Clinical Trial Details
— Status: Terminated
Administrative data
NCT number |
NCT03929302 |
Other study ID # |
IRB 18-73 |
Secondary ID |
|
Status |
Terminated |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
November 30, 2018 |
Est. completion date |
January 31, 2020 |
Study information
Verified date |
May 2024 |
Source |
The University of Texas at Dallas |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
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 sleep 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, mild cognitive impairment (MCI) and Alzheimer's
disease (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.
Description:
Alzheimer's disease (AD) is rapidly progressing in the elder population and the
pathophysiological changes in the brain start 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 the population is 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. New
modalities for potential identification of the progression of the disease, include different
biomarkers, state-of-the-art technologies like sleep tracking and magnetic resonance
spectroscopy (MRS) may provide additional, essential tools to facilitate early detection of
disease, which may allow for earlier intervention and provide a potential gauge for a
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 healthy 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 shown impairments in brain
glucose metabolism associated with cognitive decline in MCI even before the individual
presents with clinically apparent cognitive dysfunction. Thus, measuring the ratio of energy
metabolites ATP-to-PCr (ATP/PCr) and Pi-to-PCr (Pi/PCr) offers a promising way to predict the
active status of the 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. 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). 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 a significant 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
about 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 to
healthy 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 essential to understand this connection as genes
regulate the synthesis of appropriate protein/enzymes like ABCA7 transporter protein for
glucose metabolism leading to energy production.
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 response to attenuate
upper airway obstruction in sleep by using continuous positive airway pressure (CPAP) was
shown also to improve cognitive functioning in AD patients with OSA. 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 have been in clinical use for over 20 years without any serious adverse
effects in treating patients with primary snoring to severe sleep apnea 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 have already been published.
As per FDA cleared label MyTAP® OA family of intra-oral devices are intended for the
treatment of night-time snoring and mild to moderate obstructive sleep apnea in patients 18
years of age or older.
All eligible participant agreeing to sign the consent form and participate in the study will
be divided into 3 groups - Cognitively Normal Adults, MCI and AD based on Mini Mental Status
Examination (MMSE) and California Verbal Learning Task (CVLT). All participants will
initially undergo the mandatory set of study procedures for neurocognitive testing, genetic
testing, MRS scan and sleep assessment. Interested participants in all the 3 groups,
presenting with abnormal sleep and upper airway obstruction parameters during the sleep
assessment will then be offered the optional therapeutic intervention Intraoral anti-snoring
device for snoring and obstructive sleep apnea for three months.