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.

摘要 我们建议评估和优化便携式，家庭为基础的产品-电脑嗅觉训练 计划（COT）-作为一种疾病修饰干预措施，用于预防进行性认知衰退， 早期阿尔茨海默病（AD）中的进行性痴呆。COT使用经过验证的神经保护嗅觉 刺激物强烈地接合初级和次级嗅觉皮层，刺激参数 克服嗅觉习惯化，配合计算机化的嗅觉认知训练任务， 增强相同的大脑区域;目的是增加对AD的结构和功能弹性 进展第一阶段的研究和开发达到或超过了规定的技术里程碑：COT 干预导致轻度ApoE 4携带者在6个月和12个月后的嗅觉和认知功能增加， 认知障碍和早期痴呆。在12个月随访访视的完成者中，COT变钝 内嗅皮层和海马体萎缩的轨迹。此外，气味剂的急性效应 COT中调节睡眠中断和情绪反应的分子增加了COT的潜在价值 用于治疗晚期AD的行为功能障碍。阿尔茨海默病是一个重大的公共卫生危机 无论是在美国还是全世界。迄今为止，没有任何治疗方法在以下方面表现出显著的有效性： 改变AD从早期到晚期的进展。大多数假定的疾病修饰 针对淀粉样蛋白生物合成和淀粉样蛋白β（Aβ）积累的各个步骤的治疗剂具有以下任一种 在III期临床试验中未能逆转认知能力下降或使认知能力下降恶化。然而，在这方面， 神经科学证据表明，AD病理学在嗅觉脑中早期发展，持续数十年 在出现进行性、不可逆的认知衰退和痴呆之前， 嗅觉损害加速AD进展的临床研究结果， 在AD进展的调节中靶向嗅觉结构和功能。成功使用浓缩的 气味环境在减少动物病理性神经丝聚集方面的作用激发了人们对 将嗅觉训练（OT）转化为人类AD的治疗。遗憾的是，缺乏创新 维持嗅觉参与足以影响功能和结构可塑性的方法， 临床人群，阻碍了OT转化为AD干预。我们建立了一个创新的嗅觉 家庭使用的治疗输送系统;建立了安全的神经保护植物的专有方案 克服初级嗅觉皮层中气味习惯化的气味提取物和刺激参数; 并创建了一个同步应用程序，同时管理嗅觉认知训练任务， 协同地靶向被气味刺激的相同大脑区域。这个突破性的产品， COT在我们的I期SBIR中显示出很好的逆转认知下降的前景。关键技术目标 该II期项目的目的是：（1）证明COT预防脑萎缩和认知能力下降的疗效 在早期痴呆症的有效随机临床试验中;（2）验证其安全性;（3）进一步配置平台 用户友好性、家庭使用的便携性、可接受性和营销;以及（4）探索新的适应症， 治疗中度至晚期痴呆症患者的行为障碍，以减少护理- 给予者的负担在第二阶段完成后，我们将准备将研究扩展到第三阶段疗效 研究，或通过商业伙伴关系在现实世界环境中的有效性实施研究 在这个项目的过程中发展起来。据我们所知，这将是第一次评估一个 基于家庭的、可扩展的、计算机化的、基于化学传感器的脑刺激用于AD中的疾病修饰。