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岁以上的美国人有550万(约10%)患有阿尔茨海默病(AD)，而这个数字 到2050年将翻一番以上。AD是通过对神经退行性变的尸检分析确诊的- 伴有β-淀粉样蛋白(A-β)的斑块和含有tau的神经原纤维缠结。AS β在大脑中的积聚可以比认知障碍早几十年，治疗旨在促进 在疾病难以诊断的早期阶段，清除Aβ是最有效的。不能 及早发现AD以应用有意义的干预措施是AD成功管理的主要障碍- 门槛。与年龄匹配的健康人相比，AD患者前庭功能障碍的患病率更高 对照，姿势摆动是认知评估总分的一个很好的预测因子 广告。步态测量在轻度认知障碍患者和健康对照组之间有更好的区分 巨魔，比语言流利性测试更是如此。此外，阿尔茨海默病患者难以抑制不适。 与年龄匹配的对照组相比，ENT大脑在保持平衡时发出信号。除了前庭 失衡，AD患者在背景噪音中理解语言有困难，这种缺陷被称为 听觉加工障碍(Apd)。动作电位的机制尚不清楚，但在听觉特异的回路中 众所周知，脑干的区域在语音处理和噪音掩蔽中扮演着重要角色。此外， 较好的外周频率分辨率阈值与提高听力中的噪声能力相关。 临床前模型对于检验有关AD病理生理学的假说和 评估假定的干预措施。然而，目前尚不清楚目前的AD小鼠模型是否在 在早期痴呆前期AD患者中观察到的姿势摆动、步态或动作电位。它也不是很确定的，如果 AD模型小鼠脑内Aβ沉积增多，与死后组织学相似 几乎没有认知障碍证据的患者脑内早期Aβ沉积的证据。我们 建议在5xFAD小鼠模型中测量这些早期AD症状的小鼠同源性 与小鼠杂交，没有与年龄相关的听力损失。在目标1中，我们将测量摇摆和步态抖动- 班斯。在目标2中，我们将使用同步切迹测量的听性脑干反应(ABR) 测量外围频率分辨率阈值和听觉滤波器形状的噪声。最后，我们将 确定这些缺陷是否与前庭斑块沉积、脱髓鞘或炎症有关 听觉脑干和中枢神经系统。 这项提议的影响将是开发强有力的早期AD的临床前检测，为 开发和测试未来治疗痴呆症前期AD的疗法。