Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline
Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline
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DOI：
10.1001/jama.283.12.1571
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发表时间：
2000-03-22
影响因子：
120.7
通讯作者：
Buxbaum, JD
中科院分区：
文献类型：
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作者：
Näslund, J;Haroutunian, V;Buxbaum, JD
背景阿尔茨海默病（AD）的神经病理学特征是存在含有淀粉样β肽（A β）的斑块和由异常tau蛋白组成的神经元缠结。关于A β积累的程度是否与痴呆相关以及A β改变是否在tau改变之前或之后存在相当大的争议。目的为了确定A β积累是否与认知恶化的最早迹象相关，并定义A β积累和早期tau改变之间的关系，设计，设置，对1986年至1997年期间死亡的79名临床痴呆评定（CDR）量表评分为0.0至5.0的疗养院居民进行了尸检横断面研究，比较受试者皮质中A β变体的水平，（CDR评分，0.0 [n = 16]），可疑（CDR评分，0.5 [n = 11]），轻度（CDR评分，1.0 [n = 22]），中度（CDR评分，2.0 [n = 15]）或重度（CDR评分，4.0或5.0 [n = 15]）痴呆。主要结果测量具有完整或截短的氨基末端并以氨基酸40结束的总A β肽的水平（A β x-40）或42结果A β x-40和A β x-42的水平升高，即使在可疑痴呆的病例中，（CDR评分= 0.5），并且两种肽的增加与痴呆的进展相关。在非痴呆病例中，更倾向于原纤维的A β x-42肽的水平高于A β x-40的水平，并且在检查的所有区域中，在疾病进展的整个过程中保持较高水平。最后，A β x-40和A β x-42的增加至少在额叶皮层，一个区域选择检查，因为没有神经炎的变化，在没有diseases.Conclusions在这项研究中，总A β x-40和A β x-42的水平升高早期痴呆和水平的两种肽与认知能力下降密切相关。特别令人感兴趣的是，在额叶皮层中，A β在发生显著的tau病理学之前升高。这些结果支持A β在介导AD痴呆中的初始致病事件中的重要作用，并表明应追求针对A β的形成、积累或细胞毒性作用的治疗策略。
Context Alzheimer disease (AD) is characterized neuropathologically by the presence of amyloid beta-peptide (A beta)-containing plaques and neurofibrillary tangles composed of abnormal tau protein. Considerable controversy exists as to whether the extent of accumulation of A beta correlates with dementia and whether A beta alterations precede or follow changes in tau.Objectives To determine whether accumulation of A beta correlates with the earliest signs of cognitive deterioration and to define the relationship between A beta accumulation and early tau changes,Design, Setting, and Patients Postmortem cross-sectional study of 79 nursing home residents with Clinical Dementia Rating (CDR) scale scores of 0.0 to 5.0 who died between 1986 and 1997, comparing the levels of A beta variants in the cortices of the subjects with no (CDR score, 0.0 [n = 16]), questionable (CDR score, 0.5 [n = 11]), mild (CDR score, 1.0 [n = 22]), moderate (CDR score, 2.0 [n = 15]), or severe (CDR score, 4.0 or 5.0 [n = 15]) dementia.Main Outcome Measures Levels of total A beta peptides with intact or truncated amino termini and ending in either amino acid 40 (A beta x-40) or 42 (A beta x-42) in 5 neocortical brain regions as well as levels of tau protein undergoing early conformational changes in frontal cortex, as a function of CDR score.Results The levels of both A beta x-40 and A beta x-42 were elevated even in cases classified as having questionable dementia (CDR score = 0.5), and increases of both peptides correlated with progression of dementia, Levels of the more fibril-prone A beta x-42 peptide were higher than those of A beta x-40 in nondemented cases and remained higher throughout progression of disease in all regions examined. Finally, increases in A beta x-40 and A beta x-42 precede significant tau pathology at least in the frontal cortex, an area chosen for examination because of the absence of neuritic changes in the absence of disease.Conclusions In this study, levels of total A beta x-40 and A beta x-42 were elevated early in dementia and levels of both peptides were strongly correlated with cognitive decline. Of particular interest, in the frontal cortex, A beta was elevated before the occurrence of significant tau pathology, These results support an important role for A beta in mediating initial pathogenic events in AD dementia and suggest that treatment strategies targeting the formation, accumulation, or cytotoxic effects of A beta should be pursued.