Brain Energy Metabolism and Sleep in Adults
Phase: NA
Conditions: Alzheimer Disease, Mild Cognitive Impairment, Cognitive Change, Energy Metabolism, Sleep Disturbance
Sponsor: The University of Texas at Dallas

Brain Energy Metabolism and Sleep in Adults. 
 
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Title of the Protocol: Brain Energy Metabolism and Sleep in Adults 
Principal Investigator:  Sandra Chapman, PhD. 
Funding Sponsor: UT Dallas Institutional Funding 
Version 5, September 1st 2018 
                              
 
 
 
 
 
 
 
 
 
 
 
 

Brain Energy Metabolism and Sleep in Adults. 
 
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Abbreviations  
AD: Alzheimer’s disease 
MCI: Mild Cognitive Impairment 
ATP: Adenosine Tri-Phosphate 
pH : Potential of Hydrogen 
Mg2+: Magnesium 
PET: Positron Emission Tomography 
SPECT: Single-photon emission computed tomography 
MRS: Magnetic Resonance Spectroscopy 
1H MRS: Proton Magnetic Resonance Spectroscopy 
31P MRS: Phosphorus Magnetic Resonance Spectroscopy 
NAA: N-acetyl aspartate  
PMEs: Phosphomonoesters 
PDEs: Phosphodiesters 
Pcr: Phosphocreatine 
Pi: Inorganic phosphate 
NTPs: Nucleotide Triphosphate 
NDPs: Nucleotide Diphosphate 
MMSE: Mini-Mental Status Examination 
CVLT: California Verbal Learning Task 
DKEFS: Delis- Kaplan Executive Function System 
CDR: Clinical Dementia Rating Scale 
WAIS: Wechsler Adult Intelligence Scale  
TOSL: Test of strategic learning 
COWAT: Controlled Oral Word Association Test  
BNT: Boston Naming Test 
DSFB: Digit Span Forward and Backward 
APOE Apolipoprotein  
ABCA7 ATP binding cassette-A7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Brain Energy Metabolism and Sleep in Adults. 
 
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Contents 
 
1. Introduction and Purpose 
2. Background 
 
3. Summary of the Project 
4. Study Procedures  
5. Criteria for Inclusion and Exclusion of subjects 
6. Sample size 
7. Sources of research material 
8. Potential Risks 
9. Participant safety and data safety monitoring plan 
10. Potential benefits  
11. Incentive 
13. References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Brain Energy Metabolism and Sleep in Adults. 
 
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1. Introduction and Purpose 
  
 
The main purpose of this study is to understand the impact of brain energy metabolites (BEM), 
sleep patterns and specific genes on the performance of neurocognitive measures of memory, attention, 
language and complex executive functions in cognitively normal adults, in preclinical stages of 
Alzheimer’s disease (AD) i.e., mild cognitive impairment (MCI), and Alzheimer’s disease.  The 
secondary goal is to investigate if sleep and cognition could be improved in the three cohorts with dental 
intervention to correct the airway. 
The three primary goals of this pilot will be followed by a secondary goal to test if dental intervention 
improves brain health in terms of brain’s metabolic rate and cognition. The primary and secondary goals 
are 
1. Explore the ratios of brain energy (ATP/PCr, Pi/PCr) and phospholipids (PME/PDE) metabolites as 
measured by magnetic resonance spectroscopy at 7 Tesla, and compare the differences in them with the 
performance of episodic memory, attention, language, and executive functions (abstraction, reasoning, 
verbal fluency, working memory) in three groups: cognitively normal adults, MCI and AD.  
2. Investigate the differences in sleep patterns measured by the ratio sleep quality index (Stable/ Unstable 
sleep) in cognitively normal adults, MCI and AD and its relation to the performance of episodic memory, 
attention, language, and executive functions (abstraction, reasoning, verbal fluency, working memory) in 
three groups.  
3. Investigate the differences in the variations of two genes, APOE-E4 and ABCA7, in relationship to the 
changes in the brain energy metabolites and its relation to the performance of episodic memory, attention, 
language, and executive functions (abstraction, reasoning, verbal fluency, working memory) in those with 
cognitively normal adults, MCI and AD. 
4. Investigate if dental intervention improves sleep patterns and overall cognitive behavior in the three 
cohorts. 
 

