Serum neurofilament light

ObjectiveTo explore the utility of serum neurofilament light chain (NfL) as a biomarker for primary and secondary neuroaxonal injury after ischemic stroke (IS) and study its value for the prediction of clinical outcome.MethodsWe used an ultrasensitive single-molecule array assay to measure serum NfL levels in healthy controls (n = 30) and 2 independent cohorts of patients with IS: (1) with serial serum sampling at hospital arrival (n = 196), at days 2, 3, and 7 (n = 89), and up to 6 months post stroke; and (2) with standardized MRI at baseline and at 6 months post stroke, and with cross-sectional serum sampling at 6 months (n = 95). We determined the temporal profile of serum NfL levels, their association with imaging markers of neuroaxonal injury, and with clinical outcome.ResultsPatients with IS had higher serum NfL levels compared with healthy controls starting from admission until 6 months post stroke. Serum NfL levels peaked at day 7 (211.2 pg/mL [104.7–442.6], median [IQR]) and correlated with infarct volumes (day 7: partial r = 0.736, p = 1.5 × 10−15). Six months post stroke, patients with recurrent ischemic lesions on MRI (n = 19) had higher serum NfL levels compared to those without new lesions (n = 76, p = 0.002). Serum NfL levels 6 months post stroke further correlated with a quantitative measure of secondary neurodegeneration obtained from diffusion tensor imaging MRI (r = 0.361, p = 0.001). Serum NfL levels 7 days post stroke independently predicted modified Rankin Scale scores 3 months post stroke (cumulative odds ratio [95% confidence interval] = 2.35 [1.60–3.45]; p = 1.24 × 10−05).ConclusionSerum NfL holds promise as a biomarker for monitoring primary and secondary neuroaxonal injury after IS and for predicting functional outcome.

Download Full-text

Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000679 ◽

2020 ◽

Vol 7 (3) ◽

pp. e679 ◽

Cited By ~ 2

Author(s):

Sinah Engel ◽

Falk Steffen ◽

Timo Uphaus ◽

Peter Scholz-Kreisel ◽

Frauke Zipp ◽

...

Keyword(s):

Single Molecule ◽

Leukocyte Count ◽

Cross Sectional Study ◽

Axonal Damage ◽

Oligoclonal Bands ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Igg Synthesis ◽

Healthy Donors

ObjectiveTo investigate the association of serum neurofilament light chain (sNfL) levels with CSF parameters in clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS), taking into account radiologic and clinical parameters of disease activity.MethodsSimultaneously collected serum and CSF samples of 112 untreated patients newly diagnosed with CIS or RRMS were included in this cross-sectional study. CSF parameters were obtained as part of routine diagnostic tests. sNfL levels of patients and of 62 healthy donors were measured by highly sensitive single molecule array (SiMoA) immunoassay.ResultsPatients with RRMS (n = 91, median 10.13 pg/mL, interquartile range [IQR] 6.67–17.77 pg/mL) had higher sNfL levels than healthy donors (n = 62, median 5.25 pg/mL, IQR 4.05–6.81 pg/mL, p < 0.001) and patients with CIS (n = 21, median 5.69 pg/mL, IQR 4.73–9.07 pg/mL, p < 0.001). Patients positive for oligoclonal bands (OCBs) (n = 101, median 9.19 pg/mL, IQR 6.34–16.38 pg/mL) had higher sNfL levels than OCB-negative patients (n = 11, median 5.93 pg/mL, IQR 2.93–8.56 pg/mL, p = 0.001). sNfL levels correlated with CSF immunoglobulin G (IgG) levels (r = 0.317, p = 0.002), IgG ratio (QIgG) (r = 0.344, p < 0.001), and CSF leukocyte count (r = 0.288, p = 0.002). In linear regression modeling, the CSF leukocyte count combined with the number of contrast-enhancing lesions in MRI predicted sNfL levels best.ConclusionsIn active MS, sNfL levels correlate with intrathecal pleocytosis and IgG synthesis, indicating that axonal damage is associated with both acute and chronic CNS-intrinsic inflammation.

