Can we find early phase biomarkers for ALS: What are the prospects and challenges?

Abstract

Age-related neurological disorders such as ALS (Lou Gehrig’s disease), Parkinson’s disease, and Alzheimer’s disease have few truly effective treatment options. At best, these may slow the inexorable disease progression without providing a cure. Part of the problem with therapeutic approaches may arise due to the stage at which these diseases are detected, particularly the sporadic forms. In most cases, early signs and symptoms may be insidious, thus hiding the significant damage done to the areas of the nervous system impacted prior to any firm clinical diagnosis. This situation appears to necessitate the development of earlier detection methods for “biomarkers” that might allow for much earlier phase disease state treatments that might serve to significantly slow or even halt disease progression. Currently, most biomarkers in use serve primarily as aids to disease diagnosis, at which point there are no successful treatment options. In contrast, a search for more effective early treatment options would need to identify characteristic and specific molecular signatures of disease onset and progression using methods that are simple, such as blood-based analytical assays, relatively cheap, and crucially minimally invasive.

Keywords

early disease detection / prophylaxis / non-invasive techniques / biomarkers / ALS (Lou Gehrig’s disease)

References

[1] van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, et al. Amyotrophic lateral sclerosis. Lancet. 2017; 390: 2084-98.

[2] Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, et al. Amyotrophic lateral sclerosis. Lancet. 2022; 400: 1363-80.

[3] Elman L, McCluskey L, Quinn C. Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease [Internet]. UpToDate; c2025 [cited 2025 Apr 3]. Available from: https://www.uptodate.com/contents/clinical-features-of-amyotrophic-lateral-sclerosis-and-other-forms-of-motor-neuron-disease

[4] Riva N, Domi T, Pozzi L, Lunetta C, Schito P, Spinelli EG, et al. Update on recent advances in amyotrophic lateral sclerosis. J Neurol. 2024; 271: 4693-723.

[5] Westeneng HJ, Debray TPA, Visser AE, van Eijk RPA, Rooney JPK, Calvo A, et al. Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model. Lancet Neurol. 2018; 17: 423-33.

[6] Genge A, Wainwright S, Vande Velde C. Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment. Amyotroph Lateral Scler Frontotemporal Degener. 2024; 25: 225-36.

[7] Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2002; 2: CD001447.

[8] Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017; 16: 505-12.

[9] Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, et al. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020; 383: 919-30.

[10] Xu L, Liu T, Liu L, Yao X, Chen L, Fan D, et al. Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol. 2020; 267: 944-53.

[11] Shaw CA, Morrice JR, editors. Spectrums of Amyotrophic Lateral Sclerosis: Heterogeneity, Pathogenesis and Therapeutic Directions. Boston: John Wiley and Sons; 2021.

[12] Duan QQ, Jiang Z, Su WM, Gu XJ, Wang H, Cheng YF, et al. Risk factors of amyotrophic lateral sclerosis: a global meta-summary. Front Neurosci. 2023; 17: 1177431.

[13] Paré B, Gros-Louis F. Potential skin involvement in ALS: revisiting Charcot’s observation-a review of skin abnormalities in ALS. Rev Neurosci. 2017; 28: 551-72.

[14] FULLMER HM, SIEDLER HD, KROOTH RS, KURLAND LT. A cutaneous disorder of connective tissue in amyotrophic lateral sclerosis. A histochemical study. Neurology. 1960; 10: 717-24.

[15] Ono S. The skin in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000; 1: 191-9.

[16] James PB, editor. Oxygen and the Brain: The Journey of Our Lifetime. North Palm Beach: Best Publishing Company; 2014.

[17] Neubauer RA, James P. Cerebral oxygenation and the recoverable brain. Neurol Res. 1998; 20: S33-6.

[18] Richards D, Morren JA, Pioro EP. Time to diagnosis and factors affecting diagnostic delay in amyotrophic lateral sclerosis. J Neurol Sci. 2020; 417: 117054.

