Elsevier

NeuroImage

Volume 98, September 2014, Pages 395-404
NeuroImage

Sleep deficits in mild cognitive impairment are related to increased levels of plasma amyloid-β and cortical thinning

https://doi.org/10.1016/j.neuroimage.2014.05.027Get rights and content

Highlights

  • Sleep physiology is significantly affected in aMCI subjects.

  • Disrupted slow wave sleep parallels increased Aβ42 levels in aMCI subjects.

  • Reduced REM sleep is associated with cortical thinning in aMCI subjects.

  • Increased Aβ levels are correlated with cortical thinning in aMCI subjects.

Abstract

Evidence suggests that amyloid-beta (Aβ) depositions parallel sleep deficits in Alzheimer’s disease (AD). However, it remains unknown whether impaired sleep and changes in plasma Aβ levels are related in amnestic mild cognitive impairment (aMCI) subjects, and whether both markers are further associated with cortical thinning in canonical AD regions. To jointly address this issue, we investigated relationships between changes in physiological sleep and plasma Aβ concentrations in 21 healthy old (HO) adults and 21 aMCI subjects, and further assessed whether these two factors were associated with cortical loss in each group. aMCI, but not HO subjects, showed significant relationships between disrupted slow-wave sleep (SWS) and increased plasma levels of Aβ42. We also found that shortened rapid-eye movement (REM) sleep in aMCI correlated with thinning of the posterior cingulate, precuneus, and postcentral gyrus; whereas higher levels of Aβ40 and Aβ42 accounted for grey matter (GM) loss of posterior cingulate and entorhinal cortex, respectively. These results support preliminary relationships between Aβ burden and altered sleep physiology observed in animal models of AD amyloidosis, and provide precise cortical correlates of these changes in older adults with aMCI. Taken together, these findings open new research avenues on the combined role of sleep, peripheral Aβ levels and cortical integrity in tracking the progression from normal aging to early neurodegeneration.

Introduction

The aggregation of Aβ into toxic oligomers plays a central role in the pathogenesis of Alzheimer's disease (AD), the most common cause of long-term institutionalization in persons over 65 in developing countries (Reitz et al., 2011). Aβ40 and Aβ42 isoforms are the major constituents of amyloid plaques, Aβ40 being the most common and Aβ42 more fibrillogenic and prone to pathological states (Burdick et al., 1992, Iwatsubo et al., 1994). According to the amyloid cascade hypothesis, accumulation of extraneuronal Aβ deposits results in neuronal death and synaptic failures that impair cognitive function and ultimately may lead to AD (Hardy and Selkoe, 2002). Although mechanisms of Aβ-related cognitive deficits have been extensively studied (Cleary et al., 2005, Shankar et al., 2008, Stephan et al., 2001), the impact of Aβ burden on non-cognitive symptoms of AD is unknown to date.

Sleep disturbances are one of the most troubling symptoms during progression of AD (Loewenstein et al., 1982, Prinz et al., 1982, Vitiello et al., 1990). Recent studies have revealed a link between the presence of Aβ plaques and the occurrence of sleep disturbances in a mouse model of AD amyloidosis. More specifically, disrupted sleep patterns emerged after early deposition of Aβ plaques in the hippocampus of APP-PS1 mice and reversed after active immunization with Aβ42 (Roh et al., 2012). However, it remains to be determined whether association between impaired sleep and Aβ load is extended to humans, and more precisely to early stages of neurodegeneration.

Growing evidence suggests that sleep disturbances begin years before the clinical onset of AD (Geda et al., 2004, Hita-Yañez et al., 2012, Lee et al., 2008, Westerberg et al., 2012). Accordingly, we have recently found that aMCI subjects, older adults at higher risk for AD (Petersen et al., 1999), showed reduced REM sleep and disrupted SWS (Hita-Yañez et al., 2012) together with a higher prevalence of self-reported sleep problems and sleep onset misperception when compared to HO adults (Hita-Yañez et al., 2013). MCI subjects also show significant changes in plasma Aβ levels (Mayeux et al., 2003, Schupf et al., 2008, van Oijen et al., 2006) in addition to AD lesions, confirmed histopathologically, in cingulate and parieto-temporal cortical structures (Driscoll et al., 2009, Hänggi et al., 2011, Whitwell et al., 2007). However, it remains unknown if sleep disturbances and plasma Aβ levels observed in MCI subjects are associated with loss of cortical integrity in these canonical AD regions.

