利用血浆生物标志物预测唐氏综合征患者的淀粉样蛋白和tau蛋白脑沉积及认知衰退：一项纵向队列研究。

Prediction of amyloid and tau brain deposition and cognitive decline in people with Down syndrome using plasma biomarkers: a longitudinal cohort study.

作者信息

Janelidze Shorena, Collij Lyduine E, Mattsson-Carlgren Niklas, Antill Alex, Laymon Charles M, Lott Ira, Rosas H Diana, Minhas Davneet S, Luo Weiquan, Zaman Shahid, Mapstone Mark, Head Elizabeth, Lai Florence, Hartley Sigan L, Ances Beau M, Krinsky-McHale Sharon J, Lee Joseph H, Ossenkoppele Rik, Christian Bradley T, Handen Benjamin L, Hansson Oskar

机构信息

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden; Department of Radiology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands; Brain Imaging, Amsterdam Neuroscience, Amsterdam, Netherlands.

出版信息

Lancet Neurol. 2025 Jul;24(7):591-600. doi: 10.1016/S1474-4422(25)00158-9.

DOI:10.1016/S1474-4422(25)00158-9

PMID:40541209

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12174012/

Abstract

BACKGROUND

Plasma biomarkers associated with Alzheimer's disease could improve prognostic assessment for people with Down syndrome in both clinical practice and research settings. We aimed to identify the plasma biomarkers that most accurately predict longitudinal changes in Alzheimer's disease-related pathology and cognitive functioning in individuals with Down syndrome.

METHODS

This longitudinal cohort study included data from 258 adults (aged ≥25 years) with Down syndrome who were followed up prospectively every 16 months as part of the longitudinal Alzheimer's Biomarker Consortium-Down Syndrome study (recruited from seven university sites in the USA and UK between July 13, 2016, and Jan 15, 2019). Participants had baseline and longitudinal assessments of plasma tau phosphorylated at threonine 217 (p-tau217), glial fibrillary acidic protein (GFAP), amyloid β (Aβ), neurofilament light (NfL), or total tau (t-tau). Associations of baseline plasma biomarkers and longitudinal changes in plasma biomarkers with changes in global cognitive functioning (Down Syndrome Mental Status Examination [DS-MSE] scores), Aβ-PET, and tau-PET were examined using linear regression models. Plasma biomarker-associated risk of progression to dementia was assessed using Cox regression analysis.

FINDINGS

Baseline p-tau217, as well as GFAP, NfL, or t-tau, were individually associated with longitudinal changes in DS-MSE, Aβ-PET, and tau-PET, and with progression to dementia. However, in combined models, only baseline p-tau217 remained associated with changes in DS-MSE (β -0·30 [95% CI -0·45 to -0·15], p=0·0001, n=220), tau-PET (0·42 [0·14 to 0·70], p=0·0039, n=88), and progression to dementia (hazard ratio 3·51 [95% CI 1·76-7·00], p=0·0004, n=194), whereas baseline p-tau217 (0·29 [0·14-0·45], p=0·0003) and GFAP (0·37 [0·18-0·56], p=0·0003) were associated with changes in Aβ-PET (n=106 for both). Similar associations were shown between longitudinal p-tau217 or GFAP and changes in DS-MSE (p-tau217: β -0·33 [95% CI-0·52 to -0·13], p=0·0015, n=133), tau-PET (p-tau217: 0·61 [0·40 to 0·83], p<0·0001, n=87), and Aβ-PET (p-tau217: 0·35 [0·19 to 0·50], p<0·0001; GFAP: 0·49 [0·27 to 0·70], p<0·0001, n=88).

INTERPRETATION

Baseline and longitudinal plasma p-tau217 were associated with subsequent decline in global cognition, progression to dementia, and increased tau burden, whereas baseline p-tau217 and GFAP were associated with Aβ accumulation. These findings suggest that plasma p-tau217 and GFAP might be valuable for prognostic assessment of Alzheimer's disease in people with Down syndrome in both clinical and research contexts. The results further support evaluation of these biomarkers for monitoring disease progression in clinical trials of Down syndrome-related Alzheimer's disease.

FUNDING

The European Research Council and National Institute on Aging (National Institute of Health).

摘要

背景

与阿尔茨海默病相关的血浆生物标志物可改善唐氏综合征患者在临床实践和研究环境中的预后评估。我们旨在确定最能准确预测唐氏综合征个体中阿尔茨海默病相关病理和认知功能纵向变化的血浆生物标志物。

方法

这项纵向队列研究纳入了258名年龄≥25岁的唐氏综合征成年人的数据，他们作为纵向阿尔茨海默病生物标志物联盟-唐氏综合征研究的一部分，每16个月进行一次前瞻性随访（于2016年7月13日至2019年1月15日期间从美国和英国的七个大学站点招募）。参与者接受了血浆苏氨酸217磷酸化tau蛋白（p-tau217）、胶质纤维酸性蛋白（GFAP）、淀粉样β蛋白（Aβ）、神经丝轻链（NfL）或总tau蛋白（t-tau）的基线和纵向评估。使用线性回归模型检查基线血浆生物标志物和血浆生物标志物的纵向变化与整体认知功能变化（唐氏综合征精神状态检查[DS-MSE]评分）、Aβ-PET和tau-PET之间的关联。使用Cox回归分析评估血浆生物标志物相关的痴呆进展风险。

结果

基线p-tau217以及GFAP、NfL或t-tau分别与DS-MSE、Aβ-PET和tau-PET的纵向变化以及痴呆进展相关。然而，在联合模型中，只有基线p-tau217仍与DS-MSE变化（β -0·30 [95% CI -0·45至-0·15]，p = 0·0001，n = 220）、tau-PET（0·42 [0·14至0·70]，p = 0·0039，n = 88）和痴呆进展（风险比3·51 [95% CI 1·76 - 7·00]，p = 0·0004，n = 194）相关，而基线p-tau217（0·29 [0·14 - 0·45]，p = 0·0003）和GFAP（0·37 [0·18 - 0·56]，p = 0·0003）与Aβ-PET变化相关（两者n = 106）。纵向p-tau217或GFAP与DS-MSE变化（p-tau217：β -0·33 [95% CI -0·52至-0·13]，p = 0·0015，n = 133）、tau-PET（p-tau217：0·61 [0·40至0·83]，p < 0·0001, n = 87）和Aβ-PET（p-tau217：0·35 [0·19至0·50]，p < 0·0001；GFAP：0·49 [0·27至0·70]，p < 0·0001，n = 88）之间也显示出类似的关联。

解读

基线和纵向血浆p-tau217与随后的整体认知下降、痴呆进展和tau负担增加相关，而基线p-tau217和GFAP与Aβ积累相关。这些发现表明，血浆p-tau217和GFAP在临床和研究环境中可能对唐氏综合征患者的阿尔茨海默病预后评估有价值。结果进一步支持在唐氏综合征相关阿尔茨海默病的临床试验中评估这些生物标志物以监测疾病进展。