MCI: CPAP Treatment of OSA (Memories2)

A growing number of research studies suggest that obstructive sleep apnea (OSA),
characterized by episodic nocturnal collapse of the upper airway and reduction/cessation of
breathing leading to significant nocturnal hypoxia, is associated with an increased risk of
cognitive impairment. OSA is effectively treated with continuous positive airway pressure
(CPAP), a pressurized nasal/face mask worn during sleep, but health care providers do not
often prescribe it for Mild Cognitive Impairment (MCI) because there are no large,
prospective research studies in this population confirming efficacy.

This multi-site study will have a sample size of n=460 divided into three groups followed for
one year: 1) a CPAP adherent group (approximately n=200); 2) two control groups consisting of
2a) a CPAP non-adherent control group (approximately n=160) and 2b) a no apnea control group
(n=100). This will allow us to confirm whether CPAP treatment, controlling for risk factors
such as neuroimaging findings and OSA severity at baseline, predicts the primary outcome of
cognitive function at 1-year follow-up. Study participants will also undergo an Amyloid PET
scan, use wearable activity monitors and functional/structural MRI brain scans.

This research study will thus examine the one year effects of CPAP on cognitive function and
elucidate physiological mechanisms for cognitive decline in aMCI and OSA.

Inclusion Criteria:

1. age 55-75 years;

2. moderate to severe OSA as defined by an AHI ≥ 15 events/hr, or no apnea defined by an
AHI<5 events/hr using American Academy of Sleep Medicine (AASM) diagnostic methodology
as determined on a diagnostic polysomnography;

3. Scoring education adjusted scores 28-35 (inclusive) on optional Telephone Interview
for Cognitive Status Modified (pre-screen);

4. Scoring 0-0.5 on the Clinical Dementia Rating Scale (CDR);

5. Scoring 24-30 on the Mini Mental State Examination (MMSE) (exceptions may be made for
participants with <8 years of education as determined by the clinical research team);

6. Memory impairment approximately 1.0-1.5 standard deviations below normal (adjusted for
age and education) determined by scores on the Logical Memory II a test from the
wechshler memory scale;

7. Test performance approximately 1.0 to 1. 5 standard deviations below normal (adjusted
for age and education) in NO MORE THAN ONE cognitive domain in addition to MEMORY as
determined on neuropsychological measures;

8. permitted medications (antidepressants, etc.) stable for at least 4 weeks (12 weeks
for cholinesterase inhibitors/memantine) as per ADNI3 criteria;

9. Non-depressed: Scoring < 6 on the Geriatric Depression Scale;

10. study partner, defined as an informant/caregiver who will be able to answer questions
about the study participant, and meets one of the following criteria: (a) lives with
the participant; (b) spends at least 3 times per week in-person contact with the
participant; (c) spends at least 3 times per week in phone contact with the
participant; or (d) spends at least 10 hours per week in any combination of phone or
in person contact;

11. adequate visual and auditory acuity to allow testing;

12. Post-menopause or surgically sterile;

13. testability - willing and able to complete baseline, 6-month, and 1-year outcome
measures, and willing to send in the CPAP Smartcard for adherence;

14. willing to undergo MRI and provide DNA for ApoE 4 assessments;

15. completed at least 6 grades of education; and

16. fluent in English or Spanish.

Exclusion Criteria:

1. any significant neurologic disease other than aMCI, such as Parkinson's Disease,
Huntington's disease, normal pressure hydrocephalus, progressive supranuclear palsy,
multiple sclerosis, head trauma followed by permanent neurologic deficits or known
congenital brain structure abnormalities; within the past 6 months brain tumor, or
seizure disorder, or subdural hematoma, or post-stroke (based on Modified Hachinski
Ischemic Score);

2. MRI exclusions - presence of pacemakers, aneurysm clips, artificial heart valves, ear
implants, metal fragments or foreign objects in the eyes, skin, or body; however, the
participant has the option of participating in the study without having an MRI;

3. psychiatric disorders, including uncontrolled major depression, newly diagnosed or
exacerbation in past 6 months of bipolar disorder as described in the DSM-IV,
psychotic features, agitation or behavioral problems within the past 6 months that
could lead to difficulty complying with the protocol, or history of schizophrenia
(DSM-IV criteria);

4. history of alcohol abuse or dependence within the past 6 months (DSM-IV criteria);

5. any current significant systemic illness or unstable medical condition that could lead
to difficulty in complying with the protocol (such as unstable cardiovascular
disease); current use of supplemental oxygen or hypoxemia indicated by documented
daytime oxyhemoglobin saturation <90% on room air, uncontrolled thyroid disease (to be
included must be on stable dose of thyroid medication for >6 months), uncontrolled
cirrhosis, cancer diagnosis within the past 6 months, clinically significant
laboratory abnormalities such as reported untreated folate, B12, or TSH disease, or
resident of a skilled nursing facility;

6. participation in clinical studies involving neuropsychological measures being
conducted more than twice a year;

7. currently receiving and adherent to CPAP or bi-level pressure for OSA;

8. OSA inadequately treated with CPAP alone (i.e., requiring bilevel therapy or oxygen);

9. Dementia indicated by impairment in 3-5 cognitive domains as determined by age and
education adjusted cut-off scores on neuropsychological measures making up the
diagnostic battery, referring to published diagnostic decision criteria consistent
with ADNI3.