Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Alzheimers Dement. 2013 Oct;9(5 Suppl):S124-31. doi: 10.1016/j.jalz.2012.11.009. Epub 2013 Jan 30.
Current hypothetical models of Alzheimer's disease (AD) pathogenesis emphasize the role of β-amyloid (Aβ), tau deposition, and neurodegenerative changes in the mesial temporal lobe, particularly the entorhinal cortex and hippocampus. However, many individuals with clinical AD who come to autopsy also exhibit cerebrovascular disease. The relationship between AD and vascular pathology is unclear, especially whether they represent additive and independent effects on neuronal injury. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to (1) confirm whether entorhinal cortex and hippocampal volume are associated with memory among individuals with amnestic mild cognitive impairment (MCI) who are at risk for AD; and (2) determine whether regional white matter hyperintensity (WMH) volume, a radiological marker of small-vessel cerebrovascular disease, is associated with entorhinal cortex and hippocampal volume independent of putative AD biomarkers in this group.
Cognitive test scores, entorhinal cortex volume, hippocampus volume, intracranial volume, and cerebrospinal fluid-derived phosphorylated tau and Aβ1-42 protein levels were measured in 199 subjects with amnestic MCI (mean age = 74.89 ± 7.47). Lobar WMH volumes were derived from T1-, proton-density-, and T2-weighted magnetic resonance imaging scans. We examined the association between entorhinal cortex volume and cognition. Next, we examined the association of tau and Aβ1-42 with entorhinal cortex volume and between lobar WMH and entorhinal cortex volume. Finally, tau, Aβ1-42, and regional WMH volumes were entered simultaneously to predict entorhinal cortex volume. We repeated the analyses with hippocampal volume instead of entorhinal cortex volume. The analyses were also repeated with the sample restricted to those MCI patients who transitioned to AD on subsequent ADNI follow-up visits (n = 86).
Larger entorhinal cortex volume was associated with better memory but not with performance on a task of executive functioning. Lower levels of Aβ1-42 and higher temporal WMH volumes were associated with smaller entorhinal cortex volume. When entered simultaneously, temporal lobe WMH volume was more reliably associated with entorhinal cortex volume than was Aβ1-42. The findings were similar for hippocampus volume and when the sample was restricted to MCI patients who subsequently transitioned to AD.
The findings confirm the role of entorhinal cortex and hippocampus volume in influencing memory decline in amnestic MCI, and emphasize that even in this nominally AD prodromal condition, WMH may be influencing regional neurodegeneration.
目前阿尔茨海默病（AD）发病机制的假设模型强调了β-淀粉样蛋白（Aβ）、tau 沉积和中颞叶神经退行性改变的作用，特别是在海马旁回和海马体。然而，许多在尸检中被诊断为 AD 的患者也患有脑血管疾病。AD 和血管病理学之间的关系尚不清楚，特别是它们是否代表对神经元损伤的附加和独立影响。我们使用来自阿尔茨海默病神经影像学倡议（ADNI）的数据来（1）确认在有 AD 风险的遗忘型轻度认知障碍（MCI）患者中，海马旁回和海马体体积是否与记忆有关；（2）确定在这组患者中，是否存在与 AD 生物标志物独立的区域白质高信号（WMH）体积（小血管脑血管疾病的放射学标志物）与海马旁回和海马体体积相关。
对 199 名遗忘型 MCI 患者（平均年龄 74.89 ± 7.47 岁）进行认知测试评分、海马旁回体积、海马体体积、颅内体积和脑脊液来源的磷酸化 tau 和 Aβ1-42 蛋白水平测量。从 T1-、质子密度-和 T2-加权磁共振成像扫描中提取脑叶 WMH 体积。我们检查了海马旁回体积与认知之间的关联。接下来，我们检查了 tau 和 Aβ1-42 与海马旁回体积之间的关系以及脑叶 WMH 与海马旁回体积之间的关系。最后，将 tau、Aβ1-42 和区域 WMH 体积同时输入以预测海马旁回体积。我们用海马体体积代替海马旁回体积重复了这些分析。还对在随后的 ADNI 随访中进展为 AD 的 MCI 患者（n = 86）进行了分析。
较大的海马旁回体积与更好的记忆相关，但与执行功能任务的表现无关。较低的 Aβ1-42 水平和较高的颞叶 WMH 体积与较小的海马旁回体积相关。当同时输入时，颞叶 WMH 体积与海马旁回体积的相关性比 Aβ1-42 更可靠。当使用海马体体积或当样本仅限于随后进展为 AD 的 MCI 患者时，发现结果相似。
这些发现证实了海马旁回和海马体体积在影响遗忘型 MCI 患者的记忆下降中的作用，并强调即使在这种名义上的 AD 前驱期状态下，WMH 也可能影响区域神经退行性变。
