By Alan Z. Segal, MD
Associate Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Segal reports no financial relationships relevant to this field of study.
Synopsis: Both animal studies and human data suggest that A-beta 42 amyloid is cleared from the brain during sleep, and that sleep deprivation may be a risk factor for the development of Alzheimer’s disease.
Source: Ooms S, et al. Effect of 1 night of total sleep deprivation on cerebrospinal fluid B-amyloid 42 in healthy middle-aged men: A randomized clinical trial. JAMA Neurol 2014;71:971-977.
Theories of "why we sleep" date back to the Greek and Roman philosophers, who believed that dreams were of divine origin. Kierkegaard called sleep the "highest accomplishment of genius." In more modern times, adequate, effective sleep is well known to be a major contributor to daytime alertness/vigilance, concentration, and declarative memory. Cognitive performance may be impaired by acute, total sleep deprivation for 1-2 nights or a more moderate, chronic lack of sleep (< 6 hours per night for 14 or more days).
More recent data suggest that these effects may not be transient, but rather cumulative over time and contribute to long-term cognitive decline and dementia, specifically Alzheimer’s disease (AD). Sleep has been shown to have a direct influence on the quantity of beta-amyloid (Aß) deposition in the brain as measured by PET scanning (Amyvid or Pittsburgh Compound B). Carriers of the ApoE4 genotype, who are at increased risk for developing AD, are even more prone to the disease if they suffer from poor quality sleep. Recently, increased neural activity in wakefulness has been shown to correlate with an augmentation of A-beta 42 production, with increased A-beta clearance during sleep. Groundbreaking data from the University of Rochester, recently reported in Science,1 has shown that in sleeping mice a process known as the "glymphatic" system increases the quantity of cerebrospinal fluid (CSF) "flushing" through the brain. Using a process of CSF "iontophoresis," this research showed that with an expansion of the volume of the interstitial space during sleep (a contraction of neurons), there was a 60% increase in CSF passage into the venous system. This system, likened to a "disposal system for the brain," is believed to allow for more effective clearance of toxins, specifically beta-amyloid.
In the current study, 26 middle-aged men were randomized equally to a normal night’s sleep compared with a full 24 hours awake. CSF was sequentially collected through a lumbar catheter. Subjects who slept showed a statistically significant 6% reduction in A-beta 42, where subjects who stayed awake did not demonstrate this decrease. This "morning effect" of decreased CSF A-beta 42 following sleep had previously been demonstrated in both rodents and humans but this study uniquely proved that lack of sleep would abort this effect. Not surprisingly, this difference in A-beta 42 levels did not apply to secondary markers studied such as A-beta 40 (which are a lesser contributor to plaque production) and tau (which is typically increased in much later phases of AD).
Measurement of sleep may be most accurately accomplished in a sleep laboratory with polysomnography, as was done here. Alternatively, sleep may be reported retrospectively, with nightly sleep logs or with measurement of actigraphic muscle activity or accelerometers such as the hugely popular "Fit-bit." Interestingly, the subjects studied here got poorer sleep than they might have at home. Prior to the study, these subjects all scored > 5 on the Pittsburgh Sleep Quality Index, evidence of normal sleep integrity. Studied in the lab, these individuals had a WASO (wake after sleep onset) of 92 minutes (normal < 30 min) and a sleep efficiency (total sleep time/total time in bed) of 77% (normal > 85%). It is possible that the favorable effects on A-beta 42 may have even been more pronounced with a better night’s sleep?
Commentary
These data, in combination with those in the Science report, lend credence to the theory that toxins such as A-beta 42 accumulate while we are awake and are cleared when we are asleep. This work lends biochemical support to the many behavioral studies (population-based cohorts) that have shown that short sleep times as well as sleep-onset and sleep-maintenance insomnia contribute to both immediate and long-term cognitive sequela. Obstructive sleep apnea, which has been clearly shown to contribute to dementia, is not only damaging due to hypoxia but also due to disruption of sleep integrity. Sedative-hypnotic drugs such as zolpidem or benzodiazepines may increase sleep time but impair slow-delta wave (Stage III) sleep and may have long-term deleterious cognitive effects. As we age, our ability to initiate and maintain quality sleep wanes even in the best of circumstances, but this should not stop us from trying to get as much as possible.
Reference
- Xie L, et al. Sleep drives metabolite clearance from the adult brain. Science 2013;342:373-377.