Linking olfactory deficits to memory impairment and AD neurodegeneration

嗅觉缺陷与记忆障碍和 AD 神经变性的联系

• 批准号: 10297048
• 负责人: Prasanna Rasika Karunanayaka
• 金额: $ 79.16万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297048
• 关键词: Affect; Age; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Area; Behavioral; Brain; Brain region; Cognition; Cognitive; Data; Dementia; Detection; Development; Diagnostic; Discrimination; Disease; Disease Marker; Disease Progression; Foundations; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Inferior; Insula of Reil; Joints; Knowledge; Lead; Link; Literature; Lobe; Magnetic Resonance Imaging; Medial; Memory; Memory impairment; Modeling; Nerve Degeneration; Odors; Olfactory Cortex; Olfactory dysfunction; Outcomes Research; Parkinson Disease; Participant; Pathology; Pathway interactions; Pattern; Performance; Positron-Emission Tomography; Prevention; Process; Research; Rest; Risk; Signal Transduction; Smell Perception; Structure; Temporal Lobe; Testing; To specify; Visual; age related; amnestic mild cognitive impairment; base; biomarker evaluation; clinical practice; cognitive development; cognitive function; design; entorhinal cortex; experimental study; imaging biomarker; improved; in vivo; mild cognitive impairment; network dysfunction; neuropathology; normal aging; piriform cortex; potential biomarker; pre-clinical; predictive marker; predictive modeling; prodromal Alzheimer' s disease; progressive neurodegeneration; screening; tool

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.

抽象的 嗅觉障碍可能会信号信号阿尔茨海默氏病（AD）。我们目前没有建立 可以在体内测试的模型，将AD神经变性与嗅觉和嗅觉缺陷有关 记忆。这种重要的知识差距阻碍了功能成像标记的发展 AD的评估和诊断。 我们已经开发了几种嗅觉FMRI范式，可以探测大脑区域功能障碍 早期AD神经退行性发生。我们的初步数据表明AD神经变性到功能 模型。我们假设MCI中的渐进性神经退行性破坏了嗅觉的连通性 网络（ON）通过海马到默认模式网络（DMN），导致嗅觉的早期定义 其次是记忆障碍。我们的研究旨在使用功能测试该假设的模型 静止状态fMRI和有效连通性的连通性（FC；大脑区域之间的同步）（EC；指示 大脑区域之间的相互作用）嗅觉任务fMRI；神经变性将通过体积评估 MRI（VMRI）。 AIM 1：确定认知正常受试者中与年龄相关的DMN网络的变化。 AIM 2：确定轻度认知受损受试者中的DMN网络的变化。 AIM 3：探索ON-DMN网络的渐进变化与认知之间的关系 MCI受试者的下降 拟议的研究的总体目标是严格测试AD神经变性模型，该模型 回答两个基本问题：a）与广告相关的气味识别和异味歧视防御 记忆障碍和神经退行性变化？ b）嗅觉是否会定义和渐进的破坏 DMN连通性信号AD痴呆的发展？研究成果可以提供许多途径 用于改善嗅觉测试作为广告标记。嗅觉测试，针对特定的大脑区域和过程 在AD早期受到影响的，可能会对其他其他疾病检测和预防持希望 神经变性疾病，例如帕金森氏病。