Imaging of glutamatergic system changes in Alzheimer's disease in vivo

摘要 阿尔茨海默氏病（AD）是老年痴呆症中最常见的形式，也是第六大原因 死亡在美国。超过2500万人受到这种疾病的影响，随着人口老龄化的增加， 预计到2025年这一数字将翻一番。AD的特征包括进行性记忆丧失， 认知能力和不良行为变化。AD的标志性脑神经病理学包括 细胞外淀粉样蛋白-b（Ab）斑块的积累，细胞内神经纤维缠结（NFT）形成， 所有6种tau亚型的聚集，早期突触毒性和神经递质改变，神经胶质增生，最终 神经元损失和脑萎缩。由于目前还没有AD的疾病改善治疗， 迫切需要开发可以阻止或减缓其进展的疗法。然而，研究开发 由于对AD的确切病因学的不完全理解， 疾病和缺乏对潜在的特异性症状前分子变化敏感的成像生物标志物 AD发作和进展可转化为人类研究。 新出现的数据表明，AD的早期认知变化可能是由于兴奋性神经元的调节异常， 通过可溶性Ab寡聚体的突触能神经传递，其导致tau蛋白磷酸化，过度刺激 谷氨酸受体和突触改变。寡聚体Ab也损害星形胶质细胞的正常功能， 从而导致谷氨酸介导的神经元兴奋性毒性并最终导致AD中的神经变性。 由于突触丧失是AD中记忆缺陷的最佳相关性，因此Ab斑块和/或NFT可能无法捕获 最早的变化，有助于启动阶段的AD。不断积累的数据表明， 神经元系统功能可以潜在地作为AD的进一步机制见解的目标， 开发早期生物标志物以及AD的疾病修饰疗法。 使用磁共振无创观察谷氨酸（Glu）和肌醇（MI）的变化 成像方法，可以作为替代生物标志物，以探测由于肿瘤的发生， 突触密度和星形胶质细胞密度的变化。虽然，1H磁共振 波谱（MRS）是测量这些代谢物的标准方法，它具有较低的空间分辨率 磁共振成像（MRI）。 在本提案中，我们将进一步发展和优化最近引入的化学交换饱和度 用于测量谷氨酸（GluCEST）和肌醇（MICEST）的转移（CEST）加权成像方法， 在测量谷氨酸和肌醇的灵敏度和空间分辨率方面优于1HMRS， 分别具体而言，我们将首先确定方法在测量 谷氨酸和肌醇在AD病理学中的作用。然后，我们将在AD小鼠模型（APP-KI， AD-APP-KI），其作为疾病发作和进展的函数，紧密地概括人AD，并确定 这些指标的变化与免疫组化（IHC）的变化之间的相关性， 测量突触和星形胶质细胞密度。成功完成拟议项目将导致：（i） 关于代谢能系统在疾病起始阶段起关键作用的机制信息 （ii）经验证的和临床上可翻译的测量疾病的非侵入性成像生物标志物 （iii）可用于识别的非侵入性生物标志物， 疾病靶点和纵向评估潜在的疾病修饰疗法，从而有助于 加强病人护理。

Abstract Alzheimer’s disease (AD) is the most common form of dementia in the elderly and the sixth leading cause of death in the US. Over 25 million people are affected by the disease and as the aging population increases, this number is expected to double by 2025. Characteristics of AD include progressive memory loss, decline in cognitive skills, and adverse behavioral changes. The hallmark brain neuropathologies of AD include the accumulation of extracellular amyloid-b (Ab) plaques, intracellular neurofibrillary tangles (NFTs) formed by aggregates of all 6 tau isoforms, early synaptotoxicity and neurotransmitter alterations, gliosis, and ultimately neuronal loss and brain atrophy. Since there is currently no disease modifying treatment for AD, there remains a pressing need for development of therapies that can stop or slow its progression. However, research to develop and evaluate novel AD therapies is hampered by an incomplete understanding of the precise etiology of the disease and a lack of imaging biomarkers sensitive to specific pre-symptomatic molecular changes underlying AD onset and progression that are translatable to human studies. Emerging data suggests that early cognitive changes in AD may be due to the dysregulation of excitatory glutamatergic neurotransmission by soluble Ab oligomers, which lead to tau phosphorylation, over stimulation of glutamate receptors and synaptic alterations. Oligomeric Ab also impairs the normal function of astrocytes, thereby contributing to glutamate-mediated neuronal excitotoxicity and eventually to neurodegeneration in AD. Since, synapse loss is the best correlate of memory deficits in AD, Ab plaques and/or NFTs may not capture earliest changes that contribute to the initiating stages of AD. Accumulating data suggest that changes in glutamatergic system function can potentially serve as a target for further mechanistic insights of AD and for the development of both early biomarkers as well as disease modifying therapies for AD. Changes in glutamate (Glu) and myo-inositol (MI) observable noninvasively using magnetic resonance imaging methods, may serve as surrogate biomarkers to probe dysregulation of the glutamatergic system due to changes in synaptic density and astrocytic density, respectively. Although, 1H magnetic resonance spectroscopy (MRS) is the standard approach for measuring these metabolites, it has lower spatial resolution than magnetic resonance imaging (MRI). In this proposal, we will further develop and optimize recently introduced chemical exchange saturation transfer (CEST) weighted imaging methods for measuring glutamate (GluCEST) and myo-inositol (MICEST) that out-perform 1HMRS in terms of sensitivity and hence spatial resolution in measuring glutamate and myo-inositol, respectively. Specifically, we will first establish the precision and specificity of the methods in measuring the glutamate and myo-inositol in AD pathology. Then, we will perform CEST MRI in AD mouse models (APP-KI, AD-APP-KI) that closely recapitulate human AD, as a function of disease onset and progression, and determine the association of changes in these indices with the changes in the immunohistochemistry (IHC) derived measures of synaptic and astrocytic density. Successful completion of the proposed project will lead to: (i) mechanistic information about critical role that glutamatergic system plays in the initiating stages of the disease and progression (ii) validated and clinically translatable noninvasive imaging biomarkers that measure disease at the pre-symptomatic stages and follow it longitudinally (iii) noninvasive biomarkers that can be used to identify disease targets and longitudinally evaluate potential disease modifying therapies and thereby contribute to the enhanced patient care.