Brain Sleep Clearance of Amyloid-Beta Peptides

Summary

The 'Amyloid Cascade Hypothesis' posits that the accumulation of a peptide, amyloid beta (Aβ), in the brain is the initiating event in Alzheimer's disease (AD), however, the mechanisms involved are not well understood. Recent studies support the hypothesis that Aβ dynamics in the brain are influenced by the sleep-wake cycle, with increases in the production of soluble Aβ during wakefulness and decreases during non-rapid eye movement (NREM) sleep, and more specifically on NREM stage 3 (also called slow wave sleep \[SWS\]). These changes produce a consistent diurnal pattern in the cerebrospinal fluid (CSF) that has been documented in murine models and in humans. By better understanding this sleep-wake relationship the investigators hope to identify how sleep disorders accelerate the progression of AD in the elderly (which has been demonstrated by multiple epidemiological studies) and, in turn, identify novel therapeutic targets for AD prevention.

The purpose of this study is to elucidate how soluble amyloid beta (Aβ) levels in the brain are influenced by the sleep-wake cycle in humans, and to test the directionality of this relationship through sleep disruption experiments. The investigators will test two models. The first model will test how, prior to amyloid deposition, brain soluble Aβ levels may be relatively increased in the elderly by two mechanisms: a) loss of total sleep time and SWS that occur with normal aging; and b) sleep disturbances such as Sleep Disordered Breathing (SDB) or insomnia that are common in late life (Aim 1). The second model will test how stage-specific sleep disruption may lead to increased CSF Aβ42 levels (Aim 2). A group of adults with diagnosed severe SDB and good continuous positive airway pressure (CPAP) compliance will be used to test this model sleep deprivation experiments using therapeutic CPAP vs. sham CPAP.

This project will be the first to explore the protective effect of SWS on Aβ42 dynamics in a group of cognitively normal elderly subjects as well as the effect of acute sleep disruption by CPAP withdrawal on CSF Aβ42 levels in a well characterized clinical sample of severe obstructive SDB patients on treatment with CPAP. The results from this study will improve our understanding of the nature of the Aβ diurnal pattern and the brain consequences of full night sleep disruptions as well as sleep disruptions during specific stages of sleep.

Conditions

• Obstructive Sleep Apnea
• Alzheimer's Disease

Interventions

OTHER

Continuous positive airway pressure device

GROUP B ONLY will be evaluated on two randomized counterbalanced nights, on one they will undergo a full night of therapeutic CPAP; on the other the investigators will withdraw CPAP during SWS only. A morning LP will be performed approximately 10 hours after sleep onset in both visits

Sponsors & Collaborators

• National Institute on Aging (NIA)

  collaborator NIH

• NYU Langone Health

  lead OTHER

Principal Investigators

• Ricardo Osorio, MD · NYU MEDICAL CENTER

Study Design

Allocation

NON_RANDOMIZED

Purpose

DIAGNOSTIC

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

30 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2015-10-01

Primary Completion

2017-05-31

Completion

2019-07-31

Countries

• United States

Study Locations