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文献精选 > 高引权威"阿尔茨海默病"文献

Clinical and biomarker changes in dominantly inherited Alzheimer's disease. ​

文献信息 ​

DOI10.1056/NEJMoa1202753
PMID22784036
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2012
被引次数1917
关键词阿尔茨海默病, 生物标志物, 病理变化, 认知障碍
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码795-804
期号367(9)
作者Randall J Bateman, Chengjie Xiong, Tammie L S Benzinger, Anne M Fagan, Alison Goate, Nick C Fox, Daniel S Marcus, Nigel J Cairns, Xianyun Xie, Tyler M Blazey, David M Holtzman, Anna Santacruz, Virginia Buckles, Angela Oliver, Krista Moulder, Paul S Aisen, Bernardino Ghetti, William E Klunk, Eric McDade, Ralph N Martins, Colin L Masters, Richard Mayeux, John M Ringman, Martin N Rossor, Peter R Schofield, Reisa A Sperling, Stephen Salloway, John C Morris

一句话小结 ​

本研究通过分析128名常染色体显性遗传阿尔茨海默病患者的数据，揭示了该病在症状出现前数十年的病理生理变化，包括脑脊液中淀粉样β蛋白浓度下降、tau蛋白增加以及认知能力减退等。研究结果为深入理解阿尔茨海默病的发病机制提供了重要线索，可能有助于早期诊断和干预策略的制定。

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阿尔茨海默病 · 生物标志物 · 病理变化 · 认知障碍

摘要 ​

背景
阿尔茨海默病的病理过程的顺序和程度尚不清楚，部分原因是该疾病的发展需要数年时间。常染色体显性遗传的阿尔茨海默病具有可预测的发病年龄，为确定导致症状性疾病的病理变化的顺序和程度提供了机会。

方法
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、脑成像以及脑脊液（CSF）和血液测试。我们使用参与者在基线评估时的年龄和父母出现阿尔茨海默病症状时的年龄计算预期症状出现的年数（参与者年龄减去父母症状出现时的年龄）。我们对基线数据进行了横断面分析，以确定与预期症状出现的年数相关的病理生理变化的相对顺序和程度。

结果
脑脊液中淀粉样β蛋白（Aβ）（42）的浓度在预期症状出现前25年开始下降。通过使用匹兹堡化合物B的正电子发射断层扫描（PET）检测到的Aβ沉积在预期症状出现前15年被发现。脑脊液中tau蛋白浓度的增加和脑萎缩的加剧在预期症状出现前15年被检测到。脑代谢降低和记忆能力受损在预期症状出现前10年被观察到。全球认知障碍的检测（使用简易精神状态检查和临床痴呆评级量表）在预期症状出现前5年被发现，而患者在预期症状出现后平均3年符合痴呆的诊断标准。

结论
我们发现常染色体显性遗传的阿尔茨海默病与数十年来的病理生理变化有关，这些变化包括阿尔茨海默病的脑脊液生化标志物、脑内淀粉样沉积和脑代谢的变化，以及逐渐加重的认知障碍。我们的结果需要通过纵向数据进行验证，可能不适用于散发性阿尔茨海默病患者。（资助单位包括国家老龄化研究所等；DIAN 临床试验注册号：NCT00869817。）

英文摘要 ​

BACKGROUND 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.

METHODS 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.

RESULTS 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.

CONCLUSIONS 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.).

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主要研究问题 ​

  1. 在自体显性阿尔茨海默病的研究中，如何进一步探索不同生物标志物之间的相互关系？
  2. 该研究中提到的脑部代谢减退与认知功能障碍之间的具体机制是什么？
  3. 除了阿尔茨海默病，其他类型的痴呆症是否也存在类似的病理变化序列？
  4. 在未来的研究中，如何利用纵向数据来验证这些病理变化的时间序列和相对重要性？
  5. 自体显性阿尔茨海默病的早期干预策略有哪些可能的生物标志物可以作为靶点？

核心洞察 ​

研究背景和目的 ​

阿尔茨海默病（AD）的病理过程顺序和幅度尚不清楚，部分原因是该疾病的发生需要多年时间。常染色体显性阿尔茨海默病具有可预测的发病年龄，为确定病理变化的顺序和幅度提供了机会。本研究旨在分析这一类型阿尔茨海默病的病理变化，以便更好地理解其发展过程。

主要方法/材料/实验设计 ​

本研究为前瞻性纵向研究，分析了128名参与者的数据。研究方法包括：

  • 基线临床和认知评估
  • 脑成像
  • 脑脊液（CSF）和血液测试

研究计算方法如下：

  1. 记录参与者的基线评估年龄和父母的阿尔茨海默病症状发作年龄。
  2. 估算预期症状发作的年限（参与者年龄减去父母的症状发作年龄）。
  3. 进行横断面分析，比较基线数据与预期症状发作的年限，以确定病理生理变化的相对顺序和幅度。

