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）阶段的临床、认知、影像学、遗传和生化生物标志物特征。该项目建立在nia资助的AD神经成像计划（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A2在皮层的沉积，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CSF A2降低和PET淀粉样蛋白示踪剂潴留增加。随后，脑脊液tau蛋白增加检测神经变性，FDG-PET保留检测突触功能障碍，海马萎缩显示神经元丢失（MRI测量）。这些变化最终导致记忆丧失，然后是认知能力下降和痴呆。该序列受年龄、APOE基因型、脑血管疾病和其他病理等因素的影响。我们利用ADNI1和GO的数据提出了三个总体主题和具体的操作假设。1)在一些无症状的个体中，脑脊液A2降低和淀粉样蛋白PET强度升高，提示阿尔茨海默病的早期神经生物学阶段。2)随后脑脊液tau升高，同时伴有脑糖代谢降低（FDG-PET评估）和内侧颞叶萎缩率增加。3)上述事件发生后，出现记忆障碍，最终进展为痴呆。我们的具体目标是：1：定义和招募早期失忆性MCI （EMCI）的受试者，以填补对照组和目前参加ADNI的“晚期MCI （LMCI）”受试者之间的空白。EMCI受试者将满足遗忘性MCI的临床标准，延迟段落回忆的表现比老年对照组的平均值低0.0到1.5个标准差。受试者的长期随访将通过更新ADNI （ADNI2）来完成。2：对来自ADNI1的正常受试者和LMCI受试者以及来自GO的新入组EMCI受试者进行F18淀粉样蛋白成像。这将建立一个F18淀粉样蛋白成像的国家网络，并测试关于该组脑淀粉样蛋白的患病率和严重程度的假设，将淀粉样蛋白沉积与当前和以前的临床状态、MRI、FDG PET和CSF以及ADNI1的血浆生物标志物的变化联系起来。3：继续对LMCI和ADNI1认知正常患者进行纵向研究一年。4：分析ADNI1和GO的所有现有和新的临床生化神经影像学和生物标志物数据。ADNI1的资助和提供仅用于分析第一年的数据，但现在已对受试者进行了3-4年的随访，并在GO中进行了更多随访。因此，一个大的纵向数据集将被分析。总的来说，这项GO拨款的总体影响将是：1)增加对导致阿尔茨海默氏症的事件顺序的了解；2)开发改进的临床和生物标志物方法来早期检测AD；3)改进成像/生物标志物监测AD进展，促进药物发现。

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.