In vivo Identification of Pre-Atrophic Brain Neurodegeneration in Prodromal Alzheimer Disease with Quantitative Gradient Recalled Echo MRI

阿尔茨海默病是一种神经退行性疾病，是美国和世界范围内的主要健康问题之一 以脑组织病变引起的进行性痴呆为临床特征 临床症状缩短15-20年。迫切需要诊断方法对人群进行早期筛查 (临床前)当药物干预最有效时的AD病理征象，并为 在临床药物试验中监测疗效。 最近由国家老龄化和阿尔茨海默氏症协会A/T/N(淀粉样蛋白/tau/ 神经退行性变)方法通过AD相关组织病理学的方法对AD进行分期。而大脑 淀粉样斑块和tau神经原纤维缠结现在可以使用PET示踪剂在体内测量， 通过基于MRI的形态学研究，神经退行性变主要在体内被测量为组织萎缩。然而， 组织病理学研究表明，AD时神经元的丢失明显超过组织体积的丢失。 该项目的目标是介绍一种新的、可能广泛应用的、基于体内核磁共振成像的神经成像。 一种生物标记物，可以在AD的早期阶段检测神经元的丢失，而这种丢失是不被 体积测量(萎缩前神经变性)。我们的创新方法依赖于基于MRI的 本实验室发展的定量梯度回声(QGRE)技术。初步数据显示， QGRE在临床前和轻度AD患者的海马区发现了两种组织：一种类型- 神经元含量明显较低的组织(我们称之为暗物质，因为它在qGRE图像上看起来很暗)，以及 另一种类型--具有相对保存的神经元浓度的组织(我们称之为活组织)。 在此基础上，我们计划实现以下具体目标： 目标1将建立萎缩性前神经变性作为先于神经元丢失的新的成像生物标记物 组织萎缩，可以在AD的早期、临床前期和AD阶段检测到神经元的丢失。 目标2将建立萎缩性前神经变性作为识别大脑功能丧失的生物标志物 阿尔茨海默病早期的连接和认知表现。 AIM 3将把基于定量GRE的萎缩前神经元丢失的生物标记物与血浆Aβ42/Aβ40的测定结合起来 这将显著提高QGRE和血浆Aβ42/Aβ40检测的敏感性 和早期发现AD病理的特异性。 目标4将探索AD相关基因的脑部结构与萎缩前期之间的联系 阿尔茨海默病早期的神经变性。 总而言之，成功完成本提案的目标可以显著改善当前的成像 随着时间的推移监测单个患者的范例，并用作更敏感的测量 AD病理的神经退行性方面与目前对组织萎缩的测量相比较。

Alzheimer Disease (AD), one of the major health problem in US and worldwide, is a neurodegenerative disorder that is characterized clinically by progressive dementia caused by pathological changes in brain tissue preceding clinical symptoms by 15-20 years. Diagnostic methods are urgently needed for screening populations for early (preclinical) signs of AD pathology when drug intervention could be most efficient, and providing means for monitoring therapeutic efficacy in clinical drug trials. Recently proposed by National Institute of Aging and Alzheimer Association A/T/N (amyloid/ tau/ neurodegeneration) approach classifies stages of AD by means of AD-related tissue pathology. While brain amyloid plaques and tau neurofibrillary tangles can now be measured in vivo using PET tracers, the neurodegeneration is mostly measured in vivo as tissue atrophy by MRI-based morphological studies. However, histopathological studies demonstrated that the neuronal loss in AD significantly exceeds loss of tissue volume. The objective of this project is to introduce a new, potentially widely available, in vivo MRI-based neuroimaging biomarker that would detect loss of neurons at the very earlier AD stages when this loss is not recognized by volumetric measurements (pre-atrophic neurodegeneration). Our innovative approach relies on MRI-based quantitative Gradient Recalled Echo (qGRE) technique developed in our lab. Preliminary data demonstrate that the qGRE identifies two types of tissues in the hippocampus of people with preclinical and mild AD: one type – tissue with markedly lower neuronal content (that we term Dark Matter as it appears dark on qGRE images), and another type – tissue with a relatively preserved concentration of neurons (that we term Viable Tissue). Based on this approach, we plan to achieve the following Specific Aims: Aim 1 will establish pre-atrophic neurodegeneration as a new imaging biomarker of neuronal loss that precedes tissue atrophy and can detect loss of neurons in early, preclinical, AD stages. Aim 2 will establish pre-atrophic neurodegeneration as a biomarker identifying losses of brain functional connectivity and cognitive performance in early AD. Aim 3 will integrate qGRE-based biomarker of pre-atrophic neuronal loss with plasma Aβ42/Aβ40 measurement that would significantly improve upon individual qGRE and plasma Aβ42/Aβ40 tests with regard to sensitivity and specificity for an early detection of AD pathology. Aim 4 will explore an association between brain topographies of AD-related genes and pre-atrophic neurodegeneration at earlier stages of AD. In Summary, successful completion of the aims of this proposal could significantly improve the current imaging paradigm for monitoring individual patients over time, and for use as a more sensitive measure of the neurodegenerative aspects of AD pathology as compared with current measurements of tissue atrophy.