Download Full-text

Blood-based NfL

Neurology ◽

10.1212/wnl.0000000000003680 ◽

2017 ◽

Vol 88 (10) ◽

pp. 930-937 ◽

Cited By ~ 156

Author(s):

Oskar Hansson ◽

Shorena Janelidze ◽

Sara Hall ◽

Nadia Magdalinou ◽

Andrew J. Lees ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Single Molecule ◽

Area Under The Curve ◽

Diagnostic Workup ◽

Healthy Controls ◽

Class Iii ◽

Early Disease ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Parkinsonian Disorders

Objective:To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders.Methods:The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated.Results:We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81).Conclusions:Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics.Classification of evidence:This study provides Class III evidence that blood NfL levels discriminate between PD and APD.

Download Full-text

Absence of attack-independent neuroaxonal injury in MOG antibody-associated disease: Longitudinal assessment of serum neurofilament light chain

Multiple Sclerosis Journal ◽

10.1177/13524585211063756 ◽

2021 ◽

pp. 135245852110637

Author(s):

Jae-Won Hyun ◽

So Yeon Kim ◽

Yeseul Kim ◽

Na Young Park ◽

Ki Hoon Kim ◽

...

Keyword(s):

Glial Fibrillary Acidic Protein ◽

Single Molecule ◽

Light Chain ◽

Myelin Oligodendrocyte Glycoprotein ◽

Acidic Protein ◽

Healthy Controls ◽

Longitudinal Assessment ◽

Neurofilament Light Chain ◽

Neurofilament Light

To evaluate the occurrence of attack-independent neuroaxonal and astrocytic damage in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) levels were longitudinally measured in 102 sera using a single-molecule array assay. Sera from 15 adults with relapsing MOGAD with available longitudinal samples for the median 24-month follow-up and 26 age-/sex-matched healthy controls were analyzed. sNfL levels were significantly elevated in all clinical attacks, where the levels decreased below or close to cut-off value within 6 months after attacks. sNfL levels were consistently low during inter-attack periods. In contrast, sGFAP levels did not increase in most clinical attacks and remained low during follow-up. Significant neuroaxonal damage was observed at clinical attacks, while attack-independent neuroaxonal and astrocytic injury was absent in MOGAD.

Download Full-text

Plasma neurofilament light chain concentration in the inherited peripheral neuropathies

Neurology ◽

10.1212/wnl.0000000000004932 ◽

2018 ◽

Vol 90 (6) ◽

pp. e518-e524 ◽

Cited By ~ 61

Author(s):

Åsa Sandelius ◽

Henrik Zetterberg ◽

Kaj Blennow ◽

Rocco Adiutori ◽

Andrea Malaspina ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Disease Severity ◽

Light Chain ◽

Cross Sectional Study ◽

Healthy Controls ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Charcot Marie Tooth Disease ◽

Inherited Neuropathies

ObjectiveTo perform a cross-sectional study to determine whether plasma neurofilament light chain (NfL) concentration is elevated in patients with Charcot-Marie-Tooth disease (CMT) and if it correlates with disease severity.MethodsBlood samples were collected from 75 patients with CMT and 67 age-matched healthy controls over a 1-year period. Disease severity was measured using the Rasch modified CMT Examination and neuropathy scores. Plasma NfL concentration was measured using an in-house-developed Simoa assay.ResultsPlasma NfL concentration was significantly higher in patients with CMT (median 26.0 pg/mL) compared to healthy controls (median 14.6 pg/mL, p < 0.0001) and correlated with disease severity as measured using the Rasch modified CMT examination (r = 0.43, p < 0.0001) and neuropathy (r = 0.37, p = 0.044) scores. Concentrations were also significantly higher when subdividing patients by genetic subtype (CMT1A, SPTLC1, and GJB1) or into demyelinating or axonal forms compared to healthy controls.ConclusionThere are currently no validated blood biomarkers for peripheral neuropathy. The significantly raised plasma NfL concentration in patients with CMT and its correlation with disease severity suggest that plasma NfL holds promise as a biomarker of disease activity, not only for inherited neuropathies but for peripheral neuropathy in general.

