Elsevier

Neurobiology of Aging

Volume 36, Issue 2, February 2015, Pages 1072-1074
Neurobiology of Aging

Brief communication
Total tau is increased, but phosphorylated tau not decreased, in cerebrospinal fluid in amyotrophic lateral sclerosis

https://doi.org/10.1016/j.neurobiolaging.2014.10.019Get rights and content

Abstract

In amyotrophic lateral sclerosis (ALS), objective biomarkers are needed for early diagnosis and progression monitoring. Reduced phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) has recently been proposed to provide such a biomarker in ALS. Here, we aimed to scrutinize this notion, evaluating both p-tau and total tau (t-tau) in CSF of ALS patients and control subjects. CSF p-tau and t-tau levels were measured in 60 consecutive ALS patients and 120 control subjects without neurodegenerative disease, using an established specific enzyme-linked immunosorbent assay method. Contrary to recent reports, CSF p-tau was not significantly reduced in ALS patients compared with control subjects (p = 0.287). However, CSF t-tau was significantly increased (p < 0.001). Correspondingly, the ratio of p-tau to t-tau was significantly reduced in ALS (p < 0.001). The area under the curve demonstrated poor sensitivity and specificity for p-tau, but moderate sensitivity and specificity for t-tau and p-tau/t-tau ratio. Thus, CSF p-tau by itself does not appear a suitable diagnostic biomarker for ALS, whereas CSF t-tau is a (probably unspecific) marker of the neuronal degeneration in ALS.

Introduction

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder, which is characterized by upper and lower motor neuron loss (Hardiman et al., 2011). Despite much research, no surrogate parameters for early diagnosis and progression monitoring have been identified (Tarasiuk et al., 2012). Recently, however, reduced levels of phosphorylated tau (p-tau) and a reduced ratio of p-tau to total tau (t-tau) in cerebrospinal fluid (CSF) have been proposed as potential diagnostic biomarkers for ALS (Grossman et al., 2014) based on the findings in 2 small ALS cohorts (n = 26 training cohort; n = 25 validation cohort). The neuropathologic basis of this finding remains to be ascertained because no essential changes have been observed in tau deposition and tau phosphorylation in ALS brains (Munoz et al., 1988, Murayama et al., 1990, Neumann et al., 2006). Particularly, no decrease in the histologic load of phosphorylated tau has been reported. Therefore, we aimed here to scrutinize the hypothesis that p-tau in CSF is indeed reduced in ALS by investigating CSF tau levels in large ALS and control cohorts. Although our findings reveal an increase in t-tau, which probably reflects a (unspecific) CSF marker of the ongoing neuronal degeneration in ALS, they question the proposed value of p-tau as a biomarker for the diagnosis of ALS.

Section snippets

Methods

ALS patients were recruited from the ALS outpatient clinic and the ward of the Department of Neurodegenerative Disorders, University Hospital Tübingen, and assessed by experienced neurologists (Matthis Synofzik and Walter Maetzler). All patients (n = 60 total; 26 women and 34 men) fulfilled the revised El Escorial Criteria (Brooks et al., 2000) for ALS diagnosis. Patients were aged 67.34 years (60.05–74.43 years; [numbers in brackets indicate median with lower and upper quartiles here and

Results

Levels of p-tau in patients (40.50 pg/mL; 33.00–55.75 pg/mL [median with lower and upper quartiles]; Fig. 1A) and in control subjects (41.50 pg/mL; 31.25–53.00 pg/mL) did not differ significantly (Mann-Whitney test, 1-sided, U = 3414.50, z = −0.56, p = 0.287, r = 0.04). Levels of t-tau were significantly increased in ALS patients (291.00 pg/mL; 217.00–372.50 pg/mL; Fig. 1B) compared with control subjects (219.50 pg/mL; 153.75–301.50 pg/mL) (Mann-Whitney test, 2-sided, U = 2330.50, z = −3.85, p

Discussion

CSF levels of p-tau did not differ significantly between our—comparably large—ALS and control cohorts. Our results thus do not confirm recent findings of decreased p-tau in ALS, and the observed ROC values for p-tau strongly caution its suggested use as a diagnostic CSF biomarker for ALS (Grossman et al., 2014). This finding of normal phosphorylated tau in ALS is consistent with the brain pathology of ALS where no changes in tau deposition and tau phosphorylation have been identified (Munoz

Disclosure statement

Dr Tim W. Rattay received traveling money from Ipsen Pharma. Dr Matthis Synofzik received consulting fees from Actelion Pharmaceuticals Ltd. The remaining authors report no disclosures. The authors declare that they have no competing interests.

Acknowledgements

Carlo Wilke contributed toward the design and conceptualization of the study, acquisition of the data, analysis of the data, and drafting of the manuscript. Dr Tim W. Rattay contributed toward the acquisition of the data, analysis of the data, and revision of the manuscript. Christian Deuschle, Dr Walter Maetzler, and Dr Matthis Synofzik contributed toward design and conceptualization of the study, acquisition of the data, analysis and interpretation of the data, and revision of the manuscript.

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