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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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，这一数字将增加一倍以上。 AD 是通过神经退行性疾病的尸检分析来明确诊断的。 β-淀粉样蛋白 (Aβ) 含有斑块和含有 tau 的神经原纤维缠结的存在。大脑中 Aβ 的积累可能会先于认知障碍数十年，旨在促进的治疗 Aβ 的清除在疾病难以诊断的早期阶段最有效。尽早发现 AD 并采取有意义的干预措施是 AD 成功管理的主要障碍相对于健康年龄匹配的患者，AD 患者的前庭功能障碍患病率更高。控制，姿势摇摆可以作为总体认知评估分数的出色预测指标 AD 步态指标可以更好地区分轻度认知障碍患者和健康状况良好的患者。此外，AD 患者难以抑制不一致的情况。与年龄匹配的对照组相比，在保持平衡时，大脑会发出信号。由于失衡，AD 患者在背景噪音中难以理解言语，这种缺陷被称为听觉处理障碍（APD）的机制尚不清楚，但听觉特异性的电路。众所周知，脑干区域在语音处理和噪声掩蔽中发挥作用。更好的外围频率分辨率阈值与改善噪音听力能力相关。临床前模型对于检验有关 AD 病理生理学的假设和然而，目前的 AD 小鼠模型是否表现出变化尚不清楚。姿势摇摆、步态或 APD，如在早期痴呆前期患者中观察到的，目前也尚未确定。 AD 小鼠模型脑干中 Aβ 沉积增加，与死后组织学相似几乎没有认知障碍证据的患者脑干中早期 Aβ 沉积的证据。建议在 5xFAD AD 小鼠模型中测量这些早期 AD 症状的小鼠同源物在目标 1 中，我们将测量摇摆和步态干扰。在目标 2 中，我们将使用同步陷波测量的听觉脑干反应 (ABR)。最后，我们将使用噪声来测量外围频率分辨率阈值和听觉滤波器形状。确定这些缺陷是否与斑块沉积、脱髓鞘或前庭炎症相关以及听觉脑干和中枢神经系统。该提案的影响将在于开发早期 AD 的可靠临床前检测方法，为开发和测试未来痴呆前期 AD 的治疗方法。