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

Reinert, Marie-Christine; Benkert, Pascal; Wuerfel, Jens; Michalak, Zuzanna; Ruberte, Esther; Barro, Christian; Huppke, Peter; Stark, Wiebke; Kropshofer, Harald; Tomic, Davorka; Leppert, David; Kühle, Jens; Brück, Wolfgang; Gärtner, Jutta

doi:10.1212/nxi.0000000000000749

Cited by 47 publications

(49 citation statements)

References 41 publications

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“…In multivariate analysis, for which weight was removed due to collinearity with age, age had the greatest impact on sNfL followed by male sex and CRP levels independently of seizures and fever. A very similar age dependency was described recently in a cohort of neurologically healthy children with decreasing sNfL in older children ( Khalil et al, 2020 ; Reinert et al, 2020 ). In addition, between the age of 10 and 15 years, sNfL levels appear to mark a nadir, and beyond youth, sNfL levels increase in a linear fashion until the age of about 60 years.…”

Section: Discussionsupporting

confidence: 84%

“…In addition, between the age of 10 and 15 years, sNfL levels appear to mark a nadir, and beyond youth, sNfL levels increase in a linear fashion until the age of about 60 years. Afterward, sNfL levels were reported to rise much steeper ( Khalil et al, 2020 ; Reinert et al, 2020 ). Thus, considering sNfL level during the whole life cycle from high levels in newborn infants ( Depoorter et al, 2018 ), decreasing until late childhood and then steadily increasing, sNfL levels represent a u-shaped curve.…”

Section: Discussionmentioning

confidence: 99%

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Serum Neurofilament Levels in Children With Febrile Seizures and in Controls

et al. 2020

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Objective Neuroaxonal damage is reflected by serum neurofilament light chain (sNfL) values in a variety of acute and degenerative diseases of the brain. The aim of this study was to investigate the impact of febrile and epileptic seizures on sNfL, serum copeptin, and prolactin levels in children compared with children with febrile infections without convulsions. Methods A prospective cross-sectional study was performed in children aging 6 months to 5 years presenting with fever (controls, n = 61), febrile seizures (FS, n = 78), or epileptic seizures (ES, n = 16) at our emergency department. sNfL, copeptin, and prolactin were measured within a few hours after the event in addition to standard clinical, neurophysiological, and laboratory assessment. All children were followed up for at least 1 year after presentation concerning recurrent seizures. Results Serum copeptin values were on average 4.1-fold higher in FS and 3.2-fold higher in ES compared with controls (both p < 0.01). Serum prolactin values were on average 1.3-fold higher in FS compared with controls ( p < 0.01) and without difference between ES and controls. There was no significant difference of mean sNfL values (95% CI) between all three groups, FS 21.7 pg/ml (19.6–23.9), ES 17.7 pg/ml (13.8–21.6), and controls 23.4 pg/ml (19.2–27.4). In multivariable analysis, age was the most important predictor of sNfL, followed by sex and C reactive protein. Neither the duration of seizures nor the time elapsed from seizure onset to blood sampling had an impact on sNfL. None of the three biomarkers were related to recurrent seizures. Significance Serum neurofilament light is not elevated during short recovery time after FS when compared with children presenting febrile infections without seizures. We demonstrate an age-dependent decrease of sNfL from early childhood until school age. In contrast to sNfL levels, copeptin and prolactin serum levels are elevated after FS.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Serum Neurofilament Levels in Children With Febrile Seizures and in Controls

et al. 2020

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“…This remains unexplained but could be related to a breakdown of the BBB in progressive MS linked to aging and/or a contribution from the peripheral nervous system. Ascherio’s group reported that in a military cohort, blood NfL was able to identify neuronal damage 6 years prior to the clinical disease onset, 68 thus neurodegeneration was already present at the prodromal stage of MS. A number of studies have found that disease activity as measured by clinical or MRI assessment is associated with an increase in blood NfL levels in both adult 16,32,66,69–73 and pediatric patients 74,75 . Of note, the association of blood NfL with disability was less in progressive MS, which may be related to the older age of this population that also have comorbidities 32 .…”

Section: Blood Nfl In Neurological Diseasesmentioning

confidence: 99%

Blood neurofilament light: a critical review of its application to neurologic disease

Barro

Chitnis

Weiner

2020

Ann Clin Transl Neurol

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162

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Neuronal injury is a universal event that occurs in disease processes that affect both the central and peripheral nervous systems. A blood biomarker linked to neuronal injury would provide a critical measure to understand and treat neurologic diseases. Neurofilament light chain (NfL), a cytoskeletal protein expressed only in neurons, has emerged as such a biomarker. With the ability to quantify neuronal damage in blood, NfL is being applied to a wide range of neurologic conditions to investigate and monitor disease including assessment of treatment efficacy. Blood NfL is not specific for one disease and its release can also be induced by physiological processes. Longitudinal studies in multiple sclerosis, traumatic brain injury, and stroke show accumulation of NfL over days followed by elevated levels over months. Therefore, it may be hard to determine with a single measurement when the peak of NfL is reached and when the levels are normalized. Nonetheless, measurement of blood NfL provides a new blood biomarker for neurologic diseases overcoming the invasiveness of CSF sampling that restricted NfL clinical application. In this review, we examine the use of blood NfL as a biologic test for neurologic disease.

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“…These increases accompany hippocampal atrophy in cognitively healthy older adults, which has suggested possible AD-independent, ageexpected hippocampal decline (Idland et al, 2017). However, younger children have higher serum NfL levels than older children reaching the lowest level between the age of 10 and 15 years, then increasing in a linear fashion until the age of 60 years and accelerating non-linearly afterward (Evers et al, 2020;Khalil et al, 2020;Reinert et al, 2020). There are various proposed bases for serum NfL elevation in aging, including subclinical senescence with greater neuronal apoptosis (Khalil et al, 2020) and increased disruption of blood-brain barrier (Sweeney et al, 2018).…”

Section: Neurofilament Light Chain Levels In Normal Individualsmentioning

confidence: 99%

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

2021

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Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits – neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer’s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.

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

Cited by 47 publications

References 41 publications

Serum Neurofilament Levels in Children With Febrile Seizures and in Controls

Serum Neurofilament Levels in Children With Febrile Seizures and in Controls

Blood neurofilament light: a critical review of its application to neurologic disease

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

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