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、成像、遗传和生物化学生物标志物特征。该项目建立在国家免疫局资助的AD神经影像学倡议（ADNI 1）的基础上，并作为ADNI（ADNI 2）计划更新的桥梁。我们的模型假定：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CSF A2减少和PET淀粉样蛋白示踪剂保留增加。随后，通过增加的CSF tau种类检测神经变性，通过FDG-PET保留检测突触功能障碍，并且通过海马萎缩（用MRI测量）指示神经元损失。这些变化最终导致记忆丧失，然后是一般认知能力下降和痴呆症。该序列受包括年龄、APOE基因型、脑血管疾病和其他病理的因素影响。我们提出了三个总体主题与具体的操作假设使用数据从ADNI 1和GO。1)在一些无症状的个体中存在CSF A2降低和淀粉样蛋白PET强度增加，表明AD神经生物学的早期阶段。2)随后，CSF tau增加，伴有脑葡萄糖代谢降低（通过FDG-PET评估）和内侧颞叶萎缩率增加，以及3）在上述事件后，出现记忆障碍，最终进展为痴呆。我们的具体目标是：一曰：定义并入组早期遗忘型MCI（EMCI）受试者，以填补对照组与目前入组ADNI的“晚期MCI（LMCI）”受试者之间的差距。EMCI受试者将符合遗忘型MCI的临床标准，在延迟段落回忆表现上的表现比老年对照组的平均值低0.0至1.5 SD。受试者的长期随访将通过更新ADNI（ADNI 2）完成。2：对来自ADNI 1的正常和LMCI受试者以及来自GO的新入组的EMCI受试者进行F18淀粉样蛋白成像。这将建立F18淀粉样蛋白成像的国家网络，并测试关于该组中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临床状态、MRI、FDG PET和CSF以及来自ADNI 1的血浆生物标志物的当前和先前变化相关。3：继续对LMCI和ADNI 1的认知正常人进行一年的纵向研究。4：分析来自ADNI 1和GO的所有现有和新的临床生化神经成像和生物标志物数据。ADNI 1获得了资助，仅用于分析第一年的数据，但受试者现在已经随访了3-4年，在GO中进行了更多的随访。因此，将分析大型纵向数据集。总的来说，该GO资助的总体影响将是：1）增加有关导致AD痴呆的事件序列的知识; 2）开发用于早期检测AD的改进的临床和生物标志物方法; 3）改进用于监测AD进展的成像/生物标志物，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）阶段的临床，认知，成像，遗传和生化生物标志物特征之间的关系。该项目建立在NIA目前资助的AD神经影像学倡议（ADNI 1，学术界和工业界合作研究AD生物标志物）的基础上，并作为ADNI更新的桥梁（称为ADNI 2）。该项目的总体影响将是：1）增加有关导致AD痴呆的事件序列的知识; 2）开发用于早期检测AD的改进的临床和生物标志物方法;和3）改进用于监测AD进展的成像和化学生物标志物方法，促进减缓疾病进展的治疗的临床试验，并最终有助于预防AD痴呆。

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.