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

项目总结/摘要 这一建议是一个早期的II期随机对照试验（RCT），以获得机制的初步数据 以及基于助听器的干预措施预防阿尔茨海默病风险人群认知能力下降的有效性 阿尔茨海默病相关性痴呆（AD/ADRD）。目标风险人群为55-75岁的老年人 早期年龄相关性听力损失（ARHL）和遗忘性轻度认知障碍。该RCT题为 “早期听力损失相关调查（EARHLI）”是对PAR-18-877“早期临床 老年痴呆症和阿尔茨海默氏症相关认知能力下降的试验。ARHL，第三大 老年常见慢性病，与认知障碍/AD/ADRD相关。这一发现 最近扩展到早期ARHL（纯音测听的边缘至中度听力损失[20-55 dB]）， 很少用助听器治疗。ARHL和AD/ADRD之间的联系机制尚不清楚， 已经提出了减少的社会参与和大脑组织/连接的变化。2020年柳叶刀 委员会的报告估计，消除ARHL可能与新发痴呆症减少8%有关。 至少与公认的风险因素一样多。然而，90%的目标人群没有得到治疗， 助听器的有效性研究很少，也缺乏随机对照试验来测试助听器在ARHL中的疗效。虽然研究 建议助听器改善社会参与，大脑组织/连接，并反过来，认知， 没有RCT证据支持这些观察结果。有一项正在进行的RCT（ACHIEVE，ClinicalTrials.gov NCT 03243422）检查听力干预对患有更高级认知障碍的老年人认知的影响。 阿尔。EARHLI专注于中老年早期ARHL，这是AD/ADRD预防的关键时期。 与ACHIEVE不同，EARHLI还测量大脑组织/连接。EARHLI将是一项II期1：1 RCT， 一项基于助听器的干预与对照（健康教育计划）进行了12个月， 150例有AD/ADRD风险的早期ARHL受试者（n=76例接受MRI）。总体假设是 听力干预将改善社会参与和大脑组织/连接， 与对照组相比，将导致认知改善。将对该假设进行检验，目的是- 比较听力干预组和对照组的治疗方法。目标1是比较 阿尔茨海默病临床前合作研究（Preclinical Alzheimer） 认知复合量表（ADCS-PACC; 1º结局）和ADCS-PACC领域特异性认知测试 组件（0、6、12个月）。目的2是比较通过活动衡量的社会参与的变化 参与（1º结果）和网络规模/支持（0、6、12个月）。目的3是比较大脑的变化 使用任务（视觉任务，听觉感兴趣区域，1º结果）和静息状态fMRI的组织/连接， 和扩散加权结构连接性（0、12个月）。我们将探讨社会参与和 脑组织/连接调节干预对认知结果的影响。

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.