Novel Imaging Biomarkers for Treatment Evaluation in Neurodegenerative Disorders

描述（由申请人提供）：阿尔茨海默病（AD）是美国最大的公共卫生挑战之一。目前还没有治愈阿尔茨海默病的方法，但制药公司和学术界正在研究几种针对阿尔茨海默病早期神经病理的药物，这些药物对大脑的损害是不可修复的。然而，这项研究受到进行阿尔茨海默病临床试验的巨大费用的阻碍。这些费用很高，因为很难识别患有早期症状性阿尔茨海默病或症状前阿尔茨海默病的个体，也因为阿尔茨海默病发展缓慢，需要很长时间才能发现治疗是否有效。该项目的目标是开发新的神经成像生物标志物，可以作为阿尔茨海默病脑退化的替代措施。这项研究将建立在NIH/NIA阿尔茨海默病神经成像倡议（ADNI）的成功基础上，该倡议通过在三年的时间里每半年对数百名受试者的大脑进行成像，研究了脑成像作为生物标志物的有效性。这项研究的一个关键的早期结论是，海马体的体积，从脑MRI估计，是一个高度敏感的生物标志物，可能会增加一个数量级的治疗效果检测比传统的心理测量。我们的项目将以这一发现为基础，开发新的生物标志物，更精确地检查海马体解剖结构，并考虑到这种复杂大脑结构的异质性。我们的项目不同于ADNI (a)，因为它使用专门针对海马体和周围结构的MRI方案，(b)因为它利用死后MRI和组织学数据来分析体内成像数据；(c)因为它将产生更详细的测量结果，描述海马体和相关结构（如内嗅皮层）的单个子域的体积、厚度和形状。本项目的具体目的是：(1)结合尸检组织样本和组织学的超高分辨率9.4特斯拉MRI，建立详细的人体海马和内嗅皮层三维计算图谱；(2)开发算法和软件，利用该图谱在体内MRI中自动检测海马和内嗅皮层的子区，该MRI采用t2加权协议，针对该区域；(3)比较3台和7台特斯拉MRI扫描仪对内侧颞叶成像和提取生物标志物的有效性；(4)利用健康老年人、轻度认知障碍患者、AD患者和额颞叶痴呆患者的影像学数据，评估AD进展检测和队列分层的新型生物标志物的敏感性和特异性。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the greatest public health challenges in the United States. There is no cure for AD, but pharmaceutical companies and academia are investigating several disease-modifying medicines that target early stages of AD neuropathology, before the damage to the brain is irreparable. However, this re- search is impeded by the enormous costs of conducting AD clinical trials. These costs are high because it is difficult to identify individuals who have early symptomatic or presymptomatic AD, as well as because AD develops slowly and it takes a very long time to discover whether a treatment is effective. The goal of this project is to develop novel neuroimaging biomarkers that can serve as surrogate measures of brain degeneration in AD. This study will build on the success of the NIH/NIA Alzheimer<s Disease Neuroimaging Initiative (ADNI), which has investigated the effectiveness of brain imaging as a biomarker by imaging the brains of hundreds of subjects semiannually over the course of three years. One of the key early conclusions of this study is that the volume of the hippocampus, as estimated from brain MRI, is a highly sensitive bio- marker that can likely increase the power of treatment effect detection by an order of magnitude over traditional psychometrics. Our project will build on this finding by developing novel biomarkers that examine hippocampal anatomy with greater precision and take into account the heterogeneity of this complex brain structure. Our project differs from ADNI (a) because it uses an MRI protocol that specifically targets the hippocampus and surrounding structures, (b) because it leverages postmortem MRI and histology data for the analysis of in vivo imaging data; and (c) because it will yield more detailed measurements describing the volume, thickness and shape of the individual subfields of the hippocampus and related structures such as the entorhinal cortex. The specific aims of this project are (1) to build a detailed three-dimensional computational atlas of the human hippocampus and entorhinal cortex using a combination of ultra high-resolution 9.4 Tesla MRI of autopsy tissue samples and histology; (2) to develop algorithms and software that would leverage this atlas for automatic detection of the subfields of the hippocampus and entorhinal cortex in in vivo MRI acquired with a T2-weighted protocol that targets this region; (3) to compare the effectiveness of 3 Tesla and 7 Tesla MRI scanners for imaging the medial temporal lobe and deriving biomarkers; and (4) to assess the sensitivity and specificity of the novel biomarkers for progression detection and cohort stratification in AD using imaging data from healthy elderly, individuals with mild cognitive impairment, AD patients, and patients with frontotemporal dementia. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is one of the greatest challenges public health challenges in the United States. This project aims to reduce the cost of conducting a clinical trial in Alzheimer's disease by making it easier to detect the effects of treatment in a relatively short time window and with fewer participants. If successful, this project may result in more clinical trials being launched and a greater likelihood of finding a cure for Alzheimer's disease.