Download Full-text

Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19

Neurology ◽

10.1212/wnl.0000000000010111 ◽

2020 ◽

Vol 95 (12) ◽

pp. e1754-e1759 ◽

Cited By ~ 30

Author(s):

Nelly Kanberg ◽

Nicholas J. Ashton ◽

Lars-Magnus Andersson ◽

Aylin Yilmaz ◽

Magnus Lindh ◽

...

Keyword(s):

Single Molecule ◽

Severe Disease ◽

Plasma Concentrations ◽

Neuronal Injury ◽

Cns Injury ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Plasma Biomarkers

ObjectiveTo test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury.MethodsWe recruited 47 patients with mild (n = 20), moderate (n = 9), or severe (n = 18) COVID-19 and measured 2 plasma biomarkers of CNS injury by single molecule array, neurofilament light chain protein (NfL; a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp; a marker of astrocytic activation/injury), in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort.ResultsThe patients with severe COVID-19 had higher plasma concentrations of GFAp (p = 0.001) and NfL (p < 0.001) than controls, while GFAp was also increased in patients with moderate disease (p = 0.03). In patients with severe disease, an early peak in plasma GFAp decreased on follow-up (p < 0.01), while NfL showed a sustained increase from first to last follow-up (p < 0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury.ConclusionWe show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19–related CNS damage and its relation to both clinically defined CNS events such as hypoxic and ischemic events and mechanisms more closely linked to systemic severe acute respiratory syndrome coronavirus 2 infection and consequent immune activation, as well as to evaluate the clinical utility of monitoring plasma NfL and GFAp in the management of this group of patients.

Download Full-text

Serum neurofilament light chain level associations with clinical and cognitive performance in multiple sclerosis: A longitudinal retrospective 5-year study

Multiple Sclerosis Journal ◽

10.1177/1352458519881428 ◽

2019 ◽

Vol 26 (13) ◽

pp. 1670-1681 ◽

Cited By ~ 17

Author(s):

Dejan Jakimovski ◽

Robert Zivadinov ◽

Murali Ramanthan ◽

Jesper Hagemeier ◽

Bianca Weinstock-Guttman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Performance ◽

Cognitive Processing ◽

Single Molecule ◽

Light Chain ◽

Manual Dexterity ◽

Analysis Of Covariance ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light

Background: A limited number of studies investigated associations between serum neurofilament light chain (sNfL) and cognition in persons with multiple sclerosis (PwMS). Objective: To assess cross-sectional and longitudinal associations between sNfL levels, clinical, and cognitive performance in PwMS and age-matched healthy controls (HCs). Materials: One hundred twenty-seven PwMS (85 relapsing–remitting MS/42 progressive MS), 20 clinically isolated syndrome patients, and 52 HCs were followed for 5 years. sNfL levels were measured using the single-molecule array (Simoa) assay and quantified in picograms per milliliter. Expanded Disability Status Scale (EDSS), walking, and manual dexterity tests were obtained. At follow-up, Brief International Cognitive Assessment for MS (BICAMS) was utilized. Cognitively impaired (CI) status was derived using HC-based z-scores. Age-, sex-, and education-adjusted analysis of covariance (ANCOVA) and regression models were used. Multiple comparison–adjusted values of q < 0.05 were considered significant. Results: In PwMS, sNfL levels were cross-sectionally associated with walking speed ( r = 0.235, q = 0.036), manual dexterity ( r = 0.337, q = 0.002), and cognitive processing speed (CPS; r =−0.265, q = 0.012). Baseline sNfL levels predicted 5-year EDSS scores ( r = 0.25, q = 0.012), dexterity ( r = 0.224, q = 0.033), and CPS ( r =−0.205, q = 0.049). CI patients had higher sNfL levels (27.2 vs. 20.6, p = 0.016) and greater absolute longitudinal sNfL increase when compared with non-CI patients (4.8 vs. 0.7, p = 0.04). Conclusion: Higher sNfL levels are associated with poorer current and future clinical and cognitive performance.

