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，能够提供有症状的和 疾病改良对阿尔茨海默病高危人群有好处。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 对老年人进行新颖、相对低成本、低风险和潜在高影响的治疗干预 罹患阿尔茨海默氏症的风险增加。干预包括经颅和鼻腔给药。 通过发光二极管发出的红外线(NIR)光，也称为光生物调节。在细胞和动物方面的先前研究 模型表明，红光和红外线具有神经保护作用，并被认为可以改善线粒体功能 通过促进细胞内三磷酸腺苷的产生增加。阿尔茨海默病转基因小鼠模型的建立 与假手术相比，经颅近红外反应显示β-淀粉样蛋白和神经原纤维缠结减少 刺激。初步的人体研究也显示，在年轻人和 那些患有脑外伤、失语症和阿尔茨海默氏症的人。从我们的团队，飞行员磷磁共振 老年人的波谱(31P-MRS)和认知数据支持这种作用机制，并提供 第二阶段临床试验的令人信服的证据。为了更全面地确定这种新的刺激是否 该方法有可能增强认知正常但有阿尔茨海默病“风险”的个体的认知能力 我们计划进行一项多点、双盲、随机、假对照的II期临床试验。我们的 总体假设是，暴露在近红外刺激下将通过影响对大脑健康产生有益的影响 神经网络31P MRS标志物检测线粒体功能的研究 功能连接性的改变(rs-fmri)，以及认知能力的改善。为了检验这一假设，我们 计划随机选择168名有主观认知障碍的老年人，并有一级家族史 阿尔茨海默病：假治疗组或真实治疗组，评估神经影像和认知结果 干预前后进行为期12周的经颅和鼻腔NIR-PBM干预。这个 方案将包括“实验室”和“家庭”会议，以及3个月的干预后随访。这场审判将 确定：1)与假刺激相比，近红外刺激是否改善了记忆和执行能力 阿尔茨海默病风险增加的老年人对海马体和额叶脑功能敏感的任务 疾病；2)与假刺激相比，近红外刺激是否增强了大脑功能和连接性 MRS磷酸化ATP和静息状态功能连通性的变化；以及3)在 人口学、神经成像和阿尔茨海默病相关危险因素影响大脑对近红外刺激的反应 与患阿尔茨海默病风险增加的老年人的假手术相比。结果将为以下方面提供关键的见解 这种新的近红外干预是否可以提高患阿尔茨海默氏症风险的老年人的认知能力 并将为未来的第三阶段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.