Brain Sleep Clearance of Amyloid-Beta Peptides
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.
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.