Begcevic Ilijana, Tsolaki Magda, Brinc Davor, Brown Marshall, Martinez-Morillo Eduardo, Lazarou Ioulietta, Kozori Mahi, Tagaraki Fani, Nenopoulou Stella, Gkioka Mara, Lazarou Eutichia, Lim Bryant, Batruch Ihor, Diamandis Eleftherios P
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.
F1000Res. 2018 Jul 5;7:1012. doi: 10.12688/f1000research.15095.1. eCollection 2018.
Alzheimer's disease (AD) is the most common type of dementia, with progressive onset of clinical symptoms. The main pathological hallmarks are brain deposits of extracellular amyloid beta plaques and intracellular neurofibrillary tangles (NFT). Cerebrospinal fluid reflects pathological changes in the brain; amyloid beta 1-42 is a marker of amyloid plaques, while total and phosphorylated tau are markers of NFT formation. Additional biomarkers associated with disease pathogenesis are needed, for better prognosis, more specific diagnosis, prediction of disease severity and progression and for improved patient classification in clinical trials. The aim of the present study was to evaluate brain-specific proteins as potential biomarkers of progression of AD. Overall, 30 candidate proteins were quantified in cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment (MCI) and mild, moderate and severe AD dementia (n=101) using mass spectrometry-based selected reaction monitoring assays. ELISA was used for neuronal pentraxin receptor-1 (NPTXR) confirmation. The best discrimination between MCI and more advanced AD stages (moderate and severe dementia) was observed for protein NPTXR (area under the curve, AUC=0.799). A statistically different abundance of this protein was observed between the two groups, with severe AD patients having progressively lower levels (p<0.05). ELISA confirmed lower levels in AD, in a separate cohort that included controls, MCI and AD patients. We conclude that NPTXR protein in CSF is a novel potential biomarker of AD progression and could have important utility in assessing treatment success in clinical trials.
阿尔茨海默病（AD）是最常见的痴呆类型，临床症状呈进行性发作。主要病理特征是细胞外淀粉样β斑块和细胞内神经原纤维缠结（NFT）在大脑中沉积。脑脊液反映大脑的病理变化；淀粉样β1-42是淀粉样斑块的标志物，而总tau蛋白和磷酸化tau蛋白是NFT形成的标志物。为了实现更好的预后、更特异的诊断、预测疾病严重程度和进展以及在临床试验中改善患者分类，需要与疾病发病机制相关的其他生物标志物。本研究的目的是评估脑特异性蛋白作为AD进展的潜在生物标志物。总体而言，使用基于质谱的选择反应监测分析法对来自轻度认知障碍（MCI）以及轻度、中度和重度AD痴呆患者（n = 101）的脑脊液（CSF）样本中的30种候选蛋白进行了定量分析。采用酶联免疫吸附测定（ELISA）法对神经元五聚体受体-1（NPTXR）进行验证。对于蛋白NPTXR，观察到MCI与更晚期AD阶段（中度和重度痴呆）之间的最佳区分效果（曲线下面积，AUC = 0.799）。两组之间该蛋白的丰度存在统计学差异，重度AD患者的水平逐渐降低（p < 0.05）。在一个包括对照、MCI和AD患者的独立队列中，ELISA法证实AD患者中该蛋白水平较低。我们得出结论，脑脊液中的NPTXR蛋白是AD进展的一种新型潜在生物标志物，在评估临床试验中的治疗效果方面可能具有重要作用。
