Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis
Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis
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DOI：
10.1001/jamaneurol.2019.3238
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发表时间：
2020-01-01
期刊：
影响因子：
29
通讯作者：
Ascherio, Alberto
中科院分区：
文献类型：
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作者：
Bjornevik, Kjetil;Munger, Kassandra L.;Ascherio, Alberto
多发性硬化的前驱期有多长？结果在这项巢式病例对照研究中，我们发现，血清中的神经丝轻链水平升高的情况下，多发性硬化症患者与匹配的对照组相比，6年前的临床发病。病例和对照之间的这种差异随着病例临床发作时间的减少而增加，并且临床发作与神经丝轻链水平的显著增加相关。多发性硬化症（MS）是一种常见的多发性硬化症（MS），其临床表现为多发性硬化症（MS）的早期症状。在发生时识别这些事件将对早期诊断和寻找疾病的因果因素产生影响。目的探讨MS患者血清神经丝轻链（sNfL）水平在临床发病前是否升高。设计、设置和参与者：在美国军事人员中进行巢式病例对照研究，这些人员的血清样本储存在美国国防部血清库中。从2000年至2011年收集血清样本;从2018年至2019年进行sNfL测定和数据分析。我们选择了60例MS患者，他们在发病前采集了2份样本（平均随访时间为6.3年），或在发病前采集了1份样本，在发病后采集了1份样本（平均随访时间为1.3年），在245例先前确定的病例患者中。对于每种情况，我们随机选择了2个先前确定的对照个体中的1个，这些对照个体与年龄、性别、种族/民族和样本采集日期相匹配。样本量是根据可用资金选择的。使用超灵敏单分子阵列测定（Simoa）测量血清NfL浓度。使用条件logistic回归和线性混合模型比较病例患者和对照个体中对数转换的sNfL浓度。结果基线时的平均年龄为27.5岁，120名参与者中有92名（76.7%）为男性。在临床发作前中位数为6年（范围，4-10年）采集的样本中，MS病例患者的血清NfL水平高于其匹配的对照个体（中位数，16.7 pg/mL;四分位距[IQR]，12.6-23.1 pg/mL vs 15.2 pg/m; IQR，10.3-19.9 pg/mL; P = 0.04）。这种差异随着病例临床发作时间的缩短而增加（与时间相互作用的估计系数= 0.063; P = 0.008）。症状前sNfL水平的个体内升高与MS风险升高相关（升高>= 5 pg/mL的率比，7.50; 95%CI，1.72-32.80）。临床发作与sNfL水平显著升高相关（中位值，25.0; IQR，17.1-41.3 vs 45.1;症状前和发作后MS样本的IQR，27.0-102.7 pg/mL; P = 0.009）。结论和相关性sNfL的水平增加6年前临床MS发病，表明MS可能有一个前驱期持续数年，神经轴突损伤已经发生在此phase.This巢式病例对照研究评估血清神经丝轻链的水平在前驱个体多发性硬化症，以确定前驱期的疾病。
Question How long is the prodromal phase of multiple sclerosis? Findings In this nested case-control study, we found that serum levels of neurofilament light chain were elevated in case patients with multiple sclerosis compared with matched control individuals 6 years before the clinical onset. This difference between cases and controls increased with decreasing time to the case clinical onset, and clinical onset was associated with a marked increase in neurofilament light chain levels. Meaning Multiple sclerosis may have a prodromal phase lasting several years, and neuroaxonal damage may occur already during this phase.Importance Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease. Objective To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset. Design, Setting, and Participants Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding. Exposures Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa). Main Outcomes and Measurements Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models. Results Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for >= 5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009). Conclusions and Relevance The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.This nested case-control study evaluates the levels of serum neurofilament light chain in presymptomatic individuals with multiple sclerosis to determine a prodromal phase of the disease.