Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

Oeckl, Patrick; Jardel, Claude; Salachas, François; Lamari, Foudil; Andersen, Peter M.; Bowser, Robert; Carvalho, Mamede de; Costa, Júlia; Damme, Philip Van; Gray, Elizabeth; Großkreutz, Julian; Hernández-Barral, María; Herukka, Sanna Kaisa; Huss, André; Jeromin, Andreas; Kirby, Janine; Kuźma‐Kozakiewicz, Magdalena; Amador, Maria del Mar; Mora, Jesús; Morelli, Claudia; Muckova, Petra; Petri, Susanne; Poesen, Koen; Rhode, Heidrun; Rikardsson, Anna Karin; Robberecht, Wim; Mahillo, Ana I. Rodríguez; Shaw, Pamela J.; Silani, Vincenzo; Steinacker, Petra; Turner, Martin R; Tüzün, Erdem; Yetimler, Berrak; Ludolph, Albert C.; Otto, Markus

doi:10.3109/21678421.2016.1167913

Cited by 89 publications

(65 citation statements)

References 31 publications

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“…As a result, 28 full-text articles were assessed for eligibility, of which three had no control group (Boylan et al, 2013; Tortelli et al, 2015; Weydt et al, 2016), five investigated neurofilament levels in other biological samples (Troost et al, 1992; Strong et al, 2001; Mendonca et al, 2005; Puentes et al, 2014; McCombe et al, 2015), one utilized western blot (Mendonca et al, 2011) and one measured anti-neurofilament antibodies (Fialova et al, 2010), two had overlapping data sets (Brettschneider et al, 2006; Goncalves et al, 2015) and two had a sample size <10 (Norgren et al, 2003; Petzold et al, 2003), and three did not provide sufficient data to allow construct a 2 × 2 table (Kuhle et al, 2010; Gaiottino et al, 2013; Lehnert et al, 2014), one was a systematic review and meta-analysis (Xu et al, 2016). Finally, 10 articles were included in the meta-analysis, of which two reported data on NFL only (Tortelli et al, 2012; Lu et al, 2015), five reported on pNFH only (Ganesalingam et al, 2011, 2013; Chen et al, 2016; Goncalves et al, 2016; Li et al, 2016) and three reported both (Reijn et al, 2009; Steinacker et al, 2015; Oeckl et al, 2016). A flow chart of publication selection is presented in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

“…A flow chart of publication selection is presented in Figure 1 . Of note, one study that focused on multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS enrolled participants from 15 centers across Europe and America (Oeckl et al, 2016), part of which might overlapped with other four studies (Ganesalingam et al, 2013; Lu et al, 2015; Steinacker et al, 2015; Goncalves et al, 2016). However, the multicenter study only recruited five ALS patients and five controls from each center; therefore, we reckoned that the multiple publication bias, if existed, could be ignored in view of the relative large total sample size.…”

Section: Resultsmentioning

confidence: 99%

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Neurofilaments in CSF As Diagnostic Biomarkers in Motor Neuron Disease: A Meta-Analysis

Shen

Tai

2016

Front. Aging Neurosci.

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Objective: Neurofilaments in CSF are promising biomarkers which might help in the diagnosis of motor neuron disease (MND). We aim to assess the diagnostic value of neurofilaments in CSF for MND.Methods: Pubmed, Emabase, and Web of Science were searched for relevant studies systematically. Articles in English that evaluated the utility of neurofilaments in CSF in the diagnosis of MND were included. Data were extracted by two independent investigators. Diagnostic indexes for neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were calculated separately. Stata 12.0 software with a bivariate mixed-effects model was used to summarize the diagnostic indexes from eligible studies.Results: Five studies on NFL and eight studies on pNFH met inclusion criteria. For NFL, the pooled sensitivity and specificity were 81% (95% confidence interval [CI], 72–88%) and 85% (95% CI, 76–91%), respectively; the positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 5.5 (95% CI, 3.1–9.8) and 0.22 (95% CI, 0.14–0.35), respectively; the summary diagnostic odds ratio (DOR) was 25 (95% CI, 9–70), and the area under summary receiver operator characteristic curve (AUC) was 0.90 (95% CI, 0.87–0.92). For pNFH, the pooled sensitivity, specificity, PLR and NLR were 85% (95% CI, 80–88%), 85% (95% CI, 77–90%), 5.5 (95% CI, 3.6–8.4), and 0.18 (95% CI, 0.13–0.25), respectively; the DOR was 30 (95% CI, 16–58), and the AUC was 0.91 (95% CI, 0.88–0.93).Conclusion: Neurofilaments in CSF have a high value in the diagnosis of MND, though the optimal cutoff value remains to be further investigated.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Neurofilaments in CSF As Diagnostic Biomarkers in Motor Neuron Disease: A Meta-Analysis

