Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
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临床和生物标志物在主要遗传的阿尔茨海默氏病中变化。
DOI：
10.1056/nejmoa1202753
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发表时间：
2012-08-30
期刊：
影响因子：
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通讯作者：
Dominantly Inherited Alzheimer Network
中科院分区：
文献类型：
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作者：
Bateman RJ;Xiong C;Benzinger TL;Fagan AM;Goate A;Fox NC;Marcus DS;Cairns NJ;Xie X;Blazey TM;Holtzman DM;Santacruz A;Buckles V;Oliver A;Moulder K;Aisen PS;Ghetti B;Klunk WE;McDade E;Martins RN;Masters CL;Mayeux R;Ringman JM;Rossor MN;Schofield PR;Sperling RA;Salloway S;Morris JC;Dominantly Inherited Alzheimer Network
阿尔茨海默氏病的病理过程的顺序和程度还没有很好地理解，部分原因是这种疾病发展多年。常染色体显性阿尔茨海默病的发病年龄是可预测的，并提供了一个机会，以确定最终导致症状性疾病的病理变化的顺序和程度。在这项前瞻性纵向研究中，我们分析了128名参与者的数据，这些参与者接受了基线临床和认知评估、脑成像、脑脊液（CSF）和血液检查。我们使用参与者在基线评估时的年龄和父母在阿尔茨海默病症状发作时的年龄来计算预期症状发作的估计年数（参与者的年龄减去症状发作时父母的年龄）。我们对基线数据进行了横断面分析，与预期症状发作的估计年数相关，以确定病理生理学变化的相对顺序和幅度。CSF中淀粉样蛋白β（Aβ）42的浓度似乎在预期症状发作前25年下降。在预期症状发作前15年，通过正电子发射断层扫描并使用匹兹堡化合物B检测到Aβ沉积。在预期症状发作前15年检测到CSF中tau蛋白浓度增加和脑萎缩增加。在预期症状发作前10年观察到脑代谢减退和情节记忆受损。在预期症状发作前5年，通过简易精神状态检查和临床痴呆评定量表测量的整体认知功能障碍被检测到，并且患者在预期症状发作后平均3年符合痴呆的诊断标准。我们发现，常染色体显性阿尔茨海默病与一系列的病理生理学变化，几十年来在CSF阿尔茨海默病的生化标志物，脑淀粉样蛋白沉积，脑代谢以及进行性认知障碍。我们的研究结果需要使用纵向数据进行确认，可能不适用于散发性阿尔茨海默病患者。（由国家老龄化研究所和其他机构资助; DIAN ClinicalTrials.gov编号，NCT 00869817。
The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)