[19] Gwathmey KG, Corcia P, McDermott CJ, Genge A, Sennfält S, de Carvalho M, et al. Diagnostic delay in amyotrophic lateral sclerosis. Eur J Neurol. 2023; 30: 2595-601.

[20] Martínez HR, Escamilla-Ocañas CE, Tenorio-Pedraza JM, Gómez-Almaguer D, Jaime-Perez JC, Olguín-Ramírez LA, et al. Altered CSF cytokine network in amyotrophic lateral sclerosis patients: A pathway-based statistical analysis. Cytokine. 2017; 90: 1-5.

[21] Jia R, Chen Q, Zhou Q, Zhang R, Jin J, Hu F, et al. Characteristics of serum metabolites in sporadic amyotrophic lateral sclerosis patients based on gas chromatography-mass spectrometry. Sci Rep. 2021; 11: 20786.

[22] McMackin R, Bede P, Ingre C, Malaspina A, Hardiman O. Biomarkers in amyotrophic lateral sclerosis: current status and future prospects. Nat Rev Neurol. 2023; 19: 754-68.

[23] Katzeff JS, Bright F, Phan K, Kril JJ, Ittner LM, Kassiou M, et al. Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis. Brain. 2022; 145: 1598-609.

[24] Bede P, Hardiman O. Lessons of ALS imaging: Pitfalls and future directions-A critical review. Neuroimage Clin. 2014; 4: 436-43.

[25] de Carvalho M, Scotto M, Lopes A, Swash M. Quantitating progression in ALS. Neurology. 2005; 64: 1783-5.

[26] Irwin KE, Sheth U, Wong PC, Gendron TF. Fluid biomarkers for amyotrophic lateral sclerosis: a review. Mol Neurodegener. 2024; 19: 9.

[27] Baek SH, Park J, Kim YH, Seok HY, Oh KW, Kim HJ, et al. Usefulness of diffusion tensor imaging findings as biomarkers for amyotrophic lateral sclerosis. Sci Rep. 2020; 10: 5199.

[28] Wilde JH, Sun YY, Simpson SR, Hill ER, Fu Z, Bian EJ, et al. A positron emission tomography tracer for the imaging of oxidative stress in the central nervous system. Nat Biomed Eng. 2025; 9: 716-29.

[29] Canadian Cancer Society. Prostate-specific antigen (PSA) test [Internet]. Canadian Cancer Society; c2025 [cited 2025 Apr 7]. Available from: https://cancer.ca/en/treatments/tests-and-procedures/prostate-specific-antigen-psa-test

[30] Framingham Heart Study (FHS) [Internet]. [cited 2025 Apr 7]. Available from: https://www.nhlbi.nih.gov/science/framingham-heart-study-fhs

[31] Bowser R, Turner MR, Shefner J. Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nat Rev Neurol. 2011; 7: 631-8.

[32] Huang F, Zhu Y, Hsiao-Nakamoto J, Tang X, Dugas JC, Moscovitch-Lopatin M, et al. Longitudinal biomarkers in amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2020; 7: 1103-16.

[33] Wilkins HM, Dimachkie MM, Agbas A. Blood-based Biomarkers for Amyotrophic Lateral Sclerosis. In: Araki T, editor. Amyotrophic Lateral Sclerosis. Brisbane: Exon Publications; 2021.

[34] Katzeff JS, Bright F, Lo K, Kril JJ, Connolly A, Crossett B, et al. Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation. Sci Rep. 2020; 10: 13741.

[35] Xu Z, Lee A, Nouwens A, Henderson RD, McCombe PA. Mass spectrometry analysis of plasma from amyotrophic lateral sclerosis and control subjects. Amyotroph Lateral Scler Frontotemporal Degener. 2018; 19: 362-76.

[36] Sohn AL, Ping L, Glass JD, Seyfried NT, Hector EC, Muddiman DC. Interrogating the Metabolomic Profile of Amyotrophic Lateral Sclerosis in the Post-Mortem Human Brain by Infrared Matrix-Assisted Laser Desorption Electrospray Ionization (IR-MALDESI) Mass Spectrometry Imaging (MSI). Metabolites. 2022; 12: 1096.

