, M.B.; Rametta, M.; Reder, A.T. Vitamin D and multiple sclerosis: A comprehensive review. Neurol. Ther. 2018, 7, 59–85.
    50. Ascherio, A.; Weisskopf, M.G.; O’Reilly, E.J.; Jacobs, E.J.; McCullough, M.L.; Calle, E.E.; Cudkowicz, M.; Thun, M.J. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann. Neurol. 2005, 57, 104–110.
    51. Niino, M.; Fukazawa, T.; Kikuchi, S.; Sasaki, H. Therapeutic potential of vitamin D for multiple sclerosis. Curr. Med. Chem. 2008, 15, 499–505.
    52. Ramagopalan, S.V.; Dobson, R.; Meier, U.C.; Giovannoni, G. Multiple sclerosis: Risk factors, prodromes, and potential causal pathways. Lancet Neurol. 2010, 9, 727–739.
    53. Sandberg, L.; Biström, M.; Salzer, J.; Vågberg, M.; Svenningsson, A.; Sundström, P. Vitamin D and axonal injury in multiple sclerosis. Mult. Scler. J. 2016, 22, 1027–1031.
    54. Muller, T.; Lohse, L.; Blodau, A.; Frommholz, K. Vitamin D rise enhances blood perfusion in patients with multiple sclerosis. J. Neural Transm. 2019, 126, 1631–1636.
    55. Perga, S.; Albo, A.G.; Lis, K.; Minari, N.; Falvo, S.; Marnetto, F.; Caldano, M.; Reviglione, R.; Berchialla, P.; Capobianco, M.A. Vitamin D binding protein isoforms and apolipoprotein E in cerebrospinal fluid as prognostic biomarkers of multiple sclerosis. PLoS ONE 2015, 10, e0129291.
    56. Disanto, G.; Ramagopalan, S.V.; Para, A.E.; Handunnetthi, L. The emerging role of vitamin D binding protein in multiple sclerosis. J. Neurol. 2011, 258, 353–358.
    57. Smolders, J.; Peelen, E.; Thewissen, M.; Menheere, P.; Damoiseaux, J.; Hupperts, R. Circulating vitamin D binding protein levels are not associated with relapses or with vitamin D status in multiple sclerosis. Mult. Scler. J. 2014, 20, 433–437.
    58. Talbot, K. Motor neuron disease: The bare essentials. Pract. Neurol. 2009, 9, 303–309.
    59. Martin, S.; Al Khleifat, A.; Al-Chalabi, A. What causes amyotrophic lateral sclerosis? F1000Research 2017, 6, 371.
    60. Zarei, S.; Carr, K.; Reiley, L.; Diaz, K.; Guerra, O.; Altamirano, P.F.; Pagani, W.; Lodin, D.; Orozco, G.; Chinea, A. A comprehensive review of amyotrophic lateral sclerosis. Surg. Neurol. Int. 2015, 6, 171.
    61. Luong, K.V.Q.; Nguyễn, L.T.H. Roles of vitamin D in amyotrophic lateral sclerosis: Possible genetic and cellular signaling mechanisms. Mol. Brain 2013, 6, 16.
    62. Cortese, R.; D’Errico, E.; Introna, A.; Schirosi, G.; Scarafino, A.; Distaso, E.; Nazzaro, P.; Zoccolella, S.; Simone, I. Vitamin D levels in serum of amyotrophic lateral sclerosis patients. (P2. 069). AAN Enterp. 2015, 84, 14S.
    63. Camu, W.; Tremblier, B.; Plassot, C.; Alphandery, S.; Salsac, C.; Pageot, N.; Juntas-Morales, R.; Scamps, F.; Daures, J.P.; Raoul, C. Vitamin D confers protection to motoneurons and is a prognostic factor of amyotrophic lateral sclerosis. Neurobiol. Aging 2014, 35, 1198–1205.
    64. Duong, S.; Patel, T.; Chang, F. Dementia: What pharmacists need to know. Can. Pharm. J./Rev. Pharm. Can. 2017, 150, 118–129.
