ERYTHROCYTE FATTY ACID ABERRATIONS IN AMYOTROPHIC LATERAL SCLEROSIS – CORRELATION WITH DISEASE DURATION

Fatty acid alterations in ALS

  • Rajna Minic Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade,
  • Dr Aleksandra Arsic Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade
  • Dr Milica Kojadinovic Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade
  • Dr Aleksa Palibrk Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade
  • Prof. Brižita Đorđević Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11152 Belgrade, Serbia
  • Prof. Dr Zorica Stević Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade
Keywords: Amyotrophic lateral sclerosis; metabolism; monounsaturated fatty acids; polyunsaturated fatty acids; saturated fatty acids

Abstract


Background: Recent literature data highlights the presence of metabolic changes in amyotrophic lateral sclerosis (ALS). To explore possible early metabolic changes, we aimed to analyze the fatty acids (FA) composition of erythrocytes in newly diagnosed ALS patients and to see whether fatty acid levels correlate with the ALSFRS-R score or disease duration.

Methods: The severity of motor function involvement was assessed by the ALSFRS-R scale at the initial evaluation. The study comprised 26 clinically diagnosed ALS patients, mean ALSFRS-R 38±8. Control group included 26 healthy volunteers. Fatty acid profile of erythrocyte membranes was analyzed by gas-liquid chromatography.

Results: Significantly higher levels of palmitic acid and total saturated FAs were detected in ALS patients. Total monounsaturated FA, palmitoleic, vaccenic and oleic acid were also significantly increased in ALS patients. The levels of eicosapentaenoic acid, docosapentaenoic acid, total polyunsaturated FA (PUFA) and n-6 PUFA were significantly lower in ALS patients. Additionally, α-linolenic acid, the precursor of n-3 PUFA family, was not detected in ALS patients at all. We found no significant correlation between the ALSFRS-R score and the abundance of individual FAs analyzed. Moderate negative correlation was found between disease duration and DHA level and positive correlation was detected with MUFA.

Conclusions: Experimental evidence presented may contribute to the shaping of a beneficial nutritional intervention.

 

