Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Clinical TBI Research Center, Penn Presbyterian Medical Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
Clin Biochem. 2023 Nov;121-122:110680. doi: 10.1016/j.clinbiochem.2023.110680. Epub 2023 Oct 24.
In this study, we aimed to create reference intervals (RI) using a large Canadian population-based cohort, for plasma protein biomarkers with potential utility to screen, diagnosis, prognosticate and manage a variety of neurological diseases and disorders. RIs were generated for: the ratio of amyloid beta 42 over 40 (Aβ42/40), phosphorylated tau-181 (p-tau-181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP).
900 plasma specimens from male and female participants aged 3-79 years old were obtained from the Statistics Canada Biobank, which holds specimens from the Canadian Health Measures Survey. Analysis of Aβ42/40, p-tau-181, NfL and GFAP was performed on the Quanterix Simoa HD-X analyzer using the Neurology 4-plex E and p-tau-181 assays. Discrete RIs were produced according to Clinical Laboratory Standards Institute guidelines (EP28-A3c). Continuous RIs were created using quantile regression.
For discrete RIs, significant age partitions were determined for each biomarker. No significant sex partitions were found. The following ranges and age partitions were determined: Aβ42/40: 3-<55y = 0.053-0.098, 55-<80y = 0.040-0.090; p-tau-181: 3-<12y = 1.4-5.6 pg/ml, 12-<60y = 0.8-3.1 pg/ml, 60-<80y = 0.9-4.0 pg/ml; NfL: 3-<40y = 2.6-11.3 pg/ml, 40-<60y = 4.6-17.7 pg/ml, 60-<80y = 8.1-47.1 pg/ml; GFAP; 3-<10y = 47.0-226 pg/ml, 10-<60y = 21.2-91.9 pg/ml, 60-<80y = 40.7-228 pg/ml. Continuous RIs produced smooth centile curves across the age range, from which point estimates for each year of age were calculated.
Discrete and continuous RIs for neurological plasma biomarkers will help refine normative cut-offs across the lifespan and improve the precision of interpretating biomarker levels. Continuous RIs are recommended for use in age groups, such as pediatrics and older adults, that experience rapid concentration changes by age.
本研究旨在利用加拿大大型基于人群的队列，为具有筛查、诊断、预后和管理各种神经疾病和障碍潜力的血浆蛋白生物标志物建立参考区间（RI）。生成了以下比值的 RI：β淀粉样蛋白 42 与 40（Aβ42/40）、磷酸化 tau-181（p-tau-181）、神经丝轻链（NfL）和胶质纤维酸性蛋白（GFAP）。
从加拿大统计局生物库中获得了 900 份年龄在 3-79 岁的男性和女性参与者的血浆样本，该生物库拥有加拿大健康测量调查的样本。使用 Quanterix Simoa HD-X 分析仪，使用神经科 4 plex E 和 p-tau-181 测定法，对 Aβ42/40、p-tau-181、NfL 和 GFAP 进行了分析。根据临床实验室标准协会指南（EP28-A3c）生成离散 RI。使用分位数回归创建连续 RI。
对于离散 RI，确定了每个生物标志物的显著年龄分区。未发现显著的性别分区。确定了以下范围和年龄分区：Aβ42/40：3-<55y=0.053-0.098，55-<80y=0.040-0.090；p-tau-181：3-<12y=1.4-5.6pg/ml，12-<60y=0.8-3.1pg/ml，60-<80y=0.9-4.0pg/ml；NfL：3-<40y=2.6-11.3pg/ml，40-<60y=4.6-17.7pg/ml，60-<80y=8.1-47.1pg/ml；GFAP；3-<10y=47.0-226pg/ml，10-<60y=21.2-91.9pg/ml，60-<80y=40.7-228pg/ml。连续 RI 生成了跨越整个年龄范围的平滑百分位数曲线，从中计算了每个年龄的点估计值。
神经血浆生物标志物的离散和连续 RI 将有助于完善整个生命周期的正常参考值，并提高解释生物标志物水平的精度。建议在经历快速浓度变化的年龄组（如儿科和老年人）中使用连续 RI。