    65. Cunningham, E.L.; McGuinness, B.; Herron, B.; Passmore, A.P. Dementia. Ulster Med. J. 2015, 84, 79–87.
    66. Gibson, G.E.; Hirsch, J.A.; Fonzetti, P.; Jordon, B.D.; Cirio, R.T.; Elder, J. Vitamin B1 (thiamine) and dementia. Ann. N. Y. Acad. Sci. 2016, 1367, 21.
    67. Blundo, C.; Marin, D.; Ricci, M. Vitamin B12 deficiency associated with symptoms of frontotemporal dementia. Neurol. Sci. 2011, 32, 101–105.
    68. Malaguarnera, M.; Ferri, R.; Bella, R.; Alagona, G.; Carnemolla, A.; Pennisi, G. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin. Chem. Lab. Med. 2004, 42, 1032–1035.
    69. Hegyi, J.; Schwartz, R.A.; Hegyi, V. Pellagra: Dermatitis, dementia, and diarrhea. Int. J. Dermatol. 2004, 43, 1–5.
    70. Zhang, X.Y.; Xu, Z.P.; Wang, W.; Cao, J.B.; Fu, Q.; Zhao, W.X.; Li, Y.; Huo, X.L.; Zhang, L.M.; Li, Y.F.; et al. Vitamin C alleviates LPS-induced cognitive impairment in mice by suppressing neuroinflammation and oxidative stress. Int. Immunopharmacol. 2018, 65, 438–447.
    71. Olajide, O.J.; Yawson, E.O.; Gbadamosi, I.T.; Arogundade, T.T.; Lambe, E.; Obasi, K.; Lawal, I.T.; Ibrahim, A.; Ogunrinola, K.Y. Ascorbic acid ameliorates behavioural deficits and neuropathological alterations in rat model of Alzheimer’s disease. Environ. Toxicol. Pharmacol. 2017, 50, 200–211.
    72. Sil, S.; Ghosh, T.; Gupta, P.; Ghosh, R.; Kabir, S.N.; Roy, A. Dual Role of Vitamin C on the Neuroinflammation Mediated Neurodegeneration and Memory Impairments in Colchicine Induced Rat Model of Alzheimer Disease. J. Mol. Neurosci. 2016, 60, 421–435.
    73. Yamini, P.; Ray, R.S.; Chopra, K. Vitamin D3 attenuates cognitive deficits and neuroinflammatory responses in ICV-STZ induced sporadic Alzheimer’s disease. Inflammopharmacology 2018, 26, 39–55.
    74. Briones, T.L.; Darwish, H. Vitamin D mitigates age-related cognitive decline through the modulation of pro-inflammatory state and decrease in amyloid burden. J. Neuroinflam. 2012, 9, 244.
    75. El-Din, S.S.; Rashed, L.; Medhat, E.; Aboulhoda, B.E.; Badawy, A.D.; ShamsEldeen, A.M.; Abdelgwad, M. Active form of vitamin D analogue mitigates neurodegenerative changes in Alzheimer’s disease in rats by targeting Keap1/Nrf2 and MAPK-38p/ERK signaling pathways. Steroids 2020, 156, 108586.
    76. Ertilav, E.; Barcin, N.E.; Ozdem, S. Comparison of Serum Free and Bioavailable 25- Hydroxyvitamin D Levels in Alzheimer’s Disease and Healthy Control Patients. Lab. Med. 2020, 52, 219–225.
    77. Ali, A.; Shah, S.A.; Zaman, N.; Uddin, M.N.; Khan, W.; Ali, A.; Riaz, M.; Kamil, A. Vitamin D Exerts Neuroprotection via SIRT1/Nrf-2/ NF-kB Signaling Pathways against D-Galactose-induced Memory Impairment in Adult Mice. Neurochem. Int. 2020, 4, 104893.
    78. Fan, Y.G.; Pang, Z.Q.; Wu, T.Y.; Zhang, Y.H.; Xuan, W.Q.; Wang, Z.; Yu, X.; Li, Y.C.; Guo, C.; Wang, Z.Y. Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity. Free Radic. Biol. Med. 2020, 161, 139–149.
    79. Boccardi, V.; Baroni, M.; Mangialasche, F.; Mecocci, P. Vitamin E family: Role in the pathogenesis and treatment of Alzheimer’s disease. Alzheimers Dement. 2016, 2, 182–191.
