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

MCI 和 AD 中的 PIB 结合、代谢低下、冷漠和执行功能障碍

• 批准号: 8123387
• 负责人: GAD ASHER MARSHALL
• 金额: $ 14.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123387
• 关键词: Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid deposition; Anterior; Attention; Behavior assessment; Binding; Biometry; Brain; Caregivers; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical assessments; Cognition; Cognitive; Complex; Dementia; Development; Disease; Disease Progression; Doctor of Medicine; Early Diagnosis; Early treatment; Elements; Epidemic; Epidemiology; Ethics; Functional disorder; Goals; Image; Impairment; Investigation; Knowledge; Lead; Link; Magnetic Resonance Imaging; Marshal; Measures; Medial; Memory impairment; Mentored Patient-Oriented Research Career Development Award; Metabolism; Molecular; Motivation; Neurologist; Neuronal Dysfunction; Neuropsychological Tests; Parietal; Pathology; Patients; Phase; Phenotype; Pittsburgh Compound-B; Positron-Emission Tomography; Principal Investigator; Reporting; Research; Research Design; Research Project Grants; Short-Term Memory; Staging; Symptoms; Synapses; Testing; Time; Training; Visual; Withdrawal; Work; amyloid pathology; clinically significant; cognitive function; executive function; experience; follow-up; in vivo; instrumental activity of daily living; interest; mild neurocognitive impairment; multidisciplinary; neuroimaging; neuropsychiatry; prospective; public health relevance; research clinical testing; social

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.

描述（由申请人提供）：候选人，Gad a . Marshall，医学博士，正在重新提交一份指导患者导向研究职业发展奖（K23）的申请。该候选人已经制定了一个综合的研究/教育计划，将导致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方面的课程和辅导。这种多学科的培训，以及作为一项大型衰老研究神经影像学首席研究员的经验，将促进候选人发展成为一名独立的临床研究者，作为一名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方面经验丰富，重点是开发和测试早期阿尔茨海默病（AD）的新疗法。阿尔茨海默病及其潜在的前驱阶段，健忘轻度认知障碍（MCI），已接近流行病的比例。早期神经精神症状，如冷漠，对AD和MCI患者的护理人员来说尤其麻烦。冷漠与执行功能障碍有关，并局限于额叶区域。我们提出证明在遗忘型轻度认知损伤和AD患者中，冷漠、执行功能障碍、体内皮质淀粉样蛋白沉积（通过使用匹兹堡化合物B （PIB）的正电子发射断层扫描（PET）评估）和额叶和顶叶代谢低下（通过18f -氟氧葡萄糖（FDG） PET评估）之间存在联系。我们提出了一项为期36个月的前瞻性随访研究，对80名年龄在55至90岁之间的正常认知（n=20）、遗忘性轻度轻度认知障碍（n=40）和轻度AD （n=20）的受试者进行了脑PIB PET、FDG PET和磁共振成像（MRI）的基线检查。然后他们将被纵向跟踪36个月。临床评估将在基线和每12个月进行一次，以确定疾病进展。临床评估将包括整体认知功能测试、整体功能测试、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。我们假设，尽管纤维状淀粉样蛋白沉积可能发生在前额叶和内侧顶叶区域，但这些区域的代谢低下与冷漠和执行功能障碍最相关。额叶和顶叶PIB潴存较大，额叶和顶叶FDG代谢较低，再加上冷漠和执行功能障碍，将导致日常生活工具活动（IADLs）受损，并迅速发展为临床AD。