Brain Energy Metabolism and Sleep in Adults
Condition: Alzheimer Disease; Mild Cognitive Impairment; Cognitive Change; Energy Metabolism; Sleep Disturbance
MeSH terms: Alzheimer Disease; Dyssomnias; Parasomnias; Cognitive Dysfunction
Study type: Interventional

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.
    

Detailed 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.

      The study will be concluded in two phases. In Phase-1, the eligible participant will complete
      a set of neurocognitive testing, genetic sample collection, sleep assessment, and MRS scan.
      If the 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 three months
      followed by neurocognitive testing and sleep assessment.
    

Intervention name(s): MyTAP oral appliance plus mouth shield
Intervention type(s): Device
Intervention description(s): The midline traction oral appliance (MyTAP, AMI Inc., Dallas, Texas) is currently marketed as a medical device to treat snoring and obstructive sleep apnea and is FDA cleared will be used only in Phase-2 of the study. Phase-1 doesn't include any intervention.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment