Non-invasive lighting treatment as a novel therapeutic for age-related cognitive decline

项目摘要 随着年龄的增长，认知能力下降是普遍的，据估计，目前有5000万人患有这种疾病 全世界的痴呆症。虽然这种认知退化是普遍存在的，但痴呆症背后的机制，其 潜在的神经病理学，以及为什么一些人是脆弱的，而另一些人是有弹性的，这些都是糟糕的 明白了。随着年龄的增长，昼夜节律的紊乱几乎是普遍的，并先于与年龄有关的 患痴呆症的时间长达15年。同样，血脑屏障(BBB)受昼夜节律和 睡眠，扰乱昼夜节律/睡眠导致血脑屏障功能障碍。因为血脑屏障通透性的缺陷 与年龄相关的认知退化有关，我们的建议探索了年龄相关的缺陷在 昼夜节律和由此导致的睡眠障碍会导致血脑屏障的退化和认知能力的下降 对昼夜节律退化的适应能力具有神经保护作用。我们还将应用一种新颖的非侵入性技术 由我们小组开发，用于拯救老年脆弱患者退化的昼夜节律、血脑屏障完整性和认知能力 如果成功，动物具有广泛的翻译适用性。这项技术是基于最近的发现 闪烁的伽马(40赫兹)光拯救小鼠的昼夜节律、认知功能和神经病理 阿尔茨海默病的模型。因为这种频率的闪光会引起不适，偏头痛，以及 为了避免疲劳，我们通过以下方式开发了使用40赫兹光谱闪烁(即不可见光谱闪烁)的照明 应用反相混色方法，提高感觉到闪烁的临界频率。我们的 试点数据显示，这种照明在大脑中产生40赫兹的振荡，相当于40赫兹的闪烁和 挽救老年动物行为的昼夜节律。40赫兹照明治疗尚未应用于年龄- 非阿尔茨海默氏症起源或血脑屏障完整性与年龄相关的认知衰退。目前的提案要求 两个主要问题：1)随年龄增长易受昼夜节律退化的影响与认知能力有关 通过血脑屏障的恶化和由此导致的神经炎症而下降，使小鼠对年龄相关的疾病具有弹性 昼夜节律退化抵抗BBBd和认知能力下降，2)可以无创的40赫兹ISF照明 治疗、抢救和年龄相关的BBB和认知功能的昼夜退化 脆弱的老鼠？综上所述，这些发现将加强我们对其机制和潜在机制的理解 神经病理与年龄相关的认知功能下降，也有可能广泛治疗。

Project Summary Cognitive decline is pervasive with advancing age, with an estimated 50 million people presently living with dementia worldwide. While this cognitive deterioration is widespread, the mechanisms underlying dementia, its underlying neuropathology, and why some individuals are vulnerable while others are resilient are poorly understood. With advancing age, disruptions to circadian rhythms are virtually universal and precede age-related dementia by as much as 15 years. Likewise, the blood-brain barrier (BBB) is regulated by circadian rhythms and sleep, with disruptions to circadian timing/sleep leading to BBB dysfunction. Because deficits in BBB permeability are linked to age-related cognitive deterioration, our proposal explores the possibility that age-related deficits in circadian rhythms and resulting disturbances to sleep lead to BBB degradation and cognitive decline, and that resilience to circadian degradation is neuroprotective. We will also apply a novel, non-invasive technology developed by our group to rescue degraded circadian rhythms, BBB integrity, and cognition in aged vulnerable animals that has broad translational applicability if successful. This technology is based on recent findings that flickering gamma (40 Hz) lighting rescues circadian rhythms, cognitive function, and neuropathology in mouse models of Alzheimer’s disease. Because flickering light of this frequency can cause discomfort, migraines, and fatigue, we developed lighting using ‘masked’ 40-Hz spectral flicker (i.e., Invisible Spectral Flicker (ISF)) by applying an antiphase color mixing approach that raises the critical frequency at which flicker is perceived. Our pilot data reveal that this lighting generates 40 Hz oscillations in the brain comparable to 40 Hz flicker and rescues circadian rhythms in behavior in aged animals. 40 Hz lighting treatment has not been applied to age- associated cognitive decline of non-Alzheimer’s origin or BBB integrity with aging. The present proposal asks two main questions: 1) Is vulnerability to circadian degradation with advancing age associated with cognitive decline through deterioration of the BBB and resulting neuroinflammation, with mice resilient to age-related circadian degradation resistant to BBBd and cognitive decline, and 2) Can non-invasive 40 Hz ISF lighting treatment rescue circadian degradation and age-associated degradation of the BBB and cognitive functioning in vulnerable mice? Together, these findings will enhance our understanding of the mechanisms and underlying neuropathology of age-related cognitive decline, but also have the potential for wide-ranging treatment.