BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of upper and lower motor neurons. A definitive diagnostic test or biomarker for ALS is currently unavailable, leading to a diagnostic delay following the onset of initial symptoms. Our study focused on cerebrospinal fluid (CSF) concentrations of clusterin, tau protein, phosphorylated tau protein, and beta-amyloid1-42 in ALS patients and a control group. METHODS: Our study involved 54 ALS patients and 58 control subjects. Among the ALS patients, 14 presented with bulbar-onset ALS, and 40 with limb-onset ALS. We quantified biomarker levels using enzyme-linked immunosorbent assay (ELISA) and compared the results using the Mann-Whitney U-test. RESULTS: Significant elevations in neurodegenerative markers, including tau protein (p < 0.0001), phosphorylated tau protein (p < 0.0001), and clusterin (p = 0.038), were observed in ALS patients compared to controls. Elevated levels of tau protein and phosphorylated tau protein were also noted in both bulbar and limb-onset ALS patients. However, no significant difference was observed for beta-amyloid1-42. ROC analysis identified tau protein (AUC = 0.767) and p-tau protein (AUC = 0.719) as statistically significant predictors for ALS. CONCLUSION: Our study demonstrates that neurodegenerative marker levels indicate an ongoing neurodegenerative process in ALS. Nonetheless, the progression of ALS cannot be predicted solely based on these markers. The discovery of a specific biomarker could potentially complement existing diagnostic criteria for ALS.

Department of Neurology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Olomouc Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University and Thomayer University Hospital Prague Czech Republic

Laboratory of Growth Regulators Faculty of Science and Institute of Experimental Botany of the Czech Academy of Sciences Palacky University Olomouc Olomouc Czech Republic

Laboratory of Inherited Metabolic Disorders Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Olomouc Czech Republic Olomouc Czech Republic

Zobrazit více v PubMed

Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001;344(22):1688–1700. doi: 10.1056/NEJM200105313442207. PubMed DOI

Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet J Rare Dis. 2009;4:3. doi: 10.1186/1750-1172-4-3. PubMed DOI PMC

Mathis S, Couratier P, Julian A, Vallat JM, Corcia P, Le Masson G. Management and therapeutic perspectives in amyotrophic lateral sclerosis. Expert Rev Neurother. 2017;17:263–276. doi: 10.1080/14737175.2016.1227705. PubMed DOI

Mathis S, Couratier P, Julian A, Corcia P, Le Masson G. Current view and perspectives in amyotrophic lateral sclerosis. Neural Regen Res. 2017;12:181–184. doi: 10.4103/1673-5374.200794. PubMed DOI PMC

Chiò A, Logroscino G, Traynor BJ, Simeone JC, Goldstein LA, White LA. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41:118–130. doi: 10.1159/000351153. PubMed DOI PMC

Ingre C, Ross PM, Piehl F, Kamel F, Fang F. Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol. 2015;7:181–193. PubMed PMC

Logroscino G, Piccininni M. Amyotrophic lateral sclerosis descriptive epidemiology: the origin of geographic difference. Neuroepidemiology. 2019;52:93–103. doi: 10.1159/000493386. PubMed DOI

Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR. Zoing MC Amyotrophic lateral sclerosis. Lancet. 2011;77:942–955. doi: 10.1016/S0140-6736(10)61156-7. PubMed DOI

Farníková K, Kaňovský P, Nestrašil I, Otruba P. Coexistence of parkinsonism, dementia and upper motor neuron syndrome in four Czech patients. J Neurol Sci. 2010;296:47–54. doi: 10.1016/j.jns.2010.06.011. PubMed DOI

Menšíková K, Tučková L, Kolařiková K, Bartoníková T, Vodička R, Ehrmann J, Vrtěl R, Procházka M, Kaňovský P, Kovacs GG. Atypical parkinsonism of progressive supranuclear palsy-parkinsonism (PSP-P) phenotype with rare variants in FBXO7 and VPS35 genes associated with Lewy body pathology. Acta Neuropathol. 2019;137:171–173. doi: 10.1007/s00401-018-1923-y. PubMed DOI

Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, Sobue G. Amyotrophic lateral sclerosis. Lancet. 2022;400:1363–1380. doi: 10.1016/S0140-6736(22)01272-7. PubMed DOI PMC

Goutman SA, Hardiman O, Al-Chalabi A, Chió A, Savelieff MG, Kiernan MC, Feldman EL. Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol. 2022;1:480–493. doi: 10.1016/S1474-4422(21)00465-8. PubMed DOI PMC

Peplow PV, Martinez B, Gennarelli TA. Neurodegenerative Diseases Biomarkers. 2022. Neuromethods, sv. 173. s. 155–180. Humana, New York, NY.

