Early and late-life metal exposures and Alzheimer's disease

描述(由申请人提供)：我们建议研究早年和成年期间接触金属与发展为阿尔茨海默病(AD)的风险之间的关系，以及这些暴露是否与血液和大脑中淀粉样蛋白β物种(Aβ)水平的变化有关。我们将对伊迪丝·诺斯·罗杰斯纪念贝德福德退伍军人医学中心(Bedford VA)招募的约183例病例和270名对照进行病例对照研究。此外，我们还建议进一步研究早年和晚年接触金属是否与对照组中认知功能较差有关。贝德福德退伍军人管理局提供了一个独特的适合进行这项研究的环境，因为该设施为AD患者提供服务，并有一个牙科诊所，我们可以从那里招募适当的对照人员，以获得牙齿样本。病例和对照的来源人群都是马萨诸塞州贝德福德地区的退伍军人。此外，基本上所有的临床AD病例都要进行尸检，因此可以从神经病理上确认病例状态，并收集脑组织进行分析。将通过测量成人牙釉质中的金属(使用激光消融电感耦合等离子体质谱)来评估早期接触金属的情况。控制组将从Bedford VA牙科诊所招募，当他们因其他原因拔牙时，将从病例中收集牙齿，如果他们活着时因其他原因拔牙，或 在验尸时。成人铅暴露(铅)也将使用我们过去丰富的经验的非侵入性K-壳层X射线荧光(KXRF)技术进行测量。将在研究访问中收集的血液样本和尸检时收集的颞叶皮质脑组织中测量Aβ物种。认知功能将在受试者的学习访问中进行测试。这项研究将是第一次使用暴露的生物标志物来检验成人暴露于金属与AD之间的联系，也是第一次探索人类早期生活中金属暴露与AD之间的联系--这是一个动物研究中提出的铅暴露假说，但如果没有牙齿可以提供的这种早期暴露的生物标志物，人类基本上无法测试。

DESCRIPTION (provided by applicant): We propose to study the relation between exposure to metals-in both early life and adult life-and the risk of developing Alzheimer's disease (AD), and whether those exposures are associated with changes in levels of amyloid-β species (Aβ) in blood and brain. We will conduct a case-control study with an estimated 183 cases and 270 controls recruited from the Edith Nourse Rogers Memorial Bedford VA Medical Center (Bedford VA). Furthermore, we propose to additionally examine whether early and later life metal exposures are associated with worse cognitive function among the controls. The Bedford VA provides a uniquely suited setting in which to conduct this research as the facility serves AD patients and has a dental clinic on-site from which we can recruit appropriate controls with availability of tooth samples. The source population for both cases and controls are veterans in the Bedford, MA area. In addition, essentially all clinical AD cases go to autopsy, thus case status can be confirmed neuropathologically and brain tissue can be collected for analyses. Early life exposure to metals will be assessed by measuring metals in adult tooth enamel (using laser-ablation inductively coupled plasma mass spectrometry). Controls will be recruited from the Bedford VA dental clinic when they are having a tooth extracted for other reasons, and teeth will be collected from cases if they are having a tooth extracted for other reasons while alive, or at autopsy. Adult exposure to lead (Pb) will also be measured with the non-invasive K-shell X-ray Fluorescence (KXRF) technique with which we have extensive past experience. Aβ species will be measured in blood samples collected at study visits and temporal cortex brain tissue collected at autopsy. Cognitive function will be tested among the controls at their study visit. This study will be the first to examine the association between adult exposure to metals and AD using biomarkers of exposure, and the first of any kind to explore the association between early life metal exposures and AD in humans-a hypothesis suggested for Pb exposure from animal research, but essentially untestable in humans without the biomarker of such early exposure that teeth can provide.