Normal Appearing White Matter N-Acetylaspartate Changes Impact on Fatigue in Multiple Sclerosis

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Vasilena Petrova Latchesar Traykov


Background: Fatigue is one of the most frequent complaints presented by multiple sclerosis patients. Fatigue may be multifactorial. Proton magnetic resonance spectroscopy studies have shown significant reductions in N-acetylaspartate/creatine ratios in multiple brain regions among fatigued multiple sclerosis patients in comparison to non-fatigued multiple sclerosis patients, suggesting axonal loss as a contributing factor. Females are twice as likely to develop the disease.

Aim: To evaluate gender variability in fatigue scores in relapsing-remitting multiple sclerosis patients. To explore potential gender differences in metabolite profiles of normal appearing white matter. To correlate metabolite changes distribution with fatigue severity and to evaluate the gender impact.   

Methods: We enrolled 50 relapsing-remitting multiple sclerosis patients on disease modifying treatment and 28 healthy controls. All participants underwent proton magnetic resonance spectroscopy of normal appearing white matter corresponding regions and fatigue severity evaluation.

Results: We found higher fatigue scores in the multiple sclerosis group, due to greater severity in female subjects. We found a significant decrease of N-acetylaspartate/creatine ratio with increase in N-acetylaspartate, choline, and creatine levels in multiple sclerosis subjects. N-acetylaspartate and choline levels were significantly higher in the multiple sclerosis males. Female multiple sclerosis patients presented with lower N-acetylaspartate levels than healthy controls and greater increases in Fatigue Severity Scale score. Regression analysis revealed metabolite specific relationships between fatigue against metabolite variables.

Conclusion: Proton magnetic resonance spectroscopy registered differences in metabolite profiles in normal appearing white matter male and female multiple sclerosis subjects. We might presume gender dependent specifiers in metabolite profiles in relapsing- remitting multiple sclerosis. They impact fatigue severity. N- acetyaspartate might be crucial contributor in central fatigue in multiple sclerosis. Bioenergetic role of N-acetylaspartate needs further collaborative research on genetics and electrical properties of neurons to reveal the underlying mechanism of fatigue and conductivity deterioration.

Keywords: fatigue, spectroscopy, metabolite, multiple sclerosis, gender

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How to Cite
PETROVA, Vasilena; TRAYKOV, Latchesar. Normal Appearing White Matter N-Acetylaspartate Changes Impact on Fatigue in Multiple Sclerosis. Medical Research Archives, [S.l.], v. 11, n. 10, oct. 2023. ISSN 2375-1924. Available at: <>. Date accessed: 11 dec. 2023. doi:
Research Articles