Brain Energy Metabolism and Sleep in Adults. 
 
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2. Background 
 
Alzheimer’s disease (AD) is rapidly progressing in the elder population and the pathophysiological 
changes in the brain starts at least 1-2 decades before the disease onset. During this period of slow 
progression individuals may notice subtle changes in the memory and this subset of population are termed 
as Mild Cognitive Impairment (MCI). MCI is a pre-clinical stage of Alzheimer’s disease (AD) in which 
individuals have memory complaints but are functionally independent and not yet clinically diagnosed 
with dementia[39]. New modalities for potential identification of the progression of the disease, includes 
different biomarkers, state-of-the-art technologies like sleep tracking and magnetic resonance 
spectroscopy (MRS) may provide an additional, important tools to facilitate early detection of disease, 
which may allow for earlier intervention and provide a potential gauge for response to treatment.    
The first goal of this research project aims to understand the variations in the brain energy and 
phospholipid metabolites as measured by magnetic resonance spectroscopy at 7 Tesla across three groups: 
cognitively normal adults, MCI, and AD. The brain requires a lot of energy in the form of adenosine 
triphosphate (ATP) to support the neuronal activity and it has a rich source of phospholipids to maintain 
biological functions. Therefore, abnormalities in the mechanism of energy supply and phospholipids can 
affect a wide range of function in the neuronal cells. Previous literature using 18FDG PET scan has 
showed impairments in brain glucose metabolism associated with cognitive decline in MCI even before 
the individual presents with clinically apparent cognitive dysfunction [19, 27]. Thus, measuring the ratio 
of energy metabolites ATP-to-PCr (ATP/PCr) and Pi-to-PCr (Pi/PCr) offers a promising way to predict 
energetic status of resting brain. Additionally, the levels of phospholipids start to decrease by the age of 
twenty (20) and more pronounced decline is noticed after the age of 80 years [10,47]. Thus, aging and 
diseased brains are more susceptible to the changes in the levels of phospholipids metabolites which can 
lead to neurodegenerative disorders. Two classes of phospholipid metabolites that can be studied using 
31P MRS are phosphomonoesters (PMEs) and phosphodiesterase (PDEs) [1]. PMEs are the essential 
building blocks for cell/neuronal membrane synthesis whereas PDEs are the metabolites from the 
breakdown of the cell/neuronal phospholipids membrane. A higher ratio of PMEs-to-PDEs can, therefore, 
reflect as an improvement in brain health leading to neurogenesis, with the opposite suggesting 
neurodegeneration. Thus, 31P MRS has opened a window to measure various neurochemical metabolites 
non-invasively, which could provide detailed information about important high-energy phosphate 
metabolites, as well as phospholipid metabolites in real time. 7T Ultra-high magnetic field MRI scanner, 
which is now increasingly accessible worldwide and enables fast and accurate BEM measurement, may 
provide a comprehensive approach for aiding in the diagnosis of the neurodegenerative process from 
cognitively normal adults to MCI and AD and also monitoring the treatment responses to newer drugs. 
Secondly, disturbance in sleep patterns can impact the brain’s energy metabolism by altering the ratio of 
brain energy and phospholipid metabolites, thereby causing impaired brain cognitive functions. Aging, is 
an important moderator of sleep quality, and may affect non-REM slow wave sleep (SWS), which 
facilitates the clearance of toxic material like amyloid protein. Stable sleep helps restore the 
neurobiological and neurophysiological responses in relation to energy requirements impacting the 
changes in the concentration of brain energy and phospholipid metabolism.  Currently, data are lacking 
regarding the relationship between sleep, brain energy requirement and its effect on the performance of 
cognitive domains in relation to normal aging, MCI, and AD.  
Thirdly, BEM is regulated by specific genes that support the continuous energy requirements for the 
electrical activity of the brain. Hence in this research, we are interested in investigating the effect of two 
genes APOE ε4 and ABCA7 on brain energy and phospholipids metabolites in the three groups. It is 
important to understand this connection as genes regulate the synthesis of appropriate protein/enzymes 
like ABCA7 transporter protein for glucose metabolism leading to energy production. 

Brain Energy Metabolism and Sleep in Adults. 
 
