Brain Sleep Clearance of Amyloid-Beta Peptides

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.

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.

Eligibility Criteria:
Inclusion Criteria:

Group A:

* Male and female subjects with normal cognition and 55-75 years of age
* Newly recruited or recruited on the follow-up evaluation from an existing longitudinal cohort of 180 normal elderly already enrolled in an active study (R01HL118624-01).

Group B:

* Male and female subjects with normal cognition and 30-75 years of age
* Recruited from the MSSM where there are already studies ongoing aimed at determining the consequence of disrupting REM sleep via CPAP withdrawal on the consolidation of spatial navigational memory (PI. Dr. Varga).
* Previously diagnosed moderate-severe SDB patients and on active CPAP treatment.

Group A + B:

* All subjects will be within normal limits on neurological and psychiatric examinations.
* All subjects enrolled will have both a Clinical Dementia Rating (CDR)\<0.5 and Global Deterioration Scale (GDS)\<3 (i.e. cognitively normal).
* All subjects will have an informed family member or life partner interviewed to confirm the reliability of the subject interview.
* All subjects will agree to the MRI imaging, the lumbar puncture (s), apolipoprotein E (ApoE) genotyping and DNA banking.

B. Exclusion Criteria:

* Diagnosis of any brain disease or MRI evidence of brain damage including significant trauma, hydrocephalus, seizures, mental retardation or other serious neurological disorder (e.g. Parkinson's disease or other movement disorders). Persons with silent cortical infarcts will be excluded. White matter lesions will not be exclusions.
* History of brain tumor or contraindications for LP.
* Prior history of post-LP headache.
* Significant history of alcoholism or drug abuse.
* History of major psychiatric illness (e.g., schizophrenia, bipolar or life long history of major depression)
* Geriatric Depression Scale \>7 (for subjects \> 55 y/o) or Beck Depression Inventory \>18 (for subjects \<55 y/o)
* Current pregnancy or intent to become pregnant during the period of study.
* Evidence of clinically relevant and uncontrolled cardiac (unstable and untreated coronary or peripheral artery disease), pulmonary (ventilatory failure, Cheyne-Stokes breathing, severe and inadequately controlled arterial hypertension, acute upper respiratory infection), untreated hypothyroid or uncontrolled hematological conditions. Insulin dependent diabetes and/or history of treated hypertension are not exclusions. Normal subjects with current levels of HbA1c \>5.9% or diabetics \>7.0% and/or current blood pressure levels \>140/90 mm Hg will be advised to seek referral.
* Physical impairment of such severity as to adversely affect the validity of psychological testing.
* Any prosthetic devices (e.g., pacemaker or surgical clips) that constitutes a hazard for MRI imaging.
* History of a first-degree family member with early onset AD (\< age 60) dementia.
* Prior bariatric surgery within 6 months or are currently participating in a medical weight loss program.
* Irregular sleep-wake rhythms (based on one week at home monitoring with actigraphy)
* Inability to avoid the use of alcohol, caffeine during the 48h before the NPSG .
* Patients that are professional vehicle drivers or train operators, or patients that have had a previous motor vehicle accident related to sleepiness and cannot rest the day of the LP after the sleep deprivation experiment.
* Conditions that alter normal sleep patterns: Irregular sleep-wake rhythms (based on one week at home monitoring with actigraphy) or moderate to severe SDB (AHI4%\>15 per hour) .
* Medications adversely affecting cognition or sleep will result in exclusion. The excluded medications include:

  * Narcotic analgesics (\>2 doses per week).
  * Chronic use of medications with anticholinergic activity.
  * Anti-Parkinsonian medications (carbidopa/levodopa, amantadine, bromocriptine, pergolide, selegeline).
  * Others: amphetamines, amphetamine-like compounds, appetite suppressants, phenothiazines, reserpine, buspirone, clonidine, disulfiram, guanethidine, MAO inhibitors, theophylline, tricyclic antidepressants, salicylates, cholinesterase inhibitors and memantine.