The potential of neurofilaments analysis using dry-blood and plasma spots

Lombardi, Vittoria; Carassiti, Daniele; Giovannoni, Gavin; Lu, Ching‐Hua; Adiutori, Rocco; Malaspina, Andrea

doi:10.1038/s41598-019-54310-y

Cited by 16 publications

(25 citation statements)

References 31 publications

(51 reference statements)

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“…Five of 25 participants in the football group were excluded from MRI due to a metal implant in the body ( n = 4) and orthodontic braces ( n = 1). Three serum samples in the football group were not assessed for biomarkers due to severe hemolysis, which has shown to influence the detection of biomarkers, especially NfL ( 43 ). As a result, 17 completed sets of the neuroimaging-blood biomarker data for the analysis.…”

Section: Resultsmentioning

confidence: 99%

Association Between Proteomic Blood Biomarkers and DTI/NODDI Metrics in Adolescent Football Players: A Pilot Study

et al. 2020

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While neuroimaging and blood biomarker have been two of the most active areas of research in the neurotrauma community, these fields rarely intersect to delineate subconcussive brain injury. The aim of the study was to examine the association between diffusion MRI techniques [diffusion tensor imaging (DTI) and neurite orientation/dispersion density imaging (NODDI)] and brain-injury blood biomarker levels [tau, neurofilament-light (NfL), glial-fibrillary-acidic-protein (GFAP)] in high-school football players at their baseline, aiming to detect cumulative neuronal damage from prior seasons. Twenty-five football players were enrolled in the study. MRI measures and blood samples were obtained during preseason data collection. The whole-brain, tract-based spatial statistics was conducted for six diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), axial/radial diffusivity (AD, RD), neurite density index (NDI), and orientation dispersion index (ODI). Five players were ineligible for MRIs, and three serum samples were excluded due to hemolysis, resulting in 17 completed set of diffusion metrics and blood biomarker levels for association analysis. Our permutation-based regression model revealed that serum tau levels were significantly associated with MD and NDI in various axonal tracts; specifically, elevated serum tau levels correlated to elevated MD ( p = 0.0044) and reduced NDI ( p = 0.016) in the corpus callosum and surrounding white matter tracts (e.g., longitudinal fasciculus). Additionally, there was a negative association between NfL and ODI in the focal area of the longitudinal fasciculus. Our data suggest that high school football players may develop axonal microstructural abnormality in the corpus callosum and surrounding white matter tracts, such as longitudinal fasciculus. A future study is warranted to determine the longitudinal multimodal relationship in response to repetitive exposure to sports-related head impacts.

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Section: Resultsmentioning

confidence: 99%

Association Between Proteomic Blood Biomarkers and DTI/NODDI Metrics in Adolescent Football Players: A Pilot Study

et al. 2020

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“…In 2010, single-molecule enzyme-linked immunosorbent assay (Simoa) was initially described ( Rissin et al, 2010 ) which later enabled reliable quantification of NfL in serum or plasma samples ( Gisslen et al, 2016 ) using NfL-specific monoclonal antibodies (mAb47:3) ( Norgren et al, 2002 ). More recently, Meso Scale Discovery, immunomagnetic reduction technologies and the Ella platform based on microfluidic channels have also been developed to detect low NfP levels in blood ( Liu H.C. et al, 2020 ; Lombardi et al, 2020 ; Gauthier et al, 2021 ).…”

Section: Properties Of Neurofilaments Relevant To Their Use As Biomarkersmentioning

confidence: 99%

“…(A) Low levels of NfPs in blood can be detected with single molecule array technology (Simoa/digital ELISA). A 22 kDa degradation fragment of NfL ( B , adapted from Lombardi et al, 2020 ) and full length NfH (adapted from Adiutori et al, 2018 ) were detected in blood (C) . (D) Isolated exosomes from blood (adapted from Zhang et al, 2020 ).…”

Section: Properties Of Neurofilaments Relevant To Their Use As Biomarkersmentioning

confidence: 99%

“…Identity of the NfL forms in plasma exosomes is still unclear but a 22 kDa NfL degradation fragment has been revealed with an anti-NfL antibody and shown to be increased in ALS patients ( Lombardi et al, 2020 ). Also identified are a 30 kDa fragment of NfL in Nf-containing aggregates from human blood ( Adiutori et al, 2018 ) and a 10 kDa fragment of NfL in mouse CSF.…”

Section: Properties Of Neurofilaments Relevant To Their Use As Biomarkersmentioning

confidence: 99%

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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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“…Isobaric tags and dried plasma spot (DPS) have emerged as potential measurement substrates that could reduce costs, processing times, and the need of specialized infrastructure. A recent study analyzed NfL levels in 17 individuals using DPS and Simoa ( Lombardi et al, 2020 ). They observed a good discrimination of ALS from healthy controls, which was comparable to the discrimination obtained using sNfL measures.…”

Section: Future Directionsmentioning

confidence: 99%

The Evolution of Neurofilament Light Chain in Multiple Sclerosis

et al. 2021

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Multiple sclerosis (MS) is an autoimmune, inflammatory neurodegenerative disease of the central nervous system characterized by demyelination and axonal damage. Diagnosis and prognosis are mainly assessed through clinical examination and neuroimaging. However, more sensitive biomarkers are needed to measure disease activity and guide treatment decisions in MS. Prompt and individualized management can reduce inflammatory activity and delay disease progression. Neurofilament Light chain (NfL), a neuron-specific cytoskeletal protein that is released into the extracellular fluid following axonal injury, has been identified as a biomarker of disease activity in MS. Measurement of NfL levels can capture the extent of neuroaxonal damage, especially in early stages of the disease. A growing body of evidence has shown that NfL in cerebrospinal fluid (CSF) and serum can be used as reliable indicators of prognosis and treatment response. More recently, NfL has been shown to facilitate individualized treatment decisions for individuals with MS. In this review, we discuss the characteristics that make NfL a highly informative biomarker and depict the available technologies used for its measurement. We further discuss the growing role of serum and CSF NfL in MS research and clinical settings. Finally, we address some of the current topics of debate regarding the use of NfL in clinical practice and examine the possible directions that this biomarker may take in the future.

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The potential of neurofilaments analysis using dry-blood and plasma spots

Cited by 16 publications

References 31 publications

Association Between Proteomic Blood Biomarkers and DTI/NODDI Metrics in Adolescent Football Players: A Pilot Study

Association Between Proteomic Blood Biomarkers and DTI/NODDI Metrics in Adolescent Football Players: A Pilot Study

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

The Evolution of Neurofilament Light Chain in Multiple Sclerosis

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