Hermann Peter, Canaslan Sezgi, Villar-Piqué Anna, Bunck Timothy, Goebel Stefan, Llorens Franc, Schmitz Matthias, Zerr Inga
Department of Neurology, National Reference Center for CJD Surveillance, Göttingen University Medical Center, Göttingen, Germany.
Bellvitge Biomedical Research Institute, Hospitalet de Llobregat, Spain.
Eur J Neurol. 2022 Jun;29(6):1841-1846. doi: 10.1111/ene.15302. Epub 2022 Mar 7.
Fatal familial insomnia is a rare hereditary prion disease associated with the D178N-129M PRNP mutation. Early diagnosis is difficult, because the clinical syndrome may overlap with affective disorders. In addition, most known cerebrospinal fluid biomarkers for prion diseases and magnetic resonance imaging do not show a good diagnostic accuracy for fatal familial insomnia. In this context, data on plasma biomarkers are scarce.
We analyzed levels of neurofilament light chain, glial fibrillary acidic protein, chitinase-3-like protein 1, calcium-binding protein B, and total tau protein in six serial plasma samples from a patient with fatal familial insomnia. Subsequently, plasma neurofilament light chain was analyzed in n = 25 patients and n = 19 controls. The diagnostic accuracy and associations with disease stage and duration were explored.
Among all biomarker candidates in the case study, only neurofilament light chain levels showed a constant evolution and increased over time. They discriminated fatal familial insomnia from controls with an area under the curve of 0.992 (95% confidence interval [CI] = 0.974-1) in the case-control study. Higher concentrations were associated with methionine homozygosity at codon 129 PRNP (p = 0.006), shorter total disease duration (rho = -0.467, p = 0.019, 95% CI = -0.790 to -0.015), and shorter time from sampling to death (rho = -0.467, p = 0.019, 95% CI = -0.773 to -0.019).
Plasma neurofilament light chain may be a valuable minimally invasive diagnostic biomarker for fatal familial insomnia after clinical onset. Most important, stage-related increase and association with disease duration indicate potential as a prognostic marker and as a surrogate marker in clinical trials.
致死性家族性失眠症是一种罕见的遗传性朊病毒病，与D178N - 129M PRNP突变相关。早期诊断困难，因为其临床综合征可能与情感障碍重叠。此外，大多数已知的用于朊病毒病的脑脊液生物标志物和磁共振成像对致死性家族性失眠症的诊断准确性不佳。在此背景下，关于血浆生物标志物的数据稀缺。
我们分析了一名致死性家族性失眠症患者连续6份血浆样本中的神经丝轻链、胶质纤维酸性蛋白、几丁质酶3样蛋白1（YKL-4）钙结合蛋白B和总tau蛋白水平。随后，对25例患者和19名对照者的血浆神经丝轻链进行了分析。探讨了其诊断准确性以及与疾病阶段和病程的关联。
在该病例研究中的所有生物标志物候选物中，只有神经丝轻链水平呈现持续变化且随时间升高。在病例对照研究中，它们区分致死性家族性失眠症与对照者的曲线下面积为0.992（95%置信区间[CI]=0.974 - 1）。较高浓度与PRNP密码子129处的甲硫氨酸纯合性相关（p = 0.006），与总病程较短相关（rho = -0.467，p = 0.019，95%CI = -0.790至 -0.015），与从采样到死亡的时间较短相关（rho = -0.467，p = 0.019，95%CI = -0.773至 -0.019）。
血浆神经丝轻链可能是临床发病后致死性家族性失眠症一种有价值的微创诊断生物标志物。最重要的是，与疾病阶段相关的升高以及与病程的关联表明其有潜力作为预后标志物以及临床试验中的替代标志物。
