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

阿尔茨海默氏病前驱嗅觉障碍的先进 MR 成像

• 批准号: 10377495
• 负责人: Arnold Bakker
• 金额: $ 78.3万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377495
• 关键词: Address; Affect; Aging; Air; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-Protein; Anosmia; Area; Arteries; Behavioral; Blood Vessels; Blood Volume; Brain; Brain region; Cerebrovascular Circulation; Cerebrum; Clinical; Cognition; Cognitive; Core-Binding Factor; Deltastab; Development; Diagnosis; Disease; Dropout; Early Diagnosis; Early Intervention; Early identification; Energy Metabolism; Foundations; Functional disorder; Hippocampus (Brain); Homeostasis; Human; Image; Imaging Device; Impaired cognition; Individual; Intervention; Investigation; Literature; Magnetic Resonance Imaging; Maintenance; Measurement; Measures; Medial; Mediating; Memory; Memory Loss; Metabolic; Metabolism; Methods; Morphologic artifacts; Nerve Degeneration; Neurobiology; Neurons; Olfactory Cortex; Olfactory Pathways; Olfactory dysfunction; Oxygen; Participant; Pathology; Patients; Physiological; Physiology; Population; Predisposition; Psychophysics; Resolution; Rest; Risk Factors; Sensitivity and Specificity; Severities; Signal Transduction; Sinus; Smell Perception; Staging; Stimulus; Structural defect; Structure; Sum; Symptoms; System; Temporal Lobe; Testing; Time; Venous; Visit; Work; abeta accumulation; accurate diagnosis; aging brain; arteriole; behavior measurement; behavior test; biomarker development; brain dysfunction; brain tissue; cognitive function; design; entorhinal cortex; follow-up; functional decline; high risk; imaging modality; indexing; metabolic rate; mild cognitive impairment; neural circuit; neurobiological mechanism; neuropathology; neurophysiology; neurovascular; non-invasive imaging; novel; olfactory stimulus; pre-clinical; prodromal Alzheimer' s disease; research clinical testing; response; sensory system; tau Proteins; tau-1; tool

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.

项目概要 阿尔茨海默病 (AD) 是一种破坏性的神经退行性疾病，需要准确、及时的诊断 当疾病缓解疗法可用时，这是最佳干预和指导治疗的关键。 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变 (MCI) 对 AD 具有高敏感性和特异性。嗅觉系统是最早感知信息的大脑区域之一 展示 AD 病理学，是唯一可以直接访问内嗅皮层的感觉系统 (ERC) 和海马、内侧颞叶 (MTL) 结构对于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，临床评价 嗅觉仅限于心理物理评估，这是主观的且无法提供信息 嗅觉系统潜在的生理异常。我们开发了先进的7T 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 前驱阿尔茨海默病患者和对照者的嗅觉系统的变化。在目标 1 和 2 中，我们将研究 休息时和嗅觉刺激期间微血管和代谢参数异常。重要的是， 我们将量化不同血管类型（小动脉）的每个微血管和代谢参数 特别是）分开。这些指数将比相对全球性的、非特异性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之间的关系； 通过 MRI 测量结构变化；并建立了 AD 的脑脊液生物标志物，包括 β 淀粉样蛋白、tau 蛋白和 磷酸化 tau。两年后将收集所有认知测量的纵向随访 参与者，将用于评估初次就诊时的 MRI 测量是否可以预测 这些受试者的认知能力下降。这项工作将极大地增进我们对微血管的理解 以及与 MCI 嗅觉障碍相关的代谢变化。这里使用的 MRI 测量是 非侵入性，可重复进行纵向研究，并且可以在高空间分辨率下进行 人类。拟议研究的结果可以促进用于早期识别的生物标志物的开发 和预测 AD，也有可能为 AD 早期干预的治疗研究提供信息。