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

非侵入性照明治疗作为治疗与年龄相关的认知衰退的新型疗法

• 批准号: 10681091
• 负责人: Daniela KAUFER
• 金额: $ 22.81万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681091
• 关键词: Age; Age-associated memory impairment; Aging; Albumins; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Astrocytes; Behavior; Behavioral; Blood - brain barrier anatomy; Blood Tests; Blood brain barrier dysfunction; Brain; Cells; Characteristics; Circadian Rhythms; Cognition; Cognitive; Collaborations; Color; Coupling; Data; Dementia; Denmark; Deterioration; Diagnosis; Disease; Disease Progression; Elderly; Endothelial Cells; Endothelium; Exhibits; Fatigue; Frequencies; Gene Expression; Human; Impaired cognition; Individual; Individual Differences; Infiltration; Intervention; Lead; Light; Lighting; Link; Longevity; Masks; Measures; Mediator; Migraine; Mus; Nerve Degeneration; Neuropeptides; Patients; Persons; Phase; Phototherapy; Psyche structure; Receptor Signaling; Research Personnel; Resistance; Rodent; Serum Proteins; Signal Transduction; Sleep; Sleep disturbances; Symptoms; System; Technology; Testing; Tight Junctions; Tissues; Transforming Growth Factor beta; Universities; Vulnerable Populations; Work; age related; aged; aging brain; blood-brain barrier function; blood-brain barrier permeabilization; brain dysfunction; brain health; circadian; circadian pacemaker; cognitive enhancement; cognitive function; cognitive task; improved; inhibitory neuron; juvenile animal; loss of function; middle age; mouse model; neuroinflammation; neuropathology; neuroprotection; novel; novel therapeutics; prevent; resilience; suprachiasmatic nucleus; tau Proteins; tool; transcytosis; virtual

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.

项目摘要 随着年龄的增长，认知能力的下降是普遍的，据估计，目前有5000万人生活在 全球痴呆症虽然这种认知能力的下降是普遍的，但痴呆症的潜在机制， 潜在的神经病理学，以及为什么有些人是脆弱的，而另一些人是有弹性的， 明白随着年龄的增长，昼夜节律的破坏几乎是普遍的，并先于年龄相关的 痴呆症的发病率降低了15年。同样，血脑屏障（BBB）受昼夜节律调节， 睡眠，昼夜节律定时/睡眠中断导致BBB功能障碍。因为血脑屏障通透性的不足 与年龄相关的认知衰退有关，我们的建议探讨了与年龄相关的缺陷的可能性， 昼夜节律和由此产生的睡眠障碍导致BBB退化和认知能力下降， 对昼夜节律退化的适应性是神经保护性的。我们还将应用一种新颖的非侵入性技术 由我们的小组开发，以拯救老年脆弱人群中退化的昼夜节律，BBB完整性和认知能力。 如果成功，具有广泛的翻译适用性的动物。这项技术是基于最近的发现， 闪烁伽马（40 Hz）照明拯救小鼠的昼夜节律、认知功能和神经病理学 阿尔茨海默病的模型。因为这种频率的闪烁光会导致不适、偏头痛， 疲劳，我们开发了使用“掩蔽的”40-Hz光谱闪烁的照明（即，不可见光谱闪烁（ISF） 应用反相颜色混合方法，该方法提高了感知闪烁的临界频率。我们 试验数据显示，这种照明在大脑中产生40 Hz的振荡，相当于40 Hz的闪烁， 挽救老年动物行为的昼夜节律。40赫兹的灯光治疗还没有应用到年龄- 非阿尔茨海默病起源的认知衰退或BBB完整性与衰老相关。本提案要求 两个主要问题：1）随着年龄的增长，昼夜节律退化的脆弱性是否与认知功能有关？ 通过BBB恶化和导致的神经炎症而下降，小鼠对年龄相关的 抗BBBd和认知能力下降的昼夜节律退化，以及2）可以非侵入性40 Hz ISF照明 治疗挽救昼夜节律退化和年龄相关的BBB退化和认知功能， 脆弱的老鼠总之，这些发现将加强我们对机制和潜在的理解。 年龄相关的认知能力下降的神经病理学，而且还具有广泛的治疗潜力。