Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis
Luisa Agnello
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Contribution: Data curation (lead), Formal analysis (equal), Investigation (equal), Writing - original draft (lead)
Search for more papers by this authorTiziana Colletti
ALS Clinical Research Center and Laboratory of Neurochemistry, Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
Contribution: Data curation (equal), Formal analysis (equal), Writing - original draft (equal)
Search for more papers by this authorBruna Lo Sasso
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Department of Laboratory Medicine, University Hospital “P. Giaccone”, Palermo, Italy
Contribution: Formal analysis (equal), Writing - review & editing (equal)
Search for more papers by this authorMatteo Vidali
Unit of Clinical Chemistry, Maggiore della Carità Hospital, Novara, Italy
Contribution: Formal analysis (equal), Software (equal)
Search for more papers by this authorRossella Spataro
IRCSS Bonino Pulejo, Presidio Pisani, Palermo, Italy
Contribution: Formal analysis (equal), Writing - review & editing (equal)
Search for more papers by this authorCaterina Maria Gambino
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Contribution: Data curation (equal), Writing - review & editing (equal)
Search for more papers by this authorRosaria Vincenza Giglio
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Contribution: Data curation (equal)
Search for more papers by this authorTommaso Piccoli
Unit of Neurology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
Contribution: Investigation (equal), Visualization (equal)
Search for more papers by this authorGiulia Bivona
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Contribution: Formal analysis (equal), Writing - review & editing (equal)
Search for more papers by this authorVincenzo La Bella
ALS Clinical Research Center and Laboratory of Neurochemistry, Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
Contribution: Conceptualization (lead), Supervision (lead), Validation (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Marcello Ciaccio
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Department of Laboratory Medicine, University Hospital “P. Giaccone”, Palermo, Italy
Correspondence
Marcello Ciaccio, Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Via del Vespro, 129, CAP 90127 Palermo, Sicily, Italy.
Email: [email protected]
Search for more papers by this authorLuisa Agnello
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Contribution: Data curation (lead), Formal analysis (equal), Investigation (equal), Writing - original draft (lead)
Search for more papers by this authorTiziana Colletti
ALS Clinical Research Center and Laboratory of Neurochemistry, Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
Contribution: Data curation (equal), Formal analysis (equal), Writing - original draft (equal)
Search for more papers by this authorBruna Lo Sasso
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Department of Laboratory Medicine, University Hospital “P. Giaccone”, Palermo, Italy
Contribution: Formal analysis (equal), Writing - review & editing (equal)
Search for more papers by this authorMatteo Vidali
Unit of Clinical Chemistry, Maggiore della Carità Hospital, Novara, Italy
Contribution: Formal analysis (equal), Software (equal)
Search for more papers by this authorRossella Spataro
IRCSS Bonino Pulejo, Presidio Pisani, Palermo, Italy
Contribution: Formal analysis (equal), Writing - review & editing (equal)
Search for more papers by this authorCaterina Maria Gambino
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Contribution: Data curation (equal), Writing - review & editing (equal)
Search for more papers by this authorRosaria Vincenza Giglio
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Contribution: Data curation (equal)
Search for more papers by this authorTommaso Piccoli
Unit of Neurology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
Contribution: Investigation (equal), Visualization (equal)
Search for more papers by this authorGiulia Bivona
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Contribution: Formal analysis (equal), Writing - review & editing (equal)
Search for more papers by this authorVincenzo La Bella
ALS Clinical Research Center and Laboratory of Neurochemistry, Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
Contribution: Conceptualization (lead), Supervision (lead), Validation (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Marcello Ciaccio
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Department of Laboratory Medicine, University Hospital “P. Giaccone”, Palermo, Italy
Correspondence
Marcello Ciaccio, Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Via del Vespro, 129, CAP 90127 Palermo, Sicily, Italy.
Email: [email protected]
Search for more papers by this authorVincenzo La Bella and Marcello Ciaccio shared the senior authorship and contributed equally to this paper.
Abstract
Background and purpose
To test the hypothesis that total tau (tTau), tau phosphorylated at threonine 181 (pTau) and pTau/tTau ratio in the cerebrospinal fluid (CSF) are diagnostic and prognostic biomarkers of amyotrophic lateral sclerosis (ALS), we performed a retrospective observational study in a large cohort of ALS patients and controls.