References

[1] Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Prim 2017;3:17071. https://doi.org/10.1038/nrdp.2017.71.
[2] Taylor JP, Brown RHJ, Cleveland DW. Decoding ALS: from genes to mechanism. Nature 2016;539:197–206. https://doi.org/10.1038/nature20413.
[3] Petrovic S, Arsic A, Ristic-Medic D, Cvetkovic Z, Vucic V. Lipid Peroxidation and Antioxidant Supplementation in Neurodegenerative Diseases: A Review of Human Studies. Antioxidants (Basel, Switzerland) 2020;9. https://doi.org/10.3390/antiox9111128.
[4] Desport JC, Preux PM, Magy L, Boirie Y, Vallat JM, Beaufrère B, et al. Factors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis. Am J Clin Nutr 2001;74. https://doi.org/10.1093/ajcn/74.3.328.
[5] Bouteloup C, Desport J-C, Clavelou P, Guy N, Derumeaux-Burel H, Ferrier A, et al. Hypermetabolism in ALS patients: an early and persistent phenomenon. J Neurol 2009;256:1236–42. https://doi.org/10.1007/s00415-009-5100-z.
[6] Jésus P, Fayemendy P, Nicol M, Lautrette G, Sourisseau H, Preux P-M, et al. Hypermetabolism is a deleterious prognostic factor in patients with amyotrophic lateral sclerosis. Eur J Neurol 2018;25:97–104. https://doi.org/10.1111/ene.13468.
[7] Dedic SIK, Stevic Z, Dedic V, Stojanovic VR, Milicev M, Lavrnic D. Is hyperlipidemia correlated with longer survival in patients with amyotrophic lateral sclerosis? Neurol Res 2012;34. https://doi.org/10.1179/1743132812Y.0000000049.
[8] Rafiq MK, Lee E, Bradburn M, McDermott CJ, Shaw PJ. Effect of lipid profile on prognosis in the patients with amyotrophic lateral sclerosis: Insights from the olesoxime clinical trial. Amyotroph Lateral Scler Frontotemporal Degener 2015;16:478–84. https://doi.org/10.3109/21678421.2015.1062517.
[9] Ikeda K, Hirayama T, Takazawa T, Kawabe K, Iwasaki Y. Relationships between disease progression and serum levels of lipid, urate, creatinine and ferritin in Japanese patients with amyotrophic lateral sclerosis: a cross-sectional study. Intern Med 2012;51:1501–8. https://doi.org/10.2169/internalmedicine.51.7465.
[10] Barros ANAB, Dourado METJ, Pedrosa L de FC, Leite-Lais L. Association of Copper Status with Lipid Profile and Functional Status in Patients with Amyotrophic Lateral Sclerosis. J Nutr Metab 2018;2018:5678698. https://doi.org/10.1155/2018/5678698.
[11] González De Aguilar J-L. Lipid Biomarkers for Amyotrophic Lateral Sclerosis. Front Neurol 2019;10:284. https://doi.org/10.3389/fneur.2019.00284.
[12] Chaves-filho AB, Fernanda I, Pinto D, Dantas LS, Xavier AM, Inague A, et al. Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis. Sci Rep 2019:1–14. https://doi.org/10.1038/s41598-019-48059-7.
[13] Szelechowski M, Amoedo N, Obre E, Léger C, Allard L, Bonneu M, et al. Metabolic Reprogramming in Amyotrophic Lateral Sclerosis. Sci Rep 2018;8:3953. https://doi.org/10.1038/s41598-018-22318-5.
[14] Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: A revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci 1999;169. https://doi.org/10.1016/S0022-510X(99)00210-5.
[15] Arsić A, Vučić V, Tepšić J, Mazić S, Djelić M, Glibetić M. Altered plasma and erythrocyte phospholipid fatty acid profile in elite female water polo and football players. Appl Physiol Nutr Metab 2012;37. https://doi.org/10.1139/H11-125.
[16] De Mello VDF, Erkkilä AT, Schwab US, Pulkkinen L, Kolehmainen M, Atalay M, et al. The effect of fatty or lean fish intake on inflammatory gene expression in peripheral blood mononuclear cells of patients with coronary heart disease. Eur J Nutr 2009;48. https://doi.org/10.1007/s00394-009-0033-y.
[17] Friesen RW, Innis SM. Dietary arachidonic acid to EPA and DHA balance is increased among Canadian pregnant women with low fish intake. J Nutr 2009;139. https://doi.org/10.3945/jn.109.112565.
[18] Cortinas L, Galobart J, Barroeta AC, Baucells MD, Grashorn MA. Change in α-tocopherol contents, lipid oxidation and fatty acid profile in eggs enriched with linolenic acid or very long-chain ω3 polyunsaturated fatty acids after different processing methods. J Sci Food Agric 2003;83. https://doi.org/10.1002/jsfa.1418.
[19] Cleeman JI. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). J Am Med Assoc 2001;285. https://doi.org/10.1001/jama.285.19.2486.
[20] Dupuis L, Corcia P, Fergani A, Gonzalez De Aguilar J-L, Bonnefont-Rousselot D, Bittar R, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008;70:1004–9. https://doi.org/10.1212/01.wnl.0000285080.70324.27.
[21] Dorst J, Kühnlein P, Hendrich C, Kassubek J, Sperfeld AD, Ludolph AC. Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in amyotrophic lateral sclerosis. J Neurol 2011;258:613–7. https://doi.org/10.1007/s00415-010-5805-z.
[22] Sutedja NA, van der Schouw YT, Fischer K, Sizoo EM, Huisman MHB, Veldink JH, et al. Beneficial vascular risk profile is associated with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2011;82:638–42. https://doi.org/10.1136/jnnp.2010.236752.
