Development and Evaluation of Computerized Olfactory Training Program (COT) for Cognitive Decline in Early Alzheimer's Disease (AD)

针对早期阿尔茨海默病 (AD) 认知衰退的计算机嗅觉训练计划 (COT) 的开发和评估

• 批准号: 10399659
• 负责人: Charles Chiedu Nwaokobia
• 金额: $ 124.51万
• 依托单位: EVON MEDICS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399659
• 关键词: Acute; Adult; Aftercare; Agitation; Alzheimer' s Disease; Alzheimer' s disease pathology; American; Amyloid; Amyloid beta-Protein; Anabolism; Animals; Awareness; Base of the Brain; Behavior Therapy; Behavioral; Brain; Brain region; Care given by nurses; Caregiver Burden; Caregivers; Caring; Cessation of life; Clinical; Cognitive; Collaborations; Confusion; Data; Data Set; Dementia; Development; Devices; Dimensions; Disease; Disease Progression; Eating; Effectiveness; Emotional; Emotions; Engineering; Ensure; Environment; Evaluation; FDA approved; Family Caregiver; Family member; Feedback; Financial Hardship; Functional disorder; Goals; Grant; Hippocampus (Brain); Home; Hour; Human; Impaired cognition; Impairment; Institution; Intervention; Intervention Studies; Intervention Trial; Judgment; Lead; Life; Magnetic Resonance Imaging; Manufacturer Name; Marketing; Measures; Medical; Memory Loss; Mental Health; Modification; Moods; Motivation; Neurocognitive Deficit; Neurologic; Neurosciences; Odors; Olfactory Cortex; Olfactory Pathways; Outcome; Pathologic; Patients; Performance; Persons; Phase; Phase III Clinical Trials; Placebos; Plants; Population; Prevention; Psychophysics; Public Health; Randomized Clinical Trials; Regimen; Research; Resolution; Risk; Safety; Sampling; Services; Site; Sleep; Sleep disturbances; Small Business Innovation Research Grant; Solid; Stimulant; Structure; System; Therapeutic; Time; Training; Training Programs; Translational Research; Translations; United States; Visit; abeta accumulation; actigraphy; advanced dementia; apolipoprotein E-4; base; care costs; cerebral atrophy; cognitive function; cognitive training; commercialization; computerized; cost; design; early phase clinical trial; effectiveness evaluation; effectiveness implementation study; efficacy study; entorhinal cortex; experience; feasibility trial; follow-up; habituation; innovation; intervention program; mild cognitive impairment; neurofilament; neuropathology; novel; physical conditioning; portability; prevent; preventive intervention; programs; prospective; randomized trial; research and development; resilience; stimulant use; success; therapeutic target; usability; user-friendly

ABSTRACT We propose to evaluate and optimize the portable, home-based product – the Computerized Olfactory Training Program (COT) – as a disease modifying intervention for prevention of progressive cognitive decline and progressive dementia in early Alzheimer's Disease (AD). The COT uses validated neuroprotective olfactory stimulants to intensely engage the primary and secondary olfactory cortices, with stimulation parameters that overcome olfactory habituation, paired with computerized olfactory cognitive training tasks that synergistically enhance the same brain regions; with the goal of increasing structural and functional resilience to AD progression. Phase I research and development met or exceeded stated technical milestones: COT intervention led to increased olfactory and cognitive functions 6 and 12 months later in ApoE4 carriers with mild cognitive impairment and early dementia. Among completers of 12-month follow-up visit, COT blunted trajectory in shrinkage of the entorhinal cortex and the hippocampus. Furthermore, the acute effects of odorant molecules in the COT in regulating sleep disruptions and emotional reactivity adds to a potential value of COT for treatment of behavioral dysfunctions in advanced AD. Alzheimer’s disease is a major public health crisis both in the United States and worldwide. Hitherto, no therapeutic has demonstrated significant effectiveness in modifying progression from early stages to advanced stages of AD. Most putative disease modifying therapeutics targeting various steps of amyloid biosynthesis and amyloid beta (Aβ) accumulation have either failed to reverse cognitive decline or worsened cognitive decline in Phase III clinical trials. However, neuroscience evidence that AD pathology progresses early, over several decades in the olfactory brain regions, before emergence of progressive, irreversible cognitive decline and dementia, as well as experimental and clinical findings that olfactory compromise accelerates the progression of AD, provide solid premise for targeting olfactory structure and function in the modification of AD progression. The success of use of enriched odor environment in reducing aggregation of pathological neurofilaments in animals spurred high hopes for translation of olfactory training (OT) into treatment of AD in humans. Unfortunately, lack of innovative approaches to sustain olfactory engagement sufficiently to influence functional and structural plasticity in clinical populations, hindered the translation of OT into an AD intervention. We built an innovative olfactory treatment delivery system for home use; established a proprietary regimen of safe neuroprotective plant odorant extracts and stimulation parameters that overcome odorant habituation in the primary olfactory cortex; and created a synchronized App to simultaneously administer olfactory cognitive training tasks that synergistically target the same brain regions being stimulated by the odorants. This breakthrough product, the COT showed excellent promise in reversing cognitive decline in our Phase I SBIR. Key technical objectives of this Phase II project are to: (1) demonstrate COT efficacy for prevention of brain atrophy and cognitive decline in a powered randomized clinical trial of early dementia; (2) validate its safety; (3) further configure the platform for user-friendliness, portability for home use, acceptability and marketing; and (4) explore new indications for treating behavioral disturbances in people with moderate to advanced dementia, in an effort to reduce care- giver burden. Upon completion of Phase II, we will be poised to expand the research to Phase III efficacy study, or an implementation study of effectiveness in the real-world setting through commercial partnerships developed over the course of this project. To the best of our knowledge, this will be the first evaluation of a home-based, scalable, computerized, chemosensory-based brain stimulation for disease modification in AD.