Methods
We enrolled 196 ALS patients and 91 controls, who included patients with ALS-mimicking diseases and those with non-neurodegenerative diseases. All patients underwent lumbar puncture for CSF analysis at the time of the diagnostic evaluation or to first referral. We measured tTau and pTau levels in the CSF by chemiluminescence enzyme immunoassay.
Results
Patients with ALS showed significantly higher levels of CSF tTau and a lower pTau/tTau ratio than controls (tTau: 245 vs. 146 pg/ml; p < 0.001; pTau/tTau ratio: 0.12 vs. 0.18; p < 0.001, respectively). No differences in pTau levels were detected. Receiver-operating characteristic curve analysis showed a good diagnostic accuracy of tTau and pTau/tTau ratio (tTau: area under the curve [AUC] 0.685, 95% confidence interval [CI] 0.616–0.754, p = 0.039; pTau/tTau ratio: AUC 0.777, 95% CI 0.707–0.848, p < 0.001). Among ALS patients, increased tTau levels were associated with advanced age of onset, increased revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score (ΔFS) rate of progression, and spinal onset. Multivariate analysis showed that in ALS patients, this biomarker was an independent negative predictor of overall survival.
Conclusions
Our findings suggest that tTau and pTau/tTau ratio can be diagnostic biomarkers of ALS. In addition, CSF tTau level at diagnosis might play a relevant prognostic role in the disease.
CONFLICT OF INTEREST
None declared.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ene14789-sup-0001-FigS1.tifTIFF image, 350.6 KB | Fig S1 |
| ene14789-sup-0002-TabS1.docxWord document, 15 KB | Tab S1 |
| ene14789-sup-0003-TabS2.docxWord document, 18.7 KB | Tab S2 |
| ene14789-sup-0004-TabS3.docxWord document, 13.4 KB | Tab S3 |
| ene14789-sup-0005-TabS4.docxWord document, 13.5 KB | Tab S4 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis, Andersen Peter M, Abrahams S, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) - revised report of an EFNS task force. Eur J Neurol. 2012; 19(3): 360-375.
- 2Paganoni S, Macklin EA, Lee A, et al. Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Frontotemporal Degener. 2014; 15: 453-456.
- 3Agah E, Saleh F, Sanjari Moghaddam H, Saghazadeh A, Tafakhori A, Rezaei N. CSF and blood biomarkers in amyotrophic lateral sclerosis: protocol for a systematic review and meta-analysis. Syst Rev. 2018; 7: 237.
- 4Verber NS, Shepheard SR, Sassani M, et al. Biomarkers in motor neuron disease: a state of the art review. Front Neurol. 2019; 10: 291.
- 5Lo Sasso B, Agnello L, Bivona G, Bellia C, Ciaccio M. Cerebrospinal fluid analysis in multiple sclerosis diagnosis: an update. Medicina (Kaunas). 2019; 55: 245.
- 6Gambino CM, Sasso BL, Bivona G, Agnello L, Ciaccio M. Aging and neuroinflammatory disorders: new biomarkers and therapeutic targets. Curr Pharm Des. 2019; 25: 4168-4174.
- 7Tarasiuk J, Kułakowska A, Drozdowski W, Kornhuber J, Lewczuk P. CSF markers in amyotrophic lateral sclerosis. J Neural Transm (Vienna). 2012; 119: 747-757.
- 8Verde F, Silani V, Otto M. Neurochemical biomarkers in amyotrophic lateral sclerosis. Curr Opin Neurol. 2019; 32: 747-757.
- 9Rossi D, Volanti P, Brambilla L, et al. CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis. J Neurol. 2018; 265(3): 510-521.
- 10Gagliardi D, Meneri M, Saccomanno D, Bresolin N, Comi GP, Corti S. Diagnostic and prognostic role of blood and cerebrospinal fluid and blood neurofilaments in amyotrophic lateral sclerosis: a review of the literature. Int J Mol Sci. 2019; 20: 4152.
- 11Yuan A, Rao MV, Veeranna NRA. Neurofilaments and neurofilament proteins in health and disease. Cold Spring Harb Perspect Biol. 2017; 9: a018309.
- 12Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol. 2017; 133: 665-704.
- 13Brunello CA, Merezhko M, Uronen RL, Huttunen HJ. Mechanisms of secretion and spreading of pathological tau protein. Cell Mol Life Sci. 2020; 77: 1721-1744.