以下是研究的技术路线图：

Mermaid diagram

关键结果和发现 ​

  • CSF中淀粉样β蛋白（Aβ(42)）浓度在预期症状发作前25年出现下降。
  • Aβ沉积（通过使用匹兹堡化合物B的正电子发射断层扫描检测）在预期症状发作前15年被发现。
  • CSF中tau蛋白浓度增加和脑萎缩在预期症状发作前15年被检测到。
  • 脑代谢减退和记忆障碍在预期症状发作前10年被观察到。
  • 全球认知障碍（通过简易精神状态检查和临床痴呆评定量表测量）在预期症状发作前5年被发现，患者在预期症状发作后平均3年符合痴呆的诊断标准。

主要结论/意义/创新性 ​

研究发现，常染色体显性阿尔茨海默病在几十年内伴随一系列病理生理变化，包括CSF生化标志物、脑淀粉样沉积和脑代谢的变化，以及逐渐加重的认知障碍。这些结果为理解阿尔茨海默病的早期病理过程提供了重要线索，但需要使用纵向数据进行验证，并可能不适用于散发性阿尔茨海默病患者。

研究局限性和未来方向 ​

  • 本研究的局限性在于样本量较小，且结果需要进一步的纵向数据确认。
  • 未来研究应考虑散发性阿尔茨海默病患者的病理变化，并探索早期干预的可能性，以改善患者的预后。

参考文献 ​

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引用本文的文献 ​

  1. The genetics and neuropathology of neurodegenerative disorders: perspectives and implications for research and clinical practice. - Vivianna M Van Deerlin - Acta neuropathologica (2012)
  2. Lifelong management of amyloid-beta metabolism to prevent Alzheimer's disease. - Sam Gandy - The New England journal of medicine (2012)
  3. Tracking the insidious course of Alzheimer's disease. - Nature medicine (2012)
  4. Alzheimer disease: from inherited to sporadic AD-crossing the biomarker bridge. - Harald Hampel;Simone Lista - Nature reviews. Neurology (2012)
  5. Therapeutic strategies for tau mediated neurodegeneration. - Yasumasa Yoshiyama;Virginia M Y Lee;John Q Trojanowski - Journal of neurology, neurosurgery, and psychiatry (2013)
  6. Hypothesis-driven genomics pays off. - Gregory A Petsko - Genome biology (2012)
  7. 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. - Eric M Reiman;Yakeel T Quiroz;Adam S Fleisher;Kewei Chen;Carlos Velez-Pardo;Marlene Jimenez-Del-Rio;Anne M Fagan;Aarti R Shah;Sergio Alvarez;Andrés Arbelaez;Margarita Giraldo;Natalia Acosta-Baena;Reisa A Sperling;Brad Dickerson;Chantal E Stern;Victoria Tirado;Claudia Munoz;Rebecca A Reiman;Matthew J Huentelman;Gene E Alexander;Jessica B S Langbaum;Kenneth S Kosik;Pierre N Tariot;Francisco Lopera - The Lancet. Neurology (2012)
  8. Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study. - Adam S Fleisher;Kewei Chen;Yakeel T Quiroz;Laura J Jakimovich;Madelyn Gutierrez Gomez;Carolyn M Langois;Jessica B S Langbaum;Napatkamon Ayutyanont;Auttawut Roontiva;Pradeep Thiyyagura;Wendy Lee;Hua Mo;Liliana Lopez;Sonia Moreno;Natalia Acosta-Baena;Margarita Giraldo;Gloria Garcia;Rebecca A Reiman;Matthew J Huentelman;Kenneth S Kosik;Pierre N Tariot;Francisco Lopera;Eric M Reiman - The Lancet. Neurology (2012)
  9. Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network. - John C Morris;Paul S Aisen;Randall J Bateman;Tammie L S Benzinger;Nigel J Cairns;Anne M Fagan;Bernardino Ghetti;Alison M Goate;David M Holtzman;William E Klunk;Eric McDade;Daniel S Marcus;Ralph N Martins;Colin L Masters;Richard Mayeux;Angela Oliver;Kimberly Quaid;John M Ringman;Martin N Rossor;Stephen Salloway;Peter R Schofield;Natalie J Selsor;Reisa A Sperling;Michael W Weiner;Chengjie Xiong;Krista L Moulder;Virginia D Buckles - Clinical investigation (2012)
  10. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. - Mark P Mattson - Cell metabolism (2012)

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