Brain Sleep Clearance of Amyloid-Beta Peptides
Condition: Obstructive Sleep Apnea; Alzheimer's Disease
MeSH terms: Sleep Apnea, Obstructive; Alzheimer Disease
Study type: Interventional

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.
    

Detailed description: 
      Evaluations and procedures performed by the participants in:

      Aim 1 Subjects were newly enrolled normal elderly or normal elderly recruited from
      R01HL118624-01 and evaluated according to the studies protocol.

      Visit 1: During this visit, participants will undergo a complete physical exam, neurological
      examination, psychiatric interview, sleep interview, neuropsychological testing, Heart
      testing (EKG), laboratory analysis of blood. (90cc)

      Visit 2: During this visit, participants will undergo an MRI scan and be educated on
      completing home monitoring of sleep wake cycle with actigraphy.

      Visit 3: Patients will receive one FBB PET/MR scan to establish amyloid status.

      Visit 4: Patients will undergo one night of NPSG with maze task prior to the subjects'
      scheduled morning LP with collection of CSF (15 cc).

      Aim 2 All subjects will receive a complete evaluation (outlined below). Visit 1 and visit 2
      will be used to screen subjects for inclusion.

      Visit 1: During this visit participant will undergo a complete physical exam, neurological
      examination, psychiatric interview, sleep interview, psychometric testing, heart testing
      (EKG), laboratory analysis of blood. (90cc)

      Visit 2: During this visit patient will undergo an MRI scan and be educated on completing
      home monitoring of sleep wake cycle with actigraphy.

      Visit 3: Patients will undergo one night of NPSG at MSSM with either consistent use of CPAP
      or use of Sham CPAP to model discontinuation. Approximately, 10 hours after sleep onset
      participant will have a LP with collection of CSF. They will also complete 3D Visual Maze
      task the night of in lab assessment and the morning after, right before the LP (15 cc).

      Visit 4: Patients will undergo one night of NSPG at MSSM with either consistent use of CPAP
      or use of Sham CPAP to model discontinuation. Approximately, 10 hours after sleep onset
      participant will have a LP with collection of CSF. They will also complete 3D Visual Maze
      task the night of in lab assessment and the morning after, right before the LP (15 cc)

      Incidental findings from study procedures (except for CSF analyses and ApoE genotyping) will
      be communicated to study subjects by the Study Physician.
    

Intervention name(s): Continuous positive airway pressure device
Intervention type(s): Other
Intervention description(s): 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
Other intervention name(s): CPAP
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic