Neurofilaments in pre-symptomatic ALS and the impact of genotype
Neurofilaments in pre-symptomatic ALS and the impact of genotype
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DOI：
10.1080/21678421.2019.1646769
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发表时间：
2019-08-20
影响因子：
2.8
通讯作者：
Malaspina, Andrea
中科院分区：
文献类型：
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作者：
Benatar, Michael;Wuu, Joanne;Malaspina, Andrea
目标。评估血清和脑脊液（CSF）磷酸化神经丝重（pNfH）水平，并将其与神经丝轻（NfL）水平进行比较，作为症状前ALS的生物标志物。设计。研究人群包括34名对照组、79名ALS高危个体、22名ALS患者和14名表型转化者。有风险的个体通过症状前家族性ALS （Pre-fALS）纳入研究，这是一项纵向自然病史和生物标志物研究，研究对象是任何ALS相关基因突变携带者，但在入组时没有临床疾病证据。采用已建立的酶联免疫吸附法定量血清和脑脊液中的pNfH和NfL。结果。在临床表现的ALS出现之前，血清pNfH呈纵向上升趋势。在NfL中也观察到类似的模式，但其绝对水平也经常超过规范阈值。虽然脑脊液数据比较稀疏，但在两种神经丝中观察到相似的模式，绝对水平超过表型转化前的标准阈值。在血清中，SOD1 A4V突变携带者在发病前6-12个月观察到这些变化，在FUS c.521del6突变和C9ORF72六核苷酸重复扩增的个体中分别可追溯到2年和3.5年。结论。血清和脑脊液pNfH在表型转化前升高。在脑脊液中，这些变化的时间过程与NfL相似。然而，在血清中，pNfH对症状前疾病的敏感性低于NfL。症状前疾病的持续时间，由神经纤维的变化所定义，可能因潜在的基因型而异。
Objective. To evaluate serum and cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy (pNfH), and to compare these to levels of neurofilament light (NfL), as biomarkers of pre-symptomatic ALS. Design. The study population includes 34 controls, 79 individuals at-risk for ALS, 22 ALS patients, and 14 phenoconverters. At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation, but who demonstrate no clinical evidence of disease at the time of enrollment. pNfH and NfL in serum and CSF were quantified using established enzyme-linked immunosorbent assays. Results. There is a longitudinal increase in serum pNfH in advance of the emergence of clinically manifest ALS. A similar pattern is observed for NfL, but with the absolute levels also frequently exceeding a normative threshold. Although CSF data are more sparse, similar patterns are observed for both neurofilaments, with absolute levels exceeding a normative threshold prior to phenoconversion. In serum, these changes are observed in the 6-12 months prior to disease among SOD1 A4V mutation carriers, and as far back as 2 and 3.5 years, respectively, in individuals with a FUS c.521del6 mutation and a C9ORF72 hexanucleotide repeat expansion. Conclusions. Serum and CSF pNfH increase prior to phenoconversion. In CSF, the temporal course of these changes is similar to NfL. In serum, however, pNfH is less sensitive to pre-symptomatic disease than NfL. The duration of pre-symptomatic disease, as defined by changes in neurofilaments, may vary depending on underlying genotype.