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

阿尔茨海默病（Alzheimer Disease，AD）是一种神经退行性疾病，是美国乃至世界范围内的主要健康问题之一 其临床特征是由脑组织的病理变化引起的进行性痴呆， 15-20岁时出现临床症状。迫切需要诊断方法来筛查人群的早期 当药物干预可能是最有效的，并提供手段， 在临床药物试验中监测治疗效果。 最近由国家老龄化研究所和阿尔茨海默病协会提出A/T/N（淀粉样蛋白/ tau/ 神经变性）方法通过AD相关的组织病理学对AD的阶段进行分类。而脑 淀粉样蛋白斑块和tau神经元缠结现在可以使用PET示踪剂在体内测量， 神经变性主要通过基于MRI的形态学研究在体内测量为组织萎缩。然而，在这方面， 组织病理学研究表明AD中的神经元损失显著超过组织体积的损失。 本项目的目的是介绍一种新的，可能广泛使用的，在体内基于MRI的神经成像 生物标志物，其将在非常早期的AD阶段检测神经元的损失，当这种损失未被 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 定量梯度回波（qGRE）技术。初步数据显示， qGRE鉴定了患有临床前和轻度AD的人的海马体中的两种类型的组织：一种类型- 具有明显较低神经元含量的组织（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）。 基于这一方法，我们计划实现以下具体目标： 目的1将建立萎缩前神经变性作为一种新的成像生物标志物的神经元损失之前， 组织萎缩，并且可以检测早期、临床前、AD阶段的神经元损失。 目的2将建立萎缩前神经变性作为识别脑功能丧失的生物标志物。 早期AD的连接和认知表现。 目的3将基于qGRE的萎缩前神经元丢失生物标志物与血浆Aβ42/Aβ40测量相结合 这将显著改善个体qGRE和血浆Aβ42/Aβ40检测的灵敏度 和AD病理学早期检测的特异性。 目的4：探讨AD相关基因的脑地形图与萎缩前病变的关系。 AD早期的神经退行性变。 总之，成功完成本提案的目标可以显著改善目前的成像 用于随时间监测个体患者的范例，并用作更敏感的测量。 AD病理学的神经退行性方面与组织萎缩的当前测量相比。

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.