Neurofilament light chain as an early and sensitive predictor of long-term neurological outcome in patients 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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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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Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis

Multiple Sclerosis Journal ◽

10.1177/1352458515574148 ◽

2015 ◽

Vol 21 (14) ◽

pp. 1761-1770 ◽

Cited By ~ 60

Author(s):

S Modvig ◽

M Degn ◽

H Roed ◽

TL Sørensen ◽

HBW Larsson ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Optic Neuritis ◽

Light Chain ◽

Oligoclonal Bands ◽

Enzyme Linked Immunosorbent Assay ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light

Background: Cerebrospinal fluid (CSF) biomarkers have been suggested to predict multiple sclerosis (MS) after clinically isolated syndromes, but studies investigating long-term prognosis are needed. Objective: To assess the predictive ability of CSF biomarkers with regard to MS development and long-term disability after optic neuritis (ON). Methods: Eighty-six patients with ON as a first demyelinating event were included retrospectively. Magnetic resonance imaging (MRI), CSF leukocytes, immunoglobulin G index and oligoclonal bands were registered. CSF levels of chitinase-3-like-1, osteopontin, neurofilament light-chain, myelin basic protein, CCL2, CXCL10, CXCL13 and matrix metalloproteinase-9 were measured by enzyme-linked immunosorbent assay. Patients were followed up after 13.6 (range 9.6–19.4) years and 81.4% were examined, including Expanded Disability Status Scale and MS functional composite evaluation. 18.6% were interviewed by phone. Cox regression, multiple regression and Spearman correlation analyses were used. Results: Forty-six (53.5%) developed clinically definite MS (CDMS) during follow-up. In a multivariate model MRI ( p=0.0001), chitinase 3-like 1 ( p=0.0033) and age ( p=0.0194) combined predicted CDMS best. Neurofilament light-chain predicted long-term disability by the multiple sclerosis severity scale ( p=0.0111) and nine-hole-peg-test ( p=0.0202). Chitinase-3-like-1 predicted long-term cognitive impairment by the paced auditory serial addition test ( p=0.0150). Conclusion: Neurofilament light-chain and chitinase-3-like-1 were significant predictors of long-term physical and cognitive disability. Furthermore, chitinase-3-like-1 predicted CDMS development. Thus, these molecules hold promise as clinically valuable biomarkers after ON as a first demyelinating event.

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Long-term prognostic value of longitudinal measurements of blood neurofilament levels

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000856 ◽

2020 ◽

Vol 7 (5) ◽

pp. e856 ◽

Cited By ~ 2

Author(s):

Dieter A. Häring ◽

Harald Kropshofer ◽

Ludwig Kappos ◽

Jeffrey A. Cohen ◽

Anuja Shah ◽

...

Keyword(s):

Multiple Sclerosis ◽

Light Chain ◽

Prognostic Value ◽

Long Term Outcomes ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Longitudinal Measurements ◽

Relapsing Remitting ◽

Edss Score

ObjectiveTo assess the long-term prognostic value of an integral of longitudinal measurements of plasma neurofilament light chain levels (NfLlong) over 12 and 24 months vs single neurofilament light chain (NfL) measurements in patients with relapsing-remitting MS (RRMS) and its additional value when combined with clinical and MRI measures.MethodsThis analysis included continuously fingolimod-treated patients with RRMS from the 24-month FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)/12-month Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) phase 3 trials and their long-term extension, LONGTERMS. Patients were classified into high (≥30 pg/mL, n = 110) and low (<30 pg/mL, n = 164) NfL categories based on the baseline (BL) NfL value or the geometric mean NfLlong calculated over 12 and 24 months to predict disability-related outcomes and brain volume loss (BVL). The additional prognostic value of NfL was quantified using the area under the receiver operating characteristic (ROC) curve.ResultsA single high (vs low) NfL measure at BL was prognostic of a higher risk of reaching Expanded Disability Status Scale (EDSS) score ≥4 earlier (hazard ratio [HR] = 2.19; 95% CI = 1.21–3.97) and higher BVL over 120 months (difference: −1.12%; 95% CI = −2.07 to −0.17). When NfLlong was measured over 24 months, high NfL was associated with a higher risk of reaching EDSS score ≥4 (HR = 7.91; 95% CI = 2.99–20.92), accelerated 6-month confirmed disability worsening (HR = 3.14; 95% CI = 1.38–7.11), and 20% worsening in the Timed 25-Foot Walk Test (HR = 3.05; 95% CI = 1.38–6.70). Area under the ROC curve was consistently highest in models combining NfL with clinical and MRI measures.ConclusionsNfLlong had a higher prognostic value than single NfL assessments on long-term outcomes in RRMS. Combining it with clinical and MRI measures increased sensitivity and specificity to predict long-term disease outcomes.Classification of evidenceThis study provides Class I evidence that NfLlong was more strongly associated with long-term outcomes than single NfL assessments in patients with RRMS.

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Neurofilament Light Chain (NfL) as a Potential Biomarker of Treatment Response in Hereditary TransthyretinMediated (hATTR) Amyloidosis: Patisiran Global OLE Study

10.5327/1516-3180.200 ◽

2021 ◽

Author(s):

Fernanda Reis de Azevedo ◽

Michael Polydefkis ◽

Simina Ticau ◽

David Erbe ◽

Anastasia McManus ◽

...

