Revitalizing Cognition in Older Adults at Risk for Alzheimer's Disease with Near-Infrared Photobiomodulation

摘要 非常需要有效的治疗和预防疗法，其可以提供对症和有效的治疗。 对那些有患阿尔茨海默病风险的人的疾病改善益处。建议的多站点协作 该项目汇集了佛罗里达大学（UF）和亚利桑那大学（UA）的研究团队，以测试一种 一种新的、相对低成本、低风险和潜在高影响的治疗干预，用于老年人， 患老年痴呆症的风险增加。干预包括经颅和鼻内递送近 通过发光二极管发出红外线（NIR）光，也称为光生物调节。在细胞和动物方面的研究 模型表明，红光和红外光具有神经保护作用，并被认为可以改善线粒体功能。 通过促进细胞内ATP的产生。阿尔茨海默病的转基因小鼠模型 与假手术相比，经颅NIR显示β-淀粉样蛋白和神经元缠结减少 刺激.初步的人类研究也显示了在年轻人中有希望的行为发现， 创伤性脑损伤失语症和老年痴呆症患者来自我们团队的试点磷磁共振 老年人的31 P MRS和认知数据支持这种作用机制，并提供了 II期临床试验的有力证据。为了更全面地确定这种新的刺激是否 一种方法有可能提高认知正常但有患阿尔茨海默病风险的个体的认知能力 疾病，我们计划进行一项多中心双盲随机假对照II期临床试验。我们 总的假设是，暴露于近红外刺激将通过影响大脑健康产生有益的影响， 对线粒体功能的影响，如通过基于31 P MRS的ATP标记物、神经网络 功能连接（rs-fMRI）的变化，以及认知能力的改善。为了验证这个假设，我们 计划随机抽取168名有主观认知障碍的老年人，他们有一级家族病史， 阿尔茨海默氏病与假或真实的治疗组的比较，并评估神经影像学和认知结果 测量，之前和之后的12周干预，涉及经颅和鼻内NIR-PBM。的 方案将包括“实验室”和“家庭”会议，以及干预后3个月的随访。本试验将 确定：1）相对于假手术，NIR刺激是否改善了记忆和执行能力的表现 阿尔茨海默病风险增加的老年人对海马和额叶脑功能敏感的任务 2）相对于假手术，NIR刺激是否增强了脑功能和连接性， MRS磷ATP和静息状态功能连接的变化;以及3） 人口统计学、神经影像学和阿尔茨海默病相关风险因素影响大脑对NIR刺激的反应 而在老年人中，老年痴呆症的风险增加。结果将提供关键的见解， 这种新的近红外干预是否可以增强老年人的认知能力， 并将为未来的III期随机临床试验提供必要的数据。

ABSTRACT There is a great need for effective treatments and prevention therapies that can provide symptomatic and disease modifying benefits for those at risk for Alzheimer’s disease. The proposed multi-site collaborative project brings together research teams at the University of Florida (UF) and University of Arizona (UA) to test a novel, relatively low cost, low risk, and potentially high impact therapeutic intervention in older adults who are at increased risk for Alzheimer’s disease. The intervention involves transcranial and intranasal delivery of near infrared (NIR) light via light emitting diodes, aka photobiomodulation. Prior research in cellular and animal models suggest that red and infrared light are neuroprotective and thought to improve mitochondrial function by promoting increased production of intracellular ATP. Transgenic mouse models of Alzheimer’s disease demonstrate reduced beta-amyloid and neurofibrillary tangles in response to transcranial NIR versus sham stimulation. Preliminary human studies have also shown promising behavioral findings in young adults and those with TBI, aphasia, and Alzheimer’s disease. From our team, pilot phosphorous magnetic resonance spectroscopy (31P MRS) and cognitive data in older adults support this mechanism of action and provide compelling evidence for a Phase II clinical trial. To more fully determine whether this novel stimulation approach has potential for enhancing cognition in cognitively normal but “at risk” individuals for Alzheimer’s disease, we plan to conduct a multi-site double blinded randomized sham-controlled Phase II clinical trial. Our overall hypothesis is that exposure to NIR stimulation will have beneficial effects on brain health via influence on mitochondrial function as measured by changes in 31P MRS-based markers of ATP, neural network changes in functional connectivity (rs-fMRI), and improved cognitive performance. To test this hypothesis, we plan to randomize 168 older adults with subjective cognitive complaints, and a first-degree family history of Alzheimer’s disease to sham or real treatment groups and evaluate neuroimaging and cognitive outcome measures, before and after a 12-week intervention involving transcranial and intranasal NIR-PBM. The protocol will involve “lab” and “home” sessions, and a 3 month post-intervention follow-up. This trial will determine: 1) whether NIR stimulation, relative to sham, improves performance on memory and executive tasks sensitive to hippocampal and frontal brain function in older adults with increased risk for Alzheimer’s disease; 2) whether NIR stimulation, relative to sham, enhances brain function and connectivity measured by changes in MRS phosphorous ATP and resting state functional connectivity; and 3) how differences in demographic, neuroimaging, and Alzheimer-related risk factors influence the brain response to NIR stimulation versus sham in older adults with increased risk for Alzheimer’s disease. Results will provide key insights into whether this novel NIR intervention can enhance cognition in older adults with increased risk for Alzheimer’s disease and will provide the necessary data for a future Phase III randomized clinical trial.