    80. Yu, L.; Chen, Y.; Wang, W.; Xiao, Z.; Hong, Y. Multi-vitamin B supplementation reverses hypoxia-induced tau hyperphosphorylation and improves memory function in adult mice. J. Alzheimers Dis. 2016, 54, 297–306.
    81. Huang, J.K.; Jarjour, A.A.; Oumesmar, B.N.; Kerninon, C.; Williams, A.; Krezel, W.; Kagechika, H.; Bauer, J.; Zhao, C.; Baron-Van Evercooren, A. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat. Neurosci. 2011, 14, 45.
    82. Maden, M.; Holder, N. The involvement of retinoic acid in the development of the vertebrate central nervous system. Dev. Suppl. 1991, 113, 87–94.
    83. Chakrabarti, M.; McDonald, A.J.; Will Reed, J.; Moss, M.A.; Das, B.C.; Ray, S.K. Molecular signaling mechanisms of natural and synthetic retinoids for inhibition of pathogenesis in Alzheimer’s disease. J. Alzheimers Dis. 2016, 50, 335–352.
    84. Lane, M.A.; Bailey, S.J. Role of retinoid signalling in the adult brain. Prog. Neurobiol. 2005, 75, 275–293.
    85. Lee, H.-P.; Casadesus, G.; Zhu, X.; Lee, H.-G.; Perry, G.; Smith, M.A.; Gustaw-Rothenberg, K.; Lerner, A. All-trans retinoic acid as a novel therapeutic strategy for Alzheimer’s disease. Exp. Rev. Neurotherap. 2009, 9, 1615–1621.
    86. Niewiadomska-Cimicka, A.; Krzyżosiak, A.; Ye, T.; Podleśny-Drabiniok, A.; Dembélé, D.; Dollé, P.; Krężel, W. Genome-wide analysis of RARβ transcriptional targets in mouse striatum links retinoic acid signaling with Huntington’s disease and other neurodegenerative disorders. Mol. Neurobiol. 2017, 54, 3859–3878.
    87. Rataj-Baniowska, M.; Niewiadomska-Cimicka, A.; Paschaki, M.; Szyszka-Niagolov, M.; Carramolino, L.; Torres, M.; Dollé, P.; Krężel, W. Retinoic acid receptor β controls development of striatonigral projection neurons through FGF-dependent and Meis1- dependent mechanisms. J. Neurosci. 2015, 35, 14467–14475.
    88. Moutinho, M.; Codocedo, J.F.; Puntambekar, S.S.; Landreth, G.E. Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation. Ann. Rev. Pharmacol. Toxicol. 2019, 59, 237–261.
    89. Li, J.Y.; Popovic, N.; Brundin, P. The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies. NeuroRx 2005, 2, 447–464.
    90. Liu, D.; Ke, Z.; Luo, J. Thiamine deficiency and neurodegeneration: The interplay among oxidative stress, endoplasmic reticulum stress, and autophagy. Mol. Neurobiol. 2017, 54, 5440–5448.
    91. Lonsdale, D. Thiamin and protein folding. Med. Hypotheses 2019, 129, 109252.
    92. Wang, X.; Xu, M.; Frank, J.A.; Ke, Z.J.; Luo, J. Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells. Toxicol. Appl. Pharmacol. 2017, 320, 26–31.
    93. Gruber-Bzura, B.M.; Krzysztoń-Russjan, J.; Bubko, I.; Syska, J.; Jaworska, M.; Zmysłowski, A.; Rosłon, M.; Drozd, J.; Drozd, E.; Majorczyk, E. Role of thiamine in Huntington’s disease pathogenesis: In vitro studies. Adv. Clin. Exp. Med. 2017, 26, 751–760.
    94. Sidhu, A.; Diwan, V.; Kaur, H.; Bhateja, D.; Singh, C.K.; Sharma, S.; Padi, S.S. Nicotinamide reverses behavioral impairments and provides neuroprotection in 3-nitropropionic acid induced animal model ofHuntington’s disease: Implication of oxidative stress- poly (ADP- ribose) polymerase pathway. Metab. Brain Dis. 2018, 33, 1911–1921.
    95. Blanchet, M.; Prince, F.; Chouinard, S.; Messier, J. Postural stability limits in manifest and premanifest Huntington’s disease under different sensory conditions. Neuroscience 2014, 279, 102–112.
