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 认知能力下降随着年龄的增长而普遍存在，目前估计有5000万人与 全球痴呆症。尽管这种认知定义是广泛的，但痴呆症的机制 潜在的神经病理学，以及为什么有些人脆弱而其他人韧性很差 理解。随着年龄的增长，昼夜节律的干扰实际上是普遍的，并且与年龄有关 痴呆症高达15年。同样，血脑屏障（BBB）也受昼夜节律和 睡眠，昼夜节日/睡眠中断，导致BBB功能障碍。因为在BBB渗透性中定义 与年龄相关的认知确定有关，我们的建议探讨了与年龄相关的可能性。 昼夜节律和导致的灾难导致BBB降解和认知能力下降，并且 对昼夜节律降解的韧性是神经保护性的。我们还将应用一种新颖的非侵入性技术 由我们的小组开发的旨在挽救老化脆弱的昼夜节律，BBB的完整性和认知 如果成功的话，具有广泛的转化适用性的动物。该技术基于最近的发现 闪烁的伽玛（40 Hz）照明挽救了鼠标中的昼夜节律，认知功能和神经病理学 阿尔茨海默氏病的模型。因为这种频率的闪烁可能会引起不适，所以偏头痛和 疲劳，我们使用“蒙版”的40 Hz光谱闪烁（即，通过看不见的光谱闪烁（ISF））开发了照明。 应用一种反相颜色混合方法，该方法提高了闪烁的临界频率。我们的 飞行员数据显示，该照明在大脑中产生40 Hz的振荡，可与40 Hz闪烁和 挽救老年动物行为的昼夜节律。 40 Hz照明处理尚未应用于年龄 非alzheimer的起源或衰老的BBB完整性的相关认知下降。目前的提议要求 两个主要问题：1）易受昼夜节律降解的脆弱性，而与认知相关的年龄也会发展 通过定义BBB和由此产生的神经炎症的衰落，小鼠有弹性与年龄有关 昼夜节日降解对BBBD和认知能力下降，2）可以非侵入性40 Hz ISF照明 治疗野合昼夜节律降解和与年龄相关的BBB和认知功能的降解 脆弱的老鼠？这些发现将共同增强我们对机制和基础的理解 与年龄相关的认知能力下降的神经病理学，但也具有大范围治疗的潜力。