PET imaging of activated microglia in Alzheimer's Disease

描述(由申请人提供)：越来越多的临床前证据表明，中枢神经系统炎症在阿尔茨海默病(AD)的进展中起着重要作用。在病理学研究中，小胶质细胞从静止状态到激活状态的转变是阿尔茨海默病神经炎症的关键。尽管有强有力的临床前证据，但还没有关于小胶质细胞激活在AD预后中的作用的临床研究。这项研究的假设是，在选定的大脑区域，激活的小胶质细胞数量越多，随着时间的推移，认知和功能衰退的速度就会越快。候选人建议使用PET配体11G-PK11195来成像早期AD患者体内的小胶质细胞激活，该配体与外周苯二氮卓类受体结合，后者与大脑中激活的小胶质细胞的数量相关。 方法：40例特征良好的早期阿尔茨海默病患者将以11C-PK11195为基线进行成像，并使用标准的临床认知、功能和神经精神病学进展测量方法每年跟踪两年。据预测，在关键脑区的脑PET扫描中，PK11195的基线保留程度(表明小胶质细胞激活更强烈，因此神经炎症更严重)将预示着临床措施的更快进展。如果11C-PK11195结合与疾病进展相关，这将提示神经炎症在AD疾病过程中的重要性，否则，神经炎症在AD疾病过程中的作用将受到质疑。培训目标：总体目标是获得新的方法学技能，足以使应聘者成为AD生物标记物的独立调查者。为了实现这些目标，应聘者寻求以下方面的培训：1)衰老和AD的临床研究设计(Lyketsos和Albert博士)；2)PET成像和分析(Pomper和Wong博士)；3)纵向数据分析(Frangakis博士)；以及4)神经炎症(Nath博士)。该培训计划将这四个领域的课程作业、导师指导和研究经验整合在一起。 相关性：这一建议可能导致开发一种反映神经炎症的生物标记物，用于预测AD的预后。建议的深入而广泛的培训经验将利用约翰霍普金斯大学丰富的智力资源，使候选人能够成为AD生物标记物的独立研究员。

DESCRIPTION (provided by applicant): There is increasing preclinical evidence for a central the role of neuroinflammation in the progression of Alzheimer disease (AD). In pathologic studies, the transition of microglia from a quiescent to activated state is critical to neuroinflammation in AD. Despite strong preclinical evidence there have been no clinical studies of the role of microglial activation in the prognosis of AD. The hypothesis of this study is that greater numbers of activated microglia in selected brain regions will be associated with a more rapid rate of cognitive and functional decline over time. The candidate proposes to image microglial activation in in vivo patients with early AD using the PET ligand 11G-PK11195 which binds to peripheral benzodiazepine receptors which are associated with the number of activated microglia in the brain. METHOD: Forty well- characterized patients with early AD will be imaged with 11C-PK11195 at baseline and followed annually for two years using standard clinical cognitive, functional, and neuropsychiatric measures of progression. It is predicted that the degree of baseline retention of PK11195 in brain PET scans in key brain areas (indicative of more intense microglial activation and hence greater neuroinflammation) will be predictive of more rapid progression in the clinical measures. If 11C-PK11195 binding is associated with disease progression this would suggest the importance of neuroinflammation in AD disease course, and if not the role of neuroinflammation in AD disease course will be called into question. TRAINING GOALS: The overall goal is to acquire new methodological skills sufficient to allow the candidate to pursue a career as an independent investigator of biomarkers of AD. To accomplish these goals the candidate seeks training in: 1) Clinical study design in aging and AD (Drs. Lyketsos and Albert); 2) PET imaging and analysis (Drs. Pomper and Wong); 3) longitudinal data analysis (Dr. Frangakis); and 4) neuroinflammation (Dr. Nath). The training program integrates coursework, tutorials with mentors, and research experience in these four areas. RELEVANCE: This proposal could lead to the development of a biomarker reflecting neuroinflammation that for predicting prognosis of AD. The deep and broad training experience proposed will utilize the rich intellectual resources of Johns Hopkins to allow the candidate to become an independent investigator of biomarkers of AD.