Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis

Feneberg, Emily; Oeckl, Patrick; Steinacker, Petra; Verde, Federico; Barro, Christian; Damme, Philip Van; Gray, Elizabeth; Großkreutz, Julian; Jardel, Claude; Kuhle, Jens; Koerner, Sonja; Lamari, Foudil; Amador, Maria del Mar; Mayer, Benjamin; Morelli, Claudia; Muckova, Petra; Petri, Susanne; Poesen, Koen; Raaphorst, Joost; Salachas, François; Silani, Vincenzo; Stubendorff, Beatrice; Turner, Martin R; Verbeek, Marcel M.; Weishaupt, Jochen H.; Weydt, Patrick; Ludolph, Albert C.; Otto, Markus

doi:10.1212/wnl.0000000000004761

Cited by 175 publications

(197 citation statements)

References 30 publications

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“…Correlations between neurofilaments and clinical parameters such as diagnostic latency and disease progression have been already been noted in previous studies in ALS [5, 6, 13, 14, 20]. We found that serum and CSF pNfH correlated significantly with progression rate at diagnosis and at the last observation, total ALSFRS-R score, and modified Rankin scale score at the last observation (albeit not at diagnosis).…”

Section: Discussionsupporting

confidence: 86%

“…It is unknown whether the better diagnostic performance of serum NfL in their study was due to to a superior analytical outcome over pNfH or the larger sample size. Moreover, in our study biological samples were gathered at the time when patients sought medical attention because of disturbances due to UMN signs, which implies a shorter disease duration at the time of sampling compared to the abovementioned study, a fact which might have had an impact on neurofilament concentrations [5, 14]. Larger prospective studies comparing the the diagnostic performances of the 2 neurofilaments’ isoforms are therefore required to clarify which biomarker in serum is more functional for distinguishing between UMN syndromes at an early phase.…”

Section: Discussionmentioning

confidence: 99%

“…This may explain the longer disease durations that were present in the PLS and hSP groups, which could have had an impact on neurofilament release; indeed, in a recent study serum and CSF pNfH were proven to be higher in early-phase ALS compared to late-phase ALS [5], but it might be that patients presenting early after symptom onset have an aggressive form of disease independently of the time from symptom appearance. On the other hand, there is no evidence so far that neurofilament concentrations may vary during the course of hSP or PLS, which might require further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…ALS biomarker research has flourished, bringing forth neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) as promising candidates for differentiating ALS from mimic syndromes already at an early stage [5]. …”

Section: Introductionmentioning

confidence: 99%

“…In previous studies comparing the performance status of neurofilaments’ isoforms, pNfH has been proven to be a more specific and sensitive biomarker for ALS when measured in cerebrospinal fluid (CSF) [6] and serum [5]. Neurofilaments are major axonal cytoskeleton proteins which contribute to maintenance of the diameter of large myelinated axons and the integrity of nerve conduction [7].…”

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

et al. 2018

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Background: Patients presenting with upper motor neuron (UMN) signs may widely diverge in prognosis, ranging from amyotrophic lateral sclerosis (ALS) to primary lateral sclerosis (PLS) and hereditary spastic paraplegia (hSP). Neurofilaments are emerging as potential diagnostic and prognostic biomarkers for ALS, but the diagnosis of UMN syndromes still relies mostly on clinical long-term observation and on familiarity or genetic confirmation. Objectives: To test whether phosphorylated neurofilament heavy chain (pNfH) may discriminate different UMN syndromes at diagnosis and to test their prognostic role among these diseases. Methods: We measured the cerebrospinal fluid (CSF) and serum pNfH of 30 patients presenting with UMN signs and diagnosed with ALS, hSP, and PLS, plus 9 healthy controls (HC). Results: ALS patients had higher levels of pNfH in CSF and serum compared to HC (p < 0.001 and p < 0.001 in CSF and serum, respectively) and PLS (p = 0.015 and p = 0.038) and hSP (p = 0.003 and p = 0.001) patients. PLS and hSP patients had similar CSF and serum pNfH concentrations, but a higher CSF pNfH concentration, compared to HC (p = 0.002 and p = 0.003 for PLS and hSP, respectively). Receiver operating characteristic curves for discriminating ALS from PLS and hSP showed an area under the curve of 0.79 for CSF and 0.81 for serum. In multivariable survival analysis including relevant clinical factors CSF pNfH represented the strongest variable predicting survival (HR 40.43; 95% CI 3.49–467.79, p = 0.003) independently of clinical group. Conclusions: Despite some statistical instability of the results due to limitations in sample size, our study supports the role of CSF pNfH as a prognostic biomarker for motor neuron diseases presenting with UMN signs. A potential power to discriminate between ALS and other UMN syndromes at presentation, and between all of the examined MND and HC, has been detected for both CSF and serum pNfH.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

