Evidence of blood–brain barrier dysfunction and CSF immunoglobulin synthesis in Down Syndrome Regression Disorder

IF 4.4 2区医学 Q1 CLINICAL NEUROLOGY

Annals of Clinical and Translational Neurology Pub Date : 2025-02-25 DOI:10.1002/acn3.52299

Jonathan D. Santoro, Neetha Paul Eduthan, Mellad M. Khoshnood, Saba Jafarpour, Natalie K. Boyd, Benjamin N. Vogel, Lina Nguyen, Lilia Kazerooni, Eleanor Britton, Hannah R. Lyford, Matthew D. Galbraith, Angela L. Rachubinski, Joaquin M. Espinosa

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Abstract

Objectives

This study sought to evaluate proteomic, metabolomic, and immune signatures in the cerebrospinal fluid of individuals with Down Syndrome Regression Disorder (DSRD).

Methods

A prospective case–control study comparing proteomic, metabolomic, and immune profiles in individuals with DSRD was performed. Samples were obtained from a biorepository of affected individuals and compared to clinically available data and previously obtained neurodiagnostic studies. Individuals with DSRD were compared to individuals with established neuroinflammatory conditions (e.g., multiple sclerosis), and neurotypical controls undergoing a lumbar puncture for headaches. Samples underwent high-throughput proteomic, metabolomic, and immune marker profiling. Data was compared across groups and clinical phenotypes. Gene set enrichment analysis and pathway analyses were utilized to analyze the data.

Results

In total, 34 individuals with DSRD, 22 neuroinflammatory controls, and 27 neurotypical controls were enrolled in the study. We observed a highly significant concordance in dysregulated proteomics signatures in DSRD and neuroinflammatory controls versus healthy controls, most prominently upregulation of many immunoglobulin sequences. In addition, individuals with DSRD displayed strong upregulation of liver-derived plasma proteins and erythrocyte proteins in the CSF, indicating poor blood–brain barrier integrity. The immune marker profile of DSRD is clearly similar to other neuroimmunological conditions, including strong elevation of MIP3-α, eotaxin, and IFN-γ.

Interpretation

Individuals with DSRD have unique CSF proteomic and metabolomic signatures consistent with neuroinflammation and increased blood–brain barrier permeability. The CSF of individuals with DSRD was more comparable to individuals with neuroinflammatory disorders than neurotypical controls, indicating the potential for an immune etiology of disease.

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唐氏综合征退行性障碍患者血脑屏障功能障碍和脑脊液免疫球蛋白合成的证据。

目的：本研究旨在评估唐氏综合征退行性障碍（DSRD）患者脑脊液中的蛋白质组学、代谢组学和免疫特征。方法：进行一项前瞻性病例对照研究，比较dsd患者的蛋白质组学、代谢组学和免疫谱。从受影响个体的生物库中获得样本，并与临床可用数据和先前获得的神经诊断研究进行比较。将患有DSRD的个体与患有神经炎症（如多发性硬化症）的个体以及接受腰穿刺治疗头痛的神经典型对照组进行比较。样品进行了高通量蛋白质组学、代谢组学和免疫标记分析。比较各组间数据和临床表型。利用基因集富集分析和通路分析对数据进行分析。结果：共有34名DSRD患者、22名神经炎症对照组和27名神经正常对照组被纳入研究。我们观察到，与健康对照组相比，dsd和神经炎症对照组中失调的蛋白质组学特征具有高度显著的一致性，最显著的是许多免疫球蛋白序列上调。此外，DSRD患者在脑脊液中表现出肝源性血浆蛋白和红细胞蛋白的强烈上调，表明血脑屏障完整性较差。DSRD的免疫标志物谱与其他神经免疫疾病明显相似，包括MIP3-α、eotaxin和IFN-γ的强烈升高。解释：患有dsd的个体具有独特的脑脊液蛋白质组学和代谢组学特征，与神经炎症和血脑屏障通透性增加一致。与神经典型对照相比，DSRD患者的脑脊液与神经炎症性疾病患者的脑脊液更具可比性，这表明该疾病可能存在免疫病因。

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来源期刊

Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)

CiteScore

9.10

自引率

1.90%

发文量

218

审稿时长

8 weeks

期刊介绍： Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.