Helen Wills Neuroscience Institute, University of California, Berkeley.
Institute of Personality and Social Research, University of California, Berkeley.
JAMA Neurol. 2013 Dec;70(12):1512-9. doi: 10.1001/jamaneurol.2013.4013.
Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort.
Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning.
For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography).
Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention.
Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD.
临床前阿尔茨海默病（AD）的标准提出β-淀粉样蛋白（Aβ）斑块在 AD 受影响区域内引发神经退行性变。然而，一些认知正常的老年人也存在与 AD 患者相似的神经损伤，而没有同时存在 Aβ 负担。这些发现对所提出的序列提出了挑战，并表明 AD 典型神经退行性模式的基础是 Aβ 独立的前体。目的： 检查认知正常老年人中 Aβ 与非 Aβ 因素以及 AD 区域内神经退行性变之间的关系。该研究使用成像生物标志物来量化神经退行性异常，并检查与 Aβ 沉积、白质病变（WML）的横断面关系，WML 是脑血管疾病的标志物；以及认知功能。
设计、设置和参与者： 在伯克利老龄化队列的社区便利样本中进行了一项横断面研究，共有 72 名认知正常的老年人（平均[标准差]年龄 74.9[5.7]岁；48 名女性；平均[标准差]17.0[1.9]年教育）。
每位个体都接受了标准化的神经心理学测试、磁共振成像和正电子发射断层扫描。
对于每个个体，测量了 3 种 AD 敏感的神经退行性变生物标志物：海马体积、葡萄糖代谢和灰质厚度，后两者从皮质 AD 受影响区域取样。为了量化神经退行性异常，每个生物标志物都进行了年龄调整，分为正常或异常状态（使用从独立的 AD 样本中得出的截断阈值），并汇总为 0、1 或多个异常神经退行性变生物标志物。评估了神经退行性异常的程度和拓扑模式，并评估了它们与认知功能、WML 体积和 Aβ 沉积（使用碳 11 标记的匹兹堡化合物 B 正电子发射断层扫描进行量化）之间的关系。
在我们的认知正常老年人中，40%（n=29）表现出至少 1 种异常神经退行性变生物标志物，其中 26%（n=19）没有 Aβ 保留升高的证据。在被归类为皮质厚度异常的人群中，神经退行性变的程度和拓扑特异性与 AD 患者相似。神经退行性变异常的积累与记忆和执行功能差以及更大的 WML 体积有关，但与 Aβ 保留升高无关。
我们的研究证实，相当一部分认知正常的老年人存在神经退行性变，而没有 Aβ 负担。神经退行性变与脑血管疾病和认知表现的关联表明，神经退行性病变可以通过 AD 受影响最大区域的非 Aβ 途径出现。
