From the Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Italy (G.B., F.P.P., L.G., L.P.); and Unit of Neurology 5 and Neuropathology (C.M.G.D.L., F.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Neurology. 2022 Aug 2;99(5):195-205. doi: 10.1212/WNL.0000000000200878. Epub 2022 Jun 3.
Parkinson disease (PD) is the second most common neurodegenerative disease, and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset and progression. Although neuropathologic changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Because α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in patients with PD would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis. Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These techniques enable the detection of minimal amounts of prions in CSF and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded alpha-synuclein (α-syn) in CSF, olfactory mucosa, submandibular gland biopsies, skin, and saliva of patients with Parkinson disease (PD) and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLBs) from control subjects, even in the prodromal stages of the disease. In differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from nonsynucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (LBDs) (PD and DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives.
帕金森病（PD）是第二常见的神经退行性疾病，也是最常见的突触核蛋白病，因为α-突触核蛋白（α-syn）作为一种类朊病毒蛋白，在其发病和进展中起着重要的病理生理作用。尽管神经病理学改变早在运动表现出现多年前就开始了，但诊断仍然依赖于识别运动症状，这阻碍了早期诊断的制定。由于α-syn 错误折叠和聚集先于临床表现，因此在 PD 患者中识别这些现象的可能性将使我们能够在最早的、运动前阶段识别疾病，从而实现从临床诊断到分子诊断的转变。种子扩增检测（SAA）是一组目前支持朊病毒亚急性脑病（如克雅氏病）诊断的技术。这些技术能够在脑脊液和其他受影响患者的基质中检测到微量的朊病毒。最近，SAA 已成功应用于检测帕金森病（PD）和其他突触核蛋白病患者的脑脊液、嗅黏膜、颌下腺活检、皮肤和唾液中的错误折叠的α-突触核蛋白（α-syn）。在这些类别中，它们可以将 PD 和路易体痴呆（DLB）与对照患者区分开来，即使在疾病的前驱阶段也是如此。在鉴别诊断中，SAA 能够令人满意地区分 PD、DLB 和多系统萎缩（MSA）与非突触核蛋白病帕金森病。SAA 荧光谱的动力学分析允许识别突触核蛋白病依赖的α-syn 纤维构象，通常称为菌株，这些菌株在区分突触核蛋白病方面具有诊断潜力，特别是在路易体疾病（LBD）（PD 和 DLB）和 MSA 之间。在这些极具前景的数据面前，SAA 检测到的α-syn 接种活性被认为是突触核蛋白病最有前途的诊断生物标志物，但仍然存在分析前和分析问题，主要与检测标准化有关，这些问题需要解决。在这篇综述中，我们讨论了支持 SAA 检测α-syn 以识别 PD 和其他突触核蛋白病的关键发现、未满足的需求和未来展望。
