Longitudinal Changes in Auditory Function Among Veterans with Diabetes

 描述(由申请人提供)： 糖尿病(DM)是一种代谢性疾病，会导致微血管和神经并发症，影响20%-30%的退伍军人。有证据支持糖尿病和听力损失之间的联系。越来越多的证据--包括我们自己的实验室--表明，与DM相关的有害影响改变了耳蜗、听神经和大脑，影响了外周、中枢和认知水平的听觉处理。由于已知听力损失对个人的社会、情绪和经济健康的不利影响，即使是轻微的外周听力损失，当与中枢和认知能力下降相结合时，也具有隐匿性，并且在这一人群中可能出现视力和听力双重感觉丧失，因此，揭示与DM相关的听觉衰老的病理生理和组织病理学机制是重要的。 像大多数以前考虑听力损失和糖尿病的研究一样，来自NCRAR的初步发现是在横断面研究中建立的。我们发表的结果支持这样一种观点，即糖尿病的影响在年轻人群中更显著，这让人想起老年非糖尿病患者以及患有更严重疾病、需要胰岛素的退伍军人中老年性耳聋的变化(Austin等人，2009年；Konrad-Martin等人，2010年)。然而，从历史上看，我们没有解决随着时间的推移听力障碍的进展，或者这些听力变化如何影响言语理解或生活质量。我们目前处于对患有和不患有糖尿病的退伍军人进行的为期4年的听觉功能纵向研究的最后一年，其中一些人在5-17年前首次出现在我们的DM研究中，从而提供了额外的纵向对比。像许多队列研究一样，这种纵向研究随着观察时间的延长而变得更有价值。 我们建议继续对这一有价值的糖尿病相关退伍军人队列进行纵向监测 并通过对2型糖尿病小鼠模型中与糖尿病相关的听觉衰老的纵向评估来补充研究结果。拟议的研究旨在更准确地确定与单纯衰老相比，糖尿病在人类和小鼠中的纵向变化，包括估计听觉和认知功能障碍关键指标的影响大小和发病年龄。我们在这两个物种中引入了时间处理的测量方法，因为它对人类的语音理解很重要，而且在动物模型中，神经和行为水平的时间处理受损与DM可能过早发生的外周听觉变化有关。 具体目的：(1)比较退伍军人2型糖尿病患者听功能的纵向变化，并评估其与正常年龄的差异。具体目的(2)确定2型糖尿病加重小鼠耳蜗性老年性耳聋的程度。明确目的(3)明确退伍军人中DM的特点和伴发疾病是导致听力障碍的危险因素。 我们希望结果表明，糖尿病先于外周疾病的下降并导致其下降， 退伍军人的中枢-听觉和认知加工，尽管DM效应的时间轨迹因个体而异。由于一些糖尿病的并存可以通过严格的代谢控制来缓解，如果听觉通路的过早恶化能够被证明与糖尿病的严重程度密切相关，那么就存在一个潜在的预防机制，可以在未来的临床试验中进行测试。通过研究人类和小鼠听觉功能的纵向变化以及糖尿病的纵向趋势，我们将能够更好地确定这种复杂疾病中听觉功能障碍的生物原因，从而找到预防或延缓损害的方法。结果将包括预测模型，该模型识别给定个体DM风险因素概况的关键听觉测量的可能纵向轨迹。适当的干预可能会减轻听力和认知的损害，从而提高糖尿病患者的生活质量。因此，这项研究无可争议地促进了退伍军人改善健康和福祉的退伍军人使命。

 DESCRIPTION (provided by applicant): Diabetes Mellitus (DM) is a metabolic disease that causes microvascular and neurologic complications and affects 20-30% of Veterans. Evidence supports a link between DM and hearing loss. A growing body of evidence-including from our own laboratory-suggests that DM-related harmful effects alter the cochlea, auditory nerve, and brain, impacting auditory processing at peripheral, central, and cognitive levels. Because ofthe documented adverse effects of hearing loss on an individual's social, emotional and economic well-being, the insidious nature of even a mild peripheral hearing loss when combined with central and cognitive declines,and the potential for dual sensory loss of vision and hearing in this population, it is important that the pathophysiologic and histopathologic mechanisms of DM-related auditory senescence be revealed. Like most previous studies considering hearing loss and DM, initial findings originating from the NCRAR were established in cross-sectional studies. Our published results support the notion that DM effects are more notable in a younger population, reminiscent of changes from presbycusis among non-diabetics who are much older, and among Veterans with more severe disease, requiring insulin (Austin et al 2009; Konrad-Martin et al., 2010). However, historically, we did not address progression in auditory dysfunction over time, or how these hearing changes impact speech understanding or quality of life. We are currently in the last year of a 4-year longitudinal study of auditory function among Veterans with and without DM, some of whom were first seen in our DM studies 5-17 years ago, thereby providing additional longitudinal contrasts. Like many cohort studies, this longitudinal study becomes more valuable the longer the observation is continued. We propose to continue longitudinal surveillance in this valuable cohort of Veterans with DM-related auditory and cognitive changes and to augment findings with a longitudinal assessment of DM-related auditory senescence in a mouse model of type 2 DM. Proposed research aims to more precisely determine the longitudinal changes from DM compared to changes from aging alone in humans and mice, including estimating effect sizes and the age of onset of key measures of auditory and cognitive dysfunction. We introduce measures of temporal processing in both species because of its importance for speech understanding in humans and because, in animal models, impaired temporal processing at neural and behavioral levels has been linked to peripheral-auditory changes that may occur prematurely with DM. Specific Aim (1) Benchmark longitudinal changes in auditory function among Veterans with type 2 DM and estimate the differences from normal aging. Specific Aim (2) Determine the extent to which type 2 DM exacerbates presbycusis in the mouse cochlea. Specific Aim (3) Determine the DM characteristics and comorbidities that are risk factors for auditory dysfunction in Veterans. We expect results to demonstrate that DM precedes and contributes to declines over time in peripheral, central-auditory and cognitive processing among Veterans, although the temporal trajectory of the DM effects will vary across individuals. Since some DM comorbidities can be mitigated by strict metabolic control, if premature deterioration of the auditory pathway can be shown to associate strongly with DM severity, there exists a potential mechanism for prevention that can be tested in a future clinical trial. By studying longitudinal changes in auditory function in humans and mice together with longitudinal trends in DM, we will be better able to determine the biological causes of auditory dysfunction in this complex disease, and thus ways to prevent or delay the damage. Results will include prediction models that identify the likely longitudinal trajectory of key auditory measures for an individual given their DM risk factor profile. Appropriate intervention could potentially mitigate impairments of hearing and cognition, leading to improved quality of life for those with DM. Therefore, this study indisputably promotes the VA mission of improved health and well-being of our nation's Veterans.