Proteomics-based Multimarker Model Improves Neurofilament Light Chain for Predicting Neurological Outcome after Cardiac Arrest

Abstract Background: Out of hospital cardiac arrest (OHCA) is a life-threatening event. Continuous advances in management increased initial survival, but the rate of favorable neurological outcome remains low. We have previously shown the usefulness of proteomics to identify novel biomarkers to predict this outcome. Neurofilament light chain (NfL), a marker of axonal damage, has since emerged as a promising single marker. The aim of this study was thus to assess the predictive value of NfL and compare it to our established model.Methods: NfL was measured in plasma samples from OHCA drawn at 48 hours after the event using single molecule assays. Neurological function at discharge from ICU was recorded on the cerebral performance category (CPC) scale. Predictive ability was assessed for NfL and compared to an established multimarker model.Results: Seventy patients were included into this analysis, of whom 21 (30%) showed a favorable outcome (CPC 1-2) compared to 49 (70%) with an unfavorable outcome (CPC 3 - 5). NfL increased from CPC 1 to 5 (16.5 pg/ml to 641 pg/ml, p<0.001). NfL alone performed moderately well with an area under the ROC (AUROC) of 79.4%. Prediction was significantly improved by combination of NfL with the established best performing model (F = 6.83, p = 0.01) with an AUROC to 89.7% (p for comparison = 0.017).Conclusion:The combination of NfL with other plasma and clinical markers is superior to that of either model alone and achieves a very good AUROC in this relatively small sample. Trial registration: ClinicalTrials.gov NCT01960699. Registered 08 October 2013.

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Serum neurofilament measurement improves clinical risk scores for outcome prediction after cardiac arrest: results of a prospective study

Critical Care ◽

10.1186/s13054-021-03459-y ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Sabina Hunziker ◽

Adrian Quinto ◽

Maja Ramin-Wright ◽

Christoph Becker ◽

Katharina Beck ◽

...

Keyword(s):

Cardiac Arrest ◽

Single Molecule ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Area Under The Curve ◽

Risk Scores ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Clinical Risk ◽

Poor Neurological Outcome

Abstract Background A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. Methods This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. Results Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p < 0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p < 0.001) and CAHP score (from AUC 0.89 to 0.92, p < 0.05). Adding NfL to both scores also resulted in significant improvement in reclassification statistics with a Net Reclassification Index (NRI) of 0.58 (p < 0.001) for OHCA and 0.83 (p < 0.001) for CAHP. Conclusions Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

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Neurofilament light chain as an early and sensitive predictor of long-term neurological outcome in patients after cardiac arrest

International Journal of Cardiology ◽

10.1016/j.ijcard.2012.12.016 ◽

2013 ◽

Vol 168 (2) ◽

pp. 1322-1327 ◽

Cited By ~ 19

Author(s):

Obaida R. Rana ◽

Jörg W. Schröder ◽

Julia K. Baukloh ◽

Esra Saygili ◽

Karl Mischke ◽

...

Keyword(s):

Cardiac Arrest ◽

Light Chain ◽

Neurological Outcome ◽

Neurofilament Light Chain ◽

Neurofilament Light

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Serum Neurofilament Measurement Improves Clinical Risk Score for Outcome Prediction After Cardiac Arrest: Results of A Prospective Study

10.21203/rs.3.rs-92711/v1 ◽

2020 ◽

Author(s):

Sabina Hunziker ◽

Adrian Quinto ◽

Maja Ramin-Wright ◽

Christoph Becker ◽

Katharina Beck ◽

...

