Banner Alzheimer's Institute, Phoenix, AZ, USA.
Lancet Neurol. 2012 Dec;11(12):1048-56. doi: 10.1016/S1474-4422(12)70228-4. Epub 2012 Nov 6.
We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease.
Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations, and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests.
44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008) and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers.
Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease.
Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.
我们曾对存在晚发性阿尔茨海默病遗传风险的年轻成年人的大脑功能异常进行了描述。为了进一步了解阿尔茨海默病的临床前期，我们试图对携带早发性阿尔茨海默病高外显率常染色体显性突变的年轻成年人进行结构性和功能性磁共振成像（MRI）、脑脊液（CSF）和血浆生物标志物的研究。
2010 年 1 月至 8 月，来自哥伦比亚麦德林安蒂奥基亚州哥伦比亚阿尔茨海默病预防倡议登记处的携带早发性阿尔茨海默病 PSEN1 E280A 突变的 18-26 岁个体及其非携带者接受了结构性 MRI、联想记忆编码过程中的功能 MRI 检查、新视图和对照任务以及认知评估。同意的参与者还进行了腰椎穿刺和静脉穿刺。主要终点是任务相关的海马体或海马旁回激活和楔前叶或后扣带回失活，以及区域性灰质减少、CSF Aβ（1-42）、总 tau 和磷酸化 tau（181）浓度以及血浆 Aβ（1-42）浓度和 Aβ（1-42）：Aβ（1-40）比值。使用自动脑映射算法和与阿尔茨海默病相关的搜索区域比较结构和功能 MRI 数据。使用曼-惠特尼检验比较认知和液体生物标志物。
共纳入 44 名参与者：20 名 PSEN1 E280A 突变携带者和 24 名非携带者。携带者和非携带者在痴呆评分、神经心理学测试分数或载脂蛋白 E（APOE）ε4 携带者比例方面无显著差异。与非携带者相比，携带者的右侧海马体和海马旁回激活更明显（分别校正多重比较后 p=0.001 和 p<0.014），楔前叶和后扣带回失活更不明显（所有校正后 p<0.010），并且几个顶叶区域的灰质更少（所有校正后 p<0.002，右顶叶搜索区域校正后 p=0.009）。在接受腰椎穿刺和静脉穿刺的 20 名参与者（10 名 PSEN1 E280A 突变携带者和 10 名非携带者）中，突变携带者的 CSF Aβ（1-42）浓度（p=0.008）和血浆 Aβ（1-42）浓度（p=0.01）均高于非携带者。
携带常染色体显性阿尔茨海默病遗传风险的年轻成年人存在功能和结构 MRI 发现以及 CSF 和血浆生物标志物发现，与 Aβ（1-42）过度产生一致。尽管大脑下变化的程度是神经退行性的还是发育性的仍有待确定，但本研究显示了认知正常的人在遗传上存在常染色体显性阿尔茨海默病风险的最早已知的生物标志物变化。
Banner Alzheimer 基金会、Nomis 基金会、匿名基金会、Forget Me Not 倡议、波士顿大学心理学系、哥伦比亚国家科学技术研究院、美国国家老龄问题研究所、美国国家神经疾病和中风研究所和亚利桑那州。