et al. 2018

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Serum Neurofilament Light Chain for Prognosis of Outcome After Cardiac Arrest

et al. 2019

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Prognostication of neurologic outcome after cardiac arrest is an important but challenging aspect of patient therapy management in critical care units. OBJECTIVE To determine whether serum neurofilament light chain (NFL) levels can be used for prognostication of neurologic outcome after cardiac arrest. DESIGN, SETTING AND PARTICIPANTS Prospective clinical biobank study of data from the randomized Target Temperature Management After Cardiac Arrest trial, an international, multicenter study with 29 participating sites. Patients were included between November 11, 2010, and January 10, 2013. Serum NFL levels were analyzed between August 1 and August 23, 2017, after trial completion. A total of 782 unconscious patients with out-of-hospital cardiac arrest of presumed cardiac origin were eligible. EXPOSURES Serum NFL concentrations analyzed at 24, 48, and 72 hours after cardiac arrest with an ultrasensitive immunoassay. MAIN OUTCOMES AND MEASURES Poor neurologic outcome at 6-month follow-up, defined according to the Cerebral Performance Category Scale as cerebral performance category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). RESULTS Of 782 eligible patients, 65 patients (8.3%) were excluded because of issues with aliquoting, missing sampling, missing outcome, or transport problems of samples. Of the 717 patients included (91.7%), 580 were men (80.9%) and median (interquartile range [IQR]) age was 65 (56-73) years. A total of 360 patients (50.2%) had poor neurologic outcome at 6 months. Median (IQR) serum NFL level was significantly increased in the patients with poor outcome vs good outcome at 24 hours (1426 [299-3577] vs 37 [20-70] pg/mL), 48 hours (3240 [623-8271] vs 46 [26-101] pg/mL), and 72 hours (3344 [845-7838] vs 54 [30-122] pg/mL) (P < .001 at all time points), with high overall performance (area under the curve, 0.94-0.95) and high sensitivities at high specificities (eg, 69% sensitivity with 98% specificity at 24 hours). Serum NFL levels had significantly greater performance than the other biochemical serum markers (ie, tau, neuron-specific enolase, and S100). At comparable specificities, serum NFL levels had greater sensitivity for poor outcome compared with routine electroencephalogram, somatosensory-evoked potentials, head computed tomography, and both pupillary and corneal reflexes (ranging from 29.2% to 49.0% greater for serum NFL level). CONCLUSIONS AND RELEVANCE Findings from this study suggest that the serum NFL level is highly predictive marker of long-term poor neurologic outcome at 24 hours after cardiac arrest and may be a useful complement to currently available neurologic prognostication methods.

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Serum neurofilament heavy chains as early marker of motor neuron degeneration

Schaepdryver

Goossens

Meyer

et al. 2019

Ann Clin Transl Neurol

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ObjectiveTo determine whether serum phosphorylated neurofilament heavy chain (pNfH) levels are elevated before patients were diagnosed with sporadic or familial ALS, and what the prognostic value of these prediagnostic pNfH levels is.MethodspNfH was measured via ELISA in leftovers of serum drawn for routine purposes before the time of diagnosis. These prediagnostic samples were retrieved from the biobank of the University Hospitals Leuven for 95 patients who in follow‐up received a diagnosis of ALS. Additionally, 35 patients with mild cognitive impairment (MCI) and 85 healthy controls (HC) were included in this retrospective study.ResultsThe median disease duration (range) from onset to prediagnostic sampling and from onset to diagnosis was 6.5 (−71.9–36.1) and 9.9 (2.0–40.7) months, respectively. Fifty‐eight percent of the prediagnostic samples had serum pNfH levels above the 95th percentile of pNfH levels measured in HC. Serum pNfH levels (median (range)) were elevated up to 18 months before the diagnosis of ALS (91 pg/mL (6–342 pg/mL)) in comparison with HC (30 pg/mL (6–146 pg/mL); P = 0.05), and increased during the prediagnostic stage, which was not observed in patients with MCI. Furthermore, prediagnostic pNfH levels were a univariate predictor of survival in ALS (hazard ratio (95% CI): 2.16 (1.20–3.87); P = 0.01).InterpretationOur findings demonstrate that serum pNfH is elevated well before the time of diagnosis in mainly sporadic ALS patients. These results encourage to prospectively explore if pNfH has an added value to shorten the diagnostic delay in ALS.

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Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis

Abstract: This study provides Class II evidence that CSF and serum Nf concentrations discriminate ALS with early symptom onset from other neurologic diseases.

Cited by 175 publications

References 30 publications

Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

Serum Neurofilament Light Chain for Prognosis of Outcome After Cardiac Arrest

Serum neurofilament heavy chains as early marker of motor neuron degeneration

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