Shen

Tai

2016

Front. Aging Neurosci.

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“…We found a similar diagnostic sensitivity, specificity, and AUC for CSF pNfH levels in this study; however, the optimal cutoff for pNfH (>1104 pg/mL) in our study was higher than in most other studies (437–1,200 pg/mL). We speculate that this difference may be related to research design, control-group choice, disease-progression rate, and disease duration (27, 28). A statistically significant inverse correlation was found between CSF pNfH level and disease duration, suggesting that the concentration of pNfH may be higher early in the disease course.…”

Section: Discussionmentioning

confidence: 99%

“…The NfL diagnostic sensitivity, specificity, and AUC in our study were lower than they were in this meta-analysis. In addition, to the reasons mentioned above, we consider that this may be the related to NfL stability or severity of disease (28, 29). NfL levels are higher in patients with more severe disease presentation.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Performance of Neurofilaments in Chinese Patients With Amyotrophic Lateral Sclerosis: A Prospective Study

Ren

Jeromin

et al. 2018

Front. Neurol.

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Several studies have attempted to reduce diagnostic delay and identify biomarkers for drug development in amyotrophic lateral sclerosis (ALS). In this study, we aimed to evaluate the diagnostic accuracy for ALS of cerebrospinal fluid (CSF) neurofilament (Nf), Tau protein, and inflammatory factors such as interleukin (IL)-2, IL-6, IL-10, IL-15, and granulocyte-macrophage colony-stimulating factor (GMCSF) in Chinese patients. Our prospective study measured the concentration of phosphorylated Nf heavy chain (pNfH), Nf light chain (NfL), Tau, pTau, and inflammatory factors in the CSF of 85 patients. Detailed clinical data and laboratory, neuroimaging, and neurophysiological findings were recorded. The concentrations of pNfH and NfL were higher in the ALS group than in the control group. At the 1104 pg/mL pNfH cutoff, the specificity was 68.8%, the sensitivity 100%, and the area under the curve (AUC) 0.907. At the 1,139 pg/mL NfL cutoff, the specificity was 56.3%, the sensitivity 96.2%, and the AUC 0.775. There was no significant difference in the concentrations of Tau, pTau, IL-2, IL-6, IL-10, IL-15, and GMCSF between the ALS and control groups (p > 0.05). In the ALS group, the concentration of pNfH in the CSF was correlated with disease duration (r = −0.475, p < 0.001). This is the first prospective study to confirm the diagnostic value of Nf for ALS in Chinese patients.

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“…Early studies identified increased phosphorylated neurofilament heavy chain (pNFH) in the CSF of patients with ALS when compared with healthy controls and other neurodegenerative diseases [28,29]. Additional studies have demonstrated a utility for pNFH or a ratio of pNFH to complement C3 in the CSF as a diagnostic marker for ALS [30][31][32][33]. pNFH levels in the CSF or blood also have prognostic utility and can be used to assess the rate of disease progression and survival [30,34], where disease progression is measured via the rate of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) score.…”

Section: Neurofilament Proteinsmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

Abstract: Values in ALS patients are already comparable between most centers, supporting eventual implementation into clinical routine. However, continuous quality control programs will be necessary for inclusion in the diagnostic work-up.

Cited by 89 publications

References 31 publications

Neurofilaments in CSF As Diagnostic Biomarkers in Motor Neuron Disease: A Meta-Analysis

Neurofilaments in CSF As Diagnostic Biomarkers in Motor Neuron Disease: A Meta-Analysis

Diagnostic Performance of Neurofilaments in Chinese Patients With Amyotrophic Lateral Sclerosis: A Prospective Study

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

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