Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly

Andrew W Varga, Margaret E Wohlleber, Sandra Giménez, Sergio Romero, Joan F Alonso, Emma L Ducca, Korey Kam, Clifton Lewis, Emily B Tanzi, Samuel Tweardy, Akifumi Kishi, Ankit Parekh, Esther Fischer, Tyler Gumb, Daniel Alcolea, Juan Fortea, Alberto Lleó, Kaj Blennow, Henrik Zetterberg, Lisa Mosconi, Lidia Glodzik, Elizabeth Pirraglia, Omar E Burschtin, Mony J de Leon, David M Rapoport, Shou-En Lu, Indu Ayappa, Ricardo S Osorio, Andrew W Varga, Margaret E Wohlleber, Sandra Giménez, Sergio Romero, Joan F Alonso, Emma L Ducca, Korey Kam, Clifton Lewis, Emily B Tanzi, Samuel Tweardy, Akifumi Kishi, Ankit Parekh, Esther Fischer, Tyler Gumb, Daniel Alcolea, Juan Fortea, Alberto Lleó, Kaj Blennow, Henrik Zetterberg, Lisa Mosconi, Lidia Glodzik, Elizabeth Pirraglia, Omar E Burschtin, Mony J de Leon, David M Rapoport, Shou-En Lu, Indu Ayappa, Ricardo S Osorio

Abstract

Study objectives: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (Aβ). We thus aimed to examine relationships between concentrations of Aβ42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects.

Methods: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF Aβ42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into "high" and "low" Aβ42 groups to compare SWS bout length using survival analyses.

Results: A significant inverse correlation was found between CSF Aβ42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF Aβ42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF Aβ42.

Conclusions: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF Aβ42, suggesting that disturbed sleep might drive an increase in soluble brain Aβ levels prior to amyloid deposition.

Keywords: Alzheimer disease; amyloid beta; elderly; prevention; sleep.

© 2016 Associated Professional Sleep Societies, LLC.

Figures

Figure 1
Figure 1
Scatter plots of natural log of Aβ42 and F4 slow wave activity (full night) and slow wave sleep duration.