    96. Montero-Odasso, M.; Pieruccini-Faria, F.; Bartha, R.; Black, S.E.; Finger, E.; Freedman, M.; Greenberg, B.; Grimes, D.A.; Hegele, R.A.; Hudson, C.; et al. Motor phenotype in neurodegenerative disorders: Gait and balance platform study design protocol for the ontario neurodegenerative research initiative (ONDRI). J. Alzheimers Dis. 2017, 59, 707–721.
    97. Wilczynski, J.; Pedrycz, A.; Mucha, D.; Ambrozy, T.; Mucha, D. Body posture, postural stability, and metabolic age in patients with Parkinson’s disease. BioMed Res. Int. 2017, 2017, 3975417.
    98. Aghajanian, P.; Hall, S.; Wongworawat, M.D.; Mohan, S. The roles and mechanisms of actions of vitamin C in bone: New developments. J. Bone Min. Res. 2015, 30, 1945–1955.
    99. Rebec, G.V.; Barton, S.J.; Marseilles, A.M.; Collins, K. Ascorbate treatment attenuates the Huntington behavioral phenotype in mice. Neuroreport 2003, 14, 1263–1265.
    100. Mahmoud, S.; Gharagozloo, M.; Simard, C.; Gris, D. Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells 2019, 8, 184.
    101. Rebec, G.V. Dysregulation of corticostriatal ascorbate release and glutamate uptake in transgenic models of Huntington’s disease. Antiox. Redox Sig. 2013, 19, 2115–2128.
    102. Dorner, J.L.; Miller, B.R.; Klein, E.L.; Murphy-Nakhnikian, A.; Andrews, R.L.; Barton, S.J.; Rebec, G.V. Corticostriatal dysfunction underlies diminished striatal ascorbate release in the R6/2 mouse model of Huntington’s disease. Brain Res. 2009, 1290, 111–120.
    103. Sahay, M.; Sahay, R. Rickets–vitamin D deficiency and dependency. Indian J. Endocrinol. Metab. 2012, 16, 164.
    104. Rejnmark, L. Effects of vitamin d on muscle function and performance: A review of evidence from randomized controlled trials. Ther. Adv. Chronic. Dis. 2011, 2, 25–37.
    105. Molnar, M.F.; Torok, R.; Szalardy, L.; Sumegi, E.; Vecsei, L.; Klivenyi, P. High-dose 1,25-dihydroxyvitamin D supplementation elongates the lifespan of Huntington’s disease transgenic mice. Acta Neurobiol. Exp. 2016, 76, 176–181.
    106. Peyser, C.E.; Folstein, M.; Chase, G.A.; Starkstein, S.; Brandt, J.; Cockrell, J.R.; Bylsma, F.; Coyle, J.T.; McHugh, P.R.; Folstein, S.E. Trial of d-!a-tocopherol in Huntington’s disease. Am. J. Psychiatry. 1995, 152, 1771–1775.
    107. Kašparová, S.; Sumbalová, Z.; Bystrický, P.; Kucharská, J.; Liptaj, T.; Mlynárik, V.; Gvozdjáková, A. Effect of coenzyme Q10 and vitamin E on brain energy metabolism in the animal model of Huntington’s disease. Neurochem. Int. 2006, 48, 93–99.
    108. Fragoso, Y.D.; Stoney, P.N.; McCaffery, P.J. The evidence for a beneficial role of vitamin A in multiple sclerosis. CNS Drugs 2014, 28, 291–299.
    109. Khosravi-Largani, M.; Pourvali-Talatappeh, P.; Rousta, A.M.; Karimi-Kivi, M.; Noroozi, E.; Mahjoob, A.; Asaadi, Y.; Shahmohammadi, A.; Sadeghi, S.; Shakeri, S.; et al. A review on potential roles of vitamins in incidence, progression, and improvement of multiple sclerosis. eNeurologicalsci 2018, 10, 37–44.
    110. Torkildsen, O.; Loken-Amsrud, K.I.; Wergeland, S.; Myhr, K.M.; Holmoy, T. Fat-soluble vitamins as disease modulators in multiple sclerosis. Acta Neurol. Scand. 2013, 127, 16–23.