Keyword(s):

Cardiac Arrest ◽

Single Molecule ◽

Neurological Outcome ◽

Outcome Prediction ◽

Cerebral Performance Category ◽

Neuron Specific Enolase ◽

Risk Scores ◽

Neurofilament Light Chain ◽

Clinical Risk ◽

Poor Neurological Outcome

Abstract Background: A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest risk scores.Methods: This prospective, single-center study included 164 consecutive adult cardiac arrest patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score.Results: Poor neurological outcome (CPC≥3) was found in 60% (98/164) of patients, and 55% (91/164) died. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685±1787 vs. 49±111pg/mL), with an adjusted odds ratio of 3.4 (95%CI 2.1 to 5.6, p<0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p<0.001) and CAHP score (from AUC 0.89 to 0.92, p<0.05). Admission NfL showed better outcome prediction compared to neuron-specific enolase (NSE) (AUC 0.84 vs.0.69, p=0.01).Conclusions: This study confirms the high performance of admission NfL alone and in combination with two clinical risk scores to prognosticate clinical outcome in patients after cardiac arrest. NfL should be considered as a standard laboratory measures in the evaluation of cardiac arrest patients.

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Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2021-326914 ◽

2021 ◽

pp. jnnp-2021-326914

Author(s):

Dario Saracino ◽

Karim Dorgham ◽

Agnès Camuzat ◽

Daisy Rinaldi ◽

Armelle Rametti-Lacroux ◽

...

Keyword(s):

Single Molecule ◽

Light Chain ◽

Rate Of Change ◽

Longitudinal Change ◽

Youden Index ◽

Clinical Genetic ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Link Type ◽

Therapeutic Trials

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.

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Circulating Neurofilament Light Chain Is Associated With Survival After Pediatric Cardiac Arrest*

Pediatric Critical Care Medicine ◽

10.1097/pcc.0000000000002294 ◽

2020 ◽

Vol 21 (7) ◽

pp. 656-661

Author(s):

Matthew P. Kirschen ◽

Nadir Yehya ◽

Kathryn Graham ◽

Todd Kilbaugh ◽

Robert A. Berg ◽

...

Keyword(s):

Cardiac Arrest ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light

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Sustained reduction of serum neurofilament light chain over 7 years by alemtuzumab in early relapsing–remitting MS

Multiple Sclerosis Journal ◽

10.1177/13524585211032348 ◽

2021 ◽

pp. 135245852110323

Author(s):

Jens Kuhle ◽

Nadia Daizadeh ◽

Pascal Benkert ◽

Aleksandra Maceski ◽

Christian Barro ◽

...

Keyword(s):

Single Molecule ◽

Light Chain ◽

Interferon Beta ◽

Efficacy And Safety ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Highly Active ◽

Sustained Reduction ◽

Relapsing Remitting ◽

Healthy Control

Background: Alemtuzumab efficacy and safety was demonstrated in CARE-MS I and extension studies (CAMMS03409; TOPAZ). Objective: Evaluate serum neurofilament light chain (sNfL) in CARE-MS I patients and highly active disease (HAD) subgroup, over 7 and 2 years for alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), respectively. Methods: Patients received SC IFNB-1a 44 µg 3×/week or alemtuzumab 12 mg/day at baseline and month 12, with further as-needed 3-day courses. sNfL was measured using single-molecule array (Simoa™). HAD definition was ⩾2 relapses in year before randomization and ⩾1 baseline gadolinium-enhancing lesion. Results: Baseline median sNfL levels were similar in alemtuzumab ( n = 354) and SC IFNB-1a–treated ( n = 159) patients (31.7 vs 31.4 pg/mL), but decreased with alemtuzumab versus SC IFNB-1a until year 2 (Y2; 13.2 vs 18.7 pg/mL; p < 0.0001); 12.7 pg/mL for alemtuzumab at Y7. Alemtuzumab-treated patients had sNfL at/below healthy control median at Y2 (72% vs 47%; p < 0.0001); 73% for alemtuzumab at Y7. HAD patients ( n = 102) had higher baseline sNfL (49.4 pg/mL) versus overall population; alemtuzumab HAD patients attained similar levels (Y2, 12.8 pg/mL; Y7, 12.7 pg/mL; 75% were at/below control median at Y7). Conclusion: Alemtuzumab was superior to SC IFNB-1a in reducing sNfL, with levels in alemtuzumab patients remaining stable through Y7. ClinicalTrials.gov identifier: NCT00530348, NCT00930553, NCT02255656