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Finally, based on an “improving sleep first hypothesis”, a dental intervention (MyTAP; midline traction 
oral appliance (OA) therapy) will be offered to participants presenting with abnormal sleep and upper 
airway obstruction parameters. Therapeutic intervention to attenuate upper airway obstruction in sleep by 
using continuous positive airway pressure (CPAP) was shown to also improve cognitive functioning in 
AD patients with OSA(Cooke et al. 2009). In most cases, upper airway obstruction can also be acutely 
corrected using a simple fitted, clinically proven, FDA-cleared midline traction design oral appliance to 
restore sleep quality and possibly improve cognition and ‘normalize’ BEM. There are currently no reports 
on the efficacy of oral appliance therapy to improve daytime sleepiness, objective sleep measures and 
cognitive function in patients with MCI or AD. The MyTAP is similar to other midline traction design 
oral appliances which has been in clinical use for over 20 years without any serious adverse effects in 
treating patients with primary snoring to severe sleep apnea. (Gershman 2002; Hoekema et al. 2008) The 
MyTAP oral appliance will be used in accordance with its indications for use and FDA-approved 
labeling. The safety and efficacy of the midline traction oral appliance has already been published. 
(Thornton & Roberts 1996) As per FDA cleared label MyTAP® OA family of intra-oral appliances are 
intended for the treatment of night-time snoring and mild to moderate obstructive sleep apnea in patients 
18 years or age or older. 
 
The study will be concluded in two phases. In Phase-1, eligible participant will complete a set of 
neurocognitive testing, genetic sample collection, sleep assessment, and MRS scan. If participant is 
interested in dental intervention they will progress to Phase-2. In Phase-2 of the study, subjects will 
complete the dental intervention for 3 months followed by neurocognitive testing and sleep assessment. 
 
3. Summary of the Project 
This study will investigate: 
1. Brain energy metabolites ratio (energy and phospholipids metabolites)  
2. Sleep quality index and its relationship with the performance of episodic memory, attention, language, 
and executive functions (abstraction, reasoning, verbal fluency, working memory) in three groups: 
cognitively normal adults, MCI, and AD.  
3. Genetic components of APOE ε4 and ABCA7  
4. Effects of dental intervention in individuals with abnormal sleep parameters and cognition. 
We will recruit up to 60 individuals in three groups of twenty each (20, Cognitively normal, 20 with MCI, 
and 20 AD) between the ages 55-85 years old. The individuals will be recruited from Dallas- Fort Worth 
areas through advertisements, flyers, social media, word of mouth, and those from the Center for 
BrainHealth who had expressed interest in future studies. Interested individuals will complete a study 
screen for medical history, demographics and memory questionnaire called Clinical Dementia Rating 
(CDR) scale.  
A waiver of consent is being requested to cover potential subjects with a diagnosis of Alzheimer’s disease 
as they participate in the phone screen (including an MRI safety screen) and an initial Clinical Dementia 
Rating (CDR) scale to assess their ability to provide written informed consent for study participation. If 
they receive a score of 1 or less, they will be deemed competent to provide their own written informed 
consent and will proceed to the second part of the competency screen. The potential subject will then be 
provided a summary of the study and will have their understanding assessed via a short quiz  using the 
competency questionnaire .They have to answer all the questions on this questionnaire appropriately to 

Brain Energy Metabolism and Sleep in Adults. 
 
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deemed competency.  They will also undergo an initial Mini Mental Status Exam. If they receive a score 
of 20 or above on the MMSE, they will be deemed competent to provide independent informed consent, 
and will continue the consent process to provide full written informed consent for study participation. 
An alteration of consent and a waiver of documentation of consent are being requested to cover potential 
subject with normal cognition or mild cognitive impairment, and the phone screen (including an MRI 
safety screen) for eligibility purposes. If these individuals are deemed eligible to participate in the study, 
they will be invited to the study site to provide full written informed consent to participate in the study. 
After completing the phone screen, the eligible participants will visit the Center for BrainHealth for 
consent and neuropsychological assessment lasting for approximately three hours. Later, either the same 
day or at another date they will complete the MRS scan at the AIRC (approximately 90 minutes). Third, 
the participant will complete an in home sleep study for four (4) consecutive nights with a brief self-
assessment sleep questionnaire for each night. Finally, the participant with upper airway obstruction and 
high snore count from sleep analysis will be offered dental intervention. The dental intervention will be 
performed at Center for BrainHealth, UTD by one of the dentist from Texas A&M Dental University i.e., 
Dr. Jason Hui, or Dr. Philip Wilson, Dr. Amrittej Virk, and Dr. Pollyana Marques de Moura. Upon 
completion of dental intervention, participant will be reassessed on their neurocognitive behavior, and 
sleep assessment. 
 