抽象的 我们建议评估和优化便携式家庭基础产品 - 计算机化的嗅觉培训 计划（COT） - 作为一种修改干预措施的疾病，以预防进行性认知能力下降和 早期阿尔茨海默氏病（AD）的进步痴呆症。婴儿床使用经过验证的神经保护嗅觉 诚实地与初级和次要嗅觉皮质相关的兴奋剂，并使用刺激参数 克服嗅觉习惯，并与计算机化的嗅觉认知训练任务配对 增强相同的大脑区域；目的是提高结构和功能弹性对广告 进展。第一阶段的研发达到或超过所陈述的技术里程碑：COT 干预导致6和12个月后的APOE4载体中的嗅觉和认知功能增加 认知障碍和早期痴呆症。在12个月后续访问的完成者中，Cot钝了 内嗅皮层和海马的收缩中的轨迹。此外，气形的急性影响 COT中的分子控制睡眠破坏和情绪反应性增加了婴儿床的潜在价值 用于治疗高级AD中的行为功能障碍。阿尔茨海默氏病是主要的公共卫生危机 在美国和全球。迄今为止，尚无治疗在 修改从早期阶段到AD高级阶段的进展。最假定的疾病修饰 针对淀粉样生物合成和淀粉样β（Aβ）积累各个步骤的治疗剂 在III期临床试验中，认知能力下降或认知能力下降无法逆转。然而， 神经科学的证据证明AD病理学在嗅觉大脑中几十年 在渐进式，不可逆转的认知下降和痴呆症出现之前的区域以及实验 嗅觉损害的临床发现加速了AD的发展，为 针对嗅觉结构和功能在AD进程的修饰中。使用丰富的成功 减少动物病理神经丝的聚集的气味环境刺激了人们对 将嗅觉训练（OT）转换为人类AD的处理。不幸的是，缺乏创新性 维持嗅觉参与的方法足以影响功能和结构可塑性 临床人群阻碍了OT转化为AD干预。我们建立了创新的嗅觉 用于家庭使用的治疗输送系统；建立了安全神经保护厂的专有疗法 气味提取物和刺激参数，这些参数克服了原发性嗅觉皮质中的气味习惯； 并创建了一个同步应用程序，以简单地管理嗅觉认知训练任务 有协同靶向被气味刺激的相同大脑区域。这个突破性产品， COT在逆转我们I期SBIR的认知能力下降方面表现出了极好的希望。关键的技术目标 该第二阶段项目是：（1）证明了预防脑萎缩和认知能力下降的COT效率 在早期痴呆的动力随机临床试验中； （2）验证其安全性； （3）进一步配置平台 用于用户友好，家庭使用的可移植性，可接受性和营销； （4）探索新的适应症 治疗中度至晚期痴呆症患者的行为灾难，以减少护理 吉夫·伯恩（Giver Burnen）。第二阶段完成后，我们将被毒化以将研究扩展到第三阶段的便利性 研究或通过商业合作伙伴关系对现实环境中有效性的实施研究 在这个项目的过程中开发。据我们所知，这将是对 基于家庭的，可扩展的，计算机化的，基于化学感应的脑模拟AD中的疾病修饰。