Rosenberg ME, Silkensen J. Clusterin: physiologic and pathophysiologic considerations. Int J Biochem Cell Biol. 1995;27(7):633–645. doi: 10.1016/1357-2725(95)00027-M. PubMed DOI

Jones SE, Jomary C. Clusterin. Int J Biochem Cell Biol. 2002;34(5):427–431. doi: 10.1016/s1357-2725(01)00155-8. PubMed DOI

Nuutinen T, Suuronen T, Kauppinen A, Salminen A. Clusterin: a forgotten player in Alzheimer´s disease. Brain Res Rev. 2009;61(2):89–104. doi: 10.1016/j.brainresrev.2009.05.007. PubMed DOI

Wilson MR, Zoubeidi A. Clusterin as a therapeutic target. Expert Opin Ther Targets. 2017;21(2):201–213. doi: 10.1080/14728222.2017.1267142. PubMed DOI

Drubin DG, Kirschner MW. Tau protein function in living cells. J Cell Biol. 1986;103(6 Pt 2):2739–2746. doi: 10.1083/jcb.103.6.2739. PubMed DOI PMC

Sergeant N, Delacourte A, Buée L. Tau protein as a differential biomarker of tauopathies. Biochim Biophys Acta. 2005;1739(2–3):179–197. doi: 10.1016/j.bbadis.2004.06.020. PubMed DOI

Spillantini MG, Goedert M. Tau protein pathology in neurodegenerative diseases. Trend Neurosci. 1998;21(10):428–433. doi: 10.1016/s0166-2236(98)01337-x. PubMed DOI

Pîrşcoveanu DFV, Pirici I, Tudorică V, Bălşeanu T-A, Albu V-C, Bondari S, Bumbea A-M, Pîrşcoveanu M. Tau protein in neurodegenerative diseases–a review. Rom J Morphol Embryol. 2017;58(4):1141–1150. PubMed

Roher AE, Palmer KC, Yurewicz EC, Ball MJ, Greenberg BD. Morphological and biochemical analyses of amyloid plaque core proteins purified from Alzheimer disease brain tissue. J Neurochem. 1993;61(5):1916–1926. doi: 10.1111/j.1471-4159.1993.tb09834.x. PubMed DOI

Brooks BR, Miller RG, Swash M, Munat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293–299. doi: 10.1080/146608200300079536. PubMed DOI

Desikan RS, Thompson WK, Holland D, Hess CP, Brewer JB, Zetterberg H, Blennow K, Andreassen OA, McEvoy LK, Hyman BT, Dale AM. The role of clusterin in amyloid-β-associated neurodegeneration. JAMA Neurol. 2014;71:180–187. doi: 10.1001/jamaneurol.2013.4560. PubMed DOI PMC

Chaplot K, Jarvela TS, Lindberg I. Secreted chaperones in neurodegeneration. Front Aging Neurosci. 2020;12:268. doi: 10.3389/fnagi.2020.00268. PubMed DOI PMC

Ganesalingam J, An J, Bowser R, Andersen PM, Shaw CE. pNfH is a promising biomarker for ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14:146–149. doi: 10.3109/21678421.2012.729596. PubMed DOI

Kaiserová M, Grambalova Z, Otruba P, Stejskal D, Prikrylova Vranova H, Mares J, Mensikova K, Kanovsky P. Cerebrospinal fluid levels of chromogranin A and phosphorylated neurofilament heavy chain are elevated in amyotrophic lateral sclerosis. Acta Neurol Scand. 2017;136:360–364. doi: 10.1111/ane.12735. PubMed DOI

Přikrylová Vranová H, Hényková E, Mareš J, Kaiserová M, Menšíková K, Vaštík M, Hluštík P, Zapletalová J, Strnad M, Stejskal D, Kaňovský P. Clusterin CSF levels in differential diagnosis of neurodegenerative disorders. J Neurol Sci. 2016;361:117–121. doi: 10.1016/j.jns.2015.12.023. PubMed DOI

Gregory JM, Elliot E, McDade K, Bak T, Pal S, Chandran S, Abrahams S, Smith C. Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2020;46:255–263. doi: 10.1111/nan.12575. PubMed DOI PMC

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;19:362–376. doi: 10.1080/21678421.2018.1433689. PubMed DOI

Bourbouli M, Rentzos M, Bougea A, Zouvelou V, Constantinides VC, Zaganas I, Evdokimidis I, Kapaki E, Paraskevas GP. Cerebrospinal fluid TAR DNA-binding protein 43 combined with tau proteins as a candidate biomarker for amyotrophic lateral sclerosis and frontotemporal dementia spectrum disorders. Dementia Geriatr Cogn Disord. 2017;44:144–152. doi: 10.1159/000478979. PubMed DOI

Wilke C, Deuschle C, Rattay TW, Maetzler W, Synofzik M. Total tau is increased, but phosphorylated tau not decreased, in cerebrospinal fluid in amyotrophic lateral sclerosis. Neurobiol Aging. 2015;36:1072–1074. doi: 10.1016/j.neurobiolaging.2014.10.019. PubMed DOI

Paladino P, Valentino F, Piccoli T, Piccoli F, La Bella V. Cerebrospinal fluid tau protein is not a biological marker in amyotrophic lateral sclerosis. Eur J Neurol. 2009;16:257–261. doi: 10.1111/j.1468-1331.2008.02405.x. PubMed DOI

Lanznaster D, Hergesheimer RC, Bakkouche SE, Beltran S, Vourc ‘H P, Andres CR, Dufour-Rainfray D, Corcia P, Blasco H. Aβ1–42 and Tau as potential biomarkers for diagnosis and prognosis of amyotrophic lateral sclerosis. Int J Mol Sci. 2020;21:2911. doi: 10.3390/ijms21082911. PubMed DOI PMC

Clusterin: a double-edged sword in cancer and neurological disorders