 
4. Study procedures 
Phase-1 will include phone screen, neuropsychological assessment, genetic sampling, sleep assessment, 
and MRS scan. Phase-2 will include dental intervention for 1 month followed by post-intervention testing 
using neuropsychological and sleep assessments. 
The detailed protocol that will be used for recruitment and completing both phase-1 and phase-2 of the 
study is as follows: 
a. Phone screen- During the initial phone call, potential participants will undergo will undergo a brief 
phone screen to assess inclusion and exclusion criteria, as well as MRI suitability followed by a memory 
questionnaire called clinical dementia rating (CDR)scale. CDR will be completed on the phone with the 
potential participant’s family member first and then completed with the participant. It covers six (6) 
cognitive domains such as memory, judgment, and problem solving, community affairs, orientation, 
personal care and hobbies.  
b. Neuropsychological assessment and Genetic testing: A clinician from the Center for BrainHealth will 
review the consent form with the participant. If the participant understands and agrees to sign and 
proceed, the form will be signed. After consenting, a buccal swab for genetic testing and vital signs 
(weight, height, blood pressure and heart rate) will be acquired. Then clinician will administer a group of 
standardized and experimental tests to each participant on neuropsychological testing. The assessment 
may last up to 3 hours, depending on the pace of the participant’s response times. The intent of the tasks 
is to assess higher-level thinking skills, memory, attention, language, working memory, and selective 
learning. The assessment will be done at the Center for BrainHealth at 2200 W. Mockingbird Lane, 
Dallas, Texas. 

Brain Energy Metabolism and Sleep in Adults. 
 
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The neuropsychological test battery will include standardized and experimental measures tests like Mini-
Mental State Examination (MMSE),Wechsler Memory Scale (WMS-III) Logical Memory (LM) subtest, 
California Verbal Learning Task (CVLT), Controlled Oral Word Association Test (COWAT), Boston 
Naming Test (BNT), Digit Span Forward and Backward (DSFB), Delis-Kaplan Executive Function 
System Card Sorting , Trails A & B, Test of Strategic Learning (TOSL), Wechsler Adult Intelligence 
Scale (WAIS) Similarities subtest, selective auditory learning task, memory of intention test, Montreal 
cognitive assessment (MoCA) and neuromotor index (Altoida app) . The following questionnaires will 
also be administered: Lawton instrumental activities of daily living scale, medical questionnaires, activity 
questionnaires, met analysis memory questionnaire (MMQ), geriatric depression scale, Cognitive Reserve 
Index Questionnaire (CRIq) to measure cognitive reserve, Epworth Sleepiness Scale, a Pittsburg Sleep 
Quality Index (PSQI), a sleepio-internet based questionnaire, and sleep dairy to measure sleep habits.  
c. Magnetic resonance spectroscopy (MRS): On the same or separate days, the participants will have 
MRS at 7Tesla at one point of time during which they will lie in the scanner while images of their brain 
will be recorded for one and half (1.5) hours.  In the scanner the participants will be asked to be awake in 
the scanner, with head placed in a pad-cushioned coil. The volume coil 1H/31P MRS imaging data will be 
acquired using the 7Tesla human MRI scanner at UT Southwestern Medical Center (UTSW).  During the 
MRS data acquisition, subjects will be positioned head-first and supine in the MRI scanner, with the back 
of the head positioned to rest in the head coil. After preparatory imaging scans, which will be is mainly 
for localization and shimming, the 31P MRS data acquisition will be followed, which will include two 
surveying scans for evaluation of shimming quality on 31P spectra and of 31P excitation profiles along HF 
direction, then a six-slice 2D Chemical Shift Imaging(CSI) scan over the whole brain.  For survey MRS 
scans, standard pulse-acquire technique will be used. Typical parameters are TR 4 s, sampling points 4 K, 
zero-filled to 8 K prior to FT, post-pulse delay 0.5 ms to filter out the broad phospholipids 31P signal. For 
CSI, slice-thickness will be 2 cm along LR direction, 4-6 slices, TR = 1 sec, NA = 4, sample points 2 K  
in-plane resolution 2x2cm2, scan time ~45 min. After 31P MRSI data acquisition, voxel-by-voxel data 
analysis will be carried out to compare the regional difference in relative concentration of the phosphoryl 
metabolites; and all the measurements will be calculated from these values. 
 
