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

项目总结 阿尔茨海默病(AD)是导致痴呆症的最常见原因。潜在的病理和生理 与阿尔茨海默病的发生和发展有关的变化被认为出现在临床之前的几年 表现形式。感觉障碍、步态异常和运动减慢可能先于AD的诊断 到十年或更长时间，呈现出一种令人兴奋的可能性，即感觉运动功能的变化可能会起到 AD的早期非侵入性生物标志物。我们小组之前的工作已经确定了认知之间的联系 表现和感觉障碍以及步态速度和变异性，使它们成为潜在的临床前标志物 公元早期的病理学。我们建议使用长达10年的现有纵向数据和持续/新数据 巴尔的摩老龄化纵向研究(BLSA)对大约1,000名老年人的收集，以检查 感觉功能、步速和可变性以及日常体力活动的自由生活测量(PA)的作用 作为认知障碍的前兆。我们还将确定感应器运动措施和 AD病理的生物标志物，包括[11C]-匹兹堡化合物B正电子发射的β沉积 CT、结构磁共振成像(MRI)脑萎缩、脑脊液的Tau和ptau 流畅，认知能力强。我们将进一步利用BLSA丰富的数据资源，开发一个 Parsimonius模型预测进展到MCI/AD的风险，并验证其在 社区动脉粥样硬化风险(ARIC)研究。更好地理解两者之间的联系 感觉运动改变、亚临床AD病理和认知表现可阐明高危表型 这与随着时间的推移认知结果不佳的风险增加有关，并增加了我们对 感觉、身体和认知功能随年龄增长而下降之间的复杂联系。为此， 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 反映阿尔茨海默病的风险增加，这可以作为临床试验的替代结果。 此外，感觉运动障碍可通过以下方式为AD预防提供可行和可修改的目标 确定听力等辅助康复技术实施的关键门槛(S) 艾滋病、矫正镜片、手术或药物治疗以矫正听力和/或视力损害(例如， 白内障手术、人工耳蜗植入)和物理治疗/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.