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AD的方法，但制药公司和学术界正在研究几种针对AD神经病理学早期阶段的疾病修饰药物，在对大脑的损害无法修复之前。 然而，进行AD临床试验的巨大成本阻碍了这项研究. 这些成本很高，因为很难识别患有早期症状或症状前AD的个体，以及因为AD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影像学生物标志物，可以作为AD脑变性的替代措施。 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，该倡议通过在三年内每半年对数百名受试者的大脑进行成像，研究了大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，根据大脑MRI估计的海马体体积是一种高度敏感的生物标志物，与传统的心理测量学相比，它可能会将治疗效果检测的能力提高一个数量级。 我们的项目将建立在这一发现的基础上，开发新的生物标志物，以更高的精度检查海马解剖结构，并考虑到这种复杂大脑结构的异质性。 我们的项目与ADNI不同，因为它使用专门针对海马和周围结构的MRI协议，（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，描述海马和相关结构（如内嗅皮层）的各个子区域的体积，厚度和形状。 本项目的具体目标是：（1）结合尸检组织样本的超高分辨率9.4特斯拉MRI和组织学，建立人类海马和内嗅皮层的详细三维计算图谱;（2）开发算法和软件，其将利用该图谱自动检测用T2-MRI采集的体内MRI中海马和内嗅皮层的子场。（3）比较3特斯拉和7特斯拉MRI扫描仪对内侧颞叶成像和导出生物标志物的有效性;和（4）使用来自健康老年人、轻度认知障碍个体、AD患者和额颞叶痴呆患者。 公共卫生相关性：阿尔茨海默病是美国公共卫生面临的最大挑战之一。 该项目旨在通过在相对较短的时间窗口和较少的参与者中更容易地检测治疗效果来降低进行阿尔茨海默病临床试验的成本。 如果成功，该项目可能会导致更多的临床试验启动，并有更大的可能性找到治愈阿尔茨海默病的方法。

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.