Amyloid Imaging, VMCI, and Analysis for ADNI

描述(由申请人提供)：我们的目标是确定阿尔茨海默病(AD)早期(痴呆前期)的临床、认知、成像、遗传和生化生物标记物特征。该项目建立在NIA资助的AD神经成像倡议(ADNI1)的基础上，并作为ADNI(ADNI2)计划更新的桥梁。我们的模型假设：AD始于皮质中的A2沉积，导致突触功能障碍、神经变性和认知/功能下降。最早可检测到的变化是脑脊液A2减少和PET淀粉样蛋白示踪剂滞留增加。随后，通过脑脊液tau种类的增加检测到神经变性，通过FDG-PET滞留检测到突触功能障碍，通过海马区萎缩(通过MRI测量)检测到神经元丢失。这些变化最终会导致记忆力丧失，进而导致认知能力下降和痴呆症。这一序列受年龄、载脂蛋白E基因、脑血管疾病和其他病理因素的影响。我们利用ADNI1和GO的数据提出了三个具有特定操作假设的总体主题。1)部分无症状个体脑脊液A2含量降低，淀粉样蛋白PET强度增高，提示AD神经生物学处于早期阶段。2)随后，脑脊液tau升高，并伴有脑葡萄糖代谢降低(FDG-PET评估)和内侧颞叶萎缩率增加，以及3)在上述事件发生后，出现记忆障碍，最终发展为痴呆。我们的具体目标是：1：定义和登记患有早期遗忘性MCI(EMCI)的受试者，以填补对照和目前在ADNI登记的“晚期遗忘性MCI(LMCI)”受试者之间的差距。EMCI受试者将符合遗忘性MCI的临床标准，在延迟段落回忆能力上的表现比老年对照组的平均值低0.0%至1.5SD。受试者的长期随访将通过ADNI(Adni2)的更新来完成。2：对ADNI1的正常受试者、LMCI受试者和GO新入选的EMCI受试者进行F18淀粉样蛋白成像。这将建立一个全国性的F18淀粉样蛋白成像网络，并在该小组中测试有关大脑淀粉样蛋白的患病率和严重性的假设，将淀粉样蛋白沉积与临床状态、MRI、FDG PET和脑脊液以及ADNI1的血浆生物标记物的当前和以前的变化联系起来。3：继续对LMCI和ADNI1认知正常人群的纵向研究，再持续一年。4：分析ADNI1和GO现有的和新的临床生化神经影像和生物标记物数据。ADNI1得到了资助，仅用于分析第一年的数据，但受试者现在已经被跟踪了3-4年，并在围棋中进行了更多的随访。因此，将对大型纵向数据集进行分析。总而言之，这笔GO赠款的总体影响将是：1)增加关于导致AD痴呆的事件序列的知识；2)开发改进的临床和生物标记物方法以早期发现AD；3)改进用于监测AD进展的成像/生物标记物，促进药物发现。 公共卫生相关性：该项目的目标是确定阿尔茨海默病(AD)早期(痴呆前期)的临床、认知、成像、遗传和生化生物标记物特征之间的关系。该项目建立在NIA目前资助的AD神经成像倡议(ADNI1，学术界和工业界合作研究AD的生物标记物)的基础上，并作为更新ADNI(称为ADNI2)的桥梁。该项目的总体影响将是：1)增加对导致阿尔茨海默病的事件顺序的了解；2)开发改进的临床和生物标记物方法以早期发现阿尔茨海默病；以及3)改进监测阿尔茨海默病进展的成像和化学生物标记物方法，促进减缓疾病进展的治疗的临床试验，最终有助于预防阿尔茨海默氏症。

DESCRIPTION (provided by applicant): Our goal is to determine the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the early (pre-dementia) stages of Alzheimer's disease (AD). The project builds on the NIA-funded AD Neuroimaging Initiative (ADNI1) and serves as a bridge to the planned renewal of ADNI (ADNI2). Our model posits: AD begins with A2 deposition in cortex, leading to synaptic dysfunction, neurodegeneration, and cognitive/ functional decline. The earliest detectable changes are decreased CSF A2 and increased PET amyloid tracer retention. Subsequently, neurodegeneration is detected by increased CSF tau species, synaptic dysfunction by FDG-PET retention and neuron loss indicated by hippocampal atrophy (measured with MRI). These changes ultimately lead to memory loss then general cognitive decline and dementia. This sequence is influenced by factors including age, APOE genotype, cerebrovascular disease, and other pathologies. We propose three overarching themes with specific operational hypotheses using data from ADNI1 and GO. 1) Reductions of CSF A2 and increased amyloid PET intensity are present in some asymptomatic individuals, indicating the early stage of AD neurobiology. 2) Subsequently, CSF tau increases accompanied by reduced brain glucose metabolism (assessed by FDG-PET) and an increased rate of medial temporal lobe atrophy, and 3) after the aforementioned events, memory impairment appears, eventually progressing to dementia. Our specific aims are: 1: Define and enroll subjects with early amnestic MCI (EMCI) to fill the gap between controls and "late MCI (LMCI)" subjects currently enrolled in ADNI. EMCI subjects will meet clinical criteria for amnestic MCI, performing between 0.0 and 1.5 SD below the mean of elderly controls on delayed paragraph recall performance. Long term follow-up of the subjects will be accomplished by the renewal of ADNI (ADNI2). 2: Perform F18 amyloid imaging on the normal and LMCI subjects from ADNI1 and the newly enrolled EMCI subjects from GO. This will establish a national network for F18 amyloid imaging, and test hypotheses concerning the prevalence and severity of brain amyloid in this group relating amyloid deposition to current and previous changes in clinical state, MRI, FDG PET and CSF and plasma biomarkers from ADNI1. 3: Continue longitudinal studies of LMCI and cognitively normals of ADNI1 for an additional year. 4: Analyze all existing and new clinical biochemical neuroimaging and biomarker data from ADNI1 and GO. ADNI1 was funded and only provided to analyze the first year's data, but subjects have now been followed for 3-4 years with more follow-up in GO. Thus a large longitudinal data set will be analyzed. Taken together, the overall impact of this GO grant will be: 1) increased knowledge concerning the sequence of events leading to AD dementia; 2) development of improved clinical and biomarker methods for early detection of AD; 3) improved imaging/biomarkers for monitoring progression of AD, facilitating drug discovery. PUBLIC HEALTH RELEVANCE: The goal of this project is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the early (pre-dementia) stages of Alzheimer's disease (AD). The project builds on the NIA- currently funded AD Neuroimaging Initiative (ADNI1, a collaboration between academia and industry to study biomarkers of AD) and serves as a bridge to the renewal of ADNI (termed ADNI2). The overall impact of this project will be: 1) increased knowledge concerning the sequence of events leading to AD dementia; 2) development of improved clinical and biomarker methods for early detection of AD; and 3) improved imaging and chemical biomarker methods for monitoring progression of AD, facilitating clinical trials of treatments to slow disease progression, and ultimately contributing to the prevention of AD dementia.