Dissecting Oligogenic Biomarkers in Ashkenazi Jews with Parkinson Disease

剖析患有帕金森病的德系犹太人的寡基因生物标志物

• 批准号: 10402022
• 负责人: Laurie J. Ozelius
• 金额: $ 35.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402022
• 关键词: Affect; Alzheimer' s disease related dementia; Anxiety; Ashkenazim; Behavior; Biological Markers; Blood specimen; Cancer Patient; Circadian Dysregulation; Circadian Rhythms; Clinical; Cognition; Data; Deltastab; Dementia; Dementia with Lewy Bodies; Drowsiness; Enrollment; Exposure to; Fatigue; Functional disorder; Gene Expression; Genes; Genetic; Genomics; Genotype; Grant; Hamilton Rating Scale for Depression; Human; Immune; Impaired cognition; Intervention; LRRK2 gene; Lead; Lewy Body Dementia; Light; Lighting; Measures; Melatonin; Mental Depression; Moods; Mutation; Nerve Degeneration; Neurobehavioral Manifestations; Parents; Parkinson Disease; Parkinson' s Dementia; Participant; Pathway interactions; Patients; Pattern; Persons; Phototherapy; Population; Public Health; Quality of life; Questionnaires; Research Personnel; Rest; Sleep; Sleep Disorders; Sleep disturbances; Stimulus; Study Subject; Suggestion; System; Time; Urine; Work; actigraphy; arm; base; circadian; cohort; depressive symptoms; design; efficacy testing; experience; improved; new technology; novel; parent grant; parent project; patient subsets; recruit; reduce symptoms; sleep behavior; sleep quality; urinary

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.

路易体痴呆(LBD)由路易体痴呆(DLB)和帕金森病(PD)组成 患有痴呆症(PDD)。大多数LBD与睡眠障碍有关，这些睡眠障碍可能先于或同时发生 认知症状。帕金森病患者静息活动节律降低，褪黑素幅度降低 提示昼夜节律紊乱，这可能是睡眠障碍和认知障碍的根本原因 在这个人口中出现了下降。光，对昼夜节律系统最强的刺激，已经被证明是改善的 睡眠和减少阿尔茨海默病及相关痴呆(ADRD)患者的疲劳和痴呆 癌症患者也是如此。我们建议1)确定睡眠障碍是否普遍存在于 患有帕金森病和帕金森病以及痴呆症的人，特别是那些带有GBA和LRRK2突变的人，与 昼夜节律紊乱和2)确定光是否可以改善睡眠从而改善认知和 通过促进帕金森病和痴呆症患者昼夜节律的改变来减少疲劳。使用新的 技术，我们建议实施和测试一个实用但科学复杂的一天的效率- 夜间照明系统(TLI)旨在提供强健的明暗模式，提高睡眠质量，减少 疲劳，改善帕金森病、帕金森病和痴呆症患者的情绪。根据我们的初步研究 显示了TLI对ADRD患者睡眠、情绪和行为的积极影响，我们建议首先 来自三个基因组(LRRK2突变PD/PD)的50名受试者的睡眠障碍特征 痴呆、GBA突变PD/PD和痴呆和特发性[无LRRK2或GBA突变]PD/PD和 痴呆症)使用动作记录仪和睡眠。第二，我们将扩展这项工作，在单一的手臂上进行调查， 受试者内部研究短期(4周)暴露于量身定制的照明干预的影响 (TLI)对睡眠(运动描记和问卷调查)、疲劳、尿褪黑素和认知的子集。我们 假设与基线相比，TLI将改善客观和主观睡眠并增加幅度 夜间褪黑激素和时钟基因的表达，表明更好的昼夜节律，以及2)更好的昼夜节律 根据Facit-F量表的评估，对齐将导致减少疲劳，7，8减少日间嗜睡，因为 由ESS测量，并减少抑郁、焦虑和冷漠的症状，由汉密尔顿测量 抑郁量表、汉密尔顿焦虑量表9份、冷漠10份。11在一个探索性的目标中，我们 将补充目标1和2的数据与来自父母拨款的基因组和表达数据相关联 来观察基因组和昼夜节律基因表达变化之间的关系，尤其是 神经退行性变、免疫和溶酶体功能障碍的主要途径。总而言之，这些目标将 能够更好地了解非运动改变如何影响帕金森病患者、帕金森病患者和痴呆症患者的生活 并将使我们能够进行简单而有效的临床干预，如果被证明是有益的，可以改善 提高生活质量，也许会减少向痴呆症后期的过渡。