Shokri-Kojori E, Wang GJ, Wiers CE, Demiral SB, Guo M, Kim SW, Lindgren E, Ramirez V, Zehra A, Freeman C, Miller G, Manza P, Srivastava T, De Santi S, Tomasi D, Benveniste H, Volkow ND. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):4483-4488. Epub 2018 Apr 9 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is an interesting study, presenting findings in line with our earlier work showing that a single night of sleep deprivation affects cerebrospinal fluid levels of Aβ (Ooms et al., 2014) and with recent work by Yu et al. (2017) indicating that slow-wave sleep disruption (and not full sleep deprivation) alone already affects CSF Aβ (Ooms et al., 2014). A likely mechanism for these changes in amyloid levels is increased amyloid production during wakefulness (or reduced production during sleep) as was recently demonstrated by Lucey et al. (2018). 

    I am a bit skeptical, however, about the present study's findings using PET-amyloid imaging. Previous work on sample size calculations to detect relevant changes in amyloid concentrations using PET-amyloid imaging (Su et al., 2016) concluded that large sample sizes are required ( > n=200 per group). I would not a priori have considered using PET-amyloid imaging in this design with n=20. In the article I missed a thorough discussion on this aspect. The same holds for the question whether it is really Aβ binding we are looking at, or, for example, differences in perfusion, and would like to hear comments from experts in nuclear medicine on these findings.

    References:

    Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 2014 Aug;71(8):971-7. PubMed.

    Yu M, Engels MM, Hillebrand A, van Straaten EC, Gouw AA, Teunissen C, van der Flier WM, Scheltens P, Stam CJ. Selective impairment of hippocampus and posterior hub areas in Alzheimer's disease: an MEG-based multiplex network study. Brain. 2017 Mar 16; PubMed.

    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.

    Su Y, Blazey TM, Owen CJ, Christensen JJ, Friedrichsen K, Joseph-Mathurin N, Wang Q, Hornbeck RC, Ances BM, Snyder AZ, Cash LA, Koeppe RA, Klunk WE, Galasko D, Brickman AM, McDade E, Ringman JM, Thompson PM, Saykin AJ, Ghetti B, Sperling RA, Johnson KA, Salloway SP, Schofield PR, Masters CL, Villemagne VL, Fox NC, Förster S, Chen K, Reiman EM, Xiong C, Marcus DS, Weiner MW, Morris JC, Bateman RJ, Benzinger TL, Dominantly Inherited Alzheimer Network. Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group. PLoS One. 2016;11(3):e0152082. Epub 2016 Mar 24 PubMed.

    View all comments by Jurgen Claassen

  2. This is a very interesting paper. The authors report increased Aβ deposition on PET scans in participants after one night of sleep deprivation. Aβ burden was increased in the right hippocampus and thalamus. I had a few observations and concerns about this paper:

    1. I would not have expected that amyloid PET would detect a change in Aβ burden after one night of sleep deprivation. A potential implication of this is that the rate of amyloid deposition per night of sleep deprivation could be determined. Then, the number of sleepless nights needed to become amyloid-positive could be calculated. An important follow-up question would be: Does the predicted number of sleepless nights make sense in the context of known sleep patterns in different populations?
    2. Aβ deposition was found to be increased in the right hippocampus and thalamus. These are not regions that develop Aβ plaques early in AD.
    3. In studies using Aβ stable isotope labeling kinetics (SILK), we see changes in Aβ42 kinetics with amyloid deposition. I would predict that sleep-deprived individuals would have altered Aβ42 kinetics if active overnight deposition was going on and we don’t see this.

    View all comments by Brendan Lucey

  3. This study further highlights the growing interest in the field on how sleep is related to the regulation of Aβ levels in the brain. This is an important emerging area in the field that deserves greater exploration as sleep disturbances are well-documented in AD populations (Peter-Derex et al., 2014). The authors' findings that sleep deprivation increases levels of Aβ deposition in the brain is generally consistent with prior work examining sleep. However, there are a few caveats that should be considered when interpreting the study’s findings:

    1. Work with both animal (Kang et al., 2009) and human (Huang et al., 2012) models has shown that levels of Aβ in the ISF and CSF, respectively, have a diurnal rhythm. The mechanism of this relationship is thought to be due to the fact that Aβ levels are known to be regulated by neuronal activity (Cirrito et al., 2005). Subsequent studies have shown, in humans, that Aβ CSF levels are tied to sleep quality (Ju et al., 2013), slow-wave sleep (Ju et al., 2017), as well as sleep deprivation (Ooms et al., 2014). The majority of the literature reports relationships between sleep and soluble forms of Aβ.

    2. Florbetaben and other PET tracers bind to Aβ plaques (Fodero-Tavoletti et al., 2012), rather than the soluble forms of Aβ previously measured in animal and human work. While increased soluble forms of Aβ likely impact plaque formation, it is unclear if this process could occur over one day. Future work should focus on establishing the biological mechanism that could potentially lead to increased plaque deposition in the brain in such a short, one day, time frame. It would also be highly interesting to measure both CSF and PET measures to establish whether subject specific increase in fluid levels of Aβ are proportional to changes seen with PET.

    3. Given the young age of the participants (mean age 43, 40 percent of the population under 40) the majority of participants would be free of any plaque pathology. This means that any PET measurements are entirely dominated by non-specific binding. Additionally the observed results are also not in areas where Aβ deposition is typically seen using PET. This raises concerns that the experimental manipulation is affecting non-specific binding, tracer kinetics, or BBB permeability rather than facilitating plaque buildup.

    References:

    Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. PubMed.

    Fodero-Tavoletti MT, Brockschnieder D, Villemagne VL, Martin L, Connor AR, Thiele A, Berndt M, McLean CA, Krause S, Rowe CC, Masters CL, Dinkelborg L, Dyrks T, Cappai R. In vitro characterization of [(18)F]-florbetaben, an Aβ imaging radiotracer. Nucl Med Biol. 2012 Apr 11; PubMed.

    Huang Y, Potter R, Sigurdson W, Santacruz A, Shih S, Ju YE, Kasten T, Morris JC, Mintun M, Duntley S, Bateman RJ. Effects of age and amyloid deposition on aβ dynamics in the human central nervous system. Arch Neurol. 2012 Jan;69(1):51-8. PubMed.

    Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, Morris JC, Holtzman DM. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013 May 1;70(5):587-93. PubMed.

    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.

    Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.

    Lucey BP, Mawuenyega KG, Patterson BW, Elbert DL, Ovod V, Kasten T, Morris JC, Bateman RJ. Associations Between β-Amyloid Kinetics and the β-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol. 2017 Feb 1;74(2):207-215. PubMed.

    Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 2014 Aug;71(8):971-7. PubMed.

    Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer's disease. Sleep Med Rev. 2014 Apr 3; PubMed.

    View all comments by Brian Gordon

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Does Amyloid Accumulate After a Single Sleepless Night?