 
 
d. Sleep quality assessment (Figure 1, 2) SleepImage (MyCardio, LLC, Broomfield, CO) recorder collects 
data on electrocardiogram (ECG), actigraphy, body position, snore, ECG-derived respiration, HRV, HR. 
The SleepImage system includes a sleep recorder that is clinically validated and FDA cleared to allow the 
non-intrusive collection of objective measures of sleep quality. The participant will complete the sleep 
study for four (4) consecutive nights using the device along with self-assessment of sleep by answering 
the PSQI questionnaire for each night.  
The sleep data will be analyzed by Dr. Preetam Schramm and Dr. Emet Schneiderman. 
  
 
 
 
 

Brain Energy Metabolism and Sleep in Adults. 
 
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Total time committed towards research will be around 37 hours excluding the time for transit. 
Dental Intervention:  
Participants whose sleep recordings (Figure 1) show the presence of clinically significant snoring (≥4 
snores/hour of sleep) will be referred for dental intervention. If the participant chooses dental 
intervention, the attending dentist will determine if the individual is eligible for oral appliance therapy 
(OA). OAs are the recommended first line therapy for snoring, obstructive sleep apnea with mild to 
moderate obstruction, and also those seeking an alternative to CPAP therapy. 
 
The OA device (Figure 2) will be used per manufacturers’ recommendations. The device has a thermal 
acrylic liner to ensure a very accurate fit. Each subject will also be custom fitted with a mandibular 
positioner (“AM Aligner” or “Morning Positioner”) to use for up to 20 minutes after awakening. This will 
assist in returning the subject to his/her normal occlusion. Appliance Acclimation: the OA will be 
adjusted / titrated to the awake patient’s maximal comfortable protrusive position by a study dentist.  
1. Fitting of an OA:  The MyTAP (Airway Management Inc., Dallas, TX) custom-fitted dental OA 
will be applied chair-side by a trained dentist. The starting position will be determined by the 
patient at a comfortable position but not less than 60% as determined by the Pro Gauge 
measurement tool. “Comfortable” is defined as the advanced mandibular position that permits the 
subject to sleep for ≥5 hours per night for at least 6 nights of the week. [Completion time: 30 
minutes)  
2. Participants are expected to wear the appliance nightly during sleep. Participants will be allowed 
to advance the jaw 0.5 mm every 2 nights (less frequently if needed to minimize transient 
discomfort) without causing discomfort at the temporal mandibular joint, masticatory muscles or 
teeth that lasts more than 1 hour after removing the appliance in the morning. 
3. Subjects will use diaries to record appliance settings and hours of sleep on each sleep recorded or 
non-recorded night. 
Figure 1: SleepImage sleep device in  
recording 
position. 
Figure 2: SleepImage sleep device actual size. 

Brain Energy Metabolism and Sleep in Adults. 
 
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The dental intervention will be performed at Center for BrainHealth, The University of Texas at Dallas by 
one of the dentists from Texas A&M Dental University i.e., either Dr. Jason Hui, Dr. Philip Wilson, or 
Dr. Amrittej Virk, or Dr. Pollyanna Marques de Moura. 
 
Safety  
The MyTAP OA and sleep recorder to be used are FDA cleared. The OA is in wide use by dental patients 
throughout the US, Europe and Australia. Both have demonstrated efficacy so that their use in the 
proposed research is consistent with what is done in routine clinical care and involves no more than 
minimal risk. All of the proposed tests are noninvasive. 
 
 
5. Criteria for inclusion and exclusion of Subjects: 
Eligible participants will be: 
 
Ages 55-85 years  
 
At least 12 years of education 
 
Right hand dominant 
 
With or without minor memory complaints, (those with a diagnosis of Alzheimer’s 
disease are also eligible for the study),  
 
Participants who can safely have an MRS scan 
 
Have motor abilities including the use of the right arm and hand for neuropsychological 
testing. 
 