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Evaluation of neurofilament light chain in the cerebrospinal fluid and blood as a biomarker for neuronal damage in experimental pneumococcal meningitis

Journal of Neuroinflammation ◽

10.1186/s12974-020-01966-3 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Ngoc Dung Le ◽

Lukas Muri ◽

Denis Grandgirard ◽

Jens Kuhle ◽

David Leppert ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Single Molecule ◽

Light Chain ◽

Pneumococcal Meningitis ◽

Neuronal Damage ◽

Neuronal Injury ◽

Health Concern ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Inflammatory Phase

Abstract Background Pneumococcal meningitis (PM) remains a global public health concern and affects all age groups. If acquired during infancy or childhood, permanent neurofunctional deficits including cognitive impairment, cerebral palsy, and secondary epilepsy are typical sequelae of neuronal injury. Determination of patients at risk for the development of brain injury and subsequent neurofunctional sequelae could help to identify patients for focused management. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released upon neuronal injury into the cerebrospinal fluid (CSF) and blood. As little is known about the course of neurofilament release in the course of PM, we measured CSF and serum NfL levels longitudinally in experimental PM (ePM). Methods Eleven-day-old infant Wistar rats were infected intracisternally with Streptococcus pneumoniae and treated with ceftriaxone. At 18 and 42 h post-infection (hpi), the blood and CSF were sampled for NfL measurements by a single molecule array technology. Inflammatory cytokines and MMP-9 in CSF were quantified by magnetic bead multiplex assay (Luminex®) and by gel zymography, respectively. Results In ePM, CSF and serum NfL levels started to increase at 18 hpi and were 26- and 3.5-fold increased, respectively, compared to mock-infected animals at 42 hpi (p < 0.0001). CSF and serum NfL correlated at 18 hpi (p < 0.05, r = 0.4716) and 42 hpi (p < 0.0001, r = 0.8179). Both CSF and serum NfL at 42 hpi strongly correlated with CSF levels of IL-1β, TNF-α, and IL-6 and of MMP-9 depending on their individual kinetics. Conclusion Current results demonstrate that during the peak inflammatory phase of ePM, NfL levels in CSF and serum are the highest among CNS disease models studied so far. Given the strong correlation of CSF versus serum NfL, and its CNS-specific signal character, longitudinal measurements to monitor the course of PM could be performed based on blood sample tests, i.e., without the need of repetitive spinal taps. We conclude that NfL in the serum should be evaluated as a biomarker in PM.

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Thirty years after anorexia nervosa onset, serum neurofilament light chain protein concentration indicates neuronal injury

European Child & Adolescent Psychiatry ◽

10.1007/s00787-020-01657-7 ◽

2020 ◽

Author(s):

Elisabet Wentz ◽

Sandra Rydberg Dobrescu ◽

Lisa Dinkler ◽

Carina Gillberg ◽

Christopher Gillberg ◽

...

Keyword(s):

