Impaired default network functional connectivity in autosomal dominant Alzheimer disease
Impaired default network functional connectivity in autosomal dominant Alzheimer disease
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DOI：
10.1212/wnl.0b013e3182a1aafe
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发表时间：
2013-08-20
期刊：
影响因子：
9.9
通讯作者：
Sperling, Reisa A.
中科院分区：
文献类型：
--
作者：
Chhatwal, Jasmeer P.;Schultz, Aaron P.;Sperling, Reisa A.
目的：研究遗传性阿尔茨海默病的致病早老素-1(PSEN1)、早老素-2(PSEN2)和淀粉样前体蛋白(APP)基因突变家系的默认模式网络(DMN)功能连接性磁共振成像(FcMRI)。使用组独立成分分析，将突变状态和临床痴呆分级进行分组比较，并与每个参与者从预期症状开始(EYO)的估计年限相关。结果：我们观察到突变携带者的DMN fcMRI随临床痴呆分级的增加而显著降低，最明显的是在楔前/后扣带回和顶叶皮质(p<；0.001)。无症状突变携带者与非携带者相比，在楔前/后扣带回(p=0.014)和右侧顶叶皮质(p=0.0016)功能磁共振成像降低。我们观察到突变携带者状态与EYO之间存在显著的交互作用，随着突变携带者接近并超过其EYO，DMN fcMRI的功能降低。结论：DMN的功能障碍在常染色体显性遗传性阿尔茨海默病的病程早期发生，在临床症状明显之前就开始，并随着损害的增加而恶化。这些发现表明，DMN fcMRI可能被证明是一种跨越广泛疾病的生物标记物，并支持DMN fcMRI在即将到来的阿尔茨海默病多中心临床试验中作为次要终点的可行性。
Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.