Yo-El S. Ju, MD - US grants

? DESCRIPTION (provided by applicant): Over 5 million Americans currently suffer from Alzheimer Disease (AD), a number predicted to increase as the population ages. Sleep disturbances are associated with brain changes of AD, even before cognitive problems. In mouse models, sleep deprivation leads to acceleration of amyloid plaque deposition, a key pathological feature of AD. The proposed project will translate this finding to humans. The overarching hypothesis for this human study is that sleep disturbance leads to decreased deep sleep or slow wave sleep (SWS), leading to relatively increased neuronal synaptic activity, leading to relatively increased monomeric amyloid-beta (A beta) release into the interstitial space, leading to chronically elevated A beta levels, leading to increased risk of aggregation of A beta into amyloid plaques, and eventually leading to increased risk of symptomatic AD. This project will test the first portion of this hypothetical cascade by examining the relationship of SWS and A beta levels using two different models: 1) An experimental model in which SWS is disrupted in normal individuals and, 2) a clinical model in which people with obstructive sleep apnea, a common sleep disorder that disrupts sleep, will have SWS and A beta levels tested before and after treatment. The long-term objective of this line of research is to determine whether sleep can be modified or improved with the goal of reducing risk of AD. The research team for this project combines expertise in sleep medicine, AD, and electrophysiology. In addition to training in the techniques and novel protocols proposed for the research experiments, the Principal Investigator will obtain formal didactic education in signal processing over the course of the award. A Safety Advisory Panel will supervise the proposed study to ensure it is completed in a safe and ethical manner, and will buttress ongoing education in the responsible conduct of research. The multidisciplinary team of world-class mentors and collaborators, and the extensive intellectual and physical resources available at Washington University, will optimize the training experience and the likelihood for successful transition to independent research. The technical, research, and career skills obtained during this award will facilitate the Principal Investigator in launching a successful career as a physician-scientist investigating the intersection of sleep and neurodegenerative diseases.

Rapid Eye Movement (REM) sleep behavior disorder (RBD) is a sleep disorder characterized by acting out of dreams. Older individuals with RBD frequently develop Parkinson Disease (PD), Dementia with Lewy Bodies (DLB), or Multiple System atrophy (MSA)?collectively termed synucleinopathies?within several years, indicating that RBD is a signal that one of these neurodegenerative diseases has taken root. RBD represents a preclinical stage of synucleionopathy, when brain changes are present but neurodegenerative symptoms have not yet appeared. Subsequently, RBD offers an opportunity to test potential treatments for synucleinopathy at the earliest stages of disease when treatment is most likely to be effective. Based on current information about treatments in the pipeline for synucleinopathies, we anticipate a clinical trial in RBD to protect against synucleinopathy in 2-3 years. However, several gaps prohibit proceeding with a clinical trial currently, including 1) lack of coordination between sites that follow relatively small cohorts, 2) no biomarkers for synucleinopathy, 3) lack of standardization of clinical assessment across sites, 4) 5) lack of a coordinated effort to direct and specifically plan for a neuroprotective clinical trial. To address these gaps, we propose to form the North American Preclinical Synucleinopathy (NAPS) Consortium. The aims are to form a joint registry of RBD patients, establish standardized assessments and biomarker collection across sites, and institute an expert panel to guide decisions for the NAPS Consortium toward a clinical trial. Through these aims, the NAPS Consortium will build the framework necessary for a successful clinical trial in RBD, including a large and ready patient cohort, standardized functional and biofluid markers, ability to easily scale to new sites, and a clear organizational structure to co-ordinate a multi-site study. The ultimately goal is a successful trial in RBD that can be extended to the general population, to identify and stop PD, DLB, and MSA before any symptoms appear.

Project Summary Alzheimer's Disease (AD) is a growing epidemic, and potential treatments are unlikely to be effective unless deployed during the earliest stages of AD, prior to cognitive symptoms. Currently there are no inexpensive, non-invasive biomarkers for effective AD screening necessary for early recognition and treatment on a broad scale. Sleep is abnormal in preclinical AD, even prior to cognitive symptoms, and disrupted sleep may in turn accelerate AD pathological mechanisms. Electroencephalography (EEG) directly measures brain function, and the stereotyped nature of sleep EEG offers a particularly rich opportunity to identify biomarkers of brain dysfunction due to AD. The central hypothesis of the proposed study is that sleep-wake brain mechanisms are abnormal very early in AD, and can be detected via subtle but distinct sleep and EEG changes. The objective is to develop sleep and EEG biomarkers of AD, to enable non-invasive and inexpensive screening on a large scale, through the following specific aims. Aim 1) Identify sleep-wake patterns across the 24-hour day characteristic of AD pathology. Ambulatory sleep-EEG data will be recorded over the 24-hour period in the home setting from a large, diverse, community-based cohort, with the hypothesis that increased sleep-wake transitions over the 24-hour day are characteristic of preclinical-to-mild AD. Aim 2) Assess slow wave integrity measures as biomarkers of AD pathology. EEG abnormalities of slow wave sleep are particularly associated with elevated amyloid-? levels and plaques. Novel analytic techniques will extract bihemispheric slow wave coherence, slow wave velocity, and slow wave intradaily ratio from EEG data collected during sleep and wake. The hypothesis is that amyloid plaques present in early AD will reduce slow wave integrity by all three measures. Aim 3) Determine the EEG signature of AD using machine learning. Machine learning techniques will be applied to EEG from a full attended overnight polysomnogram, to identify a ?signature? of AD pathology. The goal is to identify a ?signature? that can be detected with spatially limited EEG data that could be collected at home. The expected outcome of these aims is to identify sleep-EEG biomarkers of AD that can be detected noninvasively and inexpensively at home. The impact of our work will be the ability to screen large populations easily for AD pathology, so that affected individuals can be identified and treated. Moreover, sleep-EEG biomarkers could be used to track disease progression and treatment response in clinical trials for AD. Lastly, since sleep disturbance has a direct effect on AD pathology, by identifying sleep-EEG changes very early in the pathological process, we may be able to intervene, improve sleep, and potentially change the trajectory of AD. !

PROJECT SUMMARY Sleep and Circadian Rhythms in Alzhiemer?s Disease: Potential bi-directional relationship with tau Sleep and circadian rhythm disturbances have long been described in symptomatic Alzheimer?s Disease (AD). Recent studies by our group and others show that these disturbances are detectable years before the onset of cognitive impairment, during the preclinical phase of AD. Our group has shown that modulating the amount of sleep in mice has striking effects on amyloid plaque deposition, as sleep deprivation augments plaque burden while sleep enhancement reduces plaques. Moreover, we have found that levels of A? peptide in the interstitial fluid (ISF) exhibit clear diurnal rhythms which are regulated by the sleep/wake cycle and the central circadian clock, and that disruption of the circadian system and promotes amyloid plaque formation. While amyloid plaque deposition is the first known biomarker change in AD, it appears to be the ability of amyloid plaques to augment tau aggregation and spreading that is directly linked to neurodegeneration and cognitive decline in AD. Tau spreading though the brain, and the effect of A? pathology on tau aggregation, can be modeled by injection of tau-enriched AD brain lysate into the brain of A? plaque-bearing APP knock-in mice. Based on our preliminary data, we hypothesize that sleep disturbance and circadian rhythm disruption may promote tau spreading and aggregation by increasing the release of tau seeding species from neurons. We propose to examine the impact of chronically restricting or increasing sleep on neuronal tau spreading and plaque-induced tau aggregation in mice. Because apolipoprotein E (apoE) strongly influence A? and tau pathology and interacts with sleep, we will elucidate the interaction between APOE genotype, sleep deprivation, and tau spreading and aggregation. Using both genetic and environmental circadian disruption models, we will perform similar experiments to determine the effects of circadian disruption on tau spreading and A?-induced tau aggregation, and explore the interplay between circadian disruption, sleep, and apoE on A? and tau pathology. Finally, we will examine the longitudinal relationship between sleep disturbance, circadian fragmentation, and preclinical A? and tau pathology in humans. We hypothesize a bidirectional relationship between AD pathology and sleep/circadian rhythms, in which AD pathology disrupts sleep/circadian function, while sleep/circadian disruption promotes AD pathology. We will if sleep or circadian rhythm changes are associated with increased future risk of plaque deposition, tau aggregation, or cognitive decline in humans. These studies will elucidate the interaction between sleep, circadian rhythms, and tau aggregation in mice and humans, as well as the role of apoE in that process.

