CME Author: Zeena Nackerdien
Study Authors: Brendan P. Lucey, Austin McCullough, et al.
Target Audience and Goal Statement: Neurologists, geriatricians, sleep specialists, primary care physicians, family doctors, and nurses.
The goal was to analyze cognitive performance, brain imaging, and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers in participants age >60 enrolled in longitudinal studies of aging.
Questions Addressed:
- Is there a way to track individuals at risk for AD before visible cognitive decline sets in?
- Does bad sleep correlate with increased tau pathology – a marker for cognitive decline in AD?
Synopsis and Perspective:
Changes at every stage of life also include sleeping patterns. According to the National Sleep Foundation, older people in particular commonly experience problems such as difficulty falling asleep and staying asleep, and sleep patterns also shift due to alterations in circadian rhythm.
Results from several studies have suggested a bidirectional relationship between sleep and AD. Other evidence from the literature supports sleep disturbance as a marker for AD pathology and future risk of cognitive decline. Currently, AD pathology is understood to involve a clumping together of abnormal levels of the naturally occurring amyloid β (Aβ) to form plaques that collect between brain neurons and disrupt cell function, usually with signs of tau pathology.
By the time the earliest signs of cognitive decline become evident, this insidious process is well under way. Previous studies have also found that increased napping was associated with increased Aβ accumulation over time, and that decreased non–rapid eye movement (NREM) slow waves correlated significantly with Aβ burden in the medial prefrontal cortex.
Brendan Lucey, MD, and David Holtzman, MD, both of Washington University in St. Louis, and colleagues added to the growing body of evidence with their prior discovery that Aβ fluctuated in cerebrospinal fluid (CSF) with sleep-wake activity in both mice and humans. However, previous findings linking NREM sleep disruption to memory impairment did not assess tau pathology. Therefore, the team said, there was an unmet need to engage in longitudinal studies involving AD biomarkers and cognitive evaluations to establish both the sequential associations between these events and causation, especially in relation to both Aβ and tau.
For the new study, published in Science Translational Medicine, eligible participants (n=119) underwent cognitive testing, apolipoprotein E genotyping, and assessment of AD biomarkers in CSF (Aβ42, tau, phosphorylated tau [p-tau]) or positron emission tomography (PET) scans with [18F]AV-45 (florbetapir) amyloid and [18F]AV-1451 (flortaucipir) tau tracers.
Participants, on average, were 74 years old, and most (~80%) showed no signs of cognitive decline. A total of 104 people underwent spinal taps for CSF analysis, 38 underwent PET scans for the two proteins, and 27 underwent both.
Sleep was measured longitudinally in all participants over the course of 6 nights at home. Participants had a single-channel electroencephalogram (EEG) device strapped to their foreheads to measure their brain waves as they slept and wore another sensor to measure periodic limb movements. In addition, participants were studied for sleep-disordered breathing and periodic leg movements. Each participant produced at least 2 nights of EEG data, and some had as many as 6.
Notes of night-time sleep sessions and daytime napping were recorded in sleep logs. A minimum of 4 hours of artifact-free recording was obtained for all participants. Respiratory events and periodic leg movements were scored by registered polysomnographic technologists.
Following adjustments for multiple covariates (e.g., age and sex), the researchers found that NREM slow-wave activity (SWA) showed an inverse relationship with AD pathology, especially tau pathology. This relationship was most evident at the lowest frequencies of NREM SWA, particularly at 1-2 Hz, the team reported.
“What’s interesting is that we saw this inverse relationship between decreased slow-wave sleep and more tau protein in people who were either cognitively normal or very mildly impaired, meaning that reduced slow-wave activity may be a marker for the transition between normal and impaired,” Lucey said in a statement.
“The key is that it wasn’t the total amount of sleep that was linked to tau; it was the slow-wave sleep, which reflects quality of sleep,” he added. “The people with increased tau pathology were actually sleeping more at night and napping more in the day, but they weren’t getting as good quality sleep.”
One study limitation, the researchers said, was the fact that it was not possible to establish whether sleep disturbances preceded or followed the development of AD pathology. Another weakness was that there were only 38 participants in the imaging analyses, and therefore, a potential limitation to the analysis was overfitting a model with 10 covariates.
Source Reference: Science Translational Medicine, online Jan. 9, 2019; 11 (474): eaau6550
Study Highlights: Explanation of Findings
One in three older individuals die with AD or other types of dementia, according to the Alzheimer’s Association. The organization also estimates that early and accurate diagnosis could save up to $7.9 trillion in medical care and costs.
Lucey, Holtzman, and co-authors showed that NREM SWA decreased with increased evidence of Aβ deposition and tau accumulation. The estimated magnitude of this association was greater for tau, and findings with CSF tau/Aβ suggest that tau is central to this relationship. Because the study participants were mostly cognitively healthy, the results suggest that reduced NREM SWA might be associated with tau pathology, either prior to or at the earliest stages of cognitive decline, the researchers stated.
Self-reported napping time per day may therefore be an important question to screen individuals for tauopathy, the authors added.
They also cited the multiple modalities of both sleep monitoring and biomarkers for AD pathology available from all of the participants as key strengths of the study.
Another recent study reported links between excessive daytime sleepiness and longitudinal Aβ deposition in the anterior cingulate, posterior cingulate-precuneus, and parietal brain regions. But, after adjusting for multiple comparisons, the group did not find a link between 1- to 2 Hz SWA and Aβ deposition in the brain regions analyzed.
Asked for his perspective, Ron Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center in Rochester, Minnesota, who was not involved with the study, explained: “The hypothesis is that one function of sleep is to clear metabolites out of the brain, and amyloid may be one of those — to the extent that, if you get disrupted sleep, you may get into a vicious cycle where amyloid builds up.”
He noted that Lucey, McCullough, and co-authors had suggested that pending verification of the findings in larger trials, periodic assessments of NREM SWA in addition to other biomarkers may have potential application in both clinical trials and screening for AD to noninvasively monitor for AD risk or response to treatment.
“The bigger question is a chicken-and-egg one,” Petersen told MedPage Today: “Is it that your sleep is disrupted and the Alzheimer’s proteins build up — or are the Alzheimer’s proteins being deposited in the brain, disrupting sleep, and that’s where the cycle gets initiated? That still is uncertain. Nevertheless, the message is probably the same, that disrupted sleep may enhance the buildup of the proteins and enhance the Alzheimer’s process itself.”
Source: MedicalNewsToday.com
