Hearing Biomarkers in Alzheimer's Disease

摘要 阿尔茨海默病(AD)是一种常见的神经退行性疾病，具有进行性记忆丧失和 认知能力下降。早期发现是防治阿尔茨海默病和阿尔茨海默病的关键 (ADRD)。据估计，即使将痴呆症的发病时间推迟一年，也会减少 痴呆症患病率上升10%。近年来，越来越多的证据表明，AD的病理改变 可在典型AD症状出现前5-10年出现在与感觉相关的大脑区域，提示 它们可以作为AD/ADRD检测和诊断的早期生物标志物。听力是一项重要的 神经感觉。听力损失也是痴呆症的一个主要高危因素。最近的研究表明， 视觉和听觉刺激与伽马振荡循环可减少淀粉样蛋白ȕ(Aȕ)在脑内的表达 改善阿尔茨海默病小鼠的大脑和记忆力。我们假设听力在阿尔茨海默病的发生和发展中起着关键作用 进步。然而，听力是AD研究中一个研究较少的领域。关于AD诱发的听力知之甚少 改变。以往的流行病学研究表明，AD患者可能会有听力损失。然而， 由于老年人通常患有年龄相关性听力损失(ARHL)，因此很难区分由AD引起的 在这些流行病学研究中，ARHL导致听力下降。与AD病理的联系也不可能是 已经确定，但仍不清楚。在本项目中，我们将使用AD鼠标模型来识别和表征 广告引起的听觉系统功能和病理改变(目标1)。家族性AD(FAD)和 零星的AD(SAD)小鼠模型将被用来增加实验的严谨性。广告引起的功能改变 在阿尔茨海默病的发展和进展过程中，将对听觉系统进行纵向检查和评估。 这些变化将与Aȕ和Tau蛋白的表达以及听觉系统中的基因组变化有关， 这将通过RNA测序进行评估。因此，可以明确地确定AD听力标记。 在目标2中，我们将使用AD和ARHL小鼠模型来进一步区分AD引起的听力下降和 ARHL。我们还将确定听力损失对AD/ADRD发展和进展以及测试的影响 急性淋巴细胞性白血病是否会加速/加重AD/ADRD的发展和进展。这些建议的研究 可以提高我们对AD病理和听力在AD/ADRD发生和发展中的作用的理解 进步。这些信息对于理解 声刺激对阿尔茨海默病的疗效及进一步提高治疗和预防水平。

Summary Alzheimer's disease (AD) is a common neurodegenerative disease with progressive memory loss and cognitive decline. Early detection is critical for prevention and treatment of AD and AD related dementia (ADRD). It has been estimated that delay of the onset of dementia by even one year would reduce the prevalence of dementia by 10%. Recently, increasing evidence demonstrates that AD pathological changes can occur in sensory associated brain areas 5-10 years early before typical AD symptoms present, suggesting that they could serve as early biomarkers for AD/ADRD detection and diagnosis. Hearing is an important neural sense. Hearing loss also is a major high-risk factor for dementia. Recent studies demonstrated that visual and auditory stimulations with gamma oscillation cycles could reduce amyloid-ȕ (Aȕ expression in the brain and improve memory in AD mice. We hypothesize that hearing has a critical role in AD development and progression. However, hearing is an understudied field in AD study. Little is known about AD-induced hearing changes. Previous epidemiological studies demonstrated that AD patients could have hearing loss. However, since aged persons usually have age-related hearing loss (ARHL), it was hard to distinguish AD-induced hearing decline from ARHL in those epidemiological studies. The link to AD pathology also could not be determined and remained unclear. In this project, we will use AD mouse models to identify and characterize AD-induced functional and pathological changes in the auditory system (Aim 1). Both familial AD (fAD) and sporadic AD (sAD) mouse models will be used to increase experimental rigor. AD-induced functional changes in the auditory system will be longitudinally examined and assessed during AD development and progression. These changes will be linked to Aȕ and Tau protein expressions and genomic changes in the auditory system, which will be assessed by RNA sequencing. The AD hearing marker, thus, can be unambiguously determined. In Aim 2, we will use both AD and ARHL mouse models to further distinguish AD-induced hearing decline from ARHL. We will also define the impact of hearing loss on AD/ADRD development and progression and test whether ARHL can accelerate/exacerbate AD/ADRD development and progression. These proposed studies can improve our understanding AD pathology and the role of hearing in AD/ADRD development and progression. Such information is also critical and required for understanding the underlying mechanism for the therapeutic effect of acoustic stimulation against AD and further improving treatment and prevention.