1. Paul A, Comabella M and Gandhi R. Biomarkers in multiple sclerosis. Cold Spring Harb Perspect Med. 2019; 9: a029058. doi: 10.1101/cshperspect.a029058
2. Tarasiuk J, Kapica-Topczewska K, Czarnowska A, Chora M˛ Kochanowicz J, Kułakowska A. Co-occurrence of fatigue and depression in people with multiple sclerosis: a mini-review. Frontiers in Neurology. 2021; 12: 817256. doi: 10.3389/fneur.2021.817256
3. Braley TJ, Chervin RD. MS Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep. 2010; 33(8):1061–1067. doi: 10.1093/sleep/33.8.1061
4. Khan O, Shen Y, Caon C, Bao F, Ching W, Reznar M, Buccheister A, Hu J, Latif Z, Tselis A, Lisak R. Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsingremitting multiple sclerosis. Mult Scler. 2005; 11:646–651. doi:10.1191/1352458505ms1234oa
5. Ghajarzadeh M, Jalilian R, Eskandari G. et al. Fatigue in multiple sclerosis: relationship with disease duration, physical disability, disease pattern, age, and sex. Acta Neurol Belg. 2013; 113(4):411–414. doi: 10.1007/s13760-013-0198-2.
6. Narayana PA. Magnetic resonance spectroscopy in the monitoring of multiple sclerosis. J Neuroimaging. 2005; 15(4 Suppl):46S–57S. doi:10.1177/1051228405284200
7. Cercignani M, Dipasquale O, Bogdan I, et al. Cognitive fatigue in multiple sclerosis is associated with alterations in the functional connectivity of monoamine circuits. Brain Commun. 2021; 3(2): fcab023. doi: 10.1093/braincomms/fcab023
8. Novo AM, Batista S, Alves C, et al. The neural basis of fatigue in multiple sclerosis: A multimodal MRI approach. Neurol Clin Pract. 2018;8(6):492-500. doi: 10.1212/CPJ.0000000000000545
9. Petrova V, Genov K. Normal appearing white matter metabolite pattern and sex differences in multiple sclerosis patients compared to healthy controls. Folia Medica. 2022;64(5):746-753. doi:10.3897/folmed.64.e66002
10. Beck A, Ward CH, Mendelson l, Mock J, Erbaugh J. An inventory for measuring depression. Archives of General Psychiatry. 1961; 4:561–571.
11. Moffett JR, Ross B, Arun P, Madhavarao ChN, Namboodiri MAA. N-acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol. 2007;81(2): 89–131. doi: 10.1016/j.pneurobio.2006.12.003
12. Milanov I. Multiple sclerosis and autoimmune demyelinating diseases of the central nervous system. Medicine and physical education; 2014. Множествена склероза и демиелинизиращи заболявания | Българско дружество по неврология (
13. National consensus for diagnose and treatment of multiple sclerosis. March 2023. (nevrolo¬
14. Harbo HF, Gold R, Tintoré M. Sex and gender issues in multiple sclerosis. Ther Adv Neurol Disord. 2013; 6(4):237–248 doi: 10.1177/ 1756285613488434.
15. Baslow, MH. Evidence supporting a role of N-acetyl-L- aspartate as a molecular water pump in myelinated neurons in the central nervous system: an analytical review. NCI 2002;40(4): 295-300.
16. Shaw GM, Carmichael SL, Yang W, et al. Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am J Epidemiol. 2004;160(2):102-9. doi: 10.1093/aje/kwh187.
17. Craner MJ, Newcombe J, Black JA, et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. PNAS. 2004;101(21):8168–8173.
18. Grant Steen R, Ogg RJ. Abnormally high levels of brain N-acetylaspartate in children with sickle cell disease. AJNR Am J Neuroradiol. 2005; 26(3):463–8. PMID: 15760850; PMCID: PMC7976498.
19. Sun Jubao BS, Song Hao MS, Yang, Yong PhD, et al. Metabolic changes in normal appearing white matter in multiple sclerosis patients using magnetic resonance spectroscopy imaging. Medicine. 2017; 96(14): e6534. doi: 10.1097/MD.0000000000006534
20. Baslow MH. 14 N-Acetylaspartate and N-Acetylaspartylglutamate. In: Lajtha A, Oja SS, Schousboe A, Saransaari P, eds. Handbook of Neurochemistry and Molecular Neurobiology. Springer; 2007: 305-346. Assessed January 01, 2007. 14 N-Acetylaspartate and N-Acety-laspartylglutamate | SpringerLink
21. Newland P, Starkweather A, Sorenson M. Review Central fatigue in multiple sclerosis: a review of the literature. The Journal of Spinal Cord Medicine. 2016;39(4):386-399. doi: 10.1080/10790268.2016.1168587
22. Cheng HM, Mah KK, Seluakumaran K. Electrical properties of neurons. In: Defining Physiology: Principles, Themes, Concepts. Springer; 2020; 2:81-94. Assessed January 13, 2021. doi:10.1007/978-3-030-62285-5_22
23. Serles W, Li LM, Antel SB, Cendes F, Gotman J, Olivier A, Andermann F, Dubeau F, Arnold DL. Time course of postoperative recovery of N-acetyl-aspartate in temporal lobe epilepsy. Epilepsia. 2001; 42(s2):190–197.
24. Mostert JP, Sijens PE, Oudkerk M, De KJ. Fluoxetine increases cerebral white matter NAA/Cr ratio in patients with multiple sclerosis. Neurosci Lett. 2006; 402(1-2):22–4. doi: 10.1016/j.neulet.2006.03.042. Epub 2006 Apr 27.