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

项目总结 阿尔茨海默病(AD)是一种毁灭性的神经退行性疾病，其准确和及时的诊断 是最佳干预措施的关键，也是在疾病修正疗法出现时指导治疗的关键。 嗅觉功能障碍是AD临床前的核心征兆，可预测轻度认知功能障碍的转归 (MCI)对AD具有较高的敏感性和特异性。嗅觉系统是最早的大脑区域之一 显示AD病理，是唯一提供直接进入内嗅觉皮质的感觉系统 (ERC)和海马区，内侧颞叶(MTL)结构对认知和记忆至关重要 AD和MCI下降。尽管嗅觉障碍与阿尔茨海默病的病理生理学有关，但 嗅觉障碍的神经生物学基础仍然知之甚少。到目前为止，临床评估 嗅觉一直被限制在心理物理评估上，这是主观的，对 嗅觉系统潜在的生理异常。我们已经开发出先进的7T磁共振成像方法 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 前驱阿尔茨海默病患者和对照组的嗅觉系统。在目标1和目标2中，我们将检查 静息和嗅觉刺激时微血管和代谢参数异常。重要的是 我们将量化每个单独的微血管和不同血管类型(小动脉)的代谢参数 特别是)分开。这些指数将比相对全球的、非特定的指数更具生物学意义 从行为测试中获得的嗅觉功能受损的指标。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； MRI测量的结构变化；以及已建立的AD脑脊液生物标志物，包括β淀粉样蛋白、tau和 磷酸化的tau。认知测量的纵向随访将在两年后收集所有 参与者，这将用于评估首次就诊时的MRI测量是否对 这些受试者的认知能力下降。这项工作将极大地促进我们对微血管的理解 以及与MCI的嗅觉障碍相关的代谢变化。这里使用的核磁共振测量方法有 非侵入性，可重复进行纵向研究，并可在 人类。拟议研究的结果有助于开发生物标记物进行早期鉴定。 和AD的预测，也有可能为AD的早期干预的治疗研究提供信息。

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.