MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK.
National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK.
Mol Psychiatry. 2021 Oct;26(10):5955-5966. doi: 10.1038/s41380-021-01045-w. Epub 2021 Mar 5.
Prion diseases are fatal neurodegenerative conditions with highly accurate CSF and imaging diagnostic tests, but major unmet needs for blood biomarkers. Using ultrasensitive immuno-assays, we measured tau and neurofilament light chain (NfL) protein concentrations in 709 plasma samples taken from 377 individuals with prion disease during a 12 year prospective clinical study, alongside healthy and neurological control groups. This provides an unprecedented opportunity to evaluate their potential as biomarkers. Plasma tau and NfL were increased across all prion disease types. For distinguishing sCJD from control groups including clinically-relevant "CJD mimics", both show considerable diagnostic value. In sCJD, NfL was substantially elevated in every sample tested, including during early disease with minimal functional impairment and in all follow-up samples. Plasma tau was independently associated with rate of clinical progression in sCJD, while plasma NfL showed independent association with severity of functional impairment. In asymptomatic PRNP mutation carriers, plasma NfL was higher on average in samples taken within 2 years of symptom onset than in samples taken earlier. We present biomarker trajectories for nine mutation carriers healthy at enrolment who developed symptoms during follow-up. NfL started to rise as early as 2 years before onset in those with mutations typically associated with more slowly progressive clinical disease. This shows potential for plasma NfL as a "proximity marker", but further work is needed to establish predictive value on an individual basis, and how this varies across different PRNP mutations. We conclude that plasma tau and NfL have potential to fill key unmet needs for biomarkers in prion disease: as a secondary outcome for clinical trials (NfL and tau); for predicting onset in at-risk individuals (NfL); and as an accessible test for earlier identification of patients that may have CJD and require more definitive tests (NfL). Further studies should evaluate their performance directly in these specific roles.
朊病毒病是一种致命的神经退行性疾病，具有高度准确的脑脊液和成像诊断测试，但在血液生物标志物方面存在重大未满足的需求。我们使用超灵敏免疫测定法，在一项为期 12 年的前瞻性临床研究中，测量了 709 份来自 377 名朊病毒病患者的血浆样本中的 tau 和神经丝轻链（NfL）蛋白浓度，同时还测量了健康对照组和神经对照组的样本。这为评估它们作为生物标志物的潜力提供了前所未有的机会。所有朊病毒病类型的血浆 tau 和 NfL 均升高。对于将 sCJD 与包括临床相关的“CJD 模拟物”在内的对照组区分开来，这两种标志物都具有相当大的诊断价值。在 sCJD 中，在测试的每个样本中均发现 NfL 显著升高，包括在疾病早期且功能损害最小以及所有随访样本中。血浆 tau 与 sCJD 的临床进展速度独立相关，而血浆 NfL 与功能损害的严重程度独立相关。在无症状的 PRNP 突变携带者中，在症状发作前 2 年内采集的样本中，平均血浆 NfL 较高，而在更早采集的样本中则较低。我们介绍了 9 名在随访期间发病的入组时健康的 PRNP 突变携带者的生物标志物轨迹。在那些突变通常与临床疾病进展较慢相关的患者中，NfL 在发病前 2 年内就开始升高。这表明血浆 NfL 具有作为“临近标志物”的潜力，但还需要进一步工作来确定其在个体基础上的预测价值，以及在不同的 PRNP 突变中如何变化。我们得出结论，血浆 tau 和 NfL 有可能满足朊病毒病生物标志物的关键未满足需求：作为临床试验的次要终点（NfL 和 tau）；预测高危人群的发病风险（NfL）；以及作为一种易于获得的测试方法，用于更早地识别可能患有 CJD 并需要更明确测试的患者（NfL）。进一步的研究应该直接在这些特定角色中评估它们的性能。
