Advanced MR Imaging of Olfactory Impairment in Prodromal Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）是一种毁灭性的神经退行性疾病， 是最佳干预和指导治疗的关键，当疾病改善疗法变得可用时。 嗅觉功能障碍是AD的核心临床前体征，可预测轻度认知障碍的转化 (MCI)对AD的敏感性和特异性高。嗅觉系统是最早的大脑区域， 显示AD病理学，并且是提供直接进入内嗅皮层的唯一感觉系统 (ERC)和海马，内侧颞叶（MTL）结构对认知和记忆至关重要 AD和MCI下降。尽管嗅觉功能障碍与AD的病理生理学相关， 嗅觉障碍的神经生物学基础仍然知之甚少。迄今为止， 嗅觉一直局限于心理物理评估，这是主观的， 嗅觉系统潜在的生理异常我们开发了先进的7 T MRI方法， 检查嗅觉功能障碍，并将使用这些方法来研究微血管和代谢变化 嗅觉系统在前驱阿尔茨海默病患者和控制。在目标1和2中，我们将研究 在休息和嗅觉刺激期间微血管和代谢参数的异常。重要的是， 我们将量化不同血管类型（小动脉）的每个个体微血管和代谢参数 特别是）分开。这些指标将比相对全球性的、非特异性的 从行为测试中获得的受损嗅觉功能的指标。在目标3中，我们将评估 嗅觉系统神经血管异常与嗅觉行为测量的关系; 通过MRI测量的结构变化;以及已建立的AD的CSF生物标志物，包括β淀粉样蛋白、tau蛋白和 磷酸化tau蛋白。将在2年后收集所有受试者的认知测量的纵向随访结果。 受试者，将用于评价初次访视时的MRI测量值是否可预测 认知能力下降。这项工作将大大推进我们对微血管的理解， 以及与MCI中嗅觉障碍相关的代谢变化。这里使用的MRI测量是 非侵入性，可重复的纵向调查，并可以进行高空间分辨率， 人类从拟议的研究结果可以促进生物标志物的早期识别的发展 和AD的预测，也有可能为AD的早期干预治疗研究提供信息。

PROJECT SUMMARY Alzheimer's disease (AD) is a devastating neurodegenerative condition for which accurate and timely diagnosis is key for optimal intervention and for guiding treatment when disease-modifying therapies become available. Olfactory dysfunction is a core preclinical sign of AD that predicts conversion from mild cognitive impairment (MCI) to AD with high sensitivity and specificity. The olfactory system is among the earliest brain regions to demonstrate AD pathology and is the only sensory system that provides direct access to the entorhinal cortex (ERC) and hippocampus, medial temporal lobe (MTL) structures critically important for cognitive and memory decline in AD and MCI. Despite the relevance of olfactory dysfunction to the pathophysiology of AD, the neurobiological underpinnings of olfactory impairment remain poorly understood. To date, clinical evaluation of olfaction has been limited to psychophysical assessment, which is subjective and uninformative regarding underlying physiological abnormalities of the olfactory system. We have developed advanced 7T MRI methods to examine olfactory dysfunction and will use these methods to investigate microvascular and metabolic changes of the olfactory system in prodromal Alzheimer's disease patients and controls. In Aims 1 and 2, we will examine abnormalities in microvascular and metabolic parameters at rest and during olfactory stimulation. Importantly, we will quantify each individual microvascular and metabolic parameter for different blood vessel types (arterioles in particular) separately. These indices will be more biologically meaningful than the relatively global, nonspecific indicators of compromised olfactory function obtained from the behavioral tests. In Aim 3, we will assess the relationship between neurovascular abnormalities of the olfactory system and: olfactory behavioral measures; structural changes measured by MRI; and established CSF biomarkers of AD, including beta amyloid, tau and phosphorylated tau. A longitudinal follow-up of the cognitive measures will be collected after 2 years for all the participants, which will be used to evaluate whether the MRI measures at the initial visit are predictive for cognitive decline in these subjects. This work will significantly advance our understanding of the microvascular and metabolic changes associated with olfactory impairment in MCI. The MRI measures used here are noninvasive, repeatable for longitudinal investigations, and can be performed with high spatial resolution in humans. Results from the proposed studies can facilitate the development of biomarkers for early identification and prediction of AD and also has the potential to inform treatment studies for early intervention in AD.