在富含阿尔茨海默病及相关痴呆症风险的队列中，使用NULISA进行靶向蛋白质组学生物标志物分析。

Targeted proteomic biomarker profiling using NULISA in a cohort enriched with risk for Alzheimer's disease and related dementias.

作者信息

Rea Reyes Ramiro Eduardo, Wilson Rachael E, Langhough Rebecca E, Studer Rachel L, Jonaitis Erin M, Oomens Julie E, Planalp Elizabeth M, Bendlin Barbara B, Chin Nathaniel A, Asthana Sanjay, Zetterberg Henrik, Johnson Sterling C

机构信息

Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

出版信息

Alzheimers Dement. 2025 May;21(5):e70166. doi: 10.1002/alz.70166.

DOI:10.1002/alz.70166

PMID:40318118

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12046973/

Abstract

INTRODUCTION

Targeted proteomic assays may be useful for diagnosing and staging Alzheimer's disease and related dementias (ADRD). We evaluated the performance of a 120-marker central nervous system (CNS) NUcleic acid Linked Immuno-Sandwich Assay (NULISA) panel in samples spanning the Alzheimer's disease (AD) spectrum.

METHODS

Cross-sectional plasma samples (n = 252) were analyzed using NULISAseq CNS panel from Alamar Biosciences. Receiver-operating characteristic (ROC) analyses demonstrated the accuracy from NULISAseq-tau phosphorylated at threonine 217 (pTau217) in detecting amyloid (A) and tau (T) positron emission tomography (PET) positivity. Differentially expressed proteins were identified using volcano plots.

RESULTS

NULISAseq-pTau217 accurately classified A/T PET status with ROC areas under the curve of 0.92/0.86; pTau217 was upregulated in A+, T+, and impaired groups with log-fold changes of 1.21, 0.57, and 4.63, respectively, compared to A-. Of interest, TAR DNA-binding protein 43 (TDP-43) phosphorylated at serine 409 (pTDP43-409) was also upregulated in the impaired group and correlated with declining hippocampal volume and cognitive trajectories.

DISCUSSION

This study shows the potential of a targeted proteomics panel for characterizing brain changes pertinent to ADRD. The promising pTDP43-409 findings require further replication.

HIGHLIGHTS

The NULISAseq pTau217 assay was comparable to the Simoa pTau217 assay, both utilizing the ALZpath antibody, in detecting amyloid positron emission tomography (PET) positivity, each with areas under the curve greater than 90%. Nineteen proteins were differentially expressed in participants with mild cognitive impairment (MCI) compared to those who were unimpaired. Markers of non-AD proteinopathies such as pTDP43-409, oligomeric alpha-synuclein, and huntingtin (HTT), were among those upregulated in MCI. High levels of plasma pTDP43-409 were associated with worsening hippocampal atrophy and cognitive decline, clinical indicators of limbic-predominant age-related TDP-43 encephalopathy (LATE), compared to those with low pTDP43-409.

摘要

引言

靶向蛋白质组学检测可能有助于阿尔茨海默病及相关痴呆症（ADRD）的诊断和分期。我们评估了一个包含120种标志物的中枢神经系统（CNS）核酸连接免疫夹心分析（NULISA）检测板在阿尔茨海默病（AD）谱系样本中的性能。

方法

使用来自阿拉马尔生物科学公司的NULISAseq CNS检测板对横断面血浆样本（n = 252）进行分析。受试者工作特征（ROC）分析证明了NULISAseq-苏氨酸217位点磷酸化的tau蛋白（pTau217）在检测淀粉样蛋白（A）和tau蛋白（T）正电子发射断层扫描（PET）阳性方面的准确性。使用火山图鉴定差异表达的蛋白质。

结果

NULISAseq-pTau217能准确分类A/T PET状态，曲线下面积分别为0.92/0.86；与A-组相比，pTau217在A+、T+和受损组中上调，对数变化倍数分别为1.21、0.57和4.63。有趣的是，丝氨酸409位点磷酸化的TAR DNA结合蛋白43（TDP-43）（pTDP43-409）在受损组中也上调，并且与海马体积减小和认知轨迹相关。

讨论

本研究显示了靶向蛋白质组学检测板在表征与ADRD相关的脑变化方面的潜力。有前景的pTDP43-409研究结果需要进一步验证。

重点

NULISAseq pTau217检测在检测淀粉样蛋白正电子发射断层扫描（PET）阳性方面与Simoa pTau217检测相当，二者均使用ALZpath抗体，曲线下面积均大于90%。与未受损者相比，19种蛋白质在轻度认知障碍（MCI）参与者中差异表达。pTDP43-409、寡聚α-突触核蛋白和亨廷顿蛋白（HTT）等非AD蛋白病的标志物在MCI中上调。与pTDP43-409水平低的人相比，血浆pTDP43-409水平高与海马萎缩加重和认知衰退相关，海马萎缩和认知衰退是边缘型为主的年龄相关TDP-43脑病（LATE）的临床指标。