Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands.
Barcelonaßeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
Nat Commun. 2023 Sep 13;14(1):5635. doi: 10.1038/s41467-023-41122-y.
Diagnosis of dementia with Lewy bodies (DLB) is challenging and specific biofluid biomarkers are highly needed. We employed proximity extension-based assays to measure 665 proteins in the cerebrospinal fluid (CSF) from patients with DLB (n = 109), Alzheimer´s disease (AD, n = 235) and cognitively unimpaired controls (n = 190). We identified over 50 CSF proteins dysregulated in DLB, enriched in myelination processes among others. The dopamine biosynthesis enzyme DDC was the strongest dysregulated protein, and could efficiently discriminate DLB from controls and AD (AUC:0.91 and 0.81 respectively). Classification modeling unveiled a 7-CSF biomarker panel that better discriminate DLB from AD (AUC:0.93). A custom multiplex panel for six of these markers (DDC, CRH, MMP-3, ABL1, MMP-10, THOP1) was developed and validated in independent cohorts, including an AD and DLB autopsy cohort. This DLB CSF proteome study identifies DLB-specific protein changes and translates these findings to a practicable biomarker panel that accurately identifies DLB patients, providing promising diagnostic and clinical trial testing opportunities.
诊断路易体痴呆（DLB）具有挑战性，非常需要特定的生物流体生物标志物。我们采用基于邻近延伸的测定法，测量了 109 例 DLB 患者（n=109）、235 例阿尔茨海默病（AD，n=235）和认知正常对照组（n=190）的脑脊液（CSF）中的 665 种蛋白质。我们发现超过 50 种 CSF 蛋白在 DLB 中失调，其中富含髓鞘形成等过程。多巴胺生物合成酶 DDC 是失调最严重的蛋白质，能够有效地将 DLB 与对照组和 AD 区分开来（AUC：分别为 0.91 和 0.81）。分类模型揭示了一个 7-CSF 生物标志物面板，能够更好地区分 DLB 与 AD（AUC：0.93）。开发并验证了包含六个标志物（DDC、CRH、MMP-3、ABL1、MMP-10、THOP1）的定制多重检测面板，这些标志物在独立队列中得到了验证，包括 AD 和 DLB 尸检队列。这项 DLB CSF 蛋白质组学研究确定了 DLB 特异性的蛋白质变化，并将这些发现转化为可行的生物标志物面板，能够准确识别 DLB 患者，为诊断和临床试验测试提供了有前景的机会。
