ALZHEIMERS DISEASE: EFFECTS OF ORAL INFECTION INFLAMMATION AND DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 阿尔茨海默病？S病：口腔感染、炎症和疾病的影响 Pamela Stein，DMD(医学院解剖学和神经生物学)；导师：M.John Novak，David Wekstein，PhD(桑德斯-布朗老龄中心副主任) 牙周病的特征是革兰氏阴性感染，涉及中性粒细胞、单核/巨噬细胞和淋巴细胞的局部和全身炎症反应，细胞因子介导的炎症反应调节以及导致受影响区域功能丧失的细胞和细胞外病理。目前的研究表明，许多相同的机制在阿尔茨海默病的病变部位也很明显。肺炎衣原体的革兰氏阴性感染与AD的病因有关，脑内常驻巨噬细胞小胶质细胞的激活是AD的一个特征。最近的先导性前瞻性研究表明，有其他系统感染的AD患者，在感染缓解后至少会表现出持续2个月的认知障碍，并且这种损害之前会出现血清IL-1水平的升高。此外，越来越多的重要证据表明细胞因子与脑病理的病因学有关。最近，单核细胞和小胶质细胞上甲酰化肽的特异性受体的发现突显了循环中的革兰氏阴性菌激活脑部炎症系统的能力，这些炎症系统可能导致病理变化。这些受体是革兰氏阴性菌所特有的，支持革兰氏阴性菌感染可在大脑中引发炎症和病理变化的概念。在目前的研究中，我们正在与桑德斯·布朗老龄化中心合作招募受试者来测试我们的假设，即有广泛口腔感染生活史的老年人比保持最低水平口腔感染的老年人患阿尔茨海默氏病的风险更高。检验我们假设的方法包括(1)比较阿尔茨海默病-S病(AD)患者与年龄、种族和性别匹配的对照组的牙周病的患病率、程度和严重程度；(2)表征AD患者和对照组的龈下微生物生态，以确定特定的微生物特征是否与不良结局相关；(3)确定AD和牙周炎患者是否比AD患者、牙周炎患者和非AD对照组的循环炎症介质水平高。自从这一试点项目获得批准和资助以来，我们在获得IRB批准、与桑德斯·布朗调查人员建立合作安排以及开发案件报告表格方面取得了相当大的进展。我们现在已经准备好在2005年6月招收我们的第一个科目。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer?s Disease: Effects of Oral Infection, Inflammation, and Disease Pamela Stein, DMD (Anatomy & Neurobiology, College of Medicine); Mentors: M. John Novak, David Wekstein, PhD (Associate Director, Sanders-Brown Aging Center) The characteristics of periodontal disease are a Gram negative infection, a local and systemic inflammatory response involving neutrophils, monocytes/macrophages, and lymphocytes, cytokine mediated regulation of the inflammatory response and cellular and extracellular pathology that results in loss of function of the affected area. Current research suggests that many of the same mechanisms are apparent in pathologically affected sites in AD. A Gram negative infection with Chlamydia pneumoniae has been implicated in the etiology of AD and activation of the resident macrophages of the brain, microglia, is a feature. Recent, pilot, prospective studies have indicated that patients with AD who have other systemic infections, demonstrate cognitive impairment that continues for at least 2 months after resolution of the infection and that the impairment is preceded by elevated serum levels of IL-1? ?. In addition, significant evidence is accruing to implicate cytokines in the etiology of brain pathology. The ability of circulating Gram negative organisms to activate inflammatory systems in the brain that may lead to pathologic changes, has been highlighted recently by the identification of specific receptors for formylated peptides on monocytes and microglia. These receptors are specific for Gram negative organisms and support the concept that Gram negative infection can initiate inflammatory and pathologic changes in the brain. In the current study we are working with The Sanders Brown Center on Aging to recruit subjects to test our hypothesis that older adults with a life history of exposure to extensive oral infection are at higher risk for developing Alzheimer?s disease than older adults who have maintained minimal levels of oral infection. Methods for testing our hypothesis include (1) characterizing the prevalence, extent and severity of periodontal disease in a population of patients with Alzheimer?s disease (AD) when compared to age, race, and sex matched controls (2) characterizing the subgingival microbial ecology in patients with AD and controls to determine if specific microbial characteristics are associated with adverse outcomes and (3) determining if patients with AD and periodontitis have elevated levels of circulating inflammatory mediators compared to patients with AD and no periodontitis and non-AD controls. Since the approval and funding of this pilot project, we have made considerable progress in obtaining IRB approval, establishing collaborative arrangements with the Sanders Brown investigators, and developing case report forms. We are now ready to enroll our first subject in June, 2005.