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: 10256329
• 负责人: Charles Chiedu Nwaokobia
• 金额: $ 124.78万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256329
• 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; 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; 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产品--计算机化嗅觉训练 方案(COT)-作为一种疾病修正干预措施，用于预防进行性认知能力下降和 早期阿尔茨海默病(AD)中的进行性痴呆。婴儿床使用了经过验证的神经保护性嗅觉 刺激剂强烈刺激初级和次级嗅觉皮质，其刺激参数 克服嗅觉习惯化，配合计算机化的嗅觉认知训练任务，协同 增强相同的大脑区域；目标是提高结构和功能对AD的适应能力 进步。第一阶段研发达到或超过规定的技术里程碑：COT 干预导致轻度ApoE4携带者6个月和12个月后嗅觉和认知功能增强 认知障碍和早期痴呆症。在完成12个月随访的人中，COT变得迟钝 内嗅皮层和海马体萎缩的轨迹。此外，气味的急性影响 COT中调节睡眠干扰和情绪反应的分子增加了COT的潜在价值 用于治疗晚期阿尔茨海默病的行为障碍。阿尔茨海默病是一种重大的公共卫生危机 在美国和世界各地都是如此。到目前为止，还没有治疗方法显示出显著的疗效 将进展从AD的早期阶段调整到晚期阶段。最可能的疾病修饰 针对淀粉样蛋白生物合成和淀粉样β蛋白(Aβ)积累的不同步骤的治疗药物有 在第三阶段临床试验中，未能扭转认知能力下降或加重认知能力下降。然而， 神经科学证据表明，阿尔茨海默病的病理在嗅觉脑中进展较早，持续了几十年 出现进行性、不可逆转的认知衰退和痴呆症之前的区域，以及实验性 而临床研究发现，嗅觉损害加速了AD的进展，为 以嗅觉结构和功能为靶点对AD进展进行修饰。成功地使用了Enriched 气味环境在减少动物病理性神经丝聚集方面激发了人们对 将嗅觉训练(OT)转化为人类阿尔茨海默病的治疗。不幸的是，缺乏创新 维持嗅觉接触以充分影响大脑功能和结构可塑性的方法 临床人群，阻碍了OT向AD干预的转化。我们建造了一个创新的嗅觉工厂 家用治疗输送系统；建立了一种安全的神经保护植物的专利疗法 气味提取物和克服初级嗅觉皮质气味习惯化的刺激参数； 并创建了一个同步的App来同时管理嗅觉认知训练任务 协同作用，瞄准气味刺激的相同大脑区域。这款突破性的产品， 在我们的第一阶段SBIR中，COT在扭转认知能力下降方面表现出了极好的前景。的主要技术目标 这一第二阶段的项目是：(1)证明COT对预防脑萎缩和认知能力下降的有效性 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 对于用户友好性、家庭使用的便携性、可接受性和市场营销；以及(4)探索新的适应症 治疗中重度痴呆症患者的行为障碍，以努力减少护理- 给予者负担。在第二阶段完成后，我们将准备将研究扩大到第三阶段的功效 研究或实施研究通过商业伙伴关系在现实世界环境中的有效性 在这个项目的过程中开发的。据我们所知，这将是对 基于家庭的，可扩展的，计算机化的，基于化学感官的脑刺激，用于改善AD的疾病。