Dissecting Oligogenic Biomarkers in Ashkenazi Jews with Parkinson Disease

路易体痴呆（LBD）包括路易体痴呆（DLB）和帕金森病（PD） 痴呆症（PDD）大多数LBD与睡眠障碍有关，这些睡眠障碍可能早于或同时发生于LBD。 认知症状在PD中，静息-活动节律降低，褪黑激素幅度降低， 暗示昼夜节律紊乱，这可能是睡眠障碍和认知障碍的根本原因。 这一人口下降。光是昼夜节律系统最强的刺激， 睡眠和减少疲劳和痴呆在阿尔茨海默病和相关痴呆（ADRD）患者中， 以及癌症患者。我们建议1）确定睡眠障碍是否常见于 PD和PD和痴呆患者，特别是GBA和LRRK 2突变的患者，与 昼夜节律中断和2）确定光是否可以改善睡眠，从而改善认知， 通过促进昼夜节律的诱导来减少PD和痴呆的疲劳。使用新 技术，我们建议实施和测试一个实际的，但科学复杂的一天的功效- 夜间照明系统（TLI）旨在提供强大的明暗模式，改善睡眠质量，减少 疲劳，并改善PD和PD和痴呆患者的情绪。根据我们的初步研究 显示TLI对ADRD患者的睡眠、情绪和行为的积极影响，我们建议首先 在来自三个基因型组（LRRK 2突变PD/PD）的50名受试者中表征睡眠障碍 痴呆、GBA突变PD/PD和痴呆和特发性[无LRRK 2或GBA突变] PD/PD和 痴呆症）使用活动记录仪和睡眠。第二，我们将扩大这项工作，并在一个单一的手臂调查， 受试者内研究短期（4周）暴露于定制照明干预的影响 (TLI)睡眠（活动记录仪和问卷）、疲劳、尿褪黑激素和认知亚组。我们 假设与基线相比，TLI将改善客观和主观睡眠并增加振幅 夜间褪黑激素和时钟基因表达，表明更好的昼夜节律对齐，和2）更好的昼夜节律 根据FACIT-F量表的评估，对齐将导致疲劳减少，7，8减少白天嗜睡， 通过ESS测量，并减少抑郁，焦虑和冷漠的症状，如汉密尔顿测量 抑郁评定量表、9汉密尔顿焦虑评定量表、10和冷漠量表。11在一个探索性的目标，我们 将把补充目标1和2的数据与来自母基金的基因组和表达数据相关联 研究基因组和昼夜节律基因表达变化之间的关系，特别关注 神经变性、免疫和溶酶体功能障碍的主要途径。综合起来，这些目标将 更好地了解非运动改变如何影响PD和PD和痴呆患者的生活 并将使我们能够进行简单而有效的临床干预，如果显示有益，可以改善 生活质量，并可能减少向痴呆症晚期的过渡。

Lewy body dementias (LBD) are comprised of Dementia with Lewy Bodies (DLB) and Parkinson Disease (PD) with Dementia (PDD). Most LBD are associated with sleep disorders that may predate or be concurrent with cognitive symptoms. In PD there are decreased rest-activity rhythms and reduced melatonin amplitude, both suggestive of circadian disruption, which can be the underlying cause of the sleep disturbances and cognitive decline seen in this population. Light, the strongest stimulus for the circadian system, has been shown to improve sleep and reduce fatigue and dementia in persons with Alzheimer’s disease and related dementias (ADRD) as well as in cancer patients. We are proposing to 1) determine whether sleep disturbances commonly found in persons with PD and PD and dementia, and specifically those with GBA and LRRK2 mutations, are related to circadian disruption and 2) determine whether light can improve sleep and therefore improve cognition and decrease fatigue in PD and dementia by promoting entrainment of their circadian rhythms. Using new technologies, we propose to implement and test the efficacy of a practical but scientifically sophisticated day- night lighting system (TLI) designed to deliver a robust light-dark pattern and improve sleep quality, reduce fatigue, and improve mood in persons with PD and PD and dementia. Based on our preliminary studies showing a positive impact of a TLI on sleep, mood, and behavior in ADRD, we propose to first characterize sleep disturbances in 50 subjects from three genotype groups (LRRK2 mutation PD/PD dementia, GBA mutation PD/PD and dementia and idiopathic [no LRRK2 or GBA mutation] PD/PD and dementia) using actigraphy and sleep. Second, we will extend this work and investigate in a single arm, within-subjects study the impact of short-term (4 weeks) exposures to a tailored lighting intervention (TLI) on sleep (actigraphy and questionnaires), fatigue, urinary melatonin, and cognition in a subset. We hypothesize that compared to baseline, TLI will improve objective and subjective sleep and increase amplitude of nocturnal melatonin and clock gene expression, suggesting better circadian alignment, and 2) better circadian alignment will lead to reduced fatigue, as assessed by the FACIT-F Scale, 7,8 reduce daytime sleepiness, as measured by the ESS, and reduce symptoms of depression, anxiety and apathy, as measured by the Hamilton depression Rating Scale, 9 Hamilton Anxiety Rating Scale, 10 and Apathy Scale. 11 In an exploratory aim, we will correlate data from Supplement Aims 1 and 2 with the genomic and expression data from the parent grant to look at the relationship between genomic and circadian gene expression changes, with particular focus on the major pathways of neurodegeneration, immune, and lysosomal dysfunction. Taken together, these aims will enable better understanding of how non-motor alterations affect the lives of people with PD and PD and dementia and will allow us to perform simple, yet effective clinical interventions that, if shown beneficial, can improve the quality of life and perhaps decrease the transition to later stages of dementia.