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Evaluation of plasma tau and neurofilament light chain biomarkers in a 12-year clinical cohort of human prion diseases
medRxiv - Neurology Pub Date : 2020-07-29 , DOI: 10.1101/2020.07.27.20157594
Andrew Thompson , Prodromos Anastasiadis , Ron Druyeh , Ines Whitworth , Annapurna Nayak , Akin Nihat , Tzehow Mok , Peter Rudge , Jonathan Wadsworth , Jonathan Rohrer , Jonathan Schott , Amanda Heslegrave , Henrik Zetterberg , John Collinge , Graham Jackson , Simon H Mead

Prion diseases are fatal neurodegenerative conditions with highly accurate CSF and imaging diagnostic markers, 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 within 2 years of symptom onset than in samples taken earlier. We present biomarker trajectories for 9 individuals healthy at enrolment who developed symptoms during follow-up, showing potential for plasma NfL as a *proximity marker*. We conclude that plasma tau and NfL have potential to fill key unmet needs for biomarkers in prion disease: as an 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.

中文翻译:

在人类病毒疾病的12年临床队列中评估血浆tau和神经丝轻链生物标志物

on病毒疾病是致命的神经退行性疾病,具有高度精确的CSF和成像诊断标记,但血液生物标记的主要需求尚未得到满足。在一项为期12年的前瞻性临床研究中,我们通过健康和神经系统控制组,在12年的时间里对377名with病毒病患者的709份血浆样品中的tau和神经丝轻链(NfL)蛋白浓度进行了测量。这提供了前所未有的机会来评估其作为生物标志物的潜力。在所有病毒疾病类型中,血浆tau和NfL均升高。为了区分sCJD与包括临床相关的* CJD模拟物*的对照组,两者均显示出可观的诊断价值。在sCJD中,每个测试样品中的NfL均显着升高,包括在疾病早期,功能受损最小的情况下以及所有后续样本中。血浆tau与sCJD的临床进展速度独立相关,而血浆NfL与功能障碍的严重程度独立相关。在无症状的PRNP突变携带者中,症状发作2年内血浆NfL高于早期采集的样本。我们介绍了9位健康的个体的生物标记轨迹,这些个体在随访期间出现了症状,显示出血浆NfL作为*邻近标记*的潜力。我们得出结论,血浆tau和NfL有潜力满足病毒疾病中生物标志物的关键未满足需求:作为临床试验的结果(NfL和tau);用于预测高危人群的发病(NfL);并且作为一种可及性测试,用于早期识别可能患有克雅氏病并需要更多确定性测试(NfL)的患者。进一步的研究应直接评估其在这些特定角色中的表现。
更新日期:2020-07-29
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