Simon Witzel MD, André Huss PhD, Gabriele Nagel MD, Angela Rosenbohm MD, Dietrich Rothenbacher MD, Raphael S. Peter PhD, Hansjörg Bäzner MD, Axel Börtlein MD, Silke Dempewolf MD, Martin Schabet MD, Martin Hecht MD, Andreas Kohler MD, Christian Opherk MD, Andrea Naegele MD, Norbert Sommer MD, Alfred Lindner MD, Christoforos Alexudis, Franziska Bachhuber PhD, Steffen Halbgebauer PhD, David Brenner MD, Wolfgang Ruf MD, Ulrike Weiland MD, Benjamin Mayer PhD, Joachim Schuster PhD, Johannes Dorst MD, Hayrettin Tumani MD, Albert C. Ludolph MD, and the ALS Registry Swabia Study Group
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Ludolph MD, and the ALS Registry Swabia Study Group","doi":"10.1002/ana.27054","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. 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引用次数: 0
摘要
目的：神经丝蛋白轻链（NfL）和磷酸化神经丝蛋白重链（pNfH神经丝蛋白轻链（NfL）和磷酸化神经丝蛋白重链（pNfH）在以医院为基础的肌萎缩性脊髓侧索硬化症（ALS）队列中被确立为诊断和预后生物标志物，现已成为临床试验中的替代标志物。本研究将对它们的评估扩展到人群水平，目的是推进它们的全面建立，并评估生物标志物研究结果从对照队列到实际 ALS 人群的可转移性：我们测量了参与斯瓦比亚 ALS 流行病学登记的所有 ALS 患者（n = 790）和普通人群对照组（n = 570）的血清 NfL 和 pNfH 水平，为对照组提供了平台特异性（ELLA™）参考数据和 Z 值，以及 ALS 的参考数据、疾病特异性 Z 值和纵向数据。我们评估了神经丝的诊断和预后效用，并量化了ALS相关因素和非ALS混杂因素的影响：结果：神经丝在人群水平上显示出很高的诊断和预后效用，NfL优于pNfH。与绝对原始值相比，基于人群的 ALS Z 评分这一新理念大大提高了预后效用。在对照组中，这两种生物标志物随年龄的增长而增加的程度比在 ALS 中更强，年龄调整提高了诊断的准确性。我们的数据显示，在解释神经丝蛋白水平时，需要考虑疾病进展率、ALS 表型、体重指数（BMI）和肾功能；纵向神经丝蛋白水平在个体患者中通常是稳定的，尤其是在根据年龄和基线水平进行调整后：基于人群的评估提高了血清神经丝蛋白作为 ALS 诊断和预后生物标志物的实用性，并改善了从对照队列到实际人群的研究结果转化。ann neurol 2024.
Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis
Objective
Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.
Methods
We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.
Results
Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.
Interpretation
Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040–1057
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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