ABSTRACT: NAPS2 ADMINISTRATIVE CORE Synucleinopathies including Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) in aggregate afflict ~2 million Americans, and lead to progressive neurodegeneration and loss of function toward severe disability and death. Rapid eye movement (REM) Sleep Behavior Disorder (RBD) usually reflects a prodromal synucleinopathy, and presents a window of opportunity when treatment may be effective to prevent or slow the progression to overt synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium for RBD was established in 2018 to prepare for such neuroprotective treatment trials. As NAPS1?the current, R34-supported stage of NAPS?we have been very successful in engaging key RBD researchers and cohorts across North America. NAPS1 has been extremely productive: >200 participants have thus far been enrolled across 10 Sites, and have completed standardized, comprehensive assessments. We established key administrative procedures and processes in parallel with rapid enrollment, and NAPS1 functions smoothly as a transparent, efficient Consortium. To address important questions about biomarkers and phenotypic trajectories in prodromal synucleinopathy, we propose Stage 2 of NAPS, or NAPS2, to enable longitudinal followup and expanded biomarker collection. NAPS2 will build and substantially expand upon NAPS1, to establish 8 Cores that support a central research Project. The Administrative Core will formalize and streamline the administrative tasks across NAPS2 and all its components. The current Sites will come under the umbrella of the Administrative Core as they continue into NAPS2, and the Administrative Core will oversee the activities and interactions between all NAPS2 components. The Aims of the Administrative Core are to 1) coordinate all NAPS2 Cores, Sites, Project, personnel, and resources; 2) facilitate communication within and outside of NAPS; 3) safeguard data quality and consistency across the NAPS Consortium; 4) promote research in RBD; and 5) guarantee compliance with required regulatory bodies. The NAPS2 Administrative Core will oversee the inter-relationships between NAPS2 components with the goal of an efficient and productive Consortium. Through the proposed aims, the Administrative Core will enable all NAPS2 components to perform optimally, toward the goal of neuroprotective clinical trials to slow or stop the progression of synucleinopathies.

Most individuals with rapid eye movement (REM) sleep behavior disorder (RBD) develop additional neurological symptoms and are subsequently diagnosed with overt synucleinopathies, including dementia with Lewy bodies (DLB), Parkinson?s disease (PD), and multiple system atrophy (MSA), indicating that RBD represents a prodromal stage of synucleinopathy. RBD therefore offers a window of opportunity to intervene with neuroprotective treatments at the earliest stages of disease when treatment is most likely to be effective. Recognizing the importance of early intervention, key federal agencies focused on neurodegenerative disease have proposed high priority recommendations for prodromal aspects of synucleinopathies, including specifically RBD, to prepare for clinical trials. The North American Prodromal Synucleinopathy (NAPS) Consortium began in 2018 to plan for neuroprotective clinical trials in RBD. The NAPS Consortium, currently at 10 sites, has thus far enrolled 215 participants with polysomnogram-confirmed RBD, and has successfully performed comprehensive and standardized assessments and biofluids collection. The North American Prodromal Synucleinopathy Consortium for RBD, Stage 2 (NAPS2) program represents an integrated expansion of NAPS to support a longitudinal, prospective study of RBD, to address key gaps currently prohibiting neuroprotective clinical trials in RBD. NAPS2 will establish enhanced infrastructure to support long-term research in prodromal synucleinopathies. We will institute 8 Cores?Administrative; Clinical; Biofluid; Neuroimaging; Polysomnogram (PSG); Genetics; Data Management and Statistics (DMS); and Recruitment, Education, and Outreach (REO)?to augment our protocol and to support a Project to predict phenoconversion to overt synucleinopathy. NAPS2 will prospectively assess >300 participants with RBD for comprehensive clinical evaluation and collection of PSG/neurophysiological, biofluid (blood and cerebrospinal fluid), genetic, and neuroimaging (MRI and DaTscan) biomarkers. The overarching goal of NAPS is to enable neuroprotective clinical trials to prevent or delay synucleinopathies. Toward this goal, the NAPS2 aims are: 1) to conduct research on RBD as a prodromal manifestation of DLB, PD, and MSA; 2) to expand our cohort of RBD participants and add matched control participants for longitudinal, standardized collection of clinical, PSG, genetic, biofluid, and neuroimaging data; 3) to analyze collected data against longitudinal clinical outcomes to refine scales and develop biomarkers to optimally design clinical trials; 4) to share data, samples, and methods for use by the scientific community; 5) to interact with NIH, other scientific groups on RBD and overt synucleinopathies, industry partners, patients, and other groups; and 6) to prepare for large-scale clinical trials. Ultimately, synucleinopathy biomarkers and neuroprotective treatments developed in the RBD population could be applied to the larger population at risk for synucleinopathies, to delay or prevent DLB, PD, and MSA.