Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community.
Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community.
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DOI：
10.1001/jamaneurol.2015.3098
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发表时间：
2016-01
期刊：
影响因子：
29
通讯作者：
Jack CR Jr
中科院分区：
文献类型：
--
作者：
Petersen RC;Wiste HJ;Weigand SD;Rocca WA;Roberts RO;Mielke MM;Lowe VJ;Knopman DS;Pankratz VS;Machulda MM;Geda YE;Jack CR Jr
淀粉样蛋白在阿尔茨海默病(AD)病理生理学进展中的作用对随机临床试验的设计具有重要意义。淀粉样蛋白的存在已成为参加几项AD二级预防试验的先决条件，然而，淀粉样蛋白水平升高对后续临床和生物标志物事件的确切影响尚不确定。探讨淀粉样蛋白水平升高对认知和生物标志物后续变化的影响。从明尼苏达州奥姆斯特县的一项基于人群的纵向研究梅奥诊所的老龄化研究中选择了564名认知正常的人(中位年龄，78岁)进行了这项研究。本研究使用的数据收集时间为2006年1月12日至2014年1月9日。这项研究中包括的个体在基线时接受了磁共振成像、氟代脱氧葡萄糖正电子发射断层扫描(FDG-PET)和匹兹堡化合物B(PIB)PET检查，在基线时没有认知损害，并有至少一次临床随访。286名受试者也接受了连续成像。淀粉样蛋白水平升高被定义为在PIB PET上的标准化摄取值比率大于1.5。在调整了年龄和海马体体积后，评估了基线淀粉样蛋白状态以及临床和影像测量中基线和纵向变化的相关性。同时评估载脂蛋白E4的作用。认知测量包括记忆、语言、注意力/执行功能、视觉空间技能、PIB水平、海马体和脑室容量，以及FDG-PET测量。在基线时，179名(31.7%)淀粉样蛋白水平升高的个体在所有测量的领域都有较差的认知能力，海马体体积减少，FDG-PET代谢不足。基线时淀粉样蛋白水平的升高与除语言外的所有领域(0.04至0.09 z分值单位/年)的认知减退率以及淀粉样蛋白积聚(1.6%/年)、海马区萎缩(每年30mm3/年)和脑室扩大(565mm3/年)的比率较高相关。淀粉样蛋白水平升高也与轻度认知损害的风险增加有关(与非−携带者相比，PIB+APOE4携带者和PIB+非携带者的风险比分别为2.9；95%CI，1.7-5.0和1.6；95%CI，0.9-2.8)。这些联系在很大程度上独立于载脂蛋白4。在从基于人群的研究中挑选的人中，基线水平的淀粉样蛋白水平升高与基线水平的认知和成像生物标记物较差相关，并与更大的临床下降和神经变性有关。这些结果对AD的随机临床试验设计有一定的指导意义。
The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain. To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers. A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated. Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures. At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7–5.0, and hazard ratio, 1.6; 95% CI, 0.9–2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB− noncarriers). These associations were largely independent of APOE4. In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD.