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

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-05-02 DOI:10.1002/alz.70166

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

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引用次数: 0

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 log₂-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.

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在阿尔茨海默病和相关痴呆风险高的队列中使用NULISA进行靶向蛋白质组学生物标志物分析

靶向蛋白质组学分析可能有助于阿尔茨海默病和相关痴呆（ADRD）的诊断和分期。我们评估了120个标记的中枢神经系统（CNS）核酸连锁免疫夹心试验（NULISA）在阿尔茨海默病（AD）谱系样本中的表现。方法采用Alamar Biosciences公司的NULISAseq CNS面板对252份血浆样本进行横断面分析。受体工作特征（ROC）分析表明，NULISAseq-tau在苏氨酸217位点磷酸化（pTau217）检测淀粉样蛋白(A)和tau (T)正电子发射断层扫描（PET）阳性的准确性。用火山图鉴定差异表达蛋白。结果NULISAseq-pTau217准确分类A/T PET状态，ROC曲线下面积为0.92/0.86；pTau217在A+、T+和受损组中上调，与A−组相比，分别为1.21、0.57和4.63的log2倍变化。有趣的是，在409丝氨酸磷酸化的TAR dna结合蛋白43 (TDP-43) （pTDP43-409）在受损组中也上调，并与海马体积下降和认知轨迹相关。这项研究显示了靶向蛋白质组学小组在表征与ADRD相关的大脑变化方面的潜力。有希望的pTDP43-409发现需要进一步的复制。在检测淀粉样蛋白正电子发射断层扫描（PET）阳性方面，NULISAseq pTau217法与Simoa pTau217法相当，两者都使用了ALZpath抗体，曲线下面积均大于90%。轻度认知障碍（MCI）的参与者与未受损的参与者相比，有19种蛋白质的差异表达。非ad蛋白病变的标志物，如pTDP43-409，寡聚α -突触核蛋白和亨廷顿蛋白（HTT），在MCI中上调。与低pTDP43-409水平的患者相比，高水平的血浆pTDP43-409与海马萎缩恶化和认知能力下降相关，这是边缘主导的年龄相关性TDP-43脑病（LATE）的临床指标。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.