与血浆P-Tau217和已确立的阿尔茨海默病生物标志物不一致相关的临床因素

文献信息

中文摘要

背景与目的： 血浆磷酸化tau（p-tau）217正越来越多地用于阿尔茨海默病（AD）的诊断和治疗决策，但可能与已确立的AD生物标志物不一致。假阳性（FP）血浆结果可能导致过度治疗，而假阴性（FN）结果可能导致错过或延迟疾病修饰治疗。我们评估了与不一致结果相关的因素。
方法： 这项回顾性研究纳入了在Mayo Clinic参加记忆与衰老研究的参与者，其血浆p-tau217结果为“阳性”（>0.324 pg/mL）或“阴性”（<0.186 pg/mL），并有确证性AD生物标志物。以淀粉样蛋白PET和CSF p-tau181/β-淀粉样蛋白（Aβ）42为参照，将血浆结果分类为真阳性（TP）、真阴性（TN）、FP或FN。使用单变量分析比较临床和实验室变量；多变量logistic回归评估与不一致的独立关联。
结果： 在706名参与者中（中位年龄70.0[四分位距15.8]岁；54%为男性），60名（8.5%）存在不一致的血浆p-tau217结果。FN结果（5.6%）比FP结果（2.8%）更常见（p = 0.007）。不一致与年龄较大（比值比[OR]每十年1.61，95% CI 1.23-2.14）和阻塞性睡眠呼吸暂停（OR 1.94，95% CI 1.08-3.49）相关。FN（相对于TP）结果与较轻微的临床分期（总体临床痴呆评定量表[CDR] ≤0.5 vs CDR ≥1；p < 0.001）、较高的简易精神状态检查分数（OR每分1.20，95% CI 1.05-1.36）、阻塞性睡眠呼吸暂停（OR 2.01，95% CI 1.01-4.3）、较高的体重指数（OR每kg/m2 1.11，95% CI 1.03-1.20）和较高的估算肾小球滤过率（eGFR：OR每10 mL/min/1.73 m2 1.33，95% CI 1.05-1.69）相关。在年龄调整模型中，体重指数（OR 1.14，95% CI 1.03-1.25）、eGFR（OR每10 mL/min/1.73 m2 1.63，95% CI 1.22-2.16）和较早的临床分期（CDR ≤0.5）与FN结果独立相关。FP（相对于TN）结果与年龄较大（OR 2.37，95% CI 1.36-4.09）、甲状腺疾病（OR 4.41，95% CI 1.36-14.3）、较低的eGFR（OR每10 mL/min/1.73 m2 0.48，95% CI 0.31-0.66）和晚期疾病分期（CDR ≥1）相关。在年龄调整模型中，eGFR（OR每10 mL/min/1.73 m2 0.54，95% CI 0.35-0.82）和晚期疾病分期（CDR ≥ 1 vs CDR 0：OR 11.11，95% CI 2.0-50.0；vs CDR 0.5：OR 4.55，95% CI 1.12-16.67）与FP结果独立相关。
讨论： 8.5%的参与者中，血浆p-tau217结果与已确立的AD生物标志物不一致。临床分期以及与脑淀粉样蛋白清除、肾脏清除和分布容积相关的因素与不一致结果相关。这些见解可能有助于阐明不一致的机制，并识别需要确证性生物标志物检测的患者。

英文摘要

BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau (p-tau) 217 is increasingly used for Alzheimer disease (AD) diagnosis and treatment decisions but may be discordant with established AD biomarkers. False-positive (FP) plasma results may lead to overtreatment and false-negative (FN) results to missed or delayed disease-modifying therapies. We evaluated factors associated with discordant results.
METHODS: This retrospective study included participants enrolled in memory and aging studies at Mayo Clinic with "positive" (>0.324 pg/mL) or "negative" (<0.186 pg/mL) plasma p-tau217 results and confirmatory AD biomarkers. Plasma results were classified as true positive (TP), true negative (TN), FP, or FN, referencing amyloid-PET and CSF p-tau181/β-amyloid (Aβ) 42. Clinical and laboratory variables were compared using univariate analyses; multivariable logistic regression evaluated independent associations with discordance.
RESULTS: Among 706 participants (median 70.0 [interquartile range 15.8] years; 54% male), 60 (8.5%) had discordant plasma p-tau217 results. FN results (5.6%) were more frequent than FP results (2.8%; p = 0.007). Discordance was associated with older age (odds ratio [OR] 1.61 per decade, 95% CI 1.23-2.14) and obstructive sleep apnea (OR 1.94, 95% CI 1.08-3.49). FN (vs TP) results were associated with milder clinical stage (global Clinical Dementia Rating [CDR] ≤0.5 vs CDR ≥1; p < 0.001), higher Mini-Mental State Examination scores (OR 1.20 per point, 95% CI 1.05-1.36), obstructive sleep apnea (OR 2.01, 95% CI 1.01-4.3), higher body mass index (OR 1.11/kg/m2, 95% CI 1.03-1.20), and higher estimated glomerular filtration rate (eGFR: OR 1.33/10 mL/min/1.73 m2, 95% CI 1.05-1.69). In age-adjusted models, body mass index (OR 1.14, 95% CI 1.03-1.25), eGFR (OR 1.63/10 mL/min/1.73 m2, 95% CI 1.22-2.16), and earlier clinical stage (CDR ≤0.5) were independently associated with FN results. FP (vs TN) results were associated with older age (OR 2.37, 95% CI 1.36-4.09), thyroid disease (OR 4.41, 95% CI 1.36-14.3), lower eGFR (OR 0.48/10 mL/min/1.73 m2, 95% CI 0.31-0.66), and advanced disease stage (CDR ≥1). In age-adjusted models, eGFR (OR 0.54/10 mL/min/1.73 m2, 95% CI 0.35-0.82) and advanced disease stage (CDR ≥ 1 vs CDR 0: OR 11.11, 95% CI 2.0-50.0; vs CDR 0.5: OR 4.55, 95% CI 1.12-16.67) were independently associated with FP results.
DISCUSSION: Plasma p-tau217 results and established AD biomarkers were discordant in 8.5% of participants. Clinical stage and factors related to brain amyloid clearance, renal clearance, and volume of distribution were associated with discordant results. These insights may inform mechanisms of discordance and identify patients requiring confirmatory biomarker measures.