    111. Warren, T.R. The increased prevalence of multiple sclerosis among people who were born and bred in areas where goitre is endemic. Med. Hypotheses 1984, 14, 111–114.
    112. Miller, E.D.; Dziedzic, A.; Saluk-Bijak, J.; Bijak, M. A review of various antioxidant compounds and their potential utility as complementary therapy in multiple sclerosis. Nutrients 2019, 11, 1528.
    113. Jafarirad, S.; Siassi, F.; Harirchian, M.-H.; Sahraian, M.-A.; Eshraghian, M.-R.; Shokri, F.; Amani, R.; Bitarafan, S.; Mozafari, S.; Saboor-Yaraghi, A. The effect of vitamin A supplementation on stimulated T-cell proliferation with myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. J. Neurosci. Rural Pract. 2012, 3, 294–298.
    114. Løken-Amsrud, K.I.; Myhr, K.-M.; Bakke, S.J.; Beiske, A.G.; Bjerve, K.S.; Bjørnarå, B.T.; Hovdal, H.; Lilleås, F.; Midgard, R.; Pedersen, T. Retinol levels are associated with magnetic resonance imaging outcomes in multiple sclerosis. Mult. Scler. J. 2013, 19, 451–457.
    115. Mizee, M.R.; Nijland, P.G.; van der Pol, S.M.; Drexhage, J.A.; van het Hof, B.; Mebius, R.; van der Valk, P.; van Horssen, J.; Reijerkerk, A.; de Vries, H.E. Astrocyte-derived retinoic acid: A novel regulator of blood–brain barrier function in multiple sclerosis. Acta Neuropathol. 2014, 128, 691–703.
    116. Salzer, J.; Hallmans, G.; Nyström, M.; Stenlund, H.; Wadell, G.; Sundström, P. Vitamin A and systemic inflammation as protective factors in multiple sclerosis. Mult. Scler. J. 2013, 19, 1046–1051.
    117. Runia, T.; Hop, W.; De Rijke, Y.; Hintzen, R. Vitamin A is not associated with exacerbations in multiple sclerosis. Mult. Scler. Rel. Dis. 2014, 3, 34–39.
    118. Evans, E.; Piccio, L.; Cross, A.H. Use of vitamins and dietary supplements by patients with multiple sclerosis: A review. JAMA Neurol. 2018, 75, 1013–1021.
    119. Besler, H.T.; Comoglu, S.; Okcu, Z. Serum levels of antioxidant vitamins and lipid peroxidation in multiple sclerosis. Nutr. Neurosci. 2002, 5, 215–220.
    120. Polachini, C.R.; Spanevello, R.M.; Zanini, D.; Baldissarelli, J.; Pereira, L.B.; Schetinger, M.R.; da Cruz, I.B.; Assmann, C.E.; Bagatini, M.D.; Morsch, V.M. Evaluation of delta-aminolevulinic dehydratase activity, oxidative stress biomarkers, and vitamin D levels in patients with multiple sclerosis. Neurotox. Res. 2016, 29, 230–242.
    121. Tavazzi, B.; Batocchi, A.P.; Amorini, A.M.; Nociti, V.; D’Urso, S.; Longo, S.; Gullotta, S.; Picardi, M.; Lazzarino, G. Serum metabolic profile in multiple sclerosis patients. Mult. Scler. Int. 2011, 2011, 167156.
    122. Babri, S.; Mehrvash, F.; Mohaddes, G.; Hatami, H.; Mirzaie, F. Effect of intrahippocampal administration of vitamin C and progesterone on learning in a model of multiple sclerosis in rats. Adv. Pharm. Bull. 2015, 5, 83.
    123. Hernández-Pedro, N.Y.; Espinosa-Ramirez, G.; De La Cruz, V.P.; Pineda, B.; Sotelo, J. Initial immunopathogenesis of multiple sclerosis: Innate immune response. Clin. Dev. Immunol. 2013, 2013, 413465.
    124. Zhang, S.M.; Hernan, M.A.; Olek, M.J.; Spiegelman, D.; Willett, W.C.; Ascherio, A. Intakes of carotenoids, vitamin C, and vitamin E and MS risk among two large cohorts of women. Neurology 2001, 57, 75–80.