References

    1. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992;256:184–5.
    1. Kang JE, Lim MM, Bateman RJ, et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009;326:1005–7.
    1. Huang Y, Potter R, Sigurdson W, et al. Effects of age and amyloid deposition on abeta dynamics in the human central nervous system. Arch Neurol. 2012;69:51–8.
    1. Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid beta-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 2014;71:971–7.
    1. Ovsepian SV, O'Leary VB. Neuronal activity and amyloid plaque pathology: an update. J Alzheimers Dis. 2015;49:13–9.
    1. McGinty D, Szymusiak R. Keeping cool: a hypothesis about the mechanisms and functions of slow-wave sleep. Trends Neurosci. 1990;13:480–7.
    1. Steriade M, Amzica F, Contreras D. Synchronization of fast (30-40 Hz) spontaneous cortical rhythms during brain activation. J Neurosci. 1996;16:392–417.
    1. Peskind ER, Li G, Shofer J, et al. Age and apolipoprotein E4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Arch Neurol. 2006;63:936–9.
    1. Fukuda N, Honma H, Kohsaka M, et al. Gender difference of slow wave sleep in middle aged and elderly subjects. Psychiatry Clin Neurosci. 1999;53:151–3.
    1. Almeida RP, Schultz SA, Austin BP, et al. Effect of cognitive reserve on age-related changes in cerebrospinal fluid biomarkers of Alzheimer disease. JAMA Neurol. 2015;72:699–706.
    1. Osorio RS, Ayappa I, Mantua J, et al. The interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals. Neurobiol Aging. 2014;35:1318–24.
    1. Beekly DL, Ramos EM, Lee WW, et al. The National Alzheimer's Coordinating Center (NACC) database: the Uniform Data Set. Alzheimer Dis Assoc Disord. 2007;21:249–58.
    1. Glodzik L, Rusinek H, Brys M, et al. Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia. J Cereb Blood Flow Metab. 2011;31:671–9.
    1. Glodzik L, Mosconi L, Tsui W, et al. Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly. Neurobiology Aging. 2011;33:1215–27.
    1. Varga AW, Ducca EL, Kishi A, et al. Effects of aging on slow-wave sleep dynamics and human spatial navigational memory consolidation. Neurobiol Aging. 2016;42:142–9.
    1. Mander BA, Rao V, Lu B, et al. Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. Nat Neurosci. 2013;16:357–64.
    1. Yau PL, Kang EH, Javier DC, Convit A. Preliminary evidence of cognitive and brain abnormalities in uncomplicated adolescent obesity. Obesity (Silver Spring) 2014;22:1865–71.
    1. Desikan RS, Segonne F, Fischl B, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31:968–80.
    1. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8:597–619.
    1. Osorio RS, Ayappa I, Mantua J, et al. The interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals. Neurobiol Aging. 2013;35:1318–24.
    1. Feinberg I, Floyd TC. Systematic trends across the night in human sleep cycles. Psychophysiology. 1979;16:283–91.
    1. Aeschbach D, Borbely AA. All-night dynamics of the human sleep EEG. J Sleep Res. 1993;2:70–81.
    1. Wauquier A, van SB, Lagaay AM, Kemp B, Kamphuisen HA. Ambulatory monitoring of sleep-wakefulness patterns in healthy elderly males and females (greater than 88 years): the “Senieur” protocol. J Am Geriatr Soc. 1992;40:109–14.
    1. Lucey BP, Bateman RJ. Amyloid-beta diurnal pattern: possible role of sleep in Alzheimer's disease pathogenesis. Neurobiol Aging. 2014;35S2:S29–34.
    1. Ju YS, Finn MB, Sutphen CL, et al. Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid. Ann Neurol. 2016;80:154–9.
    1. Tononi G, Cirelli C. Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron. 2014;81:12–34.
    1. Born J, Feld GB. Sleep to upscale, sleep to downscale: balancing homeostasis and plasticity. Neuron. 2012;75:933–5.
    1. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342:373–7.
    1. Hosselet J, Ayappa I, Norman RG, Krieger AC, Rapoport DM. Classification of sleep-disordered breathing. Am J Respir Crit Care Med. 2001;163:398–405.
    1. Hosselet JJ, Norman RG, Ayappa I, Rapoport DM. Detection of flow limitation with a nasal cannula/pressure transducer system. Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1461–7.
    1. Ayappa I, Norman RG, Suryadevara M, Rapoport DM. Comparison of limited monitoring using a nasal-cannula flow signal to full polysomnography in sleep-disordered breathing. Sleep. 2004;27:1171–9.
    1. Maia LF, Kaeser SA, Reichwald J, et al. Increased CSF Abeta during the very early phase of cerebral Abeta deposition in mouse models. EMBO Mol Med. 2015;7:895–903.
    1. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367:795–804.
    1. Alcolea D, Martinez-Lage P, Sanchez-Juan P, et al. Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease. Neurology. 2015;85:626–33.
    1. Osorio RS, Pirraglia E, Gumb T, et al. Imaging and cerebrospinal fluid biomarkers in the search for Alzheimer's disease mechanisms. Neurodegener Dis. 2014;13:163–5.
    1. Blennow K. Cerebrospinal fluid protein biomarkers for Alzheimer's disease. Neurotherapeutics. 2004;1:213–25.
    1. Roh JH, Huang Y, Bero AW, et al. Disruption of the sleep-wake cycle and diurnal fluctuation of beta-amyloid in mice with Alzheimer's disease pathology. Sci Transl Med. 2012;4:150ra122.
    1. Lim AS, Ellison BA, Wang JL, et al. Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease. Brain. 2014;137(Pt 10):2847–61.
    1. Mander BA, Marks SM, Vogel JW, et al. beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci. 2015;18:1051–7.
    1. Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid in humans. Ann Neurol. 2006;59:512–9.
    1. Verma A, Radtke RA, VanLandingham KE, King JH, Husain AM. Slow wave sleep rebound and REM rebound following the first night of treatment with CPAP for sleep apnea: correlation with subjective improvement in sleep quality. Sleep Med. 2001;2:215–23.
    1. Bellesi M, Riedner BA, Garcia-Molina GN, Cirelli C, Tononi G. Enhancement of sleep slow waves: underlying mechanisms and practical consequences. Front Syst Neurosci. 2014;8:208.
    1. Walsh JK. Enhancement of slow wave sleep: implications for insomnia. J Clin Sleep Med. 2009;5(2 Suppl):S27–32.
    1. Walsh JK, Hall-Porter JM, Griffin KS, et al. Enhancing slow wave sleep with sodium oxybate reduces the behavioral and physiological impact of sleep loss. Sleep. 2010;33:1217–25.

Source: PubMed

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