PIB binding, hypometabolism, apathy and executive dysfunction in MCI and AD

描述（由申请人提供）：候选人，Gad A。医学博士马歇尔，正在重新提交一份申请，以指导患者为导向的研究职业发展奖（K23）。候选人已经制定了一个综合的研究/教育计划，将导致在神经影像学和临床研究设计的先进知识。候选人将参加生物统计学，研究设计，流行病学，伦理学和神经影像学的课程和辅导。这种多学科的培训，沿着的经验是一个大型的神经影像学在老龄化研究的主要研究者，将促进候选人发展成为一个独立的临床研究者谁是学术神经学家和痴呆症专家，在临床研究中使用神经影像学经验丰富，重点是开发和测试新的治疗早期阿尔茨海默氏病（AD）。 AD及其潜在的前体阶段，遗忘型轻度认知障碍（MCI），已接近流行的程度。早期的神经精神症状，如冷漠，对AD和MCI患者的照顾者来说特别麻烦。冷漠与执行功能障碍有关，并且已经局限于额叶区域。我们建议证明遗忘型MCI和AD患者的情感淡漠、执行功能障碍、使用匹兹堡化合物B（PI B）通过正电子发射断层扫描（PET）评估的体内皮质淀粉样蛋白沉积以及通过18 F-氟脱氧葡萄糖（FDG）PET评估的额叶和顶叶低代谢之间的联系。我们提出了一项为期36个月的前瞻性随访研究，80名年龄在55至90岁之间的认知正常（n=20）、遗忘型MCI（n=40）和轻度AD（n=20）受试者将在基线时接受脑PIB PET、FDG PET和磁共振成像（MRI）。然后，他们将被纵向随访36个月。将在基线和每12个月进行一次临床评估，以确定疾病进展。临床评价将包括总体认知功能、整体功能、功能评估、以冷漠为重点的行为评估和以执行功能为重点的神经心理学测试。 我们推测，虽然纤维状淀粉样蛋白沉积可能发生在前额叶和顶叶内侧区域的早期，但这些区域的低代谢与冷漠和执行功能障碍最相关。额叶和顶叶PIB保留增加，额叶和顶叶FDG代谢降低，再加上冷漠和执行功能障碍，将导致工具性日常生活活动（IADL）受损，并迅速进展为临床AD。 公共卫生相关性：在MCI阶段早期发现和治疗AD至关重要。许多针对淀粉样蛋白病理学的潜在疾病调节剂处于AD的早期临床试验中。MCI的病理是可变的，必须更好地表征，成为这样的试验的目标。这项建议提供了一个独特的机会，探讨收敛的冷漠和执行功能障碍与额叶和顶叶低代谢和淀粉样蛋白的负担，在疾病过程的早期，临床上有意义的元素，以更好地表征MCI。

DESCRIPTION (provided by applicant): The candidate, Gad A. Marshall, M.D., is resubmitting an application for a Mentored Patient-Oriented Research Career Development Award (K23). The candidate has developed an integrated research/educational plan that will lead to advanced knowledge in neuroimaging and clinical research design. The candidate will attend classes and tutorials in biostatistics, research design, epidemiology, ethics, and neuroimaging. This multidisciplinary training, along with the experience of being the principal investigator of a large neuroimaging in aging study, will facilitate the development of the candidate into an independent clinical investigator who is an academic neurologist and dementia expert, experienced in the use of neuroimaging in clinical research, with an emphasis on developing and testing new treatments for early Alzheimer's disease (AD). AD and its potential precursor stage, amnestic mild cognitive impairment (MCI), are nearing epidemic proportions. Early neuropsychiatric symptoms, such as apathy, are particularly troublesome to caregivers of patients with AD and MCI. Apathy is associated with executive dysfunction and has been localized to the frontal regions. We propose to demonstrate a connection between apathy, executive dysfunction, in vivo cortical amyloid deposition assessed by positron emission tomography (PET) using Pittsburgh Compound B (PIB), and frontal and parietal hypometabolism assessed by 18F-fluorodeoxyglocuse (FDG) PET, in amnestic MCI and AD. We propose a 36 month prospective follow-up study of 80 subjects with normal cognition (n=20), amnestic MCI (n=40) and mild AD (n=20), ages 55 to 90, who will undergo brain PIB PET, FDG PET, and magnetic resonance imaging (MRI) at baseline. They will then be followed longitudinally for 36 months. Clinical assessments will be performed at baseline and every 12 months to determine disease progression. Clinical evaluation will consist of tests of overall cognitive function, global function, functional assessments, behavioral assessments focusing on apathy, and neuropsychological tests focusing on executive function. We hypothesize that although fibrillar amyloid deposition may occur early in prefrontal and medial parietal regions, it will be hypometabolism in these regions that best correlates with apathy and executive dysfunction. Greater frontal and parietal PIB retention and lower frontal and parietal FDG metabolism, in combination with apathy and executive dysfunction, will lead to impairment in instrumental activities of daily living (IADLs), and rapid progression to clinical AD. PUBLIC HEALTH RELEVANCE: Earlier detection and treatment of AD, at the stage of MCI, is vital. Many potentially disease-modifying agents targeting amyloid pathology are in early phase clinical trials of AD. MCI pathology is variable and must be better characterized to become the target of such trials. This proposal provides a unique opportunity to explore the convergence of the clinically significant elements of apathy and executive dysfunction with frontal and parietal hypometabolism and amyloid burden, early in the disease course, in order to better characterize MCI.