Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study.
Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study.
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DOI：
10.1016/s1474-4422(12)70227-2
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发表时间：
2012-12
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影响因子：
--
通讯作者：
Reiman EM
中科院分区：
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作者：
Fleisher AS;Chen K;Quiroz YT;Jakimovich LJ;Gomez MG;Langois CM;Langbaum JB;Ayutyanont N;Roontiva A;Thiyyagura P;Lee W;Mo H;Lopez L;Moreno S;Acosta-Baena N;Giraldo M;Garcia G;Reiman RA;Huentelman MJ;Kosik KS;Tariot PN;Lopera F;Reiman EM
纤维状β - 淀粉样蛋白（Aβ）被认为在阿尔茨海默病患者出现临床损伤症状的许多年前就开始在大脑中积累。通过评估有阿尔茨海默病遗传风险的人群中Aβ的积累情况，我们可以确定在那些日后肯定会患痴呆症的个体中，临床前变化是多早开始的。我们试图描述在临床前疾病的各个阶段，早老素1（PSEN1）E280A突变携带者中与年龄相关的Aβ沉积积累情况。
2011年8月1日至12月6日期间，从哥伦比亚麦德林安蒂奥基亚大学阿尔茨海默病预防倡议登记处招募了18 - 60岁的哥伦比亚家族性阿尔茨海默病家族成员。使用氟贝他吡（florbetapir）正电子发射断层扫描（PET）对有轻度认知障碍或轻度痴呆的有症状突变携带者、无症状携带者以及无症状非携带者进行了横断面评估。这些评估是在美国亚利桑那州凤凰城的班纳阿尔茨海默病研究所进行的。使用由六个预先定义区域组成的皮质灰质掩模来测量平均皮质氟贝他吡PET结合率。采用皮质与脑桥标准摄取值比率，通过回归分析来描述携带者和非携带者中纤维状Aβ沉积的横断面积累情况，并估计纤维状Aβ沉积的轨迹。
我们纳入了一组11名有症状个体、19名症状前突变携带者和20名无症状非携带者，年龄在20 - 56岁之间。无症状的PSEN1 E280A突变携带者中的氟贝他吡结合率高于年龄匹配的非携带者。纤维状Aβ在PSEN1 E280A突变携带者中平均在28.2岁（95%置信区间27.3 - 33.4）开始积累，分别比预测的轻度认知障碍和痴呆发病的中位年龄早约16年和21年。在接下来的9.4年里，18F氟贝他吡结合率急剧上升，并在平均37.6岁（95%置信区间35.3 - 40.2）达到平台期，分别比预期的轻度认知障碍和痴呆发病的中位年龄早约6年和11年。在前扣带回和后扣带回、楔前叶、顶颞叶和额叶灰质以及基底神经节中都观察到明显的氟贝他吡结合。基底神经节中的结合并不比其他区域更早或更显著。
这些发现有助于理解临床前家族性阿尔茨海默病，并为评估淀粉样蛋白修饰治疗在预防家族性阿尔茨海默病中的作用奠定了基础。
艾维德放射性药物公司、班纳阿尔茨海默病基金会、诺米斯基金会、匿名基金会、勿忘我倡议、哥伦比亚科学技术与创新管理部门、美国国家衰老研究所和亚利桑那州。
Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer’s disease. By assessing the accumulation of Aβ in people at risk of genetic forms of Alzheimer’s disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease. Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer’s disease Colombian kindred aged 18–60 years were recruited from the Alzheimer’s Prevention Initiative’s registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer’s Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions. was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition. We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. 18F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3–40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions. These findings contribute to the understanding of preclinical familial Alzheimer’s disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer’s disease. Avid Radiopharmaceuticals, Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.