Skip to main content
Top
Published in: Journal of Neurology 10/2018

01-10-2018 | Original Communication

Diagnostic and prognostic power of CSF Tau in amyotrophic lateral sclerosis

Authors: Antonio Scarafino, Eustachio D’Errico, Alessandro Introna, Angela Fraddosio, Eugenio Distaso, Irene Tempesta, Antonella Morea, Antonella Mastronardi, Rosaria Leante, Maddalena Ruggieri, Mariangela Mastrapasqua, Isabella Laura Simone

Published in: Journal of Neurology | Issue 10/2018

Login to get access

Abstract

Background

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that still lacks reliable diagnostic biomarkers. This study aims to evaluate the diagnostic and prognostic potential of CSF total Tau (t-Tau), phospho-Tau (p-Tau) and p-Tau/t-Tau ratio in ALS patients using CSF neurofilament light (NFL) as the reference biomarker.

Methods

Eighty-five incident ALS, 30 ALS-mimicking (AM) diseases and 51 other non-neurodegenerative diseases (ONND) were included in the study.

Results

ALS patients had higher levels of CSF t-Tau and lower p-Tau/t-Tau ratio than AM (p = 0.005 and p = 0.006) and ONND (p < 0.001). CSF t-Tau levels discriminated ALS from AM with a sensitivity of 69% and specificity of 60%, and from ONND with a sensitivity of 88% and specificity of 51%. These values were lower than the accuracy of CSF NFL in ALS (sensitivity 86% and specificity 87% in distinguishing ALS from AM and sensitivity 83% and specificity 75% from ONND); CSF t-Tau correlated with progression rate and SNIP. CSF p-Tau did not show relation with any ALS clinical features. CSF NFL significantly correlated with all considered clinical parameters. High levels of CSF t-Tau and NFL were related to poor survival.

