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: 8512631
• 负责人: GAD ASHER MARSHALL
• 金额: $ 14.16万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512631
• 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 cognitive 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指导患者导向研究职业发展奖 (K23) 的申请。候选人制定了一项综合研究/教育计划，该计划将带来神经影像学和临床研究设计方面的先进知识。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教程。这种多学科培训，加上作为衰老研究中大型神经影像学主要研究者的经验，将有助于候选人发展成为一名独立的临床研究者，他是一位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。 AD 及其潜在的前兆阶段——遗忘性轻度认知障碍 (MCI) 已接近流行病的程度。早期神经精神症状，例如冷漠，对于 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，并且局限于额叶区域。我们建议证明遗忘性 MCI 和 AD 中的冷漠、执行功能障碍、通过使用匹兹堡化合物 B (PIB) 的正电子发射断层扫描 (PET) 评估的体内皮质淀粉样蛋白沉积，以及通过 18F-氟脱氧葡萄糖 (FDG) PET 评估的额叶和顶叶代谢低下之间的联系。我们建议对 80 名年龄 55 至 90 岁、认知正常 (n=20)、遗忘性 MCI (n=40) 和轻度 AD (n=20) 的受试者进行 36 个月的前瞻性随访研究，这些受试者将在基线时接受脑部 PIB PET、FDG PET 和磁共振成像 (MRI)。然后将对他们进行为期 36 个月的纵向跟踪。将在基线时和每 12 个月进行一次临床评估，以确定疾病进展。临床评估将包括整体认知功能、整体功能、功能评估、针对冷漠的行为评估以及针对执行功能的神经心理学测试。 我们假设，尽管纤维状淀粉样蛋白沉积可能早期发生在前额叶和顶叶内侧区域，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 滞留较多，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 阶段尽早发现和治疗 AD 至关重要。许多针对淀粉样蛋白病理学的潜在疾病缓解药物正处于 AD 的早期临床试验中。 MCI 病理学是可变的，必须更好地表征才能成为此类试验的目标。该提案提供了一个独特的机会，可以在病程早期探索冷漠和执行功能障碍的临床重要因素与额叶和顶叶代谢低下以及淀粉样蛋白负荷的融合，以便更好地表征 MCI。

项目成果

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study.

• DOI: 10.1186/alzrt146
• 发表时间: 2012
• 期刊: Alzheimer's research & therapy
• 作者: Ringman JM;Frautschy SA;Teng E;Begum AN;Bardens J;Beigi M;Gylys KH;Badmaev V;Heath DD;Apostolova LG;Porter V;Vanek Z;Marshall GA;Hellemann G;Sugar C;Masterman DL;Montine TJ;Cummings JL;Cole GM
• 通讯作者: Cole GM