From the Danish Dementia Research Centre (N.R., P.R., A.H.S., J.E.N.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark; Clinical Neurochemistry Laboratory (E.P., K.B., H.Z.), Sahlgrenska University Hospital; Institute of Neuroscience and Physiology (E.P., K.B., H.Z.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; and Department of Molecular Neuroscience and UK Dementia Research Institute (H.Z.), UCL Institute of Neurology, Queen Square, London, UK.
Neurology. 2018 Jan 9;90(2):e157-e163. doi: 10.1212/WNL.0000000000004799. Epub 2017 Dec 13.
A rare cause of familial frontotemporal dementia (FTD) is a mutation in the gene on chromosome 3 (FTD-3), described in a Danish family. Here we examine whether CSF biomarkers change in the preclinical phase of the disease.
In this cross-sectional explorative study, we analyzed CSF samples from 16 mutation carriers and 14 noncarriers from the Danish FTD-3 family. CSF biomarkers included total tau (t-tau) and neurofilament light chain (NfL) as a marker for neurodegeneration, phosphorylated tau (p-tau) as a marker for tau pathology, β-amyloid (Aβ) 38, 40, and 42 (Aβ, Aβ, and Aβ) to monitor Aβ metabolism, and YKL-40 as a marker of neuroinflammation. Aβ isoform concentrations were measured using a multiplexed immunoassay; t-tau, p-tau, NfL, and YKL-40 concentrations were measured using sandwich ELISAs.
CSF NfL concentration was significantly increased in mutation carriers vs noncarriers. Further, CSF NfL concentration was significantly higher in symptomatic mutation carriers compared to presymptomatic carriers, and also significantly higher in presymptomatic carriers compared to noncarriers. No differences in t-tau and p-tau and YKL-40 concentrations between controls and mutation carriers were observed. CSF concentrations of the Aβ peptides Aβ and Aβ but not Aβ were significantly lower in mutation carriers compared to noncarriers.
Increased NfL levels in presymptomatic individuals and in symptomatic patients with FTD-3 indicate a continuous process of neurodegeneration from the presymptomatic to symptomatic state. Although not specific for FTD-3 pathology, our data suggest that CSF NfL could serve as a valuable biomarker to detect onset of neurodegeneration in FTD-3 mutation carriers.
一种罕见的家族性额颞叶痴呆（FTD）病因是 3 号染色体（FTD-3）上的基因突变，该突变在一个丹麦家族中被描述。在此，我们研究了疾病的临床前期是否会改变脑脊液（CSF）生物标志物。
在这项横断面探索性研究中，我们分析了来自丹麦 FTD-3 家族的 16 名突变携带者和 14 名非携带者的 CSF 样本。CSF 生物标志物包括总 tau（t-tau）和神经丝轻链（NfL）作为神经退行性变的标志物、磷酸化 tau（p-tau）作为 tau 病理学的标志物、β-淀粉样蛋白（Aβ）38、40 和 42（Aβ1-38、Aβ1-40 和 Aβ1-42）以监测 Aβ代谢，以及 YKL-40 作为神经炎症的标志物。Aβ 同工型浓度使用多重免疫测定法进行测量；t-tau、p-tau、NfL 和 YKL-40 浓度使用夹心 ELISA 进行测量。
突变携带者的 CSF NfL 浓度明显高于非携带者。此外，与无症状突变携带者相比，有症状的突变携带者的 CSF NfL 浓度显著更高，与无症状携带者相比，也显著高于非携带者。在对照组和突变携带者之间，未观察到 t-tau 和 p-tau 以及 YKL-40 浓度的差异。与非携带者相比，突变携带者的 CSF Aβ 肽 Aβ 和 Aβ 但不是 Aβ 的浓度明显降低。
在无症状个体和 FTD-3 有症状患者中 NfL 水平升高表明从无症状前状态到有症状状态的神经退行性变的连续过程。尽管不是 FTD-3 病理学的特异性标志物，但我们的数据表明 CSF NfL 可作为检测 FTD-3 突变携带者神经退行性变开始的有价值的生物标志物。
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