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

目前，550万65岁以上的美国人（约10%）患有阿尔茨海默病（AD）， 到2050年将翻一番。AD是通过对神经退行性变的尸检分析明确诊断的， 存在含β-淀粉样蛋白（Aβ）的斑块和含tau蛋白的神经元缠结。作为 Aβ在大脑中的积累可以在认知障碍之前几十年， Aβ的清除在疾病难以诊断的早期阶段最有效。无法 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， 我是说。AD患者的前庭损害患病率高于年龄匹配的健康人。 对照组，姿势摇摆作为整体认知评估评分的良好预测因子， AD.步态指标更好地区分轻度认知障碍患者和健康对照患者， 比语言流畅度测试更重要此外，AD患者难以抑制不一致， 与年龄匹配的对照组相比，当保持平衡时，除了前庭 不平衡，AD患者在背景噪音中难以理解语音，这是一种称为 听觉处理障碍（APD）。APD的机制尚不清楚，但神经元特异性的电路 已知脑干的区域在语音处理和噪声掩蔽中起作用。此外，委员会认为， 更好的周边频率分辨率阈值与改善的噪声中的听力能力相关。 临床前模型对于检验关于AD病理生理学的假设和 评估假定的干预措施。然而，尚不清楚目前的AD小鼠模型是否表现出以下改变： 姿势摇摆、步态或APD，如在早期痴呆前AD患者中观察到的。也没有很好地确定， AD小鼠模型脑干中Aβ沉积增加，与死后组织学检查结果相似。 在几乎没有认知障碍证据的患者脑干中存在早期Aβ沉积的证据。我们 建议在5xFAD AD小鼠模型中测量这些早期AD症状的小鼠同源物 与无年龄相关性听力损失的小鼠品系杂交。在目标1中，我们将测量摇摆和步态障碍。 - 是的在目标2中，我们将使用同步切迹测量的听性脑干反应（ABR）， 噪声，以测量周边频率分辨率阈值和听觉滤波器形状。最后，我们将 确定这些缺陷是否与前庭中的斑块沉积、脱髓鞘或炎症相关 听觉脑干和中枢神经系统 该提案的影响将是开发早期AD的可靠临床前测定，为以下方面铺平道路： 开发和测试未来的痴呆前AD治疗方法。

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.