Impact of Alterations in Homocysteine, Asymmetric Dimethylarginine and Vitamins-Related Pathways in Some Neurodegenerative Diseases: A Narrative Review
Abstract
1. Introduction
2. Methods
3. Homocysteine and Hypovitaminosis in Parkinson’s Disease
4. ADMA in Parkinson’s Disease
5. Homocysteine and Hypovitaminosis in Alzheimer’s Disease
6. ADMA in Alzheimer’s Disease
7. Homocysteine and Hypovitaminosis in Multiple Sclerosis
8. ADMA in Multiple Sclerosis
9. Strengths and Limitations
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
25(OH)D | 25-hydroxyvitamin D |
27-OHC | 27-hydroxycholesterol |
5LO | 5-lipoxygenase |
AA | Anthranilic acid |
AD | Alzheimer’s disease |
ADMA | Asymmetric dimethylarginine |
ALA | Alpha-lipoic acid |
ApoE | Apolipoprotein E |
APP | Amyloid precursor protein |
Aβ | Amyloid β |
BBB | Blood–brain barrier |
BHMT | Betaine-homocysteine methyltransferase |
CBF | Cerebral blood flow |
cECs | Cerebral endothelial cells |
CH2THF | 5,10-Methylenetetrahydrofolate |
CH3THF | 5-methyltetrahydrofolate |
CNS | Central nervous system |
COMT | Catechol-O-methyltransferase |
CSF | Cerebrospinal fluid |
DDAH | Dimethylarginine dimethylaminohydodrolase |
DMA | Dimethylamine |
DMG | Dimethylglycine |
DM-PP2Ac | De-methylated PP2A catalytic subunit |
DR4/5 | Death receptor 4 and 5 |
EAE | Autoimmune encephalomyelitis |
EDSS | Expanded Disability Status Score |
ET | Endothelin |
FAD | Flavin adenine dinucleotide |
HAA | 3-hydroxyanthranilic acid |
HCs | Healthy controls |
HCTL | Homocysteine thiolactone |
Hcy | Homocysteine |
HHcy | Hyperhomocysteinemia |
HK | 3-hydroxykynurenine |
iNOS | inducible Nitric Oxide Synthase |
KA | Kynurenic acid |
KAT | Kynurenine aminotransferase |
Kyn | kynurenine |
KYNU | Kynureninase |
MBP | Myelin basic protein |
MCI | Mild Cognitive Impairment |
MeSe | Methionine synthase |
MMA | Methylmalonic acid |
MOG | Myelin oligodendrocyte glycoprotein |
M-PP2Ac | Methylated PP2A catalytic subunit |
MS | Multiple sclerosis |
MSSS | Multiple Sclerosis Severity Score |
MTHFR | Methylenetetrahydrofolate reductase |
NMO | Neuromyelitis optica |
NO | Nitric oxide |
NOS | Nitric oxide synthase |
ONDs | Other neurologic diseases |
PD | Parkinson’s disease |
PLP | Pyridoxal 5-phosphate |
PP2A | Protein phosphatase 2A |
PRMT-1 | Protein arginine methyltransferases-1 |
PRMT-4 | Protein arginine methyltransferase-4 |
PS1 | Presenilin 1 |
pS262-tau | Ser262 hyperphosphorylated tau |
PTMs | Post-translational modifications |
ROS | Reactive oxygen species |
RR | Relapsing–remitting |
SAH | S-adenosyl homocysteine |
SAM | S-adenosyl methionine |
SDMA | Symmetric dimethylarginine |
SP | Secondary progressive |
TCA | Tricarboxylic acid |
THF | Tetrahydrofolate |
tHcy | Total homocysteine |
VCID | Cognitive impairment and dementia |
XA | Xanthurenic acid |
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Vitamins | Parkinson’s Disease | Alzheimer’s Disease | Multiple Sclerosis |
---|---|---|---|
Vitamin B12 | Vitamin B12 was deficient in PD patients [16,25] and correlated negatively with tHcy levels [1,17,26,27]. Supplementation could have positive effects in reducing tHcy, ADMA levels, and in neuroprotection [22,26,27] or be ineffective [9,16,37]. | Reduced B12 concentrations were associated with cognitive decline [47,48,49]. Supplementation in AD patients could be beneficial in reducing tHcy, improving cognitive functions and visual impairments [38,50,51,60], or be ineffective [52,53]. | Vitamin B12 levels in MS patients were associated with HHcy and disease relapses [89], but other studies did not observe this association [81,82,83,84,87]. |
Vitamin B9 | HHcy correlated negatively with B9 levels [1,17]. Supplementation could have positive effects on reducing tHcy, ADMA levels, and vascular events [22,23] or be ineffective [9,16,37]. | Reduced B9 concentrations were associated with cognitive decline [50]. Supplementation in AD patients could be beneficial in reducing tHcy, APP, PS1, and Aβ protein levels, improving neuronal and visual functions [38,50,51,55,56,60], or be ineffective [52,53]. | No significant differences were observed compared to the control group and in children with early-onset MS [87,89]. |
Vitamin B6 | It was deficient in PD subjects [16,32]. Dietary intake of vitamin B6 exhibited preventive effect of developing PD [16] or be ineffective [9,37]. | No significant differences were observed in children with early-onset MS [87]. | |
Vitamin B2 | Supplementation could neutralize the effects of the MTHFR C677T polymorphism and decrease Hcy levels [34,35]. | ||
Vitamin D | Vitamin D deficiency may be involved in learning and memory. Co-supplementation with vitamins B could have positive effects on vitamin D and SAM metabolism [54]. | Evidence has associated lower vitamin D levels with an elevated risk of developing MS or symptom relapse [95,96,97,98]. | |
Vitamin A | Vitamin A supplement seems to be useful in neuronal plasticity and could improve cognitive ability [105,106]. |
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Saija, C.; Currò, M.; Ientile, R.; Caccamo, D.; Bertuccio, M.P. Impact of Alterations in Homocysteine, Asymmetric Dimethylarginine and Vitamins-Related Pathways in Some Neurodegenerative Diseases: A Narrative Review. Int. J. Mol. Sci. 2025, 26, 3672. https://doi.org/10.3390/ijms26083672
Saija C, Currò M, Ientile R, Caccamo D, Bertuccio MP. Impact of Alterations in Homocysteine, Asymmetric Dimethylarginine and Vitamins-Related Pathways in Some Neurodegenerative Diseases: A Narrative Review. International Journal of Molecular Sciences. 2025; 26(8):3672. https://doi.org/10.3390/ijms26083672
Chicago/Turabian StyleSaija, Caterina, Monica Currò, Riccardo Ientile, Daniela Caccamo, and Maria Paola Bertuccio. 2025. "Impact of Alterations in Homocysteine, Asymmetric Dimethylarginine and Vitamins-Related Pathways in Some Neurodegenerative Diseases: A Narrative Review" International Journal of Molecular Sciences 26, no. 8: 3672. https://doi.org/10.3390/ijms26083672
APA StyleSaija, C., Currò, M., Ientile, R., Caccamo, D., & Bertuccio, M. P. (2025). Impact of Alterations in Homocysteine, Asymmetric Dimethylarginine and Vitamins-Related Pathways in Some Neurodegenerative Diseases: A Narrative Review. International Journal of Molecular Sciences, 26(8), 3672. https://doi.org/10.3390/ijms26083672