Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
J Neurol. 2024 Apr;271(4):1680-1706. doi: 10.1007/s00415-023-12093-3. Epub 2023 Dec 16.
Parkinsonian disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), exhibit overlapping early-stage symptoms, complicating definitive diagnosis despite heterogeneous cellular and regional pathophysiology. Additionally, the progression and the eventual conversion of prodromal conditions such as REM behavior disorder (RBD) to PD, MSA, or DLB remain challenging to predict. Extracellular vesicles (EVs) are small, membrane-enclosed structures released by cells, playing a vital role in communicating cell-state-specific messages. Due to their ability to cross the blood-brain barrier into the peripheral circulation, measuring biomarkers in blood-isolated speculative CNS enriched EVs has become a popular diagnostic approach. However, replication and independent validation remain challenging in this field. Here, we aimed to evaluate the diagnostic accuracy of speculative CNS-enriched EVs for parkinsonian disorders.
We conducted a PRISMA-guided systematic review and meta-analysis, covering 18 studies with a total of 1695 patients with PD, 253 with MSA, 21 with DLB, 172 with PSP, 152 with CBS, 189 with RBD, and 1288 HCs, employing either hierarchical bivariate models or univariate models based on study size.
Diagnostic accuracy was moderate for differentiating patients with PD from HCs, but revealed high heterogeneity and significant publication bias, suggesting an inflation of the perceived diagnostic effectiveness. The bias observed indicates that studies with non-significant or lower effect sizes were less likely to be published. Although results for differentiating patients with PD from those with MSA or PSP and CBS appeared promising, their validity is limited due to the small number of involved studies coming from the same research group. Despite initial reports, our analyses suggest that using speculative CNS-enriched EV biomarkers may not reliably differentiate patients with MSA from HCs or patients with RBD from HCs, due to their lesser accuracy and substantial variability among the studies, further complicated by substantial publication bias.
Our findings underscore the moderate, yet unreliable diagnostic accuracy of biomarkers in speculative CNS-enriched EVs in differentiating parkinsonian disorders, highlighting the presence of substantial heterogeneity and significant publication bias. These observations reinforce the need for larger, more standardized, and unbiased studies to validate the utility of these biomarkers but also call for the development of better biomarkers for parkinsonian disorders.
帕金森病（PD）、多系统萎缩（MSA）、路易体痴呆（DLB）、进行性核上性麻痹（PSP）和皮质基底节综合征（CBS）等帕金森氏症障碍表现出重叠的早期症状，尽管存在异质的细胞和区域性病理生理学，但仍使明确诊断变得复杂。此外，前驱症状（如 REM 行为障碍（RBD））向 PD、MSA 或 DLB 的进展和最终转化仍然难以预测。细胞外囊泡（EVs）是由细胞释放的小的、膜包裹的结构，在传递细胞状态特异性信息方面发挥着重要作用。由于它们能够穿过血脑屏障进入外周循环，因此测量血液中分离的富含 CNS 的推测性 EVs 中的生物标志物已成为一种流行的诊断方法。然而，在该领域中，复制和独立验证仍然具有挑战性。在这里，我们旨在评估富含 CNS 的推测性 EVs 对帕金森氏症障碍的诊断准确性。
我们进行了 PRISMA 指导的系统评价和荟萃分析，共涵盖了 18 项研究，其中包括 1695 例 PD 患者、253 例 MSA 患者、21 例 DLB 患者、172 例 PSP 患者、152 例 CBS 患者、189 例 RBD 患者和 1288 例 HC 患者，采用基于研究规模的分层双变量模型或单变量模型。
区分 PD 患者与 HC 患者的诊断准确性为中等，但存在高度异质性和显著的发表偏倚，表明感知诊断效果的膨胀。观察到的偏差表明，非显著或较小效应量的研究不太可能被发表。尽管区分 PD 患者与 MSA 或 PSP 和 CBS 患者的结果似乎很有希望，但由于来自同一研究小组的研究数量较少，其有效性受到限制。尽管有初步报告，但我们的分析表明，由于准确性较低且研究之间的变异性较大，使用富含 CNS 的推测性 EV 生物标志物可能无法可靠地区分 MSA 患者与 HC 患者或 RBD 患者与 HC 患者，并且由于存在大量发表偏倚，情况进一步复杂化。
我们的研究结果突出了富含 CNS 的推测性 EV 生物标志物在区分帕金森氏症障碍方面的中等但不可靠的诊断准确性，突出了存在大量异质性和显著的发表偏倚。这些观察结果强调了需要进行更大、更标准化和无偏倚的研究来验证这些生物标志物的效用，但也呼吁开发更好的帕金森氏症生物标志物。
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