[37] Scarcella S, Brambilla L, Quetti L, Rizzuti M, Melzi V, Galli N, et al. Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics. Brain Commun. 2025; 7: fcaf114.

[38] Di Minno A, Gelzo M, Caterino M, Costanzo M, Ruoppolo M, Castaldo G. Challenges in Metabolomics-Based Tests, Biomarkers Revealed by Metabolomic Analysis, and the Promise of the Application of Metabolomics in Precision Medicine. Int J Mol Sci. 2022; 23: 5213.

[39] Torres P, Pradas I, Fernàndez-Bernal A, Povedano M, Dominguez R, Jové M, et al. Exploring platelet metabolomics and fatty acid profiles for ALS prognosis and diagnosis. Sci Rep. 2025; 15: 34236.

[40] Goutman SA, Guo K, Savelieff MG, Patterson A, Sakowski SA, Habra H, et al. Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts. Brain. 2022; 145: 4425-39.

[41] Franco R, Garrigós C, Lillo J, Rivas-Santisteban R. The Potential of Metabolomics to Find Proper Biomarkers for Addressing the Neuroprotective Efficacy of Drugs Aimed at Delaying Parkinson’s and Alzheimer’s Disease Progression. Cells. 2024; 13: 1288.

[42] Hunter TR, Santos LE, Tovar-Moll F, De Felice FG. Alzheimer’s disease biomarkers and their current use in clinical research and practice. Mol Psychiatry. 2025; 30: 272-84.

[43] Steinbach R, Gaur N, Stubendorff B, Witte OW, Grosskreutz J. Developing a Neuroimaging Biomarker for Amyotrophic Lateral Sclerosis: Multi-Center Data Sharing and the Road to a "Global Cohort". Front Neurol. 2018; 9: 1055.

[44] Qin J, Wang X, Fan G, Zhang W, Wu X, Wang B, et al. Identifying amyotrophic lateral sclerosis using diffusion tensor imaging, and correlation with neurofilament markers. Sci Rep. 2024; 14: 28110.

[45] Verber NS, Shepheard SR, Sassani M, McDonough HE, Moore SA, Alix JJP, et al. Biomarkers in Motor Neuron Disease: A State of the Art Review. Front Neurol. 2019; 10: 291.

[46] Neuwirth C, Barkhaus PE, Burkhardt C, Castro J, Czell D, de Carvalho M, et al. Motor Unit Number Index (MUNIX) detects motor neuron loss in pre-symptomatic muscles in Amyotrophic Lateral Sclerosis. Clin Neurophysiol. 2017; 128: 495-500.

[47] Wilke C, Gillardon F, Deuschle C, Dubois E, Hobert MA, Müller vom Hagen J, et al. Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease. Curr Alzheimer Res. 2016; 13: 654-62.

[48] Steinacker P, Huss A, Mayer B, Grehl T, Grosskreutz J, Borck G, et al. Diagnostic and prognostic significance of neurofilament light chain NF-L, but not progranulin and S100B, in the course of amyotrophic lateral sclerosis: Data from the German MND-net. Amyotroph Lateral Scler Frontotemporal Degener. 2017; 18: 112-9.

[49] Noto Y, Shibuya K, Sato Y, Kanai K, Misawa S, Sawai S, et al. Elevated CSF TDP-43 levels in amyotrophic lateral sclerosis: specificity, sensitivity, and a possible prognostic value. Amyotroph Lateral Scler. 2011; 12: 140-3.

[50] Patin F, Corcia P, Madji Hounoum B, Veyrat-Durebex C, Respaud E, Piver E, et al. Biological follow-up in amyotrophic lateral sclerosis: decrease in creatinine levels and increase in ferritin levels predict poor prognosis. Eur J Neurol. 2015; 22: 1385-90.

[51] Chiò A, Calvo A, Bovio G, Canosa A, Bertuzzo D, Galmozzi F, et al.; Piemonte and Valle d’Aosta Register for Amyotrophic Lateral Sclerosis. Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study. JAMA Neurol. 2014; 71: 1134-42.