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

点击翻译按钮获取中文摘要

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.