Saturday, May 4, 2024
5/4/2024
Project Summary/Abstract By age 75, individuals sleep about 1.5 hr. less per night, take longer to fall asleep, wake up more frequently at night and are more likely to nap during the day than at age 25. Alzheimer’s disease, Parkinson’s disease/Lewy body dementia, and fronto-temporal lobe dementia exacerbate these problems. We hypothesize that the changes in wake-sleep and circadian behavior during aging are due to subclinical neurodegeneration of wake-sleep and circadian circuitry as a continuous process during aging. This would be similar to REM sleep behavior disorder, which often occurs 10-15 years before a diagnosable synucleinopathy. We further hypothesize that different neurodegenerative disorders may affect different patterns of wake- sleep and circadian cell groups and cause different behavioral changes. If this hypothesis is correct, it may be possible to use specific sleep and circadian disturbances as biomarkers to identify early, preclinical stages of these disorders. We propose here to test these hypotheses using two unique sets of subjects from the Rush Memory and Aging cohorts, who have actigraphic recording of rest-activity behaviors. In the first set of subjects, who have had actigraphy within one year of death and a brain autopsy, we will analyze the actigraphy for sleep time, sleep fragmentation, and sleep efficiency during the night, nap time during the day, and circadian activity phase and amplitude. We expect to find that cell loss will be associated with deposition of pathological proteins in wake-sleep and circadian cell groups, and specific patterns of wake-sleep and circadian behavioral deficits, even if there was no diagnosable neurodegenerative disorder during life. In Aim 1, we will look at wake-promoting (orexin, tuberomammillary, A10, raphe, pedunculopontine, parabrachial, and locus coeruleus), sleep promoting (ventrolateral preoptic, MCH), and circadian (suprachiasmatic vasopressin and VIP neurons) cell groups for association between deposition of neurodegenerative pathological protein deposits (beta-amyloid, phospho-tau, phospho-a-synuclein, phospho- TDP-43) and reduced numbers of surviving neurons. In Aim 2, we will look for association of changes in sleep time, efficiency, fragmentation, and napping, as well as changes in circadian amplitude or phase with numbers of remaining neurons and deposition of neurodegenerative proteins in the same cell groups as Aim 1. In Aim 3, we will test a separate validation cohort of patients who had actigraphy 2 or more years prior to death and clinical and pathological diagnosis at the time of death, to determine whether specific wake-sleep or circadian deficits predict later neurodegenerative diagnoses. We hope to be able to identify patterns of wake-sleep and circadian deficits during life using actigraphy, an inexpensive, non-invasive, and widely available tool, that predict and act as biomarkers for subclinical presence of Alzheimer’s disease and other neurodegenerative disorders, similar to the relationship of REM sleep behavior disorder and synucleinopathies.
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