Download Full-text

Serum neurofilament light chain (sNfL) values in a large cross-sectional population of children with asymptomatic to moderate COVID-19

Journal of Neurology ◽

10.1007/s00415-021-10554-1 ◽

2021 ◽

Author(s):

Tobias Geis ◽

◽

Susanne Brandstetter ◽

Antoaneta A. Toncheva ◽

Otto Laub ◽

...

Keyword(s):

Single Molecule ◽

Light Chain ◽

Quantitative Methods ◽

Neuronal Damage ◽

Multivariate Regression Analysis ◽

Clinical Severity ◽

Healthy Children ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light

Abstract Background Serum neurofilament light chain (sNfL) is an established biomarker of neuro-axonal damage in multiple neurological disorders. Raised sNfL levels have been reported in adults infected with pandemic coronavirus disease 2019 (COVID-19). Levels in children infected with COVID-19 have not as yet been reported. Objective To evaluate whether sNfL is elevated in children contracting COVID-19. Methods Between May 22 and July 22, 2020, a network of outpatient pediatricians in Bavaria, Germany, the Coronavirus antibody screening in children from Bavaria study network (CoKiBa), recruited healthy children into a cross-sectional study from two sources: an ongoing prevention program for 1–14 years, and referrals of 1–17 years consulting a pediatrician for possible infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We determined sNfL levels by single molecule array immunoassay and SARS-CoV-2 antibody status by two independent quantitative methods. Results Of the 2652 included children, 148 (5.6%) were SARS-CoV-2 antibody positive with asymptomatic to moderate COVID-19 infection. Neurological symptoms—headache, dizziness, muscle aches, or loss of smell and taste—were present in 47/148 cases (31.8%). Mean sNfL levels were 5.5 pg/ml (SD 2.9) in the total cohort, 5.1 (SD 2.1) pg/ml in the children with SARS-CoV-2 antibodies, and 5.5 (SD 3.0) pg/ml in those without. Multivariate regression analysis revealed age—but neither antibody status, antibody levels, nor clinical severity—as an independent predictor of sNfL. Follow-up of children with pediatric multisystem inflammatory syndrome (n = 14) showed no association with sNfL. Conclusions In this population study, children with asymptomatic to moderate COVID-19 showed no neurochemical evidence of neuronal damage.

Download Full-text

Plasma tau is increased in frontotemporal dementia

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-317260 ◽

2018 ◽

Vol 89 (8) ◽

pp. 804-807 ◽

Cited By ~ 16

Author(s):

Martha S Foiani ◽

Ione OC Woollacott ◽

Carolin Heller ◽

Martina Bocchetta ◽

Amanda Heslegrave ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Single Molecule ◽

Neurodegenerative Disorder ◽

Primary Progressive Aphasia ◽

Personality Change ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Brain Volumes ◽

Genetic Groups

BackgroundFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations in GRN, MAPT and C9orf72 being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP-43 inclusions during life.MethodsThis study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in either MAPT (n=12), GRN (n=9) or C9orf72 (n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression.ResultsHigher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only the MAPT group had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross-sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration.ConclusionPlasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only in MAPT mutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies.

Download Full-text

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.

Download Full-text

Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19

Journal of Neurology ◽

10.1007/s00415-021-10517-6 ◽

2021 ◽

Author(s):

Anne Hege Aamodt ◽

Einar August Høgestøl ◽

Trine Haug Popperud ◽

Jan Cato Holter ◽

Anne Ma Dyrhol-Riise ◽

...

Keyword(s):

Nervous System ◽

Single Molecule ◽

Linear Models ◽

Clinical Signs ◽

Repeated Measurements ◽

Cns Injury ◽

Serum Concentrations ◽

Blood Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light

Abstract Objective To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. Methods Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. Results In total, 21% (n = 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (n = 6). Non-survivors had higher serum concentrations of NfL (p < 0.001) upon admission than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10–7) and unadjusted analyses (p = 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (p = 0.02). Conclusion Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.

Download Full-text