Able to speak, read, and comprehend English fluently 
 
Non-pregnant, and not on Hormone replacement therapy  
 
Exclusion criteria will be: 
 
Pregnancy 
 
Use of Hormone Replacement therapy 
 
Less than 12 years of education 
 
Left hand dominant 
 
Unable to speak, read and write English fluently (Testing and training material are 
validated in English). 
 
 
 
Neurological Disorders, e.g., stroke, brain tumor, cerebral hemorrhage. 

Brain Energy Metabolism and Sleep in Adults. 
 
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 
Autoimmune disorders like fibromyalgia, systemic lupus erythematosus (SLE), Multiple 
sclerosis and rheumatoid arthritis. 
 
Metabolic diseases such as diabetes mellitus, thyroid disorders that are not currently 
managed by a physician  
 
Psychiatric disorders such as bipolar disorder, major depressive disorder, pervasive 
developmental disorder, schizophrenia, anxiety disorder. 
 
Current drug or alcohol abuse 
 
Head injuries with an Ohio State University TBI Identification (Short Form) score greater 
than 3.  
 
Cancer treated with radiation and/or chemotherapy  
 
General anesthesia within the prior six months  
 
Uncorrected vision and hearing problems. 
 
Active pain requiring treatment 
 
BMI ≥35 
 
Previously treated for diagnosed sleep disorders 
 
Known chronic obstructive pulmonary disease(COPD) 
 
Exclusion for imaging criteria (includes the following, or any other concerns by the 
AIRC staff) 
o Permanent Makeup. 
o Exclusions for metal safety include questionable ferrous implants, bullets, BB's, 
shrapnel,  
o Medical devices which are unsafe in MRI. 
o Hearing aid that cannot be removed. 
6. Sample Size 
In pilot data we tested 12 variables for mean change following training and estimated effect sizes for 
the set of variables that were significant at a 10% false discovery rate (FDR).  The equivalent alpha level 
for a 10% FDR in our set of pilot data was estimated to be 0.055to account for the potential increase in 
false positives due to the multiple tests, and the minimum effect size for the set of variables that satisfied 
the FDR level was 0.6 standard units.  Using the pilot data estimate of an FDR-equivalent alpha level we 
calculated power for a range of effect sizes and for a sample size of N=60 (shown in figure below).    
  

Brain Energy Metabolism and Sleep in Adults. 
 
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Given the parameters specified above, the figure shows a power level of at least 0.60 when the effect size 
is at least 0.7 standard units.  Based on our pilot data we expect to be sufficiently powered, with multiple 
testing accommodation, using N=60 subjects for tests of mean change. 
 
 
 
 
7. Sources of Research Material 
Materials obtained for research purposes include demographic information, survey/questionnaire data, 
neuropsychological testing battery, brain imaging MRS 7T data, genetic data and sleep data in cognitively 
normal adults and mild cognitive impairment.  A swab of the cheek/saliva will be collected for a DNA 
sample.  All of the data will be obtained for research purposes. 
8. Potential Risks: 
Neuropsychological assessment risk: There are no known risks associated with the neuropsychological 
testing other than possible fatigue and frustration. If the participants feel tired they will be allowed to rest.  
If they become frustrated, they can rest or stop participation at any time.  
MRI Risk: The magnetism of the MRI scanner will attract certain metal objects and could cause serious 
harm. Subjects will be asked to fill out an MRI screening form which has questions about their health, 
previous surgeries and the presence of metal or implanted devices in their body. People with metal or 
device implants such as pacemakers, infusion pumps, aneurysm clips, shunts, clips, metal plates, rods, 
joints or screws, certain IUD implants, shrapnel or metal in the eyes, and permanent eyeliner or eyebrows 
may be excluded from participation in this study. Subjects are encouraged to please tell the researchers if 
there is any possibility of metal in their body. Researchers will carefully screen subjects to determine if it 
is safe for them to have an MRI. There are no known risks from exposure to magnetic fields. Subjects 
may experience nervousness and/or anxiety due to the loud banging made by the machine while it is 
taking pictures and from confinement in a tight space (claustrophobia). If they become anxious, they can 

Brain Energy Metabolism and Sleep in Adults. 
 