- 14Agnello L, Piccoli T, Vidali M, et al. Diagnostic accuracy of cerebrospinal fluid biomarkers measured by chemiluminescent enzyme immunoassay for Alzheimer disease diagnosis. Scand J Clin Lab Invest. 2020; 80: 313-317.
- 15Brettschneider J, Petzold A, Süssmuth SD, Ludolph AC, Tumani H. Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology. 2006; 66: 852-856.
- 16Paladino 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.
- 17Süssmuth SD, Sperfeld AD, Hinz A, et al. CSF glial markers correlate with survival in amyotrophic lateral sclerosis. Neurology. 2010; 74: 982-987.
- 18Süssmuth SD, Tumani H, Ecker D, Ludolph AC. Amyotrophic lateral sclerosis: disease stage related changes of tau protein and S100 beta in cerebrospinal fluid and creatine kinase in serum. Neurosci Lett. 2003; 353: 57-60.
- 19Wilke 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.
- 20Schreiber S, Spotorno N, Schreiber F, et al. Significance of CSF NfL and tau in ALS. J Neurol. 2018; 265: 2633-2645.
- 21Jiménez-Jiménez FJ, Hernánz A, Medina-Acebrón S, et al. Tau protein concentrations in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neurol Scand. 2005; 111: 114-117.
- 22Bourbouli M, Rentzos M, Bougea A, et al. Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders. Dement Geriatr Cogn Disord. 2017; 44: 144-152.
- 23Grossman M, Elman L, McCluskey L, et al. Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. JAMA Neurol. 2014; 71: 442-448.
- 24Scarafino A, D'Errico E, Introna A, et al. Diagnostic and prognostic power of CSF Tau in amyotrophic lateral sclerosis. J Neurol. 2018; 265: 2353-2362.
- 25Lanznaster D, Hergesheimer RC, Bakkouche SE, et al. Aβ1-42 and Tau as potential biomarkers for diagnosis and prognosis of amyotrophic lateral sclerosis. Int J Mol Sci. 2020; 21: 2911.
- 26Abu-Rumeileh S, Vacchiano V, Zenesini C, et al. Diagnostic-prognostic value and electrophysiological correlates of CSF biomarkers of neurodegeneration and neuroinflammation in amyotrophic lateral sclerosis. J Neurol. 2020; 267: 1699-1708.
- 27Kasai T, Kojima Y, Ohmichi T, et al. Combined use of CSF NfL and CSF TDP-43 improves diagnostic performance in ALS. Ann Clin Transl Neurol. 2019; 6: 2489-2502.
- 28Brooks BR, Miller RG, Swash M, Munsat TL. World federation of neurology research group on motor neuron diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000; 1: 293-299.
- 29 ALS Cntf Treatment Phase I-II Study Group. The amyotrophic lateral sclerosis functional rating scale. Assessment of activities of daily living in patients with amyotrophic lateral sclerosis. Arch Neurol. 1996; 53: 141-147.
- 30Kimura F, Fujimura C, Ishida S, et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006; 66: 265-267.
- 31del Campo M, Mollenhauer B, Bertolotto A, et al. Recommendations to standardize preanalytical confounding factors in Alzheimer's and Parkinson's disease cerebrospinal fluid biomarkers: an update. Biomark Med. 2012; 6: 419-430.
- 32Kollhoff AL, Howell JC, Hu WT. Automation vs. Experience: Measuring Alzheimer's Beta-Amyloid 1–42 Peptide in the CSF. Front Aging Neurosci. 2018; 10: 253.
- 33Bayart JL, Hanseeuw B, Ivanoiu A, et al. Analytical and clinical performances of the automated Lumipulse cerebrospinal fluid Aβ42 and T-Tau assays for Alzheimer's disease diagnosis. J Neurol. 2019; 266: 2304-2311.
- 34Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci. 2007; 8: 663-672.
- 35Vickers JC, Mitew S, Woodhouse A, et al. Defining the earliest pathological changes of Alzheimer's disease. Curr Alzheimer Res. 2016; 13: 281-287.
- 36Pijnenburg YA, Verwey NA, van der Flier WM, Scheltens P, Teunissen CE. Discriminative and prognostic potential of cerebrospinal fluid phosphoTau/tau ratio and neurofilaments for frontotemporal dementia subtypes. Alzheimers Dement (Amst). 2015; 1: 505-512.
