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Daytime Sleepiness, Brain Pathology: A 2-Way Street?

— Amyloid buildup may be both effect and cause of sleep-wake abnormalities in elderly

MedpageToday

BOSTON -- Older individuals with normal cognition reporting excessive daytime sleepiness showed relatively greater increases in beta-amyloid plaque burdens in their brains, according to a new analysis from the longitudinal Mayo Clinic Study of Aging reported here.

Among 283 study participants undergoing serial brain scans with the beta-amyloid tracer Pittsburgh Compound B, the fastest rates of amyloid accumulation were seen in those who indicated frequent daytime sleepiness, said Diego Carvalho, MD, of the Mayo Clinic in Rochester, Minn., speaking at the American Academy of Neurology (AAN) annual meeting.

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Citing previous research as well, he laid out a model -- still to be verified in future studies -- in which sleep disruption and increasing beta-amyloid burdens feed off and worsen each either.

In particular, Carvalho said, sleep "fragmentation" (shortened but more frequent sleep intervals) lead to decreased overall amounts of slow wave sleep, which in turn leads to increased synaptic overload and decreased clearance of waste proteins in the brain. These process foster accumulation of beta-amyloid, which in turn can negatively affect slow-wave sleep and increase synaptic overload in its own right.

Eventually, he concluded, the effects advance to the point that neurodegeneration prevents normal sleep, and the cycle continues.

"It's becoming more accepted in the behavioral neurology world ... that patients who have mild cognitive impairment or early Alzheimer's disease [show] an accumulation of amyloid that correlates with hours of sleep," commented Michael Jaffee, MD, of the University of Florida in Gainsville, who served as discussant at the AAN session.

"We've now opened up a window into a non-demented population, which then has some clinical implications," Jaffee continued. "Does that mean sleep is a risk factor that could lead to development or progression of cognitive decline, or MCI, or early AD? Or is this an implication for some of the newer diagnostic criteria now being used in Alzheimer's, which is now known as preclinical Alzheimer's disease?"

Alternatively, perhaps disordered sleep is a "reversible risk factor" that could be a target for intervention, he suggested.

For the study, Carvalho's group picked out those participants in the long-running, community-based Mayo Clinic Study of Aging who were at least age 70 without dementia, and who had undergone at least two PiB-PET scans. Excessive daytime sleepiness was defined as an Epworth Sleepiness Scale score of at least 10. Associations between brain amyloid burden and the presence of excessive sleepiness were adjusted for more than a dozen potential confounders, including baseline age, APOE4 status, sex, education, sleep apnea symptoms, and interval between scans.

The presence of excessive daytime sleepiness predicted increases in brain amyloid burden both in all participants and in those who were positive for brain amyloid at the initial scan, Carvalho said. Specific regions showing amyloid accumulation associated with excessive sleepiness included the anterior cingulate and cingulate/precuneus regions in both analyses. Also, those with initial PiB-positivity and excessive sleepiness had amyloid buildup in the parietal region; that was not the case in the overall group, but initially PiB-negative participants showed amyloid accumulation in the orbitofrontal region.

Carvalho said the findings, if confirmed, could have an important clinical implication: that excessive daytime sleepiness is a marker for vulnerability to beta-amyloid accumulation and thus warrants early treatment (assuming that an effective disease-modifying treatment becomes available, of course).

Disclosures

Carvalho disclosed no relevant relationships with industry.

Primary Source

American Academy of Neurology

Carvalho D, et al "Excessive daytime sleepiness predicts increased ß-amyloid accumulation in non-demented elderly: a longitudinal PiB-PET study" AAN 2017; Abstract S14.004.