To jointly address this issue, we first determined whether plasma Aβ levels are related to changes in sleep physiology and/or cortical thinning in aMCI subjects. Second, we investigated if sleep deficits and/or increased Aβ levels reported in aMCI subjects accounted for patterns of cortical loss characteristic of incipient neurodegeneration.

Section snippets

Subjects

Twenty-one older adults with aMCI (6 females, mean age: 69.8 ± 6.4 yr) and 21 HO subjects (10 females, mean age: 66.9 ± 5.5 yr) were enrolled in the study. Participants were primarily recruited from older people's associations, normal community health screening, and hospital outpatient services. All of them gave informed consent prior to experiments. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Human Research Ethics Committee of the Pablo de Olavide

Demographic and cognitive profile

Both groups were statistically similar in age, gender and years of education. As expected, they differed in global cognitive status and memory function (Table 1). In particular, aMCI showed lower MMSE scores (P = 0.01), impaired immediate (P = 3 × 10 6) and delayed recall (P = 5 × 10 9) compared to HO subjects.

Plasma Aβ levels

Table 2 shows mean values of plasma Aβ levels in HO and aMCI. Overall, plasma Aβ levels differed between the two groups (F3,36 = 4.41, P = 0.01). Univariate analyses revealed that aMCI subjects showed

Discussion

Evidence suggests that Aβ levels are modulated by the sleep-wake cycle in mice and humans, peaks occurring in periods of greatest physical activity and valleys coinciding with sleep (Bateman et al., 2007, Huang et al., 2012, Kang et al., 2009). Understanding relationships between Aβ levels and sleep might have deep implications for the slowing of AD progression, given that sleep disturbances are considered among the most troubling symptoms of AD (Loewenstein et al., 1982, Prinz et al., 1982,

Conclusions

The present study shows that increased plasma Aβ42 levels are significantly associated with fragmented SWS in aMCI subjects, suggesting that sleep disruptions may signal Aβ burden in persons at increased risk for AD. We further showed that both reduced REM sleep and plasma Aβ levels in aMCI subjects were significantly related to thinning of cortical regions targeted by AD neuropathology. Collectively, these results provide a preliminary link between altered sleep physiology, increased plasma Aβ

Acknowledgments

This work was supported by research grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-25463, PSI2011-24922), the Regional Ministry of Innovation, Science and Enterprise, Junta de Andalucia (P12-CTS-2327), and CIBERNED (CB06/05/1111).

References (118)

  • R. Giess et al.

    Localisation and association of pathomorphological changes at the brainstem in Alzheimer's disease

    Mech. Ageing Dev.

    (1995)
  • H. Hampel et al.

    Biomarkers for Alzheimer's disease therapeutic trials

    Prog. Neurobiol.

    (2011)
  • O. Hansson et al.

    Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer's disease in patients with mild cognitive impairment

    Neurobiol. Aging

    (2010)
  • T. Iwatsubo et al.

    Visualization of Abeta 42(43) and Abeta 40 in senile plaques with end-specific Abeta monoclonals: evidence that an initially deposited species is Abeta 42(43)

    Neuron

    (1994)
  • R.J. Loewenstein et al.

    Disturbances of sleep and cognitive functioning in patients with dementia

    Neurobiol. Aging

    (1982)
  • K. Nishitsuji et al.

    The E693Delta mutation in amyloid precursor protein increases intracellular accumulation of amyloid β oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells

    Am. J. Pathol.

    (2009)
  • G. Pengas et al.

    Focal posterior cingulate atrophy in incipient Alzheimer's disease

    Neurobiol. Aging

    (2010)
  • P.N. Prinz et al.

    Sleep, EEG and mental function changes in senile dementia of the Alzheimer's type

    Neurobiol. Aging

    (1982)
  • F. Segonne et al.

    A hybrid approach to the skull stripping problem in MRI

    NeuroImage

    (2004)
  • American Sleep Disorder Association

    EEG arousals: scoring rules and examples

    Sleep

    (1992)
  • L.G. Apostolova et al.

    Three-dimensional gray matter atrophy mapping in mild cognitive impairment and mild Alzheimer disease

    Arch. Neurol.

    (2007)
  • D.M. Araujo et al.