Keyword(s):

Placebo Group ◽

Treatment Response ◽

Light Chain ◽

Open Label ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Term Change ◽

Potential Biomarker ◽

Open Label Extension

Introduction: Patisiran is approved for the treatment of hATTR amyloidosis with polyneuropathy and its long-term efficacy/safety is being studied in a Global OLE. Plasma biomarkers are being investigated for utility in facilitating earlier diagnosis and monitoring disease /treatment response. Objective: Evaluate long-term change in neurofilament light chain (NfL) levels in response to patisiran in patients enrolled in the Global Open-Label Extension (OLE) study. Methods: NfL plasma levels were measured in duplicate in healthy controls and patients with ATTRv amyloidosis with polyneuropathy using the Quanterix Simoa platform. Patient samples were analyzed from the APOLLO study at baseline and 18 months, and also measured at 12 and 24 months following APOLLO in patients who rolled into the Global OLE. Results: NfL levels at APOLLO baseline were 63.2 (placebo) and 72.1 pg/ mL (patisiran). NfL increased during APOLLO in the placebo group (99.5 pg/mL), whereas a significant decrease was observed at 18 months following patisiran (48.8 pg/mL). Reduced NfL levels were maintained in the APOLLO-patisiran group through 24 months of additional patisiran treatment in the Global OLE (44.0 pg/mL), consistent with maintained improvement in mNIS+7. Upon initiation of patisiran in the Global OLE, the APOLLO-placebo group experienced a reduction in NfL levels through 24 months (44.2 pg/mL), reaching a similar level to the APOLLO-patisiran group. Conclusions: NfL may serve as a biomarker of active nerve damage and polyneuropathy, making it useful as a potential biomarker of disease progression, treatment response and for earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and monitoring disease.

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Serum Neurofilament Light Chain as a Marker of Progression in Parkinson’s Disease: Long-Term Observation and Implications of Clinical Subtypes

Journal of Parkinson s Disease ◽

10.3233/jpd-212866 ◽

2021 ◽

pp. 1-14

Author(s):

Emil Ygland Rödström ◽

Niklas Mattsson-Carlgren ◽

Shorena Janelidze ◽

Oskar Hansson ◽

Andreas Puschmann

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Progression ◽

Light Chain ◽

Progression Rate ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Clinical Biomarkers ◽

Combined Models

Background: Biochemical and clinical biomarkers correlate with progression rate and disease severity in Parkinson’s disease (PD) but are not sufficiently studied in late PD. Objective: To examine how serum neurofilament light chain (S-NfL) alone or combined with clinical classifications predicts PD outcome in later disease stages. Methods: Eighty-five patients with 7.9±5.1 years of PD duration were included in an observational cohort. Clinical scores were obtained at two separate examinations 8.2±2.0 years apart. S-NfL levels were determined with single molecule array (SiMoA). Five predefined disease progression milestones were assessed. After affirming combination potential of S-NfL and either of two clinical classifications, three combined models were constructed based on these factors and age at onset in different combinations. Results: S-NfL levels showed significant hazard ratios for four out of five disease progression milestones: walking-aid usage (HR 3.5; 95% CI 1.4–8.5), nursing home living (5.1; 2.1–12.5), motor end-stage (6.2; 2.1–17.8), and death (4.1; 1.7–9.7). Higher S-NfL levels were associated with lower ability in activities of daily living and poorer cognition at baseline and/or at follow-up. Combined models showed significantly improved area under receiver operating characteristic curves (0.77–0.91) compared to S-NfL levels alone (0.68–0.71) for predicting the five disease milestones. Conclusion: S-NfL levels stratified patients according to their likelihood to reach clinically relevant progression milestones during this long-term observational study. S-NfL alone reflected motor and social outcomes in later stages of PD. Combining S-NfL with clinical factors was possible and exploratory combined models improved prognostic accuracy.

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383 Neurofilament Light Chain as a Marker for Cerebral Anoxia in Out-of-Hospital Cardiac Arrest

Annals of Emergency Medicine ◽

10.1016/j.annemergmed.2018.08.388 ◽

2018 ◽

Vol 72 (4) ◽

pp. S150-S151

Author(s):

S. Gul ◽

K. Huesgen ◽

T. Youn ◽

M.A. Chowdhury ◽

S. Cohen ◽

...

Keyword(s):

Cardiac Arrest ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cerebral Anoxia ◽

Hospital Cardiac Arrest

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Serum neurofilament light chain predicts long term clinical outcomes in multiple sclerosis

Scientific Reports ◽

10.1038/s41598-020-67504-6 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Simon Thebault ◽

Mohammad Abdoli ◽

Seyed-Mohammad Fereshtehnejad ◽

Daniel Tessier ◽

Vincent Tabard-Cossa ◽

...

Keyword(s):

Multiple Sclerosis ◽

Clinical Outcomes ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light

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Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Molecular Neurodegeneration ◽

10.1186/s13024-021-00471-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Melanie Barth ◽

Mehtap Bacioglu ◽

Niklas Schwarz ◽

Renata Novotny ◽

Janine Brandes ◽

...

Keyword(s):

Human Brain ◽

Light Chain ◽

Culture Medium ◽

Alpha Synuclein ◽

Human Antibody ◽

Neurofilament Light Chain ◽

Intact Mouse ◽

Neurofilament Light ◽

Adult Human

Abstract Background Proteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression. Methods Alpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed. Results To study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2–3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture’s genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-year-old donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions. Conclusion The successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments.

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