Anorexia Nervosa ◽

Single Molecule ◽

Light Chain ◽

Axonal Degeneration ◽

Neuronal Injury ◽

Serum Levels ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

National Patient ◽

History Of

Abstract Little is known about the long-term consequences of anorexia nervosa (AN) in terms of possible brain neuronal injury. We aimed at investigating whether women with adolescent-onset AN exhibit increased serum levels of neurofilament light chain protein (NfL), a biomarker for neuronal injury, compared with matched controls at 30-year follow-up. Blood samples were collected from 34 women with adolescent-onset AN and 38 matched healthy comparison women (COMP), at a mean age of 44 years (range 38–48 years). NfL was measured in serum using the in-house single molecule array (Simoa) method. The individuals were asked whether they or their parents had been diagnosed with dementia. The Swedish National Patient Register was searched for diagnoses related to dementia. Serum NfL concentrations were significantly higher in the AN group (AN 27.7 pg/ml; COMP 19.0 pg/ml; p = 0.041). When individuals with medical/neurological disorders in the AN and COMP groups were excluded, there was a statistically non-significant trend towards higher concentrations in the AN group (AN 27.4 pg/ml; COMP 18.8 pg/ml; p = 0.060). None of the participants had been diagnosed with dementia. There was no significant correlation between serum NfL and AN duration (r = 0.15). There was a moderate negative correlation between the serum NfL concentration and the current BMI in the AN group (r = 0.44). This is the first time that serum NfL has been assessed in middle-aged women with a history of adolescent-onset AN. The results suggest that there might be increased axonal degeneration as a sequel of AN. Individuals remaining underweight had higher serum NfL concentrations than those with a normal/high BMI. Additional studies are needed to confirm increased serum NfL concentrations in individuals recovered from AN. There is a need for further study of axonal degeneration as a consequence of AN.

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Neurofilament Light Chain as A Biomarker for Brain Metastases

Cancers ◽

10.3390/cancers12102852 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2852 ◽

Cited By ~ 1

Author(s):

Anne Winther-Larsen ◽

Claus Vinter Bødker Hviid ◽

Peter Meldgaard ◽

Boe Sandahl Sorensen ◽

Birgitte Sandfeld-Paulsen

Keyword(s):

Lung Cancer ◽

Brain Metastasis ◽

Brain Metastases ◽

Cancer Patients ◽

Single Molecule ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Lung Cancer Patients ◽

Potential Biomarker

Background: Brain metastases are feared complications in cancer. Treatment by neurosurgical resection and stereotactic radiosurgery are only available when metastatic lesions are limited and early detection is warranted. The neurofilament light chain (NfL) is a sensitive neuron-specific biomarker released following neuronal decay. We explored serum NfL as a biomarker of brain metastases. Methods: Serum was collected from 43 stage IV lung cancer patients with brain metastases and 25 stage I lung cancer patients. Serum was collected at time of cancer diagnosis and at time of brain metastasis diagnosis. In nine patients with brain metastases, additional samples were available between the two time points. NfL was quantified by Single Molecule Array (Simoa)™. Results: The median NfL level was significantly higher in patients with brain metastases than in patients without (35 versus 16 pg/mL, p = 0.001) and separated patients with an area under the curve of 0.77 (0.66–0.89). An increase in NfL could be measured median 3 months (range: 1–5) before the brain metastasis diagnosis. Further, a high level of NfL at time of brain metastasis diagnosis correlated with an inferior survival (hazard ratio: 2.10 (95% confidence interval: 1.11–3.98)). Conclusions: This study implies that NfL could be a potential biomarker of brain metastases.

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Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000749 ◽

2020 ◽

Vol 7 (4) ◽

pp. e749 ◽

Cited By ~ 4

Author(s):

Marie-Christine Reinert ◽

Pascal Benkert ◽

Jens Wuerfel ◽

Zuzanna Michalak ◽

Esther Ruberte ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Treatment Response ◽

Single Molecule ◽

Light Chain ◽

Interferon Beta ◽

Class Iii ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Potential Biomarker

ObjectiveTo investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS).MethodsIn this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12–105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated.ResultsUntreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), p < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], p < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], p = 0.015). Higher values were associated with a relapse <90 days ago (+51.1%; CI [1.184, 1.929], p < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], p = 0.048). In patients treated with interferon beta-1a/b (n = 27), sNfL levels declined from 14.7 to 7.9 pg/mL after 6 ± 2 months (CI [0.339, 0.603], p < 0.001). Patients with insufficient control of clinical or MRI disease activity under treatment with interferon beta-1a/b or glatiramer acetate who switched to fingolimod (n = 18) showed a reduction of sNfL levels from 16.5 to 10.0 pg/mL 6 ± 2 months after switch (CI [0.481, 0.701], p < 0.001).ConclusionssNfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. This study provides Class III evidence that sNfL levels are associated with disease activity in pediatric MS.

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