Contribution of sensorimotor function to risk and pathogenic mechanisms of Alzheimer's disease and related dementias

项目摘要 阿尔茨海默病（AD）是痴呆症最常见的原因。潜在的病理和生理 据信，与AD的发作和进展相关的变化在临床治疗前几年出现。 表现。感觉障碍、步态异常和运动减慢可能先于AD的诊断 十年或更长时间，提出了令人兴奋的可能性，即感觉运动功能的变化可能会作为 AD的早期非侵入性生物标志物。我们小组以前的工作已经确定了认知和行为之间的联系。 性能和感觉障碍以及步态速度和变异性，使其成为潜在的临床前标志物 早期AD病理学我们建议使用长达10年的现有纵向数据和正在进行的/新的数据 在巴尔的摩老龄化纵向研究（BLSA）中，收集了大约1,000名老年人的样本， 感觉功能、步态速度和变异性以及日常体力活动（PA）的自由生活措施的作用 是认知障碍的前兆我们还将确定感觉运动测量与 AD病理学的生物标志物，包括使用[11 C]-匹兹堡化合物B正电子发射的A β沉积 断层扫描，使用结构磁共振成像（MRI）的脑萎缩，来自脑脊液的Tau和pTau 流体和认知性能。我们会进一步利用劳工统计局丰富的数据资源， 进展为MCI/AD风险的parsimonius预测模型，并验证其在 社区动脉粥样硬化风险（ARIC）研究。更好地理解这些联系， 感觉运动改变、亚临床AD病理学和认知表现可能阐明了高风险表型 随着时间的推移，这与认知结果不佳的风险增加有关，并增加我们对 随着年龄的增长，感觉、身体和认知功能的下降之间存在着复杂的联系。为此目的， 未来的AD预防干预研究可能会将感觉运动障碍作为高危表型进行筛查 这反映了发展AD的风险增加，这可以作为临床试验中的替代结果。 此外，感觉运动障碍可能是预防AD的可行和可修改的目标， 确定实施听力等辅助和康复技术的关键门槛 助听器、矫正镜片、矫正听力和/或视力损伤的外科或药物程序（例如， 白内障手术，人工耳蜗植入），以及物理治疗/运动训练的时机和协调， 纠正步态异常。

PROJECT SUMMARY Alzheimer's disease (AD) is the most common cause of dementia. Underlying pathological and physiological changes related to the onset and progression of AD are believed to emerge several years prior to clinical manifestations. Sensory impairments, gait abnormalities, and motor slowing may precede the diagnosis of AD by a decade or more, presenting the exciting possibility that changes in sensorimotor functioning may act as early noninvasive biomarkers for AD. Previous work by our group has identified links between cognitive performance and sensory impairment and gait speed and variability, making them potential preclinical markers of early AD pathology. We propose to use up to 10 years of existing longitudinal data, and ongoing/new data collection in approximately 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examine the roles of sensory function, gait speed and variability, and free-living measures of daily physical activity (PA) as precursors to cognitive impairment. We will also determine the link between sensorimotor measures and biomarkers of AD pathology, including Aβ deposition using [11C]-Pittsburgh compound B positron emission tomography, brain atrophy using structural magnetic resonance imaging (MRI), Tau and pTau from cerebrospinal fluid, and cognitive performance. We will further utilize the rich data resources of the BLSA to develop a parsimonius prediction model for risk of progression to MCI/AD, and validate its performance in the Atherosclerosis Risk in Communities (ARIC) study. A better understanding of the associations among sensorimotor changes, subclinical AD pathology, and cognitive performance may elucidate a high-risk phenotype that is associated with increased risk of poor cognitive outcomes over time and increase our understanding of the complex associations among declines in sensory, physical, and cognitive functioning with age. To this end, future intervention studies of AD prevention might screen for sensorimotor impairments as a high-risk phenotype reflective of increased risk for developing AD, which could serve as surrogate outcomes in clinical trials. Moreover, sensorimotor impairments may present feasible and modifiable targets for AD prevention by identifying critical threshold(s) for implementation of assistive and rehabilitative technologies such as hearing aids, corrective lenses, surgical or pharmacologic procedures to correct hearing and/or vision impairment (e.g., cataract surgery, cochlear implants), and physical therapy/timing and coordination of movement training to correct gait abnormalities.