Sensory and Perceptual Measures as Biomarkers of Alzheimer's Disease Pathology

 描述（由申请人提供）：我目前是印第安纳州大学医学院放射学和成像科学系神经成像中心的助理研究教授。我的研究生和研究生工作主要集中在神经成像生物标志物，用于检测和诊断阿尔茨海默病（AD）和其他痴呆症的临床前和前驱阶段。我的长期职业目标是成为一名独立的研究者，专注于开发用于检测和诊断神经退行性疾病（如AD）的工具。作为实现我的长期职业目标的工具，同时扩展我的知识和专业知识，我的短期目标是评估临床前和前驱AD患者样本中多个领域的感觉功能变化，以更好地了解现有证据表明的多感觉变化，这些变化与疾病早期的AD病理生理学同时发生，并可能先于AD病理生理学。视觉功能测量（使用倍频技术评估对比敏感度）、视网膜形态学（通过光学相干断层扫描测量的视网膜萎缩），一种嗅觉识别的测量方法（宾夕法尼亚大学听觉识别测试），以及音调听觉和中枢听觉处理的测量（纯音测听;两分句识别、两分数字测试、具有同侧竞争消息的合成句识别），将在老年人中进行评估（60岁或60岁以上）在没有心理测量缺陷1或遗传背景的情况下，由于存在主观认知下降而有进展为AD的风险（家族AD史和/或APOE e4等位基因携带者），以及患有遗忘型轻度认知障碍，AD前驱期，和年龄匹配的认知正常的健康对照，没有投诉或已知的遗传风险。我将研究以下具体目标：[1]检验以下假设，即结合多种感觉方式将提供关于微妙认知变化的补充信息，并预测老年人在AD临床前和前驱期的未来衰退;[2]检验AD临床前和前驱期的多感觉功能减退是由大脑淀粉样蛋白沉积和/或神经变性驱动的假设，以确定AD的阶段-关于AD 2的当前理论框架的感觉功能障碍的特异性; [3]测试感觉网络内改变的大脑连接与临床前和前驱AD中多感觉功能的测量相关的假设。这项研究的长期目标是更好地了解临床前和前驱AD感觉变化的病理生理学基础，以及建立感觉测量作为检测早期AD神经病理学的新型，非侵入性和廉价的生物标志物。经过验证后，我希望这些措施将用于临床环境中的筛选和/或诊断，以改善患者的护理，针对那些最有可能进展为AD的治疗或生活方式干预。经验证的感觉生物标志物也可用于新的AD治疗试验，以改善筛选，样品富集，并可能作为疗效结果的措施。

 DESCRIPTION (provided by applicant): I am currently an Assistant Research Professor at the Center for Neuroimaging in the Department of Radiology and Imaging Sciences at the Indiana University School of Medicine. My graduate and post-graduate work has focused on neuroimaging biomarkers for detection and diagnosis of Alzheimer's disease (AD) and other dementias in preclinical and prodromal stages. My long-term career goal is to become an independent investigator with a focus on developing tools for detection and diagnosis of neurodegenerative diseases such as AD. As a vehicle toward achieving my long-term career goals while expanding my knowledge and expertise, my short-term goal is to assess changes in sensory function in multiple domains in a sample of individuals with preclinical and prodromal AD to better understand the poly-sensory changes that available evidence suggests develop concurrent with and possibly precede AD pathophysiology in early stages of disease. Measures of visual function (contrast sensitivity assessed using frequency doubling technology), retinal morphology (retinal atrophy measured by optical coherence tomography), a measure of olfactory identification (University of Pennsylvania Smell Identification Test), and measures of tonal hearing and central auditory processing (pure tone audiometry; Dichotic Sentence Identification, Dichotic Digits Test, Synthetic Sentence Identification with Ipsilateral Competing Message) , will be evaluated in older adults (aged 60 or older) at risk for progression to AD due to the presence of subjective cognitive decline in the absence of psychometric deficits1 or genetic background (family AD history and/or APOE e4 allele carrier), as well as patients with amnestic mild cognitive impairment, a prodromal stage of AD, and age-matched cognitively normal healthy controls without complaints or known genetic risk. I will investigate the following specific aims: [1] test the hypothesis that combining multiple sensory modalities will provide complementary information about subtle cognitive change and predict future decline in older adults in preclinical and prodromal stages of AD; [2] test the hypothesis that multi- sensory decline in preclinical and prodromal stages of AD is driven by cerebral amyloid deposition and/or neurodegeneration to determine the stage-specificity of sensory dysfunction with regard to the current theoretical framework of AD2; [3] test the hypothesis that altered brain connectivity within sensory networks is associated with measures of multi-sensory function in preclinical and prodromal AD. The long-term goal of this research is to better understand the pathophysiology underlying sensory changes in preclinical and prodromal AD, as well as to establish sensory measures as novel, non-invasive, and inexpensive biomarkers for detecting AD neuropathology in early stages. After validation, I expect these measures will be used in clinical settings for screening and/or diagnosis to improve patient care by targeting those most likely to progress to AD for therapeutic or lifestyle intervention. Validated sensory biomarkers could also be used in trials of new AD treatments to improve screening, sample enrichment, and potentially as efficacy outcome measures.