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Lucey BP, Hicks TJ, McLeland JS, Toedebusch CD, Boyd J, Elbert DL, Patterson BW, Baty J, Morris JC, Ovod V, Mawuenyega KG, Bateman RJ. Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics. Ann Neurol. 2018 Jan;83(1):197-204. PubMed.
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University of Wisonsin
This is a fascinating new study from WashU that adds to a growing body of literature indicating that sleep disruption is linked to amyloid. Sleep has been linked to features of Alzheimer’s disease in a number of studies—both rodent and human—but an outstanding question that has been difficult to address (especially in humans) is whether disrupted sleep contributes to brain amyloid accumulation via increased amyloid production, decreased clearance, or both.
This study is really well done. Not only are amyloid levels monitored over an extended period of time using a lumbar catheter in sleep-deprived and non-deprived participants, but the investigators use a method developed by their group (Bateman et al., 2006) to quantify the production and clearance rates of CNS proteins.
Comparing sleep-deprived to non-deprived participants, the investigators found increased amyloid production in the sleep-deprived group. Markers of amyloid in CSF increased by up to 30 percent, which is substantial. Importantly, their modeling technique suggested no group differences in clearance. Given that higher amyloid concentration is associated with greater brain amyloid accumulation, the obvious question that should be addressed next is whether treating sleep disorders can reduce risk for AD by lowering amyloid concentrations.
Participants in this study were cognitively healthy, were not likely accumulating brain amyloid, and overall were fairly young. It would be interesting to see how sleep/wake amyloid kinetics differ in older age, or in participants who are already accumulating brain amyloid, given that these factors were shown in a previous study from this group to affect amyloid kinetics.
As an aside, I think the study is also relevant to the interpretation of CSF biomarkers in studies that are not focused on sleep, since we typically do not characterize sleep quality in participants who undergo lumbar puncture for research studies on AD. One way to guard against misinterpretation of high Aβ42 levels (brought on by a prior night of poor sleep), is to use Aβ42/ Aβ40 ratios.
References:
Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006 Jul;12(7):856-61. PubMed.
View all comments by Barbara BendlinRadboud University Nijmegen Medical Center
I have read this pilot study performed by Lucey and colleagues with much interest. It is a carefully performed physiological study that, despite its small sample size, provides exciting new insights in the relationship between sleep and Alzheimer's disease.
In 2014, we published the results of what I think was the first attempt to translate mouse models of sleep deprivation to human physiology. We succeeded in sleep depriving 13 healthy middle-aged men during one night, with an equal-sized control group, using an indwelling catheter to sample cerebrospinal fluid levels of Aβ (40 and 42) and tau. We found that on average, CSF Aβ42 decreased (by 10 percent) after normal sleep, but remained stable after sleep deprivation. This suggested that, like in mice, sleep deprivation may increase Aβ levels in humans, and we, like others in this field had already done, postulated that repeated episodes of sleep deprivation could contribute to gradually increasing levels of Aβ, which in turn may initiate or aggravate Alzheimer pathology. It also appeared that it was the loss of slow-wave sleep that resulted mostly in the increase in amyloid levels, however, our study was not powered to prove that. Important other questions that remained were whether the increase in amyloid levels was due to increased production or to reduced clearance.
This study by Lucey et al. makes several important points. First, it replicates, in a new population, the observation that sleep deprivation affects amyloid levels in healthy humans. Second, it adds important information on amyloid production, using a laborious but precise method developed in Bateman's lab (SILK), showing that at least in some subjects, sleep deprivation leads to a strong increase in amyloid production. A strong point is that more than one amyloid species was measured, from which we learn that the increase in amyloid appears nonspecific to Aβ42. In our study we found changes in Aβ42 but not 40. This difference may be due to different assays, and I think most evidence now points toward an increase in both 40 and 42 (and 38). Third, this study finds no evidence of altered clearance processes related to sleep, indicating that the changes in amyloid levels are related to production and not clearance. In addition to the arguments provided by the authors (which mainly concern the pharmacodynamics of the SILK method) I also note that the study, which elegantly included a very strong increase in slow-wave sleep in one arm, was designed so that it could have picked up the hypothesized effects of slow-wave sleep on clearance. In a recent study from the same department (Yu, et al., 2017), specific inhibition of slow-wave sleep was applied, leading to increases in CSF amyloid levels, but not in other CSF proteins that would have been expected to be affected by clearance. Together, these studies, along with our 2014 study, replicate in humans the effects of sleep deprivation on CSF amyloid levels, but fail to replicate the animal studies suggesting a “glymphatic” clearance mechanism for amyloid.
Of course, sample size is small (but do not underestimate the tremendous complexity of this study), however, physiological studies can provide reliable and relevant insights even with small sample sizes. Also, inter-individual variability is strong, and will likely be a topic for further investigation. These arguments however, in my opinion, should cast no doubts on the relevance of this pilot study.
References:
Ju YS, Ooms SJ, Sutphen C, Macauley SL, Zangrilli MA, Jerome G, Fagan AM, Mignot E, Zempel JM, Claassen JA, Holtzman DM. Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain. 2017 Aug 1;140(8):2104-2111. PubMed.
View all comments by Jurgen ClaassenMake a Comment
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