Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, arise from the structural conversion of the monomeric, cellular prion protein (PrPC) into its multimeric scrapie form (PrPSc). These pathologies comprise a group of intractable, rapidly evolving neurodegenerative diseases. Currently, a definitive diagnosis of TSE relies on the detection of PrPSc and/or the identification of pathognomonic histological features in brain tissue samples, which are usually obtained postmortem or, in rare cases, by brain biopsy (antemortem). Over the past two decades, several paraclinical tests for antemortem diagnosis have been developed to preclude the need for brain samples. Some of these alternative methods have been validated and can provide a probable diagnosis when combined with clinical evaluation. Paraclinical tests include in vitro cell-free conversion techniques, such as the real-time quaking-induced conversion (RT-QuIC), as well as immunoassays, electroencephalography (EEG), and brain bioimaging methods, such as magnetic resonance imaging (MRI), whose importance has increased over the years. PrPSc is the main biomarker in TSEs, and the RT-QuIC assay stands out for its ability to detect PrPSc in cerebrospinal fluid (CSF), olfactory mucosa, and dermatome skin samples with high sensitivity and specificity. Other biochemical biomarkers are the proteins 14-3-3, tau, neuron-specific enolase (NSE), astroglial protein S100B, α-synuclein, and neurofilament light chain protein (NFL), but they are not specific for TSEs. This paper reviews the techniques employed for definite diagnosis, as well as the clinical and paraclinical methods for possible and probable diagnosis, both those in use currently and those no longer employed. We also discuss current criteria, challenges, and perspectives for TSE diagnosis. An early and accurate diagnosis may allow earlier implementation of strategies to delay or stop disease progression.

中文翻译：

---

人类传染性海绵状脑病生前诊断的挑战和进展


传染性海绵状脑病 (TSE)，也称为朊病毒病，是由单体细胞朊病毒蛋白 (PrPC) 结构转变为其多聚体痒病形式 (PrPSc) 引起的。这些病症包括一组棘手的、快速发展的神经退行性疾病。目前，TSE 的明确诊断依赖于 PrPSc 的检测和/或脑组织样本中病理组织学特征的识别，这些样本通常在死后获得，或者在极少数情况下通过脑活检（死前）获得。在过去的二十年中，已经开发了几种用于生前诊断的临床旁测试，以排除对脑样本的需求。其中一些替代方法已经过验证，与临床评估相结合可以提供可能的诊断。临床旁试验包括体外无细胞转换技术，例如实时震动诱导转换 (RT-QuIC)，以及免疫分析、脑电图 (EEG) 和脑生物成像方法，例如磁共振成像 (MRI) ，其重要性多年来不断增加。 PrPSc 是 TSE 的主要生物标志物，RT-QuIC 检测因其能够以高灵敏度和特异性检测脑脊液 (CSF)、嗅粘膜和皮区皮肤样本中的 PrPSc 而脱颖而出。其他生化生物标志物包括蛋白质 14-3-3、tau、神经元特异性烯醇化酶 (NSE)、星形胶质细胞蛋白 S100B、α-突触核蛋白和神经丝轻链蛋白 (NFL)，但它们并非 TSE 特异性。本文回顾了用于明确诊断的技术，以及用于可能和可能诊断的临床和临床旁方法，包括目前使用的和不再使用的方法。 我们还讨论了 TSE 诊断的当前标准、挑战和前景。早期准确的诊断可能有助于更早实施延迟或阻止疾病进展的策略。