Early Age-Related Hearing Loss Investigation (EARHLI): A Randomized Controlled Trial to Assess Mechanisms Linking Early Age-Related Hearing Loss and Alzheimer's Disease and Related Dementias

项目摘要/摘要 这项建议是一项早期的II期随机对照试验(RCT)，以获得有关机制的初步数据 以助听器为基础的干预预防阿尔茨海默病高危人群认知能力下降的有效性 疾病和阿尔茨海默病相关痴呆(AD/ADRD)。目标风险人群为55-75岁人群 伴有早期年龄相关性听力损失(ARHL)和遗忘性轻度认知障碍。RCT，题为 《早期年龄相关性听力损失调查(EARHLI)》是对PAR-18-877《早期临床》的回应 阿尔茨海默氏症和与年龄相关的认知功能减退的试验。ARHL，第三大 晚年常见的慢性疾病，与认知障碍/AD/ADRD有关。这一发现已经 最近扩展到早期ARHL(纯音测听中临界至中度听力损失[20-55分贝])， 很少用助听器治疗。ARHL和AD/ADRD之间的联系机制尚不清楚，但 已经提出了减少社会参与和改变大脑组织/连接的建议。2020年的《柳叶刀》 委员会的一份报告估计，消除ARHL可能与减少8%的新痴呆症有关 病例，至少与公认的风险因素一样多。然而，90%的目标人口没有得到治疗 助听器，目前还缺乏测试助听器在急性淋巴细胞性白血病中疗效的随机对照试验。虽然研究表明 建议的助听器可以改善社会参与度、大脑组织/连通性，进而提高认知能力 没有随机对照试验的证据支持这些观察。有一项正在进行的随机对照试验(ACELE，ClinicalTrials.gov NCT03243422)研究听力干预对患有晚期听力障碍的老年人认知的影响 ARHL。EARHLI侧重于中老年早期ARHL，这是预防AD/ADRD的关键时期。 与ACEIVE不同，EARHLI还测量大脑组织/连接性。EARHLI将是第二阶段1：1 RCT 一项基于助听器的干预与对照(健康教育计划)相比，在 150名早期ARHL患者(76例接受MRI检查)有AD/ADRD的风险。最重要的假设是 听力干预将改善社会参与度和大脑组织/连接性， 与对照ARM相比，将导致认知能力的提高。检验这一假设的目的是-- 听力干预与对照臂对照的治疗方法。目标1是比较 阿尔茨海默病临床前合作研究的认知能力测量 认知复合测验(ADCS-PACC；1？结果)和ADCS-PACC的领域特定认知测验 成分(0、6、12个月)。目标2是比较通过活动衡量的社交参与度的变化 参与度(1：结果)和网络规模/支持(0、6、12个月)。目标3是比较大脑的变化 使用任务(视觉任务、感兴趣的听觉区域、1：结果)和静息状态功能磁共振成像的组织/连接， 和扩散加权的结构连通性(0、12个月)。我们将探讨社会参与度和 大脑组织/连通性在干预对认知结果的影响中起中介作用。

PROJECT SUMMARY/ABSTRACT This proposal is an early phase II randomized controlled trial (RCT) to obtain preliminary data on mechanisms and efficacy of a hearing aid-based intervention to prevent cognitive decline in those at risk for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD). The target risk group is 55-75-year old people with early-stage age-related hearing loss (ARHL) and amnestic mild cognitive impairment. The RCT, entitled “Early Age-Related Hearing Loss Investigation (EARHLI)” is in response to PAR-18-877, “Early Stage Clinical Trials for the Spectrum of Alzheimer’s Disease and Age-related Cognitive Decline.” ARHL, the third most common chronic condition in later life, is associated with cognitive impairment/AD/ADRD. This finding has recently been extended to early ARHL (borderline-to-moderate hearing loss [20-55 dB] on pure tone audiometry), which is rarely treated with hearing aids. The mechanisms linking ARHL and AD/ADRD are unknown, but reduced social engagement and changes in brain organization/connectivity have been proposed. A 2020 Lancet Commissions report estimated that eliminating ARHL could be associated with an 8% reduction in new dementia cases, at least as much as well-established risk factors. Yet, 90% of the target population is not treated with hearing aids and there is a dearth of RCTs testing the efficacy of hearing aids in ARHL. While studies have suggested hearing aids improve social engagement, brain organization/connectivity, and, in turn, cognition, there is no RCT evidence supporting these observations. There is one ongoing RCT (ACHIEVE, ClinicalTrials.gov NCT03243422) examining the effect of a hearing intervention on cognition in older adults with more advanced ARHL. EARHLI focuses on early ARHL in middle and early older age, a critical time for AD/ADRD prevention. Unlike ACHIEVE, EARHLI also measures brain organization/connectivity. EARHLI will be a phase II 1:1 RCT of a hearing aid-based intervention versus a comparator (health education program) conducted over 12 months in 150 participants (n=76 undergoing MRI) with early ARHL at risk for AD/ADRD. The overarching hypothesis is that the hearing intervention will lead to improved social engagement and brain organization/connectivity that will lead to improved cognition compared with the comparator arm. This hypothesis will be tested with an intent- to-treat approach comparing the hearing intervention and comparator arms. Aim 1 is to compare change in cognitive performance measured with the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC; 1º outcome) and by domain-specific cognitive testing on ADCS-PACC components (0, 6, 12 months). Aim 2 is to compare change in social engagement measured by activity participation (1º outcome) and network size/support (at 0, 6, 12 months). Aim 3 is to compare changes in brain organization/connectivity using task (visual task, auditory regions of interest,1º outcome) and resting-state fMRI, and diffusion-weighted structural connectivity (at 0, 12 months). We will explore whether social engagement and brain organization/connectivity mediate the effects of the intervention on cognitive outcomes.