    Differential alteration of various cholinergic markers in cortical and subcortical regions of human brain in Alzheimer's disease

    J. Neurochem.

    (1988)
  • R.J. Bateman et al.

    Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker

    Neurology

    (2007)
  • P. Böhm et al.

    Clinical validity and utility of the interview for deterioration of daily living in dementia for Spanish-speaking communities

    Int. Psychogeriatr.

    (1998)
  • A. Brun et al.

    Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading

    Histopathology

    (1981)
  • N. Canessa et al.

    Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment

    Am. J. Respir. Crit. Care Med.

    (2011)
  • S.M. Chafekar et al.

    Increased Aβ1–42 production sensitizes neuroblastoma cells for ER stress toxicity

    Curr. Alzheimer Res.

    (2008)
  • G. Chetelat et al.

    Mapping gray matter loss with voxel-based morphometry in mild cognitive impairment

    Neuroreport

    (2002)
  • G. Chetelat et al.

    Independent contribution of temporal beta-amyloid deposition to memory decline in the pre-dementia phase of Alzheimer's disease

    Brain

    (2011)
  • J.P. Cleary et al.

    Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function

    Nat. Neurosci.

    (2005)
  • R.S. Desikan et al.

    Selective disruption of the cerebral neocortex in Alzheimer's disease

    PLoS One

    (2010)
  • I. Driscoll et al.

    Longitudinal pattern of regional brain volume change differentiates normal aging from MCI

    Neurology

    (2009)
  • I. Driscoll et al.

    Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques

    Acta Neuropathol.

    (2012)
  • A. Drzezga et al.

    Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden

    Brain

    (2011)
  • F. Fazekas et al.

    MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging

    Am. J. Roentgenol.

    (1987)
  • B. Fischl et al.

    Measuring the thickness of the human cerebral cortex from magnetic resonance images

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • B. Fischl et al.

    High-resolution intersubject averaging and a coordinate system for the cortical surface

    Hum. Brain Mapp.

    (1999)
  • B. Fischl et al.

    Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex

    IEEE Trans. Med. Imaging

    (2001)
  • A.M. Fjell et al.

    CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment and Alzheimer's disease

    J. Neurosci.

    (2010)
  • M.S. Forman et al.

    Cortical biochemistry in MCI and Alzheimer disease: lack of correlation with clinical diagnosis

    Neurology

    (2007)
  • H. Fukumoto et al.

    Age but not diagnosis is the main predictor of plasma amyloid beta-protein levels

    Arch. Neurol.

    (2003)
  • Y.E. Geda et al.

    De novo genesis of neuropsychiatric symptoms in mild cognitive impairment (MCI)

    Int. Psychogeriatr.

    (2004)
  • T. Gomez-Isla et al.

    Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease

    J. Neurosci.

    (1996)
  • J. Goñi et al.

    Selective brain gray matter atrophy associated with APOE ε4 and MAPT H1 in subjects with mild cognitive impairment

    J. Alzheimers Dis.

    (2013)
  • N.R. Graff-Radford et al.

    Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease

    Arch. Neurol.

    (2007)
  • S. Greyer et al.

    Areas 3a, 3b, and 1 of human primary somatosensory cortex

    NeuroImage

    (1999)
  • M. Grothe et al.

    Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer's disease

    Cereb. Cortex

    (2010)
  • J. Hänggi et al.

    Volumes of lateral temporal and parietal structures distinguish between healthy aging, mild cognitive impairment, and Alzheimer's disease

    J. Alzheimers Dis.

    (2011)
  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

    Science

    (2002)
  • V. Haroutunian et al.

    Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease

    Arch. Neurol.

    (1998)
  • Cited by (49)

    • Chronic sleep restriction increases soluble hippocampal Aβ-42 and impairs cognitive performance

      2020, Physiology and Behavior
      Citation Excerpt :

      Given the far greater genetic diversity of the human population, compared to experimental animal models most frequently utilized, it is probable that this would be true to an even greater extent in human experiments. Nonetheless, despite this complexity, evidence demonstrates that sleep loss leads to alterations in cognition and pathological hallmarks of AD in healthy individuals, as well as in patients diagnosed with preclinical AD or mild cognitive impairment [22,23,42–44]. Thus, there appears to be a clear general trend in the literature indicating that sleep loss - regardless the experimental methodology or cause - is detrimental to cognitive functioning and exacerbates AD-related pathology.

    View all citing articles on Scopus
    View full text