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stop the procedure at any time. They may also experience some discomfort and fatigue from lying still 
during imaging. If they have any metal clips or plates in their body, they are encouraged to tell the 
investigator. MRI may not be appropriate if subjects are pregnant or are trying to become pregnant.  
MRI may not be appropriate if subjects have permanent eyeliner or eyebrows or any pieces of metal in 
their body, such as the following: 
 
heart pacemaker, heart valve replacement, or aortic clips 
 
metal fragments in your eyes, skin, or elsewhere in the body 
 
brain clips or pieces of metal used in aneurysm surgery or intracranial bypass 
 
venous umbrella 
 
pieces of metal in the body resulting from work as a sheet-metal worker or welder 
 
clips placed in an internal organ 
 
prosthetic devices, such as middle ear, eye, joint, or penile implants 
 
joint replacement. 
 
hearing aid that cannot be removed 
 
neurostimulator 
 
insulin pump 
 
intrauterine device (IUD) 
 
shunts or stents 
 
metal mesh or coil implants 
 
 metal plate, pin, screws, or wires, or any other metal implants  
 
Women who are pregnant or suspect pregnancy may not participate in this study. Women of 
childbearing potential will have a urine pregnancy test. 
Loss of Confidentiality: Any time information is collected; there is a potential risk of loss of 
confidentiality. Every effort will be made to keep subject's information confidential; however, this 
cannot be guaranteed. 
Risks to an Embryo, Fetus or Breast-fed Infant   Females: If females are part of this study while 
pregnant or breast-feeding an infant, it is possible that they may expose the unborn child or infant to 
risks. For that reason, pregnant and breast-feeding females cannot participate in the study. If subjects 
can become pregnant, a pregnancy test will be done (from a urine sample), and it must be negative 
before they can be a part of this study. If subjects do become pregnant during this study, they must 
tell the researchers immediately. 
Other Risks: There may possibly be other side effects that are unknown at this time. If subjects are 
concerned about other, unknown side effects, they are encouraged to please discuss this with the 
researchers. 
7T Magnet Potential Risks: This procedure is experimental and the long-term risks of the high 
magnetic field are unknown. Exposure to high magnetic fields may have effects on the normal 
electrical activity of the body including changes in nerve and heart function. Changes in the heart rate 
or rhythm could occur. Blood pressure, temperature, and pulse rate may change. Studies with an 8 
Tesla MRI have not shown any significant effects. A subject may feel dizzy when moving the head 
quickly while in the magnetic field. This is a relatively frequent sensation, perhaps occurring in 30% 
or more of subjects. In studies at 8 Tesla, 1 subject out of 200 has vomited as the result of being in the 

Brain Energy Metabolism and Sleep in Adults. 
 
14 
 
magnet. A relatively common sensation is a metallic taste in the mouth while entering or exiting the 
scanner. A subject might see tiny light flashes similar to those that occur when you rub your eyes in 
the dark. This is less common and has no known harmful effects. Claustrophobia (uneasiness at being 
in a confined space) is a common contraindication in any MRI procedure at any magnetic field 
strength (tesla).  Exposure to the rapidly changing magnetic fields could cause twitching of the 
subject’s muscles. This effect, known as peripheral nerve stimulation (PNS), is temporary.   It is 
possible that radio frequency energy in a 7 Tesla MRI system may be absorbed in an unexpected 
manner by human subjects. Local heating of the leg may occur. Studies with an 8 Tesla MRI have not 
shown any significant effects in studies of the head.   As with all MRI, any metal in the body or in 
clothing represents a risk. Metallic objects can be accelerated by the magnetic field and become 
dangerous. A metal implant or foreign object in the body could be displaced by the magnetic field. 
There can be increased heating near metal structures.    
Sleep recorder risk:  The minor physical risk associated with the sleep-monitoring aspects of this 
study are no more than those involved with standard tests of bodily (physiological) functions, for 
example wearing a heart monitor or polysomnography. We do not anticipate any significant physical 
risk to subjects from using the sleep recorder while participating in this study. It is not anticipated that 
the 2 hypoallergenic adhesive electrodes used with the recorder will cause itching or rashes. The 
adhesive used to attach the electrodes is medical grade meant for use on human skin similar to a 
bandage and is disposed and replaced with new adhesive electrodes with each use.   
Genetic data risk:  Finally, there is no associated risk with genetic testing other than potential loss of 
confidentiality which will be guarded against.  The results of the genetic testing will not be shared 
with the participants.   
Dental Intervention Risk: The minor physical risk associated with the sleep-monitoring aspects of 
this study are no more than those involved with standard tests of bodily (physiological) functions, for 
example wearing a heart monitor. The OA may cause pain in the jaw joint and teeth, and difficulty in 
opening or closing the jaw; these conditions are usually temporary. In the long term, the OA may cause 
changes in tooth position and in the bite (occlusion), as well as damage to the teeth and gums. 
We do not anticipate any significant physical risk from participating in this study. Though not impossible, 
we do not expect the adhesive hypoallergenic electrodes of the SleepImage device to cause itching or 
rashes. By wearing an OA, a subject may experience some discomfort and/or reduced function of the jaw 
joint (temporomandibular joint) and muscles of the jaw (chewing muscles) and of the face during and 
after treatment. Subjects may also experience some reduction in sleep quality due to discomfort while 
acclimating to wearing the OA. Other minor risks include temporary irritation of the mouth and oral 
cavity due to contact with the OA, and excessive salivation or dry mouth from mouth breathing. 
Repositioning of the lower jaw and tooth movement may also occur, but are typically minor and 
reversible. Also highly unlikely, a subject could swallow or aspirate part of an OA should it break. 
Participants will be carefully monitored for all of these risks by one or more of the study dentists. A 
telephone number and email address will be given to participants in case of questions and emergencies. 
 
