Principles of olfactory reward processing in the human brain

摘要 阿尔茨海默病引起的痴呆或轻度认知障碍影响着数百万美国人。临床上 其特征在于一般认知能力下降和显著的记忆障碍。然而，第一批 在阿尔茨海默病中受到影响的功能是嗅觉。事实上，嗅觉功能障碍往往先于 其他认知和记忆障碍的发生。在大脑中，嗅觉信息是沿着 外侧嗅束（LOT），连接嗅球和皮质区的白质束， 梨状皮质和内嗅皮质。阿尔茨海默病患者的嗅觉知觉缺陷， 尸检研究表明，神经变性首先在嗅觉脑区域观察到， 球和内嗅皮层。基于这一证据，我们假设嗅觉障碍和认知障碍 早期阿尔茨海默病的发病率下降与LOT中的神经变性有关。的完整性 可以使用扩散加权磁共振在体内测量人脑中的白质通路 dMRI成像。然而，嗅觉结构的dMRI技术具有挑战性，因为突出的信号 这些区域中的丢失和图像变形。为了克服这些挑战，家长的一个主要目标是 项目（R 01 DC 015426）旨在开发一种新的dMRI方案和分析管道，以对人体LOT进行成像。我们 母项目目标3的初步结果表明，我们现在能够对人类LOT进行成像 前所未有的质量。此应用程序的目标是行政补充是使用我们的新成像 技术来直接测试我们关于阿尔茨海默病中LOT神经变性的假设。我们 建议在患有早期阿尔茨海默病和年龄的参与者中测量LOT的完整性- 匹配认知正常的对照组参与者。我们将比较各组之间的批次完整性，并测试是否 这些测量与嗅觉知觉缺陷和认知下降相关。拟议的工作将 使用体内成像技术表征阿尔茨海默病中的LOT神经变性，并建立 为阿尔茨海默病的新生物标志物的基础，是敏感的认知能力下降。这些生物标志物将 非侵入性，因此可用于在认知能力下降发生之前识别高危人群。此外，本发明还提供了一种方法， 该项目的结果可能会为阿尔茨海默病的机械模型提供信息，并有助于 针对特定大脑区域神经退化的新疗法。

ABSTRACT Dementia or mild cognitive impairment due to Alzheimer’s disease affect millions of Americans. Clinically, it is characterized by general cognitive decline and prominent memory impairments. However, one of the first functions to be affected in Alzheimer’s disease is the sense of smell. In fact, olfactory dysfunction often precedes the onset of other cognitive and memory impairments. In the brain, olfactory information is processed along the lateral olfactory tract (LOT), a white-matter bundle that connects the olfactory bulb to cortical areas including the piriform cortex and entorhinal cortex. Paralleling olfactory perceptual deficits in Alzheimer’s disease, post- mortem studies show that neurodegeneration is first observable in olfactory brain regions such as the olfactory bulb and entorhinal cortex. Based on this evidence, we hypothesize that olfactory impairments and cognitive decline in early-stage Alzheimer’s disease are both related to neurodegeneration in the LOT. The integrity of white-matter pathways in the human brain can be measured in vivo using diffusion-weighted magnetic resonance imaging (dMRI). However, dMRI in olfactory structures is technically challenging because of prominent signal dropout and image deformations in these areas. To overcome these challenges, a major goal of the parent project (R01DC015426) is to develop a novel dMRI protocol and analysis pipeline to image the human LOT. Our preliminary results of aim 3 of the parent project demonstrate that we are now able to image the human LOT with unprecedented quality. The goal of this application for administrative supplement is to use our new imaging technologies to directly test our hypothesis regarding LOT neurodegeneration in Alzheimer’s disease. We propose to measure the integrity of the LOT in participants with early-stage Alzheimer’s disease and age- matched cognitively normal control participants. We will compare LOT integrity between groups, and test whether these measures correlate with olfactory perceptual deficits and cognitive decline. The proposed work will characterize LOT neurodegeneration in Alzheimer’s disease using in vivo imaging techniques, and build the basis for novel biomarkers for Alzheimer’s disease that are sensitive to cognitive decline. Such biomarkers will be non-invasive and thus can be used to identify at-risk populations before cognitive decline occurs. In addition, the results from this project may inform mechanistic models of Alzheimer’s disease and aid the development of new treatments that target neurodegeneration in specific brain areas.