[23] Chiò A, Calvo A, Ilardi A, Cavallo E, Moglia C, Mutani R, et al. Lower serum lipid levels are related to respiratory impairment in patients with ALS. Neurology 2009;73:1681–5. https://doi.org/10.1212/WNL.0b013e3181c1df1e.
[24] Yang JW, Kim SM, Kim HJ, Kim JE, Park KS, Kim SH, et al. Hypolipidemia in patients with amyotrophic lateral sclerosis: A possible gender difference? J Clin Neurol 2013;9. https://doi.org/10.3988/jcn.2013.9.2.125.
[25] Veyrat-Durebex C, Bris C, Codron P, Bocca C, Chupin S, Corcia P, et al. Metabo-lipidomics of Fibroblasts and Mitochondrial-Endoplasmic Reticulum Extracts from ALS Patients Shows Alterations in Purine, Pyrimidine, Energetic, and Phospholipid Metabolisms. Mol Neurobiol 2019;56. https://doi.org/10.1007/s12035-019-1484-7.
[26] Tracey TJ, Steyn FJ, Wolvetang EJ, Ngo ST. Neuronal lipid metabolism: Multiple pathways driving functional outcomes in health and disease. Front Mol Neurosci 2018;11. https://doi.org/10.3389/fnmol.2018.00010.
[27] Henriques A, Blasco H, Fleury M-C, Corcia P, Echaniz-Laguna A, Robelin L, et al. Blood Cell Palmitoleate-Palmitate Ratio Is an Independent Prognostic Factor for Amyotrophic Lateral Sclerosis. PLoS One 2015;10:e0131512. https://doi.org/10.1371/journal.pone.0131512.
[28] Area-Gomez E, Larrea D, Yun T, Xu Y, Hupf J, Zandkarimi F, et al. Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders. Sci Rep 2021;11. https://doi.org/10.1038/s41598-021-92112-3.
[29] O’Reilly ÉJ, Bjornevik K, Furtado JD, Kolonel LN, Le Marchand L, McCullough ML, et al. Prediagnostic plasma polyunsaturated fatty acids and the risk of amyotrophic lateral sclerosis. Neurology 2020;94:e811–9. https://doi.org/10.1212/WNL.0000000000008676.
[30] Popovic T, Ranic M, Bulajic P, Milicevic M, Arsic A, Vucic V, et al. Effects of n-3 fatty acids supplementation on plasma phospholipids fatty acid composition in patients with obstructive jaundice - A pilot study. J Clin Biochem Nutr 2009;45. https://doi.org/10.3164/jcbn.09-54.
[31] Anderson BM, Ma DWL. Are all n-3 polyunsaturated fatty acids created equal? Lipids Health Dis 2009;8:33. https://doi.org/10.1186/1476-511X-8-33.
[32] Arsic A, Takic M, Kojadinovic M, Petrovic S, Paunovic M, Vucic V, et al. Metabolically healthy obesity: Is there a link with PUFA intake and status? Can J Physiol Pharmacol 2020. https://doi.org/10.1139/cjpp-2020-0317.
[33] Alashmali SM, Lin L, Trépanier M-O, Cisbani G, Bazinet RP. The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus. J Neuroinflammation 2019;16:237. https://doi.org/10.1186/s12974-019-1615-0.
[34] Ngo ST, Steyn FJ, Huang L, Mantovani S, Pfluger CMM, Woodruff TM, et al. Altered expression of metabolic proteins and adipokines in patients with amyotrophic lateral sclerosis. J Neurol Sci 2015;357. https://doi.org/10.1016/j.jns.2015.06.053.
[35] Bazan NG, Molina MF, Gordon WC. Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer’s, and other neurodegenerative diseases. Annu Rev Nutr 2011;31:321–51. https://doi.org/10.1146/annurev.nutr.012809.104635.
[36] Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci 2014;15:771–85. https://doi.org/10.1038/nrn3820.
[37] Carver JD, Benford VJ, Han B, Cantor AB. The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects. Brain Res Bull 2001;56:79–85. https://doi.org/10.1016/s0361-9230(01)00551-2.
[38] Ilieva E V, Ayala V, Jové M, Dalfó E, Cacabelos D, Povedano M, et al. Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain 2007;130:3111–23. https://doi.org/10.1093/brain/awm190.
[39] Hong S, Gronert K, Devchand PR, Moussignac R-L, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J Biol Chem 2003;278:14677–87. https://doi.org/10.1074/jbc.M300218200.
[40] Kabagambe EK, Ordovas JM, Hopkins PN, Tsai MY, Arnett DK. The relation between erythrocyte trans fat and triglyceride, VLDL- and HDL-cholesterol concentrations depends on polyunsaturated fat. PLoS One 2012;7:e47430. https://doi.org/10.1371/journal.pone.0047430.
[41] Yip PK, Pizzasegola C, Gladman S, Biggio ML, Marino M, Jayasinghe M, et al. The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis. PLoS One 2013;8:e61626–e61626. https://doi.org/10.1371/journal.pone.0061626.
[42] Boumil EF, Vohnoutka RB, Liu Y, Lee S, Shea TB. Omega-3 Hastens and Omega-6 Delays the Progression of Neuropathology in a Murine Model of Familial ALS. Open Neurol J 2017;11:84–91. https://doi.org/10.2174/1874205X01711010084.
[43] Harris WS, Pottala J V, Varvel SA, Borowski JJ, Ward JN, McConnell JP. Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: Observations from 160,000 patients. Prostaglandins Leukot Essent Fat Acids 2013;88. https://doi.org/10.1016/j.plefa.2012.12.004.
Published
2023/04/20
Section
Original paper