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申请指导的注重患者的研究职业发展奖（K23）。候选人制定了一项综合研究/教育计划，该计划将导致神经影像学和临床研究设计的高级知识。候选人将参加生物统计学，研究设计，流行病学，伦理和神经影像学的课程和教程。这项多学科培训以及成为衰老研究中大型神经影像学的主要研究者的经验，将促进候选人发展为独立的临床研究者，他是一位学术神经科学家和痴呆症专家，在临床研究中使用神经影像学方面经验丰富，并强调开发和测试早期阿尔兹氏病（AD）的新治疗（AD）。 AD及其潜在的前体阶段，敏感的轻度认知障碍（MCI）接近流行比例。早期的神经精神症状，例如冷漠，对于AD和MCI患者的护理人员特别麻烦。冷漠与执行功能障碍有关，并已定位到额叶区域。我们建议证明使用匹兹堡化合物B（PIB）和额叶和骨parietal型超高替代物评估，通过正电子发射断层扫描（PET）评估了冷漠，执行功能障碍，体内皮质淀粉样蛋白沉积之间的联系，并由18F-氟二甲状腺素（FDG）PET，AMNESTART和AD AD AD AD AD ADMCI评估。我们提出了36个月的前瞻性随访研究，对80名患有正常认知的受试者（n = 20），羊膜MCI（n = 40）和轻度AD（n = 20），年龄在55至90岁中，他们将在基线时接受脑PIB PET，FDG PET和磁共振成像（MRI）。然后，他们将纵向遵循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。临床评估将包括对整体认知功能，全球功能，功能评估，集中于冷漠的行为评估以及着重于执行功能的神经心理学测试。 我们假设，尽管原纤维淀粉样蛋白沉积可能发生在前额叶和内侧顶部区域的早期，但在这些区域中，低代谢将与冷漠和执行功能障碍最有联系。更大的额叶和顶叶保留率，下部和顶叶壁FDG代谢以及冷漠和执行功能障碍的结合将导致日常生活（IADLS）的工具活动受损，并迅速发展为临床AD。 公共卫生相关性：在MCI阶段对AD的早期检测和治疗至关重要。在AD的早期临床试验中，许多靶向淀粉样蛋白病理学的潜在疾病调整剂。 MCI病理学是可变的，必须更好地表征以成为此类试验的目标。该提案提供了一个独特的机会，可以在疾病课程的早期探索冷漠和执行功能障碍与额叶和顶叶低代谢和淀粉样蛋白负担的临床意义因素的融合，以便更好地表征MCI。