Thomas Eleanor V, Han Changee, Kim Woo Jae, Asress Seneshaw, Li Yingjie, Taylor Jennifer A, Gearing Marla, Fournier Christina N, McEachin Zachary T, Seyfried Nicholas T, Glass Jonathan D
Department of Neurology, Emory University, Atlanta, Georgia, 30322, USA.
Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, 30322, USA.
Ann Clin Transl Neurol. 2025 Apr;12(4):714-723. doi: 10.1002/acn3.70001. Epub 2025 Feb 6.
We performed a pilot screen to assess the utility of the NULISA™ (Nucleic-acid-Linked Immuno-Sandwich Assay) platform in the identification of amyotrophic lateral sclerosis (ALS) biomarkers.
Plasma from 86 individuals (48 ALS, 18 asymptomatic C9orf72 repeat expansion carriers (AsymC9), and 20 healthy controls) was analyzed via a multiplexed NULISA™ assay that includes 120 neurodegeneration-associated proteins. Statistical analysis of NULISA™ results was performed to identify proteins differentially expressed in plasma and their correlation with disease-associated parameters.
ALS plasma showed elevation of the established biomarkers, neurofilament light chain (NEFL) and neurofilament heavy chain (NEFH). Compared to controls and AsymC9, microtubule-associated protein tau (MAPT), phosphorylated tau 181 (pTau181), phosphorylated tau 217 (pTau217), phosphorylated tau 231 (pTau231), and phosphorylated TDP-43 (pTDP-43) were elevated in ALS. NEFL levels positively correlated with pTau181, pTau217, pTau231, and pTDP-43. MAPT and pTDP-43 were also correlated with pTau181, pTau217 and pTau231. Elevated pTau was negatively correlated with survival and ALSFRS-R. Spinal onset ALS was associated with higher pTau181, pTau217, and pTau231.
We confirm previous reports showing elevated pTau181 in ALS plasma and show elevation of other phosphorylated tau forms, pTau217 and pTau231, typically observed in Alzheimer's disease. We provide preliminary data showing the detection and elevation of pTDP-43-409/410 in a subset of ALS samples compared to healthy controls. Neurofilament and tau levels are highly correlated suggesting their elevation may reflect a common pathology and disease state. Total and phosphorylated tau are correlated with multiple disease measures, such as ALS duration, ALSFRS-R, and site of onset.
我们进行了一项初步筛查，以评估NULISA™（核酸连接免疫夹心测定）平台在鉴定肌萎缩侧索硬化症（ALS）生物标志物方面的效用。
通过包含120种神经退行性疾病相关蛋白的多重NULISA™测定法，对86名个体（48例ALS患者、18名无症状C9orf72重复扩增携带者（AsymC9）和20名健康对照）的血浆进行分析。对NULISA™结果进行统计分析，以鉴定血浆中差异表达的蛋白及其与疾病相关参数的相关性。
ALS患者血浆中已确定的生物标志物神经丝轻链（NEFL）和神经丝重链（NEFH）升高。与对照组和AsymC9相比，ALS患者中微管相关蛋白tau（MAPT）、磷酸化tau 181（pTau181）、磷酸化tau 217（pTau217）、磷酸化tau 231（pTau231）和磷酸化TDP-43（pTDP-43）升高。NEFL水平与pTau181、pTau217、pTau231和pTDP-43呈正相关。MAPT和pTDP-43也与pTau181、pTau217和pTau231相关。磷酸化tau升高与生存率和ALS功能评定量表修订版（ALSFRS-R）呈负相关。脊髓起病的ALS与较高的pTau181、pTau217和pTau231相关。
我们证实了先前关于ALS患者血浆中pTau181升高的报道，并发现了通常在阿尔茨海默病中观察到的其他磷酸化tau形式pTau217和pTau231也升高。我们提供的初步数据显示，与健康对照相比，在一部分ALS样本中检测到pTDP-43-409/410升高。神经丝和tau水平高度相关，表明它们的升高可能反映了共同的病理和疾病状态。总tau和磷酸化tau与多种疾病指标相关，如ALS病程、ALSFRS-R和起病部位。
