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

描述(由申请人提供)：候选人，医学博士加德·A·马歇尔，正在重新提交以患者为导向的研究职业发展奖(K23)的申请。应聘者已经制定了一项综合研究/教育计划，将导致神经成像和临床研究设计方面的高级知识。候选人将参加生物统计学、研究设计、流行病学、伦理学和神经成像方面的课程和教程。这种多学科的培训，加上作为一项大型老年神经成像研究的首席研究员的经验，将有助于候选人发展成为一名独立的临床调查员，他是一名学术神经学家和痴呆症专家，在临床研究中使用神经成像方面经验丰富，重点是开发和测试早期阿尔茨海默病(AD)的新疗法。AD及其潜在的前驱阶段--遗忘性轻度认知障碍(MCI)--正接近流行阶段。早期的神经精神症状，如冷漠，对AD和MCI患者的照顾者来说尤其麻烦。冷漠与执行功能障碍有关，并局限于额叶区域。我们建议证明在健忘型MCI和AD中，冷漠、执行功能障碍、使用匹兹堡化合物B(PIB)的正电子发射断层扫描(PET)评估的活体皮质淀粉样蛋白沉积与18F-氟代脱氧葡萄糖(FDG)PET评估的额叶和顶叶低代谢之间存在联系。我们对80名认知正常(n=20)、遗忘性MCI(n=40)和轻度AD(n=20)、年龄在55-90岁的受试者进行了36个月的前瞻性随访研究，这些受试者将在基线时接受脑PIB PET、FDG PET和磁共振成像(MRI)。然后，他们将被纵向跟踪36个月。临床评估将在基线上进行，每12个月进行一次，以确定疾病进展。临床评估将包括总体认知功能、整体功能、功能评估、侧重于冷漠的行为评估和侧重于执行功能的神经心理测试。我们推测，尽管纤维淀粉样蛋白沉积可能早期发生在前额叶和内侧顶叶区域，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，将导致日常生活工具能力(IADL)受损，并迅速发展为临床AD。 公共卫生相关性：在MCI阶段及早发现和治疗AD是至关重要的。许多针对淀粉样蛋白病理的潜在疾病改良剂正在进行AD的早期临床试验。MCI病理是可变的，必须更好地描述才能成为此类试验的靶点。这一建议提供了一个独特的机会来探索临床上有意义的冷漠和执行功能障碍的因素与额叶和顶叶代谢不足以及淀粉样蛋白负荷在病程早期的汇聚，以便更好地描述MCI的特征。

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.