Brain Amyloid- Retention During Wakefulness and Following Emergence From Sleep in Healthy People

Objective:

To assess if there are differences in [18F]florbetaben uptake following the first 120 minutes
of its injection (reflecting amyloid-beta or Ab load and/or docked Ab) in subjects during
rested wakefulness (RW) after normal sleep compared to wakefulness after 24 hrs of sleep
deprivation (SD). Specifically, we hypothesize that during RW after a normal night s sleep
there will be less [18F]florbetaben binding measured as distribution volume ratios (DVR) in
precuneus relative to cerebellum (reflecting normal brain clearing of Ab overnight) when
compared to wakefulness after SD, which would interfere with Ab removal from the brain s
interstitial space. Though we will be measuring Ab in whole brain our analysis will focus in
precuneus since this is the brain region that shows the higher levels of Ab accumulation in
contrast to cerebellum where there is no accumulation of Ab. Therefore, overall Ab load in
precuneus (as reflected by [18F]florbetaben DVR) will be lower during RW compared to SD. MRI
and 1H-MRS will be used secondarily to assess if there are differences in connectivity,
function and neurochemistry in precuneus between RW and SD. Because the rate of CSF
production as

well as Ab clearance from CSF differs as a function of age the current study will also allow
us to assess if the higher Ab brain levels reported in older than in younger individuals
reflect greater Ab clearance in younger than older individuals.

Study population:

Two groups consisting of healthy young adults (18 - 40 years of age) and healthy older adults
(>40 years of age). Males and females will be included.

Design:

Observational study. We will complete testing in 15 healthy controls in each group for a
total of thirty subjects (n=30) to assess the brain uptake of [18F]florbetaben (scan done for
120 minutes following tracer injection). The order of the scans (RW vs SD will be
randomized). MRI scans will be obtained either before or after the PET scanning session done
following [18F]florbetaben injection.

Outcome measures:

Uptake of [18F]florbetaben in the brain will be measured after RW and after SD. Primary
outcomes will be differences in uptake and clearance of [18F]florbetaben in precuneus
(reflecting A beta load and/or docked A beta) in subjects after SD compared to after RW as
measured with distribution volume ratios using cerebellum as reference region and that
clearance of Ab brain (difference between RW and SD) will be greater in younger than in older
participants . We hypothesize that Ab load in precuneus [18F]florbetaben DVR) will be higher
after SD than RW and that this difference will be larger for younger than older participants.
We also predict that older individuals will have higher brain accumulation of Ab than younger
ones. In addition we will assess differences in mean water diffusivity in brain, lactate
concentration, functional connectivity at rest and functional activation during an attention
task between RW and SD conditions. We predict lower fMRI signals in dorsal attention network
(DAN) during attention task, lower functional connectivity in the default mode network (DMN),
and lower functional connectivity and mean diffusivity for SD than for RW. We further predict
higher concentration of lactate, a marker of anaerobic metabolism for SD than for RW. As
exploratory analysis we will also assess based on the scans obtained after RW if individuals
with higher brain Ab accumulation will have worse cognitive performance on neuropsychological
tests than those with low brain Ab.

- INCLUSION CRITERIA:

1. Male or females.

2. Young group (18-40 years of age)

3. Older group (>40 years of age)

4. Ability to provide written informed consent

EXCLUSION CRITERIA:

1. Pregnant and/or breast feeding. Females of childbearing potential must have negative
urine pregnancy test and not be currently breastfeeding. Post-menopausal or surgically
sterile (tubal ligation or hysterectomy) females satisfy these criteria.

2. Positive urine drug test for controlled substances (cocaine, methamphetamine,
amphetamines, opioids, cannabinoids, benzodiazepines and barbiturates) on each visit
involving imaging studies and/or neuropsychological assessment.

3. Head trauma with loss of consciousness for more than 30 minutes as determined by
self-report and/or medical history.

4. Subjects with problematic insomnia as determined by self-report (reports having
trouble sleeping on most days).

5. Subjects with any of the following: narcolepsy, obstructive sleep apnea (OSA) and/or
abnormal sleeping patterns (including but not limited to those who use a CPAP machine,
sleeping during the day, using medication to fall asleep, sleeps less than 5 hours per
night, night shift workers) as determined by self-report and/or medical history.

6. Use, in the past two weeks, of psychoactive medications (four weeks for fluoxetine) or
medications that may affect brain function (including but not limited to opioid
analgesics, antidepressants, antipsychotics, benzodiazepines and barbiturates,
stimulants) as determined by self-report and/or medical history.

7. Current DSM 5 diagnosis of affective disorder, addiction (other than nicotine of
caffeine), PTSD, or schizophrenia.

8. Individuals with cognitive impairment as identified with a score of lower than 24 in
the MMSE will be excluded. Further, individuals with impairment sufficient to affect
consent capacity even if MMSE is less than 24 will be excluded. We will consult the
Ability to Consent Assessment Team (ACAT) in those whose capacity to consent may be
questionable.

9. Severe medical problems that can permanently impact brain function (e.g., problems of
the CNS; cardiovascular; metabolic, autoimmune, endocrine) as determined by history
and clinical exam.

10. Individuals with a medical history of a neurodegenerative disease.

11. Heavy alcohol users. Heavy alcohol users are those individuals who consume more than 5
drinks in one seating (if males) or more than 4 drinks in one seating (if females)
more than twice a week will be excluded.

12. Uncontrolled hypertension.

13. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the
head (including but not limited to pacemakers or other implanted electrical devices,
brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses,
permanent eyeliner, implanted delivery pump, or shrapnel fragments) or fear of
enclosed spaces as determined by the self-report checklist.

14. Fear of enclosed spaces (claustrophobia) as determined by self-report and medical
history.

15. Cannot lie comfortably flat on the back for up to 2 hours in the MRI scanner as
determined by self-report.

16. Body weight > 250 kg. This is the upper limit that the bed of the MR scanner can
accommodate (clinical exam).

17. Have had previous radiation exposure (from X-rays, PET scans, or other exposure) that,
with the exposure from this study, would exceed NIH annual research limits as
determined by medical history and physical exam.

18. Study investigators and staff, as well as their superiors, subordinates and immediate
family members (adult children, spouses, parents, siblings).