African American Alzheimer's Progression Markers - CSF and Neuro-Imaging

描述（由申请人提供）：非裔美国人占美国人口的约10%，但在生物标志物相关的衰老研究中代表性不足，如阿尔茨海默病神经成像倡议（ADNI）和全球ADNI。流行病学研究表明，与非西班牙裔白色（NHW）美国人相比，非洲裔美国人（AA）更容易发展为轻度认知障碍（MCI）和阿尔茨海默病（AD），具有不同的发展AD的遗传风险，并且在治疗后经历不同的认知下降率。 出现认知症状。所有这些都表明AA存在MCI/AD内表型，尽管这些流行病学研究中很少涉及与AD病理学和进展相关的现代化学或成像生物标志物。使用已接受CSF分析的AA受试者（n=36）进行的初步研究显示，AA MCI受试者比NHW MCI受试者更可能具有正常的CSF AD生物标志物，但同时MRI上的海马萎缩更大。我们假设内皮功能障碍是一种替代机制，其以种族无关的方式独立地导致具有亚阈值AD病理学的AA受试者的认知损害，并且内皮功能障碍以种族依赖的方式进一步增强AD相关脑变化的神经毒性。我们建议在埃默里纪念登记处成功招募AA志愿者参与记忆和衰老研究的基础上，招募一个由75名AA受试者和75名认知正常、轻度认知障碍或轻度AD的NHW受试者组成的横断面队列，沿着。我们将通过两个目标来检验我们的假设。在目标1中，我们将通过测量脑脊液（CSF）中AD、内皮和炎症标志物的水平，确定内皮功能障碍是否独立地导致AA和NHW受试者的认知下降。每例受试者还将接受白色高信号总面积的MRI分析，作为内皮功能障碍的成像标志物。基于我们的假设，我们预测AA MCI/AD受试者比NHW MCI受试者更可能具有正常CSF AD生物标志物、异常CSF内皮标志物以及MRI上更多数量和面积的白色高信号。在目标2中，我们将确定AA特有的内皮标志物-细胞间粘附分子1或ICAM-1 -基因变体是否增强AD神经毒性，以解释AA MCI受试者中更大的海马萎缩。与低ICAM-1水平相关的Lys 56 Met ICAM 1基因变体在16-20%的AA中独特地发现，并且这些受试者可能具有受损的脑啡肽酶（一种Ab降解酶）的下游活化。如果我们的假设是正确的，与Lys 56 Met基因变异的AA受试者将更有可能有海马萎缩，颞顶叶脑灌注不足，大脑淀粉样蛋白沉积比AA受试者和NHW受试者没有基因变异。如果低脑啡肽酶水平导致Ab 42水平增加，则这可能发生在CSF Ab 42假正常化的情况下。

DESCRIPTION (provided by applicant): African Americans represent about 10% of the population in the US, but are under-represented in biomarker- related aging studies such as the Alzheimer's Disease Neuro-imaging Initiative (ADNI) and World Wide ADNI. Epidemiologic studies show that, compared to non-Hispanic white (NHW) Americans, African Americans (AA) are more likely to develop mild cognitive impairment (MCI) and Alzheimer's disease (AD), have different genetic risks of developing AD, and experience different rates of cognitive decline after cognitive symptoms develop. All these point to the existence of an MCI/AD endophenotype for AA, although few of these epidemiological studies involve modern chemical or imaging biomarkers associated with AD pathology and progression. Preliminary studies using AA subjects who have undergone CSF analysis (n=36) show that AA MCI subjects are more likely to have normal CSF AD biomarkers than NHW MCI subjects, yet at the same time greater hippocampal atrophy on MRI. We hypothesize that endothelial dysfunction is an alternate mechanism which independently contributes to cognitive impairment in AA subjects with sub-threshold AD pathology in a race-independent fashion, and endothelia dysfunction further enhances the neurotoxicity of AD- associated brain changes in a race-dependent fashion. We propose to build on our success in recruiting AA volunteers into memory and aging studies at the Emory's Registry for Remembrance to recruit a cross- sectional cohort of 75 AA subjects along with 75 NHW subjects with normal cognition, MCI, or mild AD. We will test our hypothesis through two aims. In Aim 1, we will determine whether endothelial dysfunctions independently contribute to cognitive decline in AA and NHW subjects by measuring cerebrospinal fluid (CSF) levels of AD, endothelial, and inflammatory markers. Each subject will also undergo MRI analysis for total area of white matter hyperintensities as an imaging marker of endothelial dysfunction. Based on our hypothesis, we predict that AA MCI/AD subjects are more likely than NHW MCI subjects to have normal CSF AD biomarkers, abnormal CSF endothelial markers, and greater number and area of white matter hyperintensities on MRI. In Aim 2, we will determine if an endothelial marker - intercellular adhesion molecule 1 or ICAM-1 - gene variant unique to AA enhances AD neurotoxicity to explain the greater hippocampal atrophy among AA MCI subjects. The Lys56Met ICAM1 gene variant associated with low ICAM-1 levels is uniquely found in 16-20% of AA, and these subjects may have impaired downstream activation of neprilysin, an Ab-degrading enzyme. If our hypothesis is true, AA subjects with the Lys56Met gene variant will be more likely to have hippocampal atrophy, temporal-parietal cerebral hypoperfusion, and cerebral amyloid deposition than AA subjects and NHW subjects without the gene variant. This may occur in the setting of CSF Ab42 pseudo-normalization if low neprilysin levels lead to increased Ab42 levels.