    125. Najafi, M.R.; Shaygannajad, V.; Mirpourian, M.; Gholamrezaei, A. Vitamin B12 deficiency and multiple sclerosis; is there any association? Int. J. Prev. Med. 2012, 3, 286.
    126. Kruman, I.I.; Culmsee, C.; Chan, S.L.; Kruman, Y.; Guo, Z.; Penix, L.; Mattson, M.P. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J. Neurosci. 2000, 20, 6920–6926.
    127. Moghaddasi, M.; Mamarabadi, M.; Mohebi, N.; Razjouyan, H.; Aghaei, M. Homocysteine, vitamin B12 and folate levels in Iranian patients with multiple sclerosis: A case control study. Clin. Neurol. Neurosurg. 2013, 115, 1802–1805.
    128. Reynolds, E.; Bottiglieri, T.; Laundy, M.; Crellin, R.; Kirker, S. Vitamin B12 metabolism in multiple sclerosis. Arch. Neurol. 1992, 49, 649–652.
    129. Reynolds, E.; Linnell, J.; Faludy, J. Multiple sclerosis associated with vitamin B12 deficiency. Arch. Neurol. 1991, 48, 808–811.
    130. Weinstein, S.J.; Hartman, T.J.; Stolzenberg-Solomon, R.; Pietinen, P.; Barrett, M.J.; Taylor, P.R.; Virtamo, J.; Albanes, D. Null association between prostate cancer and serum folate, vitamin B6, vitamin B12, and homocysteine. Cancer Epid. Prev. Biomark. 2003, 12, 1271–1272.
    131. Lempriere, S. Vitamin B3 promotes remyelination. Nat. Rev. Neurol. 2020, 16, 184–185.
    132. Costantini, A.; Nappo, A.; Pala, M.I.; Zappone, A. High dose thiamine improves fatigue in multiple sclerosis. BMJ Case Rep. 2013, 2013, bcr2013009144.
    133. Bitarafan, S.; Saboor-Yaraghi, A.; Sahraian, M.A.; Nafissi, S.; Togha, M.; Moghadam, N.B.; Roostaei, T.; Siassi, F.; Eshraghian, M.R.; Ghanaati, H.; et al. Impact of vitamin A supplementation on disease progression in patients with multiple sclerosis. Arch. Iran Med. 2015, 18, 435–440.
    134. Loken-Amsrud, K.I.; Myhr, K.M.; Bakke, S.J.; Beiske, A.G.; Bjerve, K.S.; Bjornara, B.T.; Hovdal, H.; Lilleas, F.; Midgard, R.; Pedersen, T.; et al. Alpha-tocopherol and MRI outcomes in multiple sclerosis—Association and prediction. PLoS ONE 2013, 8, e54417.
    135. Gianforcaro, A.; Hamadeh, M.J. Dietary vitamin D3 supplementation at 10× the adequate intake improves functional capacity in the G93A transgenic mouse model of ALS, a pilot study. CNS Neurosci. Ther. 2012, 18, 547–557.
    136. Gianforcaro, A.; Solomon, J.A.; Hamadeh, M.J. Vitamin D(3) at 50× AI attenuates the decline in paw grip endurance, but not disease outcomes, in the G93A mouse model of ALS, and is toxic in females. PLoS ONE 2013, 8, e30243.
    137. Solomon, J.A.; Gianforcaro, A.; Hamadeh, M.J. Vitamin D3 deficiency differentially affects functional and disease outcomes in the G93A mouse model of amyotrophic lateral sclerosis. PLoS ONE 2011, 6, e29354.
    138. Libonati, L.; Onesti, E.; Gori, M.C.; Ceccanti, M.; Cambieri, C.; Fabbri, A.; Frasca, V.; Inghilleri, M. Vitamin D in amyotrophic lateral sclerosis. Funct. Neurol. 2017, 32, 35.
    139. Soto, C.; Satani, N. The intricate mechanisms of neurodegeneration in prion diseases. Trends Mol. Med. 2011, 17, 14–24.
    140. Kupfer, L.; Hinrichs, W.; Groschup, M. Prion protein misfolding. Curr. Mol. Med. 2009, 9, 826–835.
    141. Atkinson, C.J.; Zhang, K.; Munn, A.L.; Wiegmans, A.; Wei, M.Q. Prion protein scrapie and the normal cellular prion protein. Prion 2016, 10, 63–82.
