Early auditory and imbalance measures in a mouse model of Alzheimer's Disease-Supplement

阿尔茨海默病小鼠模型的早期听觉和不平衡测量-补充剂

• 批准号: 10283003
• 负责人: ANNE E LUEBKE
• 金额: $ 33.29万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283003
• 关键词: AD transgenic mice; Acoustic Nerve; Age; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; American; Amyloid beta-Protein; Animals; Antibodies; Auditory; Auditory Brainstem Responses; Auditory Perceptual Disorders; Autopsy; Behavioral; Biological Assay; Biological Markers; Brain; Brain Pathology; Brain Stem; CBA/CaJ Mouse; Cell physiology; Clinical; Clinical Research; Cochlea; Dementia; Demyelinations; Deposition; Diagnosis; Disease; Disease Marker; Early Diagnosis; Equilibrium; Event; Exhibits; Financial Hardship; Frequencies; Functional disorder; Future; Gait; Gait abnormality; Health; Hearing Tests; High Prevalence; Histologic; Histology; Homologous Gene; Human; Impaired cognition; Impairment; Inflammation; Intervention; Labyrinth; Masks; Measures; Modeling; Mouse Strains; Mus; Mutation; Names; Nerve Degeneration; Neurofibrillary Tangles; Noise; Outer Hair Cells; Pathology; Patients; Peripheral; Pharmacology; Play; Population; Posture; Pre-Clinical Model; Presbycusis; Process; Resolution; Role; Shapes; Signal Transduction; Symptoms; Testing; Therapeutic; Time; Toxic effect; Transgenes; Translating; abeta accumulation; abeta deposition; auditory processing; balance testing; base; cognitive testing; early onset; human old age (65+); human very old age (85+); improved; mild cognitive impairment; mouse model; notch protein; otoacoustic emission; pre-clinical; response; speech in noise; speech processing; tau Proteins

Currently, 5.5 million Americans (~10%) over age 65 have Alzheimer's disease (AD), and this number will more than double by 2050. AD is definitively diagnosed from post-mortem analyses of neurodegenera- tion with the presence of β-amyloid (Aβ) containing plaques and tau-containing neurofibrillary tangles. As Aβ accumulation in the brain can precede cognitive impairment by decades, treatments aimed at facilitating clearance of Aβ are most effective at early stages, when the disease is difficult to diagnose. The inability to detect AD early enough to apply meaningful interventions is a major barrier to AD's successful manage- ment. AD patients have a higher prevalence of vestibular impairment relative to healthy age-matched controls, with postural sway serving as an excellent predictor of the overall cognitive assessment score in AD. Gait metrics discriminated better between patients with mild cognitive impairments and healthy con- trols, more so than verbal-fluency tests. Additionally, patients with AD have difficulty suppressing incongru- ent brain signals when maintaining balance compared to age-matched controls. In addition to vestibular imbalances, AD patients have difficulties understanding speech in background noise, a deficit known as auditory processing disorder (APD). The mechanisms of APD are unclear, yet circuitry in auditory-specific regions of the brainstem are known to play a role in speech processing and noise masking. Moreover, better peripheral frequency resolution thresholds correlate with improved hearing in noise abilities. Preclinical models have been extremely useful to test hypotheses about AD pathophysiology and to assess putative interventions. However, it is unknown if current AD mouse models exhibit alterations in postural sway, gait, or APD, as observed in early pre-dementia AD patients. It is also not well established if increased Aβ deposition occurs in the brainstems of AD mouse models, similar to post-mortem histological evidence of early Aβ deposition in brainstems of patients with little evidence of cognitive impairment. We propose to measure mouse homologues of these early AD symptoms in the 5xFAD AD mouse model crossed to mouse lines without age-related hearing loss. In Aim 1, we will measure sway and gait distur- bances. In Aim 2, we will use auditory brainstem responses (ABRs) measured in simultaneous notched noise to measure peripheral frequency resolution thresholds and auditory filter shapes. Lastly, we will determine if these deficits correlate with plaque deposition, demyelination, or inflammation in the vestibular and auditory brainstem and CNS. The impact of this proposal will be in developing robust preclinical assays of early AD, paving the way to develop and test future therapeutics for pre-dementia AD.

目前，65岁以上的550万美国人（约10％）患有阿尔茨海默氏病（AD），这个数字 到2050 与含有斑块的β-淀粉样蛋白（Aβ）的存在和含Tau神经原纤维缠结的情况。作为 大脑中的Aβ积累可以在数十年之前的认知障碍之前，旨在促进 当疾病难以诊断时，在早期阶段清除Aβ最有效。无法 尽早发现广告以应用有意义的干预措施是AD成功管理的主要障碍 - 精神。 AD患者相对于健康年龄匹配的前庭障碍患病率较高 对照组，姿势滑道是对整体认知评估评分的出色预测指标 广告。步态指标在患有轻度认知障碍的患者和健康方面的患者之间得到了更好的区分 巨魔，比语言素养测试更重要。此外，AD患者难以抑制不gongru- 与年龄匹配的对照相比，保持平衡时的ENT脑信号。除前庭 不平衡，广告患者在背景噪声中很难理解语音，这种辩护被称为 听觉处理障碍（APD）。 APD的机制尚不清楚，但在特定于听觉的电路中 众所周知，脑干区域在语音处理和噪声掩盖中发挥作用。而且， 更好的外围频率分辨率阈值与提高噪声能力的听力相关。 临床前模型对于测试有关AD病理生理学和TO的假设非常有用 评估推定的干预措施。但是，尚不清楚当前的AD鼠标模型是否在 如早期的痴呆前AD患者中所观察到的，姿势摇摆，步态或APD。如果 Aβ沉积增加发生在AD小鼠模型的脑干中，类似于死亡后组织学 早期Aβ沉积在患者的脑干中的证据，几乎没有认知障碍的证据。我们 在5XFAD AD鼠标模型中测量这些早期AD症状的小鼠同源物的建议 越过小鼠线，没有与年龄相关的听力损失。在AIM 1中，我们将测量摇摆并收集干扰 在AIM 2中，我们将使用同时测量的听觉脑干响应（ABR）（ABR） 噪声以测量外围频率分辨率阈值和听觉过滤器形状。最后，我们会的 确定这些缺陷是否与前庭中斑块沉积，脱髓鞘或炎症有关 和听觉的脑干和中枢神经系统。 该提案的影响将是对早期AD的强大临床前评估，铺平了通往的方式 开发和测试未来止动物AD的疗法。