Reiman E M, Caselli R J, Chen K, Alexander G E, Bandy D, Frost J
Department of Psychiatry, University of Arizona, Tucson, AZ 85724, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3334-9. doi: 10.1073/pnas.061509598.
Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) epsilon4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal epsilon4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal epsilon4 heterozygotes and 15 epsilon4 noncarriers 50-63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The epsilon4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the epsilon4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal epsilon4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.
横断面正电子发射断层扫描（PET）研究发现，载脂蛋白E（APOE）ε4等位基因（一种常见的阿尔茨海默病易感基因）的认知正常携带者，在与阿尔茨海默病痴呆患者相同的脑区，其大脑葡萄糖代谢率（CMRgl）测量值异常低。在本文中，我们描述了认知正常的ε4杂合子中CMRgl的纵向下降情况，估计了PET检测在2年内减轻这些下降的治疗效果的能力，并考虑了如何利用这一范式有效地测试候选疗法预防阿尔茨海默病的潜力。我们研究了10名年龄在50 - 63岁、有阿尔茨海默病痴呆家族史报告的认知正常的ε4杂合子和15名ε4非携带者，前后间隔约2年。ε4杂合子在颞叶、后扣带回、前额叶皮质、基底前脑、海马旁回和丘脑附近的CMRgl有显著下降，且这些下降显著大于ε4非携带者。在测试候选一级预防疗法时，我们估计每个活性治疗组和安慰剂治疗组需要50至115名认知正常的ε4杂合子，才能在2年内以80%的检验效能和P = 0.005检测到这些CMRgl下降有25%的减轻。假设这些CMRgl下降与阿尔茨海默病痴呆的易感性有关，本研究提供了一种范式，用于测试预防该疾病的治疗潜力，而无需研究数千名研究对象或等待多年来确定治疗个体是否以及何时出现症状。