Conclusion

CSF t-Tau showed no reliable diagnostic significance but the relation between the high levels of CSF t-Tau and short survival suggests the potential prognostic role of this biomarker in ALS. However, CSF NFL was confirmed to be the most reliable and efficient tool for diagnosis and prediction of clinical progression and survival in ALS patients.
Literature
1.
go back to reference Strong M, Rosenfeld J (2003) Amyotrophic lateral sclerosis: a review of current concepts. Amyotroph Lateral Scler Other Motor Neuron Disord 4(3):136–143CrossRef Strong M, Rosenfeld J (2003) Amyotrophic lateral sclerosis: a review of current concepts. Amyotroph Lateral Scler Other Motor Neuron Disord 4(3):136–143CrossRef
2.
go back to reference Chiò A, Logroscino G, Traynor BJ et al (2013) Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 41(2):118–130CrossRef Chiò A, Logroscino G, Traynor BJ et al (2013) Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 41(2):118–130CrossRef
3.
go back to reference Chia R, Chiò A, Traynor BJ (2018) Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol 17(1):94–102CrossRef Chia R, Chiò A, Traynor BJ (2018) Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol 17(1):94–102CrossRef
4.
go back to reference Van den Berg-Vos RM, Visser J, Franssen H et al (2003) Sporadic lower motor neuron disease with adult onset: classification of subtypes. Brain 126(Pt 5):1036–1047CrossRef Van den Berg-Vos RM, Visser J, Franssen H et al (2003) Sporadic lower motor neuron disease with adult onset: classification of subtypes. Brain 126(Pt 5):1036–1047CrossRef
5.
go back to reference Chiò A, Calvo A, Moglia C, Mazzini L, Mora G, PARALS study group (2011) Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 82(7):740–746CrossRef Chiò A, Calvo A, Moglia C, Mazzini L, Mora G, PARALS study group (2011) Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 82(7):740–746CrossRef
6.
go back to reference Turner MR, Kiernan MC, Leigh PN, Talbot K (2009) Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 8(1):94–109CrossRef Turner MR, Kiernan MC, Leigh PN, Talbot K (2009) Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 8(1):94–109CrossRef
7.
go back to reference Bowser R, Turner MR, Shefner J (2011) Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nat Rev Neurol 7(11):631–638CrossRef Bowser R, Turner MR, Shefner J (2011) Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nat Rev Neurol 7(11):631–638CrossRef
8.
go back to reference Tarasiuk J, Kułakowska A, Drozdowski W, Kornhuber J, Lewczuk P (2012) CSF markers in amyotrophic lateral sclerosis. J Neural Transm 119(7):747–757CrossRef Tarasiuk J, Kułakowska A, Drozdowski W, Kornhuber J, Lewczuk P (2012) CSF markers in amyotrophic lateral sclerosis. J Neural Transm 119(7):747–757CrossRef
9.
go back to reference Tortelli R, Ruggieri M, Cortese R et al (2012) Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression. Eur J Neurol 19(12):1561–1567CrossRef Tortelli R, Ruggieri M, Cortese R et al (2012) Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression. Eur J Neurol 19(12):1561–1567CrossRef
10.
go back to reference Tortelli R, Copetti M, Ruggieri M et al (2015) Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis. Eur J Neurol 22(1):215–218CrossRef Tortelli R, Copetti M, Ruggieri M et al (2015) Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis. Eur J Neurol 22(1):215–218CrossRef
11.
go back to reference Steinacker P, Feneberg E, Weishaupt J et al (2016) Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg Psychiatry 87(1):12–20PubMed Steinacker P, Feneberg E, Weishaupt J et al (2016) Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg Psychiatry 87(1):12–20PubMed
12.
go back to reference Poesen K, De Schaepdryver M, Stubendorff B et al (2017) Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology 88(24):2302–2309CrossRef Poesen K, De Schaepdryver M, Stubendorff B et al (2017) Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology 88(24):2302–2309CrossRef
13.
go back to reference Süssmuth SD, Tumani H, Ecker D, Ludolph AC (2003) Amyotrophic lateral sclerosis: disease stage related changes of tau protein and S100 beta in cerebrospinal fluid and creatine kinase in serum. Neurosci Lett 353(1):57–60CrossRef Süssmuth SD, Tumani H, Ecker D, Ludolph AC (2003) Amyotrophic lateral sclerosis: disease stage related changes of tau protein and S100 beta in cerebrospinal fluid and creatine kinase in serum. Neurosci Lett 353(1):57–60CrossRef
14.
go back to reference Jiménez-Jiménez FJ, Hernánz A, Medina-Acebrón S et al (2005) Tau protein concentrations in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neurol Scand 111(2):114–117CrossRef Jiménez-Jiménez FJ, Hernánz A, Medina-Acebrón S et al (2005) Tau protein concentrations in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neurol Scand 111(2):114–117CrossRef
15.
go back to reference Brettschneider J, Petzold A, Süssmuth SD, Ludolph AC, Tumani H (2006) Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology 66(6):852–856CrossRef Brettschneider J, Petzold A, Süssmuth SD, Ludolph AC, Tumani H (2006) Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology 66(6):852–856CrossRef
16.
go back to reference Paladino P, Valentino F, Piccoli T, Piccoli F, La Bella V (2009) Cerebrospinal fluid tau protein is not a biological marker in amyotrophic lateral sclerosis. Eur J Neurol 16(2):257–261CrossRef Paladino P, Valentino F, Piccoli T, Piccoli F, La Bella V (2009) Cerebrospinal fluid tau protein is not a biological marker in amyotrophic lateral sclerosis. Eur J Neurol 16(2):257–261CrossRef
17.
go back to reference Goedert M (1993) Tau protein and the neurofibrillary pathology of Alzheimer’s disease. Trends Neurosci 16:460–465CrossRef Goedert M (1993) Tau protein and the neurofibrillary pathology of Alzheimer’s disease. Trends Neurosci 16:460–465CrossRef
18.
go back to reference Süssmuth SD, Reiber H, Tumani H (2001) Tau protein in cerebrospinal fluid (CSF): a blood-CSF barrier related evaluation in patients with various neurological diseases. Neurosci Lett 300(2):95–98CrossRef Süssmuth SD, Reiber H, Tumani H (2001) Tau protein in cerebrospinal fluid (CSF): a blood-CSF barrier related evaluation in patients with various neurological diseases. Neurosci Lett 300(2):95–98CrossRef
19.
go back to reference Sunderland T, Linker G, Mirza N et al (2003) Decreased beta amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289:2094–2103CrossRef Sunderland T, Linker G, Mirza N et al (2003) Decreased beta amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289:2094–2103CrossRef
20.
go back to reference Satoh K, Shirabe S, Tsujino A et al (2007) Total tau protein in cerebrospinal fluid and diffusion-weighted MRI as an early diagnostic marker for Creutzfeldt–Jakob disease. Dement Geriatr Cogn Disord 24:207–212CrossRef Satoh K, Shirabe S, Tsujino A et al (2007) Total tau protein in cerebrospinal fluid and diffusion-weighted MRI as an early diagnostic marker for Creutzfeldt–Jakob disease. Dement Geriatr Cogn Disord 24:207–212CrossRef
21.
go back to reference Grossman M, Elman L, McCluskey L et al (2014) Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. JAMA Neurol 2014;71(4):442–448CrossRef Grossman M, Elman L, McCluskey L et al (2014) Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. JAMA Neurol 2014;71(4):442–448CrossRef
22.
go back to reference Wilke C, Deuschle C, Rattay TW, Maetzler W, Synofzik M (2015) Total tau is increased, but phosphorylated tau not decreased, in cerebrospinal fluid in amyotrophic lateral sclerosis. Neurobiol Aging 36(2):1072–1074CrossRef Wilke C, Deuschle C, Rattay TW, Maetzler W, Synofzik M (2015) Total tau is increased, but phosphorylated tau not decreased, in cerebrospinal fluid in amyotrophic lateral sclerosis. Neurobiol Aging 36(2):1072–1074CrossRef
23.
go back to reference Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1(5):293–299CrossRef Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1(5):293–299CrossRef
24.
go back to reference Strong MJ, Abrahams S, Goldstein LH et al (2017) Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener 18(3–4):153–174CrossRef Strong MJ, Abrahams S, Goldstein LH et al (2017) Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener 18(3–4):153–174CrossRef
25.
go back to reference Cedarbaum JM, Stambler N, Malta E et al (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 169(1–2):13–21CrossRef Cedarbaum JM, Stambler N, Malta E et al (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 169(1–2):13–21CrossRef
26.
go back to reference Aitkens S, Lord J, Bernauer E et al (1989) Relationship of manual muscle testing to objective strength measurements. Muscle Nerve 12:173–177CrossRef Aitkens S, Lord J, Bernauer E et al (1989) Relationship of manual muscle testing to objective strength measurements. Muscle Nerve 12:173–177CrossRef
27.
go back to reference Tortelli R, Copetti M, Panza F et al (2016) Time to generalisation as a predictor of prognosis in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 87(6):678–679CrossRef Tortelli R, Copetti M, Panza F et al (2016) Time to generalisation as a predictor of prognosis in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 87(6):678–679CrossRef
28.
go back to reference Kimura F, Fujimura C, Ishida S et al (2006) Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 66:265–267CrossRef Kimura F, Fujimura C, Ishida S et al (2006) Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 66:265–267CrossRef
29.
go back to reference Miller JM, Moxham J, Green M (1985) The maximal sniff in the assessment of diaphragm function in man. Clin Sci 69:91–96CrossRef Miller JM, Moxham J, Green M (1985) The maximal sniff in the assessment of diaphragm function in man. Clin Sci 69:91–96CrossRef
30.
go back to reference Woolley SC, York MK, Moore DH et al (2010) Detecting frontotemporal dysfunction in ALS: utility of the ALS cognitive behavioral screen (ALS-CBS). Amyotroph Lateral Scler 11(3):303–311CrossRef Woolley SC, York MK, Moore DH et al (2010) Detecting frontotemporal dysfunction in ALS: utility of the ALS cognitive behavioral screen (ALS-CBS). Amyotroph Lateral Scler 11(3):303–311CrossRef
31.
go back to reference Poletti B, Solca F, Carelli L et al (2016) The validation of the Italian Edinburgh cognitive and behavioural ALS screen (ECAS). Amyotroph Lateral Scler Frontotemporal Degener 17(7–8):489–498CrossRef Poletti B, Solca F, Carelli L et al (2016) The validation of the Italian Edinburgh cognitive and behavioural ALS screen (ECAS). Amyotroph Lateral Scler Frontotemporal Degener 17(7–8):489–498CrossRef
32.
go back to reference Goldstein ME, Sternberger NH, Sternberger LA (1987) Phosphorylation protects neurofilaments against proteolysis. J Neuroimmunol 14(2):149–160CrossRef Goldstein ME, Sternberger NH, Sternberger LA (1987) Phosphorylation protects neurofilaments against proteolysis. J Neuroimmunol 14(2):149–160CrossRef
33.
go back to reference Pijnenburg YA, Verwey NA, van der Flier WM, Scheltens P, Teunissen CE (2015) Discriminative and prognostic potential of cerebrospinal fluid phosphoTau/tau ratio and neurofilaments for frontotemporal dementia subtypes. Alzheimer’s Dement 1(4):505–512 Pijnenburg YA, Verwey NA, van der Flier WM, Scheltens P, Teunissen CE (2015) Discriminative and prognostic potential of cerebrospinal fluid phosphoTau/tau ratio and neurofilaments for frontotemporal dementia subtypes. Alzheimer’s Dement 1(4):505–512
34.
go back to reference Petzold A, Altintas A, Andreoni L et al (2010) Neurofilament ELISA validation. J Immunol Methods 352(1–2):23–31CrossRef Petzold A, Altintas A, Andreoni L et al (2010) Neurofilament ELISA validation. J Immunol Methods 352(1–2):23–31CrossRef
35.
go back to reference Bourbouli M, Rentzos M, Bougea A et al (2017) 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 44(3–4):144–152CrossRef Bourbouli M, Rentzos M, Bougea A et al (2017) 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 44(3–4):144–152CrossRef
36.
go back to reference Ganesalingam J, An J, Shaw CE et al (2011) Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem 117(3):528–537CrossRef Ganesalingam J, An J, Shaw CE et al (2011) Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem 117(3):528–537CrossRef
37.
go back to reference Lehnert S, Costa J, de Carvalho M et al (2014) Multicentre quality control evaluation of different biomarker candidates for amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 15(5–6):344–350CrossRef Lehnert S, Costa J, de Carvalho M et al (2014) Multicentre quality control evaluation of different biomarker candidates for amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 15(5–6):344–350CrossRef
38.
go back to reference Labra J, Menon P, Byth K et al (2016) Rate of disease progression: a prognostic biomarker in ALS. J Neurol Neurosurg Psychiatry 87(6):628–632CrossRef Labra J, Menon P, Byth K et al (2016) Rate of disease progression: a prognostic biomarker in ALS. J Neurol Neurosurg Psychiatry 87(6):628–632CrossRef
39.
go back to reference Chiò A, Logroscino G, Hardiman O et al (2009) Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 10(5–6):310–323CrossRef Chiò A, Logroscino G, Hardiman O et al (2009) Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 10(5–6):310–323CrossRef
Metadata
Title
Diagnostic and prognostic power of CSF Tau in amyotrophic lateral sclerosis
Authors
Antonio Scarafino
Eustachio D’Errico
Alessandro Introna
Angela Fraddosio
Eugenio Distaso
Irene Tempesta
Antonella Morea
Antonella Mastronardi
Rosaria Leante
Maddalena Ruggieri
Mariangela Mastrapasqua
Isabella Laura Simone
Publication date
01-10-2018
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 10/2018
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-018-9008-3

Other articles of this Issue 10/2018

Journal of Neurology 10/2018 Go to the issue