Sleep disturbances occur frequently in neurodegenerative disease and constitute the most common reason for institutionalization. Sleep disruption has also been proposed to contribute causally to increasing amyloid beta (A?) deposition, which has fueled interest in bidirectional relationships of sleep and Alzheimer's Disease (AD), but its relationship to the other major AD neuropathology ? accumulation of pathogenic tau-related neurofibrillary tangles ? is unknown. In AD, sleep dysfunction includes sleep fragmentation, sundowning, and daytime sleepiness, measured by short sleep latencies on the multiple sleep latency test (MSLT). In contrast, we found that Progressive Supranuclear Palsy (PSP), a different tauopathy not associated with A? deposition, features marked reductions in duration of both Rapid Eye Movement (REM) sleep and Non-REM (NREM) sleep, and prolonged sleep latencies seen by MSLT. The tau neuropathologies of AD and PSP both begin subcortically, in brainstem and hypothalamus. Their divergent sleep-wake behavior profiles ? in PSP, dramatically decreased total sleep time, absent daytime sleep, vs. in AD, sleep redistributed across night & day periods, with little reduction of total sleep time ? along with contrasting tau burden in sleep- and wake-related brainstem nuclei (Prelim. Res.), provides a novel opportunity to discover the neurobiological basis of their disturbed sleep-wake rhythms. We will test the novel hypothesis that differential vulnerabilities of nuclei in wake-promoting (loss in AD > PSP) and sleep-promoting (loss in PSP > AD) neurons determines the different pattern of sleep-wake disturbances in these 2 contrasting tauopathies. The premise of this proposal is that: 1) sleep-wake disturbances are common to both of these tauopathies; 2) leveraging the subcortical anatomically distinct neurodegeneration foci seen early in PSP & AD, that segregate functionally as wake-predominant in AD and sleep-predominant nuclei in PSP, as natural lesions, will uncover mechanisms of their differential profiles of disturbed sleep and wakefulness; and 3) future design of efficient, specific treatments for sleep in PSP and AD will require understanding of their respective mechanisms. We will test our idea by determining if differences in sleep-wake behavior in PSP and AD subjects vs. healthy controls (HC) are quantitatively attributable to corresponding altered pathoanatomical measures (including total numbers of neurons and of specific neuronal subpopulations, and hp-tau burden) in nuclei involved in wake and NREM sleep regulation. We will assess quantitative clinical neurohistopathological correlates in respective subsamples of PSP, AD, and control subjects who completed sleep measures prior to death and autopsy. The project represents a unique collaborative/interdisciplinary opportunity with highly specialized brain collections and sleep analysis, whose results may yield an unprecedented disease-specific mechanistic rationale for therapeutically targeting pro-sleep circuits vs. a wakefulness-inhibition approach in AD and PSP.

Public Health Relevance

This study aims to discover the causes for sleep-wake disturbances that afflict patients with Alzheimer's Disease and Progressive Supranuclear Palsy. We will determine if the pattern of disturbed sleep in these two disorders is predicted by the loss of brain cells in key areas that regulate sleep and wake in both brain bank specimens and a subsample of patients who complete sleep measures and undergo autopsy.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Mackiewicz, Miroslaw
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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