Challenges and Opportunities for the Promising Biomarker Blood Neurofilament Light Chain

Abdelhak, Ahmed; Kuhle, Jens; Green, Ari J.

doi:10.1001/jamaneurol.2023.0394

Cited by 9 publications

(5 citation statements)

References 11 publications

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“…Real-world clinical multicentre use of blood NfL moreover often faces the challenge that samples come from different blood matrices (eg, serum vs plasma). 9 While our findings confirm differences in the absolute blood NfL concentrations between serum and plasma, they at the same time show a high consistency between both blood matrices, allowing comparability of both matrices. The calculated median ratio serum/plasma might be a first coarse help when comparing results derived from these different matrices.…”

Section: Discussionsupporting

confidence: 74%

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Linnemann,

Wilke,

Mengel

et al. 2024

J Neurol Neurosurg Psychiatry

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BackgroundBlood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL in gFTD multicentre trials by testing its (1) reliability across labs; (2) reliability to stratify gFTD disease stages; (3) comparability between blood matrices and (4) stability across recruiting sites.MethodsComparative analysis of blood NfL levels in a large gFTD cohort (GENFI) for (1)–(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, with mutations inC9orf72,GRNorMAPT; and n=139 within-family controls), each measured in three different international labs by Simoa HD-1 analyzer.ResultsNfL revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) and high reliability across the three labs (maximal bias (pg/mL) in Bland-Altman analysis: 1.12±1.20). High concordance of NfL across laboratories was moreover reflected by high areas under the curve for discriminating conversion stage against the (non-converting) presymptomatic stage across all three labs. Serum and plasma NfL were largely comparable (ICC 0.967). The robustness of NfL across 13 recruiting sites was demonstrated by a linear mixed effect model.ConclusionsOur results underline the suitability of blood NfL in gFTD multicentre trials, including cross-lab reliable stratification of the highly trial-relevant conversion stage, matrix comparability and cross-site robustness.

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Section: Discussionsupporting

confidence: 74%

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Linnemann,

Wilke,

Mengel

et al. 2024

J Neurol Neurosurg Psychiatry

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“…The total number of axons did not decline by 10 weeks post tamoxifen (Figure 4C). Serum neurofilaments (NfL) has been used as a biomarker of axonal degeneration in a variety of diseases including MS 57 . Serum NfL levels are enriched at 10 weeks post tamoxifen in both Myrf ΔiPlp1 and Myrf ΔiSox10 mice (Figure 4D).…”

Section: Resultsmentioning

confidence: 99%

Remyelination protects neurons from DLK-mediated neurodegeneration

Duncan,

Ingram,

Emberley

et al. 2023

Preprint

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SummaryChronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by effective remyelination, and the other by remyelination failure and persistent demyelination. By comparing these two models, we find that remyelination protects neurons from apoptosis, improves conduction, and promotes functional recovery. Chronic demyelination of neurons leads to activation of the mitogen-associated protein kinase (MAPK) stress pathway downstream of dual leucine zipper kinase (DLK), which ultimately induces the phosphorylation of c-Jun in the nucleus. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. These findings provide direct experimental evidence that remyelination is neuroprotective and identify DLK inhibition as a potential therapeutic strategy to protect chronically demyelinated neurons.HighlightsCharacterization of a mouse model of demyelination without subsequent remyelinationRemyelination protects neurons from axonal damage and apoptosisMAPK and c-Jun phosphorylation are increased during remyelination failureDLK is necessary for the apoptosis of chronically demyelinated neuronsAbstract Figure

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“…However, we used published crosswalks 32 to unite the two tests and minimize bias. Third, since there is no acknowledged cutoff value of blood NfL to determine the definite neurodegenerative status as yet, 46 we chose the statistical median value to categorize participants with low and high neurodegenerative burden. This cutoff value was only applicable to the current cohort of dementia‐free individuals, and the high NfL defined in our study may not reflect severe neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Olfactory function, neurofilament light chain, and cognitive trajectory: A 12‐year follow‐up of the Shanghai Aging Study

Xiao,

Wu,

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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This study aimed to determine whether blood neurofilament light chain (NfL) modifies the association of olfactory dysfunction (OD) with long‐term cognitive decline. A total of 1125 non‐demented older adults in the Shanghai Aging Study were evaluated for baseline olfaction (12‐item Sniffin’ Sticks Smell Test) and cognitive trajectory by a 12‐year follow‐up. Baseline blood NfL was quantified using Single Molecular Array assay, and dichotomized into low and high levels based on the median value of concentration. The Mini‐Mental State Examination (MMSE) and Telephone Interview for Cognitive Status‐40 were used to assess participants’ cognitive function. Cognitive decline was ascertained when dementia was diagnosed or documented in the medical record during follow‐up, or the MMSE declining rate (slope) was 1.0 SD larger than the group mean. OD participants presented a steeper trajectory of MMSE score (p interaction = 0.004) and a high risk of cognitive decline (adjusted HR [95% CI], 1.82 [1.11, 2.98]) only in those with high NfL. Participants with combined OD and high NfL showed the highest risk of cognitive decline (adjusted HR, 2.43 [1.20, 4.92]). OD, especially in combination with high blood NfL concentration, may be able to identify individuals who later incur cognitive deterioration.

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Challenges and Opportunities for the Promising Biomarker Blood Neurofilament Light Chain

Abstract: This Viewpoint describes the benefits and limitations of using neurofilament light chain (NfL) as a marker of real-time disease activity and treatment response in multiple sclerosis.

Cited by 9 publications

References 11 publications

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Remyelination protects neurons from DLK-mediated neurodegeneration

Olfactory function, neurofilament light chain, and cognitive trajectory: A 12‐year follow‐up of the Shanghai Aging Study

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