Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study.
Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study.
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DOI：
10.1016/s1474-4422(12)70228-4
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Lopera F
中科院分区：
文献类型：
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作者：
Reiman EM;Quiroz YT;Fleisher AS;Chen K;Velez-Pardo C;Jimenez-Del-Rio M;Fagan AM;Shah AR;Alvarez S;Arbelaez A;Giraldo M;Acosta-Baena N;Sperling RA;Dickerson B;Stern CE;Tirado V;Munoz C;Reiman RA;Huentelman MJ;Alexander GE;Langbaum JB;Kosik KS;Tariot PN;Lopera F
我们以前检测到功能性脑成像异常的年轻人在遗传风险为晚发性阿尔茨海默病（AD）。在这里，我们试图表征结构和功能磁共振成像（MRI），脑脊液（CSF）和血浆生物标志物异常的年轻成人常染色体显性早发性AD的风险。在早老素1（PSEN 1）E280 A突变携带者和来自世界上最大的已知常染色体显性早发性AD家系的非携带者中，对生物标志物测量进行了表征和比较，在轻度认知障碍（MCI）发生时携带者的估计中位年龄44岁之前20多年，以及在淀粉样蛋白β（Aβ）斑块沉积发生时估计年龄28岁之前。本横断面研究的生物标志物数据于2010年7月至8月在哥伦比亚的安蒂奥基亚获得。来自哥伦比亚阿尔茨海默氏症预防倡议（API）登记处的44名参与者进行了结构MRI、联想记忆编码/新奇观察和控制任务期间的功能MRI以及认知评估。他们包括20名突变携带者和24名非携带者，他们认知正常，18-26岁，性别，年龄和教育水平相匹配。20名参与者，包括10名突变携带者和10名非携带者，进行了腰椎穿刺和静脉穿刺。主要结局指标包括任务依赖性海马/海马旁激活和楔前叶/后扣带回失活、局部灰质减少、CSF Aβ1-42、总tau和磷酸化tau 181水平以及血浆Aβ1-42水平和Aβ1 -42/Aβ1-40比值。使用自动脑映射算法和AD相关搜索区域比较结构和功能MRI数据。使用Mann-Whitney检验比较认知和体液生物标志物。突变携带者和非携带者组在痴呆等级、神经心理学测试评分或载脂蛋白E（APOE）ε4携带者比例方面没有显著差异。与非携带者相比，携带者的CSF Aβ1-42水平（p= 0.008）、血浆Aβ1-42水平（p= 0.01）和血浆Aβ1-42/Aβ1-40比值（p= 0.001）更高，与Aβ1-42过度产生一致。他们也有更大的海马/海马旁激活（校正多重比较后，低至p= 0.008），楔前叶/后扣带回失活较少（校正后低至p=0·001），几个区域的灰质减少（顶骨搜索区域中p值<0·005，未校正，校正p=0·008），这与常染色体显性遗传和晚发型AD的后期临床前和临床阶段的结果相似。具有常染色体显性AD遗传风险的年轻成人存在功能和结构MRI异常，沿着CSF和血浆生物标志物结果与Aβ1-42过度产生一致。虽然潜在的大脑变化的进展或发育程度仍有待确定，但这项研究证明了认知正常人群中最早的已知生物标志物变化，这些人具有常染色体显性AD的遗传风险。横幅阿尔茨海默氏症基金会，Nomis基金会，匿名基金会，勿忘我倡议，波士顿大学心理学系，Colciencias（1115-408-20512，1115-545-31651），国家老龄化研究所（R 01 AG 031581，P30 AG 19610，UO 1 AG 024904，RO 1 AG 025526，RF 1AG 041705），国家神经疾病和卒中研究所（F31-NS 078786）和亚利桑那州。
We previously detected functional brain imaging abnormalities in young adults at genetic risk for late-onset Alzheimer’s disease (AD). Here, we sought to characterize structural and functional magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma biomarker abnormalities in young adults at risk for autosomal dominant early-onset AD. Biomarker measurements were characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the world’s largest known autosomal dominant early-onset AD kindred, more than two decades before the carriers’ estimated median age of 44 at the onset of mild cognitive impairment (MCI) and before their estimated age of 28 at the onset of amyloid-β (Aβ) plaque deposition. Biomarker data for this cross-sectional study were acquired in Antioquia, Colombia between July and August, 2010. Forty-four participants from the Colombian Alzheimer’s Prevention Initiative (API) Registry had structural MRIs, functional MRIs during associative memory encoding/novel viewing and control tasks, and cognitive assessments. They included 20 mutation carriers and 24 non-carriers, who were cognitively normal, 18-26 years old and matched for their gender, age, and educational level. Twenty of the participants, including 10 mutation carriers and 10 non-carriers, had lumbar punctures and venipunctures. Primary outcome measures included task-dependent hippocampal/parahippocampal activations and precuneus/posterior cingulate deactivations, regional gray matter reductions, CSF Aβ1-42, total tau and phospho-tau181 levels, and plasma Aβ1-42 levels and Aβ1-42/Aβ1-40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and AD-related search regions. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. The mutation carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ε4 carriers. Compared to the non-carriers, carriers had higher CSF Aβ1-42 levels (p=0·008), plasma Aβ1-42 levels (p=0·01), and plasma Aβ1-42/Aβ1-40 ratios (p=0·001), consistent with Aβ1-42 overproduction. They also had greater hippocampal/parahippocampal activations (as low as p=0·008, after correction for multiple comparisons), less precuneus/posterior cingulate deactivations (as low as p=0·001, after correction), less gray matter in several regions (p-values <0·005, uncorrected, and corrected p=0·008 in the parietal search region), similar to findings in the later preclinical and clinical stages of autosomal dominant and late-onset AD. Young adults at genetic risk for autosomal dominant AD have functional and structural MRI abnormalities, along with CSF and plasma biomarker findings consistent with Aβ1-42 over-production. While the extent to which the underlying brain changes are progressive or developmental remain to be determined, this study demonstrates the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant AD. Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias (1115-408-20512, 1115-545-31651), National Institute on Aging (R01 AG031581, P30 AG19610, UO1 AG024904, RO1 AG025526, RF1AG041705), National Institute of Neurological Disorders and Stroke (F31-NS078786) and state of Arizona.