UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
University Children's Hospital Regensburg, Hospital St Hedwig of the Order of St John, University of Regensburg, Regensburg, Germany.
Lancet Neurol. 2023 Sep;22(9):826-833. doi: 10.1016/S1474-4422(23)00210-7. Epub 2023 Jul 28.
Neurological conditions represent an important driver of paediatric disability burden worldwide. Measurement of serum neurofilament light chain (sNfL) concentrations, a specific marker of neuroaxonal injury, has the potential to contribute to the management of children with such conditions. In this context, the European Medicines Agency recently declared age-adjusted reference values for sNfL a top research priority. We aimed to establish an age-adjusted sNfL reference range database in a population of healthy children and adolescents, and to validate this database in paediatric patients with neurological conditions to affirm its clinical applicability.
To generate a paediatric sNfL reference dataset, sNfL values were measured in a population of healthy children and adolescents (aged 0-22 years) from two large cohorts in Europe (the Coronavirus Antibodies in Kids from Bavaria study, Germany) and North America (a US Network of Paediatric Multiple Sclerosis Centers paediatric case-control cohort). Children with active or previous COVID-19 infection or SARS-CoV-2 antibody positivity at the time of sampling, or a history of primary systemic or neurological conditions were excluded. Linear models were used to restrospectively study the effect of age and weight on sNfL concentrations. We modelled the distribution of sNfL concentrations as a function of age-related physiological changes to derive reference percentile and Z score values via a generalised additive model for location, scale, and shape. The clinical utility of the new reference dataset was assessed in children and adolescents (aged 1-19 years) with neurological diseases (epilepsy, traumatic brain injury, bacterial CNS infections, paediatric-onset multiple sclerosis, and myelin oligodendrocyte glycoprotein antibody-associated disease) from the paediatric neuroimmunology clinic at the University of California San Francisco (San Francisco, CA, USA) and the Children's Hospital of the University of Regensburg (Regensburg, Germany).
Samples from 2667 healthy children and adolescents (1336 [50·1%] girls and 1331 [49·9%] boys; median age 8·0 years [IQR 4·0-12·0]) were used to generate the reference database covering neonatal age to adolescence (target age range 0-20 years). In the healthy population, sNfL concentrations decreased with age by an estimated 6·8% per year until age 10·3 years (estimated multiplicative effect per 1 year increase 0·93 [95% CI 0·93-0·94], p<0·0001) and was mostly stable thereafter up to age 22 years (1·00 [0·52-1·94], p>0·99). Independent of age, the magnitude of the effect of weight on sNfL concentrations was marginal. Samples from 220 children with neurological conditions (134 [60·9%] girls and 86 [39·1%] boys; median age 14·7 years [IQR 10·8-16·5]) were used to validate the clinical utility of the reference Z scores. In this population, age-adjusted sNfL Z scores were higher than in the reference population of healthy children and adolescents (p<0·0001) with higher effect size metrics (Cohen's d=1·56) compared with the application of raw sNfL concentrations (d=1·28).
The established normative sNfL values in children and adolescents provide a foundation for the clinical application of sNfL in the paediatric population. Compared with absolute sNfL values, the use of sNfL Z score was associated with higher effect size metrics and allowed for more accurate estimation of the extent of ongoing neuroaxonal damage in individual patients.
Swiss National Science Foundation, US National Institutes of Health, and the National Multiple Sclerosis Society.
神经状况是全球儿童残疾负担的一个重要驱动因素。血清神经丝轻链（sNfL）浓度的测量，一种神经轴突损伤的特定标志物，有可能有助于管理患有此类疾病的儿童。在这种情况下，欧洲药品管理局最近宣布年龄调整后的 sNfL 参考值是一个首要的研究重点。我们的目的是在健康的儿童和青少年人群中建立一个年龄调整的 sNfL 参考范围数据库，并在患有神经疾病的儿科患者中验证该数据库，以确认其临床适用性。
为了生成儿科 sNfL 参考数据集，我们测量了来自欧洲（德国巴伐利亚冠状病毒抗体研究和美国儿科多发性硬化症中心网络儿科病例对照队列）和北美的两个大型队列中的健康儿童和青少年（0-22 岁）的 sNfL 值。在采样时患有或以前患有 COVID-19 感染或 SARS-CoV-2 抗体阳性或有原发性全身或神经状况病史的儿童被排除在外。线性模型用于回顾性研究年龄和体重对 sNfL 浓度的影响。我们通过位置、比例和形状的广义加性模型，将 sNfL 浓度的分布建模为与年龄相关的生理变化的函数，以得出参考百分位数和 Z 分数值。我们在加利福尼亚大学旧金山分校（旧金山，CA，美国）的儿科神经免疫学诊所和雷根斯堡大学儿童医院（雷根斯堡，德国）的患有神经疾病（癫痫、创伤性脑损伤、细菌性中枢神经系统感染、儿科多发性硬化症和髓鞘少突胶质细胞糖蛋白抗体相关疾病）的儿童和青少年（1-19 岁）中评估了新参考数据集的临床实用性。
我们使用了 2667 名健康儿童和青少年（1336 名[50.1%]女孩和 1331 名[49.9%]男孩；中位年龄 8.0 岁[四分位距 4.0-12.0]）的样本生成了涵盖新生儿至青春期的参考数据库（目标年龄范围为 0-20 岁）。在健康人群中，sNfL 浓度估计每年以 6.8%的速度下降，直到 10.3 岁（每增加 1 岁的估计乘法效应为 0.93[95%置信区间 0.93-0.94]，p<0.0001），此后直到 22 岁基本保持稳定（1.00[0.52-1.94]，p>0.99）。独立于年龄，体重对 sNfL 浓度的影响幅度很小。我们使用了 220 名患有神经疾病的儿童（134 名[60.9%]女孩和 86 名[39.1%]男孩；中位年龄 14.7 岁[四分位距 10.8-16.5]）的样本来验证参考 Z 分数的临床实用性。在这个人群中，年龄调整后的 sNfL Z 分数高于健康儿童和青少年的参考人群（p<0.0001），与应用原始 sNfL 浓度相比（d=1.28），具有更高的效应量度量指标（Cohen's d=1.56）。
在儿童和青少年中建立的正常 sNfL 值为 sNfL 在儿科人群中的临床应用提供了基础。与绝对 sNfL 值相比，使用 sNfL Z 分数与更高的效应量度量指标相关，并允许更准确地估计个体患者中持续的神经轴突损伤程度。
瑞士国家科学基金会、美国国立卫生研究院和国家多发性硬化症协会。