Data Storage: All data from questionnaires and cognitive tasks will be stored on a password-protected 
computer with the participant’s study number. A master link linking participant numbers to names and 
other contact information will be stored on a different computer that is also password protected. All data 
will be stored without any identifying participant information linked to the data itself. All data will be 
stored without any identifying participant information – only the participant’s study number will appear 
on the sample. 

Brain Energy Metabolism and Sleep in Adults. 
 
15 
 
Procedures to Maintain Confidentiality: We have taken a number of measures to ensure the 
confidentiality of the data and the safety of the participants. As we describe in the sections above, all data 
from the proposed study will be identified by a numerical ID code only. The information linking the 
numerical ID code to identifying information will be maintained separately and securely from the data 
themselves.  
Every effort will be made to maintain the confidentiality of study records.  Only the researchers will have 
access to any personally identifying information, that is, contact information for each participant (i.e., an 
email address or phone number).  This information will not be stored with the participant data.  An 
identification number will be assigned to each participant so that it will be possible to identify 
information to be shared with other researchers as described in the HIPAA. In data analysis, each 
participant will be identified by this number. All research materials with identifiable data, consisting of 
detailed health questionnaires, neuropsychological testing, and consent and HIPAA forms, will be kept in 
locked cabinets in the Center for BrainHealth at UTD.  Imaging data at UTSW will be stored following 
HIPAA-compliant protocol. The data from the study may be published, but all information will be 
deidentified and HIPAA compliant.  The confidentiality of the data will be maintained within the legal 
limits. Only associates listed on this study will have access to identifying data.  The Research 
Coordinator, the Principal Investigator, and co-investigators will have access to the data and to the codes, 
along with designated research associates. The researchers will destroy the personal identifiers upon 
completion of data collection for the study. 
 
9. Participant Safety and Data Safety Monitoring Plan 
 
Dr. Chapman, PI will closely monitor the following at least on a monthly basis:  
 
Study accrual rate 
Experience of study participants 
Study attrition including participant withdrawals/dropouts 
Patterns of AEs and/or unanticipated events 
Patterns of protocol deviations and/or violations 
Changes in risk/benefit 
 
10. Potential Benefits 
 
Benefit to participant:  
The only benefit participant can have in this study is from dental intervention to improve sleep quality. 
Other benefits related to MRS and genetic data are not anticipated from this study. 
Benefit to society:  
We hope the information learned from this study will help our understanding of early changes in the brain 
in individuals with normal cognitive functioning, mild cognitive impairment, and Alzheimer’s Disease, in 
the areas of neuropsychological assessment, magnetic resonance spectroscopy imaging (MRS), genetic 
sample and sleep analysis. We also are interested in learning if correction of airway through dental 
intervention will improve sleep and cognition in three cohorts. 
11. Incentive 

Brain Energy Metabolism and Sleep in Adults. 
 
16 
 
The participant will be paid $30 on successful completion of all the study parameters. 
 
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