Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study.
Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study.
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DOI：
10.1001/jamaneurol.2015.1099
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发表时间：
2015-08
期刊：
影响因子：
29
通讯作者：
Reiman EM
中科院分区：
文献类型：
--
作者：
Quiroz YT;Schultz AP;Chen K;Protas HD;Brickhouse M;Fleisher AS;Langbaum JB;Thiyyagura P;Fagan AM;Shah AR;Muniz M;Arboleda-Velasquez JF;Munoz C;Garcia G;Acosta-Baena N;Giraldo M;Tirado V;Ramírez DL;Tariot PN;Dickerson BC;Sperling RA;Lopera F;Reiman EM
常染色体显性阿尔茨海默病（ADAD）风险儿童的脑成像和液体生物标志物特征表征和比较早老素1 (PSEN1) E280A突变携带和非携带ADAD儿童的结构磁共振成像（MRI）、静息状态和任务依赖功能MRI以及血浆淀粉样蛋白-β (Aβ)测量。对18名PSEN1 E280A携带者和19名9 - 17岁哥伦比亚ADAD亲属的非携带者进行结构和功能MRI横断面测量和血浆a β测定。本研究的招募和数据收集工作于2011年8月至2012年6月在哥伦比亚麦德林的安蒂奥基亚大学和Pablo Tobon Uribe医院进行。在联想记忆编码、静息状态和认知评估期间，所有参与者都进行了血液采样、结构MRI和功能MRI。结果测量包括血浆Aβ1-42浓度和Aβ1-42:Aβ1-40比值、记忆编码依赖性激活变化、静息状态连通性和区域灰质体积。使用自动脑映射算法和搜索与AD相关的区域对结构和功能MRI数据进行比较。与成人突变携带者相似，在ADAD临床前和临床晚期，突变携带者儿童血浆Aβ1-42水平显著高于对照组（平均[SD]：携带者，18.8 [5.1]pg/mL，非携带者，13.1 [3.2]pg/mL, P < 0.001）， Aβ1-42:Aβ1-40比值显著高于对照组(平均[SD]：携带者，0.32[0.06]，非携带者，0.21 [0.03]；P < 0.001)，以及较少的顶叶区域记忆编码任务相关失活（例如，非携带者右侧楔前叶的平均[SD]参数估计值为- 0.590[0.50]，携带者为- 0.087[0.38]；未经校正的P < 0.005）。与晚期的携带者不同，携带突变的儿童表现出后扣带皮层与内侧颞叶区域的功能连通性增加（非携带者的平均[SD]参数估计值为0.038[0.070]，携带者的平均[SD]参数估计值为0.190[0.057]），以及颞区灰质体积增加(例如，左侧副海马体；P <。049，更正了多次比较)。有ADAD遗传风险的儿童有脑功能和结构改变，血浆Aβ1-42水平异常。潜在的大脑变化在多大程度上是神经退行性的还是发育性的仍有待确定。这项研究提供了与ADAD相关的最早已知生物标志物变化的额外信息。
Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation–carrying and noncarrying children with ADAD. Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellin, Colombia, between August 2011 and June 2012. All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding–dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task–related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were −0.590 [0.50] for noncarriers and −0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons). Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD.