Dissecting Oligogenic Biomarkers in Ashkenazi Jews with Parkinson Disease

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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.