Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa

Kühle, Jens; Barro, Christian; Andréasson, Ulf; Derfuss, Tobias; Lindberg, Raija L. P.; Sandelius, Åsa; Liman, Victor; Norgren, Niklas; Blennow, Kaj; Zetterberg, Henrik

doi:10.1515/cclm-2015-1195

Cited by 575 publications

(520 citation statements)

References 16 publications

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“…Our results confirm and expand on previous studies20, 21 showing that NfL can be reliably measured in serum using the Simoa technology, even at very low concentrations (down to a few pg/ml). The observed increase of NfL levels in serum with age seen in both HC and patient cohorts mirrors the age association described for CSF NfL levels,38 and it is best explained by ongoing age‐related neuronal degeneration.…”

Section: Discussionsupporting

confidence: 91%

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

Disanto

Barro

Benkert

et al. 2017

Annals of Neurology

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ObjectiveNeurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single‐molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS).MethodssNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross‐sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow‐up = 3.1 years, interquartile range [IQR] = 2.0–4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes.ResultssNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2–65.3) or both brain and spinal gadolinium‐enhancing lesions (62.5pg/ml, IQR = 42.7–71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9–41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease‐modifying treatment (β = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC‐based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21–3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07–5.42, p = 0.034).InterpretationThese results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017;81:857–870

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Section: Discussionsupporting

confidence: 91%

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

Disanto

Barro

Benkert

et al. 2017

Annals of Neurology

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1,069

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“…Serum NFL was highest in patients with tauopathies (with effect sizes ~3 to 6) and moderately high in those with AD and atypical parkinsonian syndromes (with effect sizes ~3), but was no different in those with idiopathic Parkinson's disease compared with controls, lending support to the view that this may be a useful test in distinguishing idiopathic Parkinson's disease from atypical parkinsonism. Serum NFL broadly correlated with CSF within individuals (a finding that has been corroborated by others for both serum [ 48 ] and plasma [ 49 ]) and also correlated with Mini-Mental State Examination scores. Treatment of the mouse APP-PS1 models with a β-secretase-1 inhibitor, which reduces the generation of Aβ42 and the formation of amyloid plaques, led to a reduction in both CSF and plasma NFL, which was not observed in the untreated APP-PS1 mice.…”

Section: The Candidate Approachsupporting

confidence: 76%

Blood Biomarkers for Alzheimer’s Disease: Much Promise, Cautious Progress

Keshavan

Heslegrave²,

Zetterberg

et al. 2016

Mol Diagn Ther

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Biomarkers in Alzheimer's disease (AD) have the potential to allow early and more accurate diagnosis, predict disease progression, stratify individuals and track response to candidate therapies in drug trials. The first fluid biomarkers reflecting aspects of AD neuropathology were identified in cerebrospinal fluid (CSF) in the 1990s. Three CSF biomarkers (amyloid-β 1-42, total tau and phospho-tau) have consistently been shown to have diagnostic utility and are incorporated into the new diagnostic criteria for AD. These markers have also been shown in longitudinal studies to predict conversion of mild cognitive impairment to AD. However, a key issue with the use of CSF biomarkers as a screening test is the invasiveness of lumbar puncture. Over the last 20 years there has been an active quest for blood biomarkers, which could be easily acquired and tested repeatedly throughout the disease course. One approach to identifying such markers is to attempt to measure candidates that have already been identified in CSF. Until recently, this approach has been limited by assay sensitivity, but newer platforms now allow single molecule-level detection. Another approach is identification of candidates in large multiplex panels that allow for multiple analytes to be quantified in parallel. While both approaches show promise, to date no blood-based biomarker or combination of biomarkers has sufficient predictive value to have utility in clinical practice. In this review, an overview of promising blood protein candidates is provided, and the challenges of validating and converting these into practicable tests are discussed. AQ1H. Zetterberg and J. M. Schott are joint senior author of this article. Key PointsMany studies have identified candidates for blood biomarkers of Alzheimer's disease (AD) but replication has been problematic.The two main candidates showing promise currently are plasma total tau and serum neurofilament light chain.New techniques such as multiplexing and use of more sensitive assays are likely to expand and improve blood biomarker research.

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“…4 Future studies will show if these discrepancies relate to differences in disease stage or analytical performance of bioassays with higher sensitivity like ECL or single molecule analysis technologies vs conventional ELISA. 8 Analyses of changes in brain volume require considerable follow-up and are affected by different factors not directly related to axonal loss such as fluid shifts, aging, remyelination, and astrogliosis. In our study, baseline serum NfL predicted brain atrophy over the subsequent 12 and 24 months, the latter association being the strongest.…”

Section: Resultsmentioning

confidence: 99%

Serum neurofilament is associated with progression of brain atrophy and disability in early MS

et al. 2017

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Objective: To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels.Methods: Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-b (IFN-b)-1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay.Results: Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole. Nf light chain (NfL) levels decreased over time (p 5 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p 5 0.997). Changes in NfL were correlated with EDSS change (p 5 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p 5 0.05 at 12 months and p 5 0.008 at 24 months) and this relationship became stronger at 24 months (p 5 0.024 for interaction). Higher and increasing NfL predicted higher number of gadoliniumenhancing lesions (p , 0.001 for both). 1 They determine axonal caliber and transport, and during axonal injury can be measured in the CSF and blood. Immunoassays for both NfL and NfH have been extensively published and have short-term and long-term prognostic value in various neurologic disorders. 2-5The phase II riluzole trial in participants with early multiple sclerosis (MS) was a randomized, double-blind, placebo-controlled study assessing the putative neuroprotective effect of riluzole. The primary outcome of the trial, brain atrophy, was negative. 6 Our goal was to investigate a potential treatment effect on serum NfL and NfH and the longitudinal relationship between serum Nf levels and clinical and MRI outcomes.

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Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa

Cited by 575 publications

References 16 publications

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

Blood Biomarkers for Alzheimer’s Disease: Much Promise, Cautious Progress

Serum neurofilament is associated with progression of brain atrophy and disability in early MS

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