    142. Terry, C.; Wadsworth, J.D. Recent Advances in Understanding Mammalian Prion Structure: A Mini Review. Front. Mol. Neurosci. 2019, 12, 169.
    143. Geschwind, M.D. Prion diseases. Continuum 2015, 21, 1612–1638.
    144. Benetti, F.; Biarnes, X.; Attanasio, F.; Giachin, G.; Rizzarelli, E.; Legname, G. Structural determinants in prion protein folding and stability. J. Mol. Biol. 2014, 426, 3796–3810.
    145. Prasad, K.N.; Bondy, S.C. Oxidative and inflammatory events in prion diseases: Can they be therapeutic targets? Curr. Aging Sci. 2019, 11, 216–225.
    146. Singh, N.; Singh, A.; Das, D.; Mohan, M.L. Redox control of prion and disease pathogenesis. Antioxid. Redox Signal. 2010, 12, 1271–1294.
    147. Briani, C.; Dalla Torre, C.; Citton, V.; Manara, R.; Pompanin, S.; Binotto, G.; Adami, F. Cobalamin deficiency: Clinical picture and radiological findings. Nutrients 2013, 5, 4521–4539.
    148. Calderon-Ospina, C.A.; Nava-Mesa, M.O. B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. CNS Neurosci. Ther. 2020, 26, 5–13.
    149. Rzepka, Z.; Respondek, M.; Pawlik, J.; Beberok, A.; Gryko, D.; Wrześniok, D. Cobalamin deficiency: Effect on homeostasis of cultured human astrocytes. Cells 2019, 8, 1505.
    150. Scalabrino, G. The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: Lessons learned from its deficiency. Prog. Neurobiol. 2009, 88, 203–220.
    151. Scalabrino, G.; Nicolini, G.; Buccellato, F.R.; Peracchi, M.; Tredici, G.; Manfridi, A.; Pravettoni, G. Epidermal growth factor as a local mediator of the neurotrophic action of vitamin B(12) (cobalamin) in the rat central nervous system. FASEB J. 1999, 13, 2083–2090.
    152. Scalabrino, G.; Veber, D. Cobalamin and normal prions: A new horizon for cobalamin neurotrophism. Biochimie 2013, 95, 1041–1046.
    153. Suenaga, M.; Hiramoto, Y.; Matsunaga, Y. Vitamin D2 interacts with Human PrPc (90–231) and breaks PrPc oligomerization in vitro. Prion 2013, 7, 312–318.
    154. Broadhead, G.K.; Grigg, J.R.; Chang, A.A.; McCluskey, P. Dietary modification and supplementation for the treatment of age-related macular degeneration. Nutr. Rev. 2015, 73, 448–462.
    155. Chew, E.Y.; Clemons, T.E.; Sangiovanni, J.P.; Danis, R.P.; Ferris, F.L., 3rd; Elman, M.J.; Antoszyk, A.N.; Ruby, A.J.; Orth, D.; Bressler, S.B.; et al. Secondary analyses of the effects of lute-in/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol. 2014, 132, 142–149.
    156. Tohari, A.M.; Zhou, X.; Shu, X. Protection against oxidative stress by vitamin D in cone cells. Cell Biochem. Funct. 2016, 34, 82–94.
    157. Kim, E.C.; Han, K.; Jee, D. Inverse relationship between high blood 25-hydroxyvitamin D and late stage of age-related macular degeneration in a repre-sentative Korean population. Investig. Ophthalmol. Vis. Sci. 2014, 55, 4823–4831.
    158. Di Somma, C.; Scarano, E.; Barrea, L.; Zhukouskaya, V.V.; Savastano, S.; Mele, C.; Scacchi, M.; Aimaretti, G.; Colao, A.; Marzullo, P. Vitamin D and neurological diseases: An endocrine view. Int. J. Mol. Sci. 2017, 18, 2482.
    159. Fricker, R.A.; Green, E.L.; Jenkins, S.I.; Griffin, S.M. The influence of nicotinamide on health and disease in the central nervous system. Int. J. Trypt. Res. 2018, 11, 1178646918776658.