Statistical Methods for Kidney Markers as Shared Determinants of Dementia and Physical Disability in Older Adults

肾脏标志物作为老年人痴呆和身体残疾的共同决定因素的统计方法

• 批准号: 10522857
• 负责人: Michelle Denise Shardell
• 金额: $ 79.35万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522857
• 关键词: 25-hydroxyvitamin D; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Award; Biological; Biological Aging; Biological Markers; Biology; Blood Tests; Brain; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Treatment; Code; Cognition; Cognitive; Cohort Studies; Communities; Computer software; Data; Dementia; Development; Disease; Elderly; Event; Future; GDF15 gene; Goals; Health; Homeostasis; Hormones; Human; Impaired cognition; Impairment; Intervention; Joints; Kidney; Kidney Diseases; Lead; Life Expectancy; Link; Longitudinal Studies; Marker Discovery; Measures; Methods; Minerals; Modeling; Molecular; Muscle; Musculoskeletal; Nerve Degeneration; Nervous system structure; Neurologic; Neuronal Injury; Outcome; Pathology; Persons; Physical Performance; Premature aging syndrome; Prevention; Property; Proteomics; Public Health; Renal function; Renal tubule structure; Research; Risk; Risk Factors; Skeletal Muscle; Source; Statistical Methods; Structural Models; Testing; Time; Uremia; Vitamin D; age related; aged; body system; bone; candidate marker; cofactor; cognitive performance; cohort; data harmonization; disability; epidemiology study; fibroblast growth factor 23; improved; innovation; metabolomics; multidimensional data; novel; novel marker; physically handicapped; post gamma-globulins; predictive modeling; prevent; preventive intervention; protein metabolite; therapeutic target; tool

Dementia affects over 44 million adults worldwide, and Alzheimer’s disease (AD) and related dementias (ADRD) account for 60-80% of all cases among older adults. Physical disability is often the final consequence of dementia before death. One-third of dementia cases may be attributable to modifiable factors, and due to unclear benefit of approved AD treatment, there is a need to identify intervention targets to prevent dementia and physical disability. Since both conditions may be preceded by declining cognitive and physical perform- ance by over a decade, shared biological determinants of dual cognitive-physical decline that impact neuro- logical, musculoskeletal, and other organ systems may inform therapeutic targets to prevent dementia and physical disability. Separate research on these endpoints indicates that declining kidney function, which is a model of premature aging, relates to both cognitive and physical decline. Trials of treatments to reverse kidney disease are underway, but prevention may be more effective. Thus, identifying early markers of kidney decline that are related to dual cognitive-physical decline and joint dementia-disability onset in initially health older adults is a key step toward this goal. Beyond known kidney effects on bone, a kidney-brain axis and kidney- muscle axis posit multiple mechanisms by which declining kidney health may lead to dementia and physical disability such as kidney aging, impaired mineral homeostasis, and accumulation of uremic markers. However, epidemiologic studies have not rigorously investigated whether kidney markers of these biological mechanisms affect relations and dynamics between cognitive and physical endpoints. Plus, studies of longitudinal cognitive and physical endpoints are vulnerable to survival bias and unmeasured confounding. Limitations of current statistical methods are a key barrier to accurately quantifying the strength of relations between cognitive and physical endpoints and to identifying markers of shared biological mechanisms to explain these relations. Thus, new statistical methods are needed to overcome these barriers. Specific aims of this proposal are to: 1) quantify relations between cognitive and physical endpoints over time; 2) test relations of kidney markers with cognitive-physical endpoints; and 3) develop/validate a biomarker risk score to jointly and dynamically predict dementia and disability. To this end, we propose to extend novel structural models for multivariate longitudinal and time-to-event outcomes and apply them to harmonized data from 8 cohort studies of >22,000 community- dwelling adults aged at least 65 years. We hypothesize that after addressing survival bias, cognitive and physical endpoints will have stronger relations that are explained and predicted, in part, by markers of kidney aging, impaired mineral homeostasis and by accumulation of uremic markers. New statistical methods developed as essential tools to jointly study cognitive and physical endpoints will be made available to the scientific community. The ultimate public health impact of this project is the potential for novel candidate biomarkers to inform development of new strategies to prevent ADRD and physical disability in older adults.

痴呆症影响全球超过4400万成年人，阿尔茨海默病（AD）和相关痴呆症 ADRD占老年人所有病例的60 - 80%。身体残疾往往是最终的后果 老年痴呆症的症状三分之一的痴呆症病例可能归因于可改变的因素， 批准的AD治疗的益处尚不清楚，有必要确定预防痴呆的干预目标 和身体残疾。因为这两种情况都可能伴随着认知和身体表现的下降- 十多年来，双重认知-身体衰退的共同生物决定因素影响了神经系统， 逻辑，肌肉骨骼和其他器官系统可以告知治疗目标，以预防痴呆症， 身体残疾。对这些终点的单独研究表明，肾功能下降， 过早衰老模型，涉及认知和身体衰退。逆转肾功能的治疗试验 疾病正在发生，但预防可能更有效。因此，识别肾脏衰退的早期标志物 与最初健康的老年人的双重认知-身体衰退和关节痴呆-残疾发作有关 成人是实现这一目标的关键一步。除了已知的肾脏对骨骼的影响，肾-脑轴和肾- 肌肉轴包括多种机制，通过这些机制，肾脏健康状况下降可能导致痴呆症和身体疾病。 残疾，如肾老化、矿物质稳态受损和尿毒症标志物积累。然而，在这方面， 流行病学研究尚未严格调查这些生物学机制的肾脏标志物是否 影响认知和物理端点之间的关系和动态。另外，关于纵向认知的研究 和物理终点易受生存偏倚和未测量混杂因素的影响。电流限制 统计方法是准确量化认知和行为之间关系强度的关键障碍。 物理终点，并确定共同的生物机制的标记，以解释这些关系。 因此，需要新的统计方法来克服这些障碍。本提案的具体目标是： 随着时间的推移量化认知和身体终点之间的关系; 2）测试肾脏标志物与 认知-身体终点;和3）开发/验证生物标志物风险评分，以联合和动态地预测 痴呆和残疾。为此，我们建议扩展新的结构模型，多变量纵向 和事件发生时间结果，并将其应用于来自8项队列研究的> 22，000个社区的协调数据， 成年人居住年龄至少65岁。我们假设，在解决生存偏倚后，认知和 身体终点将有更强的关系，这在一定程度上可以通过肾脏标志物来解释和预测。 衰老、矿物质稳态受损和尿毒症标志物积累。新的统计方法 作为共同研究认知和身体终点的基本工具， 科学界。该项目的最终公共卫生影响是潜在的新候选人 生物标志物，为制定预防老年人ADRD和身体残疾的新策略提供信息。