Therapeutics

Continuous Positive Airway Pressure

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Overview

Name: Continuous Positive Airway Pressure
Synonyms: CPAP
Therapy Type: Procedural Intervention
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Approved for: Sleep Apnea in US

Background

Continuous Positive Airway Pressure (CPAP) is an approved treatment using a machine and nasal mask to deliver continuous air flow and help keep the airways open during sleep. Sleep-disordered breathing and obstructive sleep apnea cause sleep fragmentation and nighttime hypoxia. People with Alzheimer’s have high rates of insomnia and other sleep disorders (e.g., Cooke et al., 2006). Beyond making them sleepy during the day, these sleep disorders are thought to worsen their cognitive impairment. Sleep-disordered breathing has been linked to cerebrospinal fluid and brain-imaging biomarker changes that predict Alzheimer's dementia, raising the question of whether hypoxia-inducing sleep disorders are a contributor to or a consequence of AD pathogenesis (Osorio et al., 2014Osorio et al., 2014Daulatzai 2013). In general, human and animal model research is implicating sleep more broadly in the pathogenesis of Alzheimer's disease (e.g., May 2014 conference storyAug 2012 conference story).  

CPAP is standard treatment for sleep-disordered breathing and sleep apnea. The rationale of testing CPAP at various stages of Alzheimer’s disease is twofold: to test whether continuous brain oxygenation during sleep delays the deterioration of memory and other existing symptoms of Alzheimer’s and related dementias, and to see whether improving brain oxygenation during sleep might even have a mechanistic effect on the underlying neurodegeneration. 

Findings

In the early 2000s, a controlled, randomized trial at the University of California, San Diego, tested a three- and a six-week course of CPAP in 52 people with mild to moderate Alzheimer’s and obstructive sleep apnea. The primary outcomes were sleep quality and daytime sleepiness as reported by patient and caregiver, and cognitive function. Published results from this trial indicated improvements in certain aspects of cognition, but were underpowered to make definitive statements. This study contacted participants a year later and compared five patients who continued to use CPAP to five others who did not. The report on this follow-up indicated a larger cognitive improvement for continued CPAP users but clearly noted insufficient power and other limitations (Chong et al., 2006Ancoli-Israel, 2008; Cooke et al., 2009; Richards 2009). These papers sparked interest in further clinical exploration of CPAP to address sleep quality as a potentially treatable factor in cognitive impairment in AD. 

In 2010, a single-center trial in Saint-Etienne, France, started evaluating a four-month course of CPAP in 100 people with mild to moderate Alzheimer's. This trial measures the effect of nightly CPAP on cognition using Behavioral Assessment of Dysexecutive Syndrome (BADS) zoo map scores; its secondary measures are rate of sleep apnea, neuropsychological tests, and a quality-of-life questionnaire. The study is set to be completed in spring 2015.

In 2012, a trial at three sites evaluated a six-month course of CPAP in 110 people with mild cognitive impairment. Primary outcome measures include several memory-test and other cognitive assessments. Secondary outcome measures include eight additional cognitive, clinical, and functional measures widely used in Alzheimer's trials, as well as three neuroimaging measures. This trial was to conclude in 2014 but results have not been announced. 

In July 2013, a small, open-label prevention trial started up at New York University. It will enroll an estimated 45 cognitively normal people aged 50 and older who have sleep-disordered breathing. Some will be offered a six-month course of CPAP; those who decline CPAP or do not comply with the CPAP regimen will be considered controls. The trial's primary outcome measures are CSF tau and Aβ42 levels, as well as two MRI measures, hippocampal volume, and cerebral vasoreactivity to CO2 challenge. The trial has an interventional component that measures these outcomes, as well as some memory functions, again after six months of CPAP treatment, and an observational component that revisits these measures at a two-year longitudinal followup. This trial is set to run until July 2017.

For all clinical trials of CPAP in Alzheimer's, see clinicaltrials.gov.

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References

News Citations

  1. Glymphatic Flow, Sleep, microRNA Are Frontiers in Alzheimer’s Research
  2. Night Owl? Early Bird? Good Night’s Sleep May Protect the Brain

Paper Citations

  1. . Continuous positive airway pressure reduces subjective daytime sleepiness in patients with mild to moderate Alzheimer's disease with sleep disordered breathing. J Am Geriatr Soc. 2006 May;54(5):777-81. PubMed.
  2. . Cognitive effects of treating obstructive sleep apnea in Alzheimer's disease: a randomized controlled study. J Am Geriatr Soc. 2008 Nov;56(11):2076-81. PubMed.
  3. . Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer's disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med. 2009 Aug 15;5(4):305-9. PubMed.
  4. . Comorbid Alzheimer's disease and OSAS: does CPAP slow cognitive decline?. J Clin Sleep Med. 2009 Aug 15;5(4):310. PubMed.
  5. . The effect of sleep-disordered breathing on stages of sleep in patients with Alzheimer's disease. Behav Sleep Med. 2006;4(4):219-27. PubMed.
  6. . The interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals. Neurobiol Aging. 2014 Jun;35(6):1318-24. Epub 2013 Dec 27 PubMed.
  7. . Imaging and Cerebrospinal Fluid Biomarkers in the Search for Alzheimer's Disease Mechanisms. Neurodegener Dis. 2013 Oct 2; PubMed.
  8. . Death by a Thousand Cuts in Alzheimer's Disease: Hypoxia-The Prodrome. Neurotox Res. 2013 Feb 12; PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . [Obstructive sleep apnea and cognitive impairment in the elderly]. Psychol Neuropsychiatr Vieil. 2010 Sep;8(3):163-9. PubMed.
  2. . [Sleep disturbances in Alzheimer's disease and other dementias]. Psychol Neuropsychiatr Vieil. 2010 Mar;8(1):15-23. PubMed.
  3. . Sleep disorders and their impacts on healthy, dependent, and frail older adults. J Nutr Health Aging. 2009 Apr;13(4):322-9. PubMed.
  4. . Continuous positive airway pressure reduces subjective daytime sleepiness in patients with mild to moderate Alzheimer's disease with sleep disordered breathing. J Am Geriatr Soc. 2006 May;54(5):777-81. PubMed.
  5. . Sleep-disordered breathing and cognitive impairment in elderly Japanese-American men. Sleep. 2003 Aug 1;26(5):596-9. PubMed.