阿尔茨海默病听觉信息整合障碍的神经机制及其早期诊断作用研究

阿尔茨海默病（AD）诊治研究的焦点已从痴呆阶段转移到痴呆前阶段，但目前仍缺乏简便无创的早期诊断标志物。听觉信息整合功能是听觉系统将双耳声学信号在知觉上整合到一起的能力，其在AD病程早期即受损，但确切的神经机制和在AD诊断中的价值仍然不清，瓶颈是缺乏有效的检测范式。课题组在前期工作中率先建立了精准的听觉信息整合功能检测范式-BIC范式，应用该范式发现散发性AD患者表现出病程依赖性的听觉信息整合障碍及听觉N1-P2成分缺失等神经电生理改变。本项目将基于家族性AD这一痴呆前阶段的理想研究人群，结合高时间分辨率的神经电生理技术和高空间分辨率的多模态核磁技术，明确听觉信息整合障碍在AD病程不同阶段的动态演变规律及其相应的神经通路、脑结构和脑功能网络改变，进而在淀粉样蛋白PET验证的散发性AD队列明确其在AD早期诊断和病情监测中的作用，从而阐明AD听觉信息整合障碍发生的神经机制，为AD的早期诊治服务。

The decades-long pre-dementia phase of Alzheimer’s disease (AD) affords a window of opportunity for early diagnosis and preventive interventions. A critical challenge in this field is to identify biomarkers that trace pre-symptomatic disease progression. While current diagnostic approaches for the pre-dementia phase of AD rely on a series of biomarkers such as cerebrospinal fluid (CSF) beta-amyloid and tau, and amyloid positron-emission tomography (PET) imaging markers, the cost and invasiveness of these approaches limit their use in routine clinical practice. Binaural integration is a cognitive process that involves the fusion of different auditory information presented to both ears simultaneously. It is important for auditory scene analyses based on source detection, identification and localization, and contributes to the “cocktail party effect”, whereby listeners are able to hear out speakers against other interfering voices in crowded listening environment. Although binaural integration dysfunction has been reported in AD patients, the underlying mechanism and its role in the early diagnosis of AD remains unclear, largely due to the lack of accurate assessments. Previously, we established the break in interaural correlation (BIC) task for accurate evaluation of binaural integration process and revealed disease stage-dependent changes of binaural integration function and the N1-P2 cortical auditory evoked potential in AD. As such, the objective of this proposal is to advance our recent work by studying the dynamic presentation of binaural integration function in pre-dementia and dementia phases of AD in a familial AD patients cohort, which gathers the core pathophysiological features of AD and thus represents an ideal population for the pre-dementia research. We will use both high-spatial-resolution MRI and high-temporal-resolution electrophysiological assessments to determine the underlying neural mechanism of binaural integration dysfunction in AD. Then we will further explore the role of BIC task in early diagnosis and disease progression evaluation in the sporadic AD patients cohort validated by amyloid PET imaging. Overall, the proposed study will unravel the neural mechanism of binaural integration dysfunction and develop potential effective approaches for early diagnosis in AD.