Sleep deficits in mild cognitive impairment are related to increased levels of plasma amyloid-β and cortical thinning
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)
- et al.
Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer’s disease
Neuroscience
(1985) - et al.
Detection of focal changes in human cortical thickness: spherical wavelets versus Gaussian smoothing
NeuroImage
(2008) - et al.
Determining the optimal level of smoothing in cortical thickness analysis: a hierarchical approach based on sequential statistical thresholding
NeuroImage
(2010) - et al.
Sleep disorders in aging and dementia
J. Nutr. Health Aging
(2010) - et al.
Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs
J. Biol. Chem.
(1992) - et al.
Cortical surface-based analysis. I. Segmentation and surface reconstruction
NeuroImage
(1999) - et al.
The relationship of plasma Aβ levels to dementia in aging individuals with mild cognitive impairment
J. Neurol. Sci.
(2011) - et al.
Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system
NeuroImage
(1999) - et al.
PET imaging of amyloid deposition in patients with mild cognitive impairment
Neurobiol. Aging
(2008) - et al.
Cortical cholinergic fibers in aging and Alzheimer's disease: a morphometric study
Neuroscience
(1989)
Localisation and association of pathomorphological changes at the brainstem in Alzheimer's disease
Mech. Ageing Dev.
Biomarkers for Alzheimer's disease therapeutic trials
Prog. Neurobiol.
Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer's disease in patients with mild cognitive impairment
Neurobiol. Aging
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
Disturbances of sleep and cognitive functioning in patients with dementia
Neurobiol. Aging
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.
Focal posterior cingulate atrophy in incipient Alzheimer's disease
Neurobiol. Aging
Sleep, EEG and mental function changes in senile dementia of the Alzheimer's type
Neurobiol. Aging
A hybrid approach to the skull stripping problem in MRI
NeuroImage
EEG arousals: scoring rules and examples
Sleep
Three-dimensional gray matter atrophy mapping in mild cognitive impairment and mild Alzheimer disease
Arch. Neurol.
Differential alteration of various cholinergic markers in cortical and subcortical regions of human brain in Alzheimer's disease
J. Neurochem.
Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker
Neurology
Clinical validity and utility of the interview for deterioration of daily living in dementia for Spanish-speaking communities
Int. Psychogeriatr.
Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading
Histopathology
Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment
Am. J. Respir. Crit. Care Med.
Increased Aβ1–42 production sensitizes neuroblastoma cells for ER stress toxicity
Curr. Alzheimer Res.
Mapping gray matter loss with voxel-based morphometry in mild cognitive impairment
Neuroreport
Independent contribution of temporal beta-amyloid deposition to memory decline in the pre-dementia phase of Alzheimer's disease
Brain
Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function
Nat. Neurosci.
Selective disruption of the cerebral neocortex in Alzheimer's disease
PLoS One
Longitudinal pattern of regional brain volume change differentiates normal aging from MCI
Neurology
Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques
Acta Neuropathol.
Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden
Brain
MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging
Am. J. Roentgenol.
Measuring the thickness of the human cerebral cortex from magnetic resonance images
Proc. Natl. Acad. Sci. U. S. A.
High-resolution intersubject averaging and a coordinate system for the cortical surface
Hum. Brain Mapp.
Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex
IEEE Trans. Med. Imaging
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment and Alzheimer's disease
J. Neurosci.
Cortