Development of Cognitive and Physical Activity Biomarkers for a Companion Dog Model of Alzheimer's Disease

尽管进行了几十年的研究，但目前还没有任何治疗或干预措施可以预防或逆转这种 阿尔茨海默病的病程。模型系统方法为体内临床前研究提供了一个强大的机会 对生命史相对较快的生物体的研究。然而，目前的模型在很大程度上依赖于实验室 转基因小鼠的数量，对转化为人类具有显著的限制。最近，伴犬 已经被认为是衰老研究中的一个有价值的模型，因为它们与 人类，包括相同的生活环境、疾病风险和负担、精算老龄化模式以及 获得先进的医疗保健系统。狗也会自发地发展与年龄相关的认知能力 伴随着神经病理的损害类似于阿尔茨海默病，使它们成为潜在的 阿尔茨海默病研究的强大模型系统。尽管实验室研究已经取得了进展，但使用 狗作为阿尔茨海默病的模型，目前评估老龄狗认知障碍的方法 依赖于在实验室外不易使用的专用设备和劳动密集型协议 环境，限制了我们利用伴侣犬模型的独特好处的能力。因此，有一个 迫切需要有效的措施和生物标记物，重点关注与认知和身体相关的障碍 阿尔茨海默氏症，这可以在与同伴狗的不同研究设计中实施。 我们将开发一套神经精神测试和体力活动生物标记物，可以尽早使用 阿尔茨海默病伴犬模型中的指标、诊断工具和结果测量。 具体地说，我们将1)调整目前的实验室神经心理学测试，以实现经济和可扩展 与同伴狗一起实施，2)开发简短的认知评估，可以通过以下方式完成 公民科学家，以及3)开发狗的体力活动生物标记物，基于预测 人类阿尔茨海默病的风险和严重程度。通过将这些措施与犬类老龄化项目相结合-a 全国范围内对10,000只伴犬的老化研究-我们将为未来的大规模研究奠定基础 研究开发阿尔茨海默病的伴侣犬模型。这项提案中制定的措施 将为狗老化项目中的现有研究提供与阿尔茨海默氏症相关的关键终点，例如 雷帕霉素在老龄犬身上的试验--实施雷帕霉素的兽医临床试验--一种有希望的药物 治疗阿尔茨海默氏症。随着这些措施的发展，研究人员将很好地 定位于研究关于内源性和外源性因素对认知的影响的各种假说 损伤和痴呆症，在一个有很大潜力转化为人类的模型中。

Despite decades of research, there are currently no treatments or interventions that can prevent or reverse the course of Alzheimer's disease. Model systems approaches provide a powerful opportunity for preclinical in vivo studies in organisms with relatively fast life histories. However, current models rely largely on laboratory populations of transgenic mice, with notable limitations for translation to humans. Recently, companion dogs have been recognized as a valuable model in aging research because they share many important features with humans, including the same living environments, disease risks and burdens, patterns of actuarial aging, and access to a sophisticated health care system. Dogs also spontaneously develop age-related cognitive impairments along with neuropathology resembling that seen in Alzheimer's disease, making them a potentially powerful model system for Alzheimer's disease research. Although laboratory studies have made progress using dogs as a model for Alzheimer's disease, current methods for assessing cognitive impairments in aging dogs rely on specialized equipment and labor-intensive protocols that are not easily employed outside laboratory settings, limiting our ability to capitalize on the unique benefits of a companion dog model. Thus, there is an urgent need for validated measures and biomarkers focused on cognitive and physical impairments associated with Alzheimer's disease which can be implemented in diverse study designs with companion dogs. We will develop a set of neuropsychiatric tests and physical activity biomarkers that can be used as early indicators, diagnostic tools, and outcome measures in a companion dog model of Alzheimer's disease. Specifically, we will 1) adapt current laboratory neuropsychological tests for economical and scalable implementation with companion dogs, 2) develop short-form cognitive assessments which can be completed by citizen scientists, and 3) develop physical activity biomarkers in dogs, based on measures that predict Alzheimer's disease risk and severity in humans. By integrating these measures with the Dog Aging Project – a nationwide study of aging in 10,000+ companion dogs – we will lay the groundwork for future large-scale research developing a companion dog model of Alzheimer's disease. The measures developed in this proposal will provide key Alzheimer's disease-related endpoints for existing studies in the Dog Aging Project, such as the Test of Rapamycin in Aging Dogs – which implements a veterinary clinical trial of Rapamycin – a promising therapeutic for Alzheimer's disease. Following the development of these measures, researchers will be well positioned to investigate diverse hypotheses about endogenous and exogenous factors contributing to cognitive impairments and dementia, in a model with strong potential for translation to humans.