Linking olfactory deficits to memory impairment and AD neurodegeneration

摘要 嗅觉障碍可能是前驱阿尔茨海默病（AD）的信号。我们目前没有一个既定的 可以在体内测试的模型，将AD神经变性与嗅觉中的特定功能缺陷相关联， 记忆这一重大的知识差距阻碍了功能性成像标记物的发展， AD的评估和诊断。 我们已经开发了几种嗅觉功能磁共振成像范例，可以探测大脑区域的功能障碍， 出现早期AD神经变性。我们的初步数据表明，AD神经变性功能 模型我们假设MCI中进行性神经变性破坏了嗅觉的连接， 通过海马将默认模式网络（ON）转换为默认模式网络（DMN），导致嗅觉早期缺陷 然后是记忆力受损我们的研究旨在使用功能测试这个假设模型 静息状态fMRI和有效连接（EC;定向）中的连接（FC;大脑区域之间的同步） 在嗅觉任务fMRI期间，脑区域之间的相互作用）;神经变性将通过体积测量来评估。 MRI（vMRI）。 目的1：确定认知正常受试者ON-DMN网络中与年龄相关的变化。 目的2：确定轻度认知障碍（MCI）受试者的ON-DMN网络变化。 目的3：探索ON-DMN网络的渐进性变化与认知功能之间的关系。 MCI受试者下降 这项研究的首要目标是严格测试AD神经退行性疾病模型， 回答了两个基本问题：a）AD中的气味识别和气味辨别缺陷如何相关 记忆力受损和神经退化和B）嗅觉缺陷和对ON的进行性破坏- DMN连接信号AD痴呆的发展？研究成果可以提供多种途径 用于改善嗅觉测试作为AD标记。嗅觉测试，针对特定的大脑区域和过程 在AD中最早受到影响的细胞，可以为其他疾病的早期疾病检测和预防提供额外的希望。 神经退行性疾病，如帕金森病。

ABSTRACT Olfactory impairment may signal prodromal Alzheimer’s disease (AD). We currently do not have an established model that can be tested, in vivo, relating AD neurodegeneration to specific functional deficits in olfaction and memory. This significant knowledge gap impedes the development of functional imaging markers for the evaluation and diagnosis of AD. We have developed several olfactory fMRI paradigms that can probe the dysfunctions in brain regions where early stage AD neurodegeneration occurs. Our preliminary data suggest an AD neurodegeneration-to-function model. We hypothesize that progressive neurodegeneration in MCI disrupts the connectivity of the olfactory network (ON) to the default mode network (DMN) via the Hippocampus, leading to early deficits in olfaction followed by memory impairment. Our research is designed to test this hypothesized model using functional connectivity (FC; synchrony among brain regions) in resting state fMRI and effective connectivity (EC; directed interactions between brain regions) during olfactory task fMRI; neurodegeneration will be evaluated by volumetric MRI (vMRI). Aim 1: Determine age-related changes in the ON-DMN network in cognitively normal subjects. Aim 2: Determine changes in the ON-DMN network in mild cognitively impaired (MCI) subjects. Aim 3: Explore the relationships between progressive changes in the ON-DMN network, and cognitive decline in MCI subjects The over-arching goal of the proposed research will be to rigorously test an AD neurodegeneration model that answers two fundamental questions: a) How are odor-identification and odor-discrimination deficits in AD related to memory impairment and neurodegeneration? and b) Do olfactory deficits and progressive disruptions to ON- DMN connectivity signal the development of AD dementia? Research outcomes can provide numerous avenues for improving olfactory testing as an AD marker. Olfactory tests, which target specific brain areas and processes that are affected earliest in AD, could hold additional promise for early disease detection and prevention in other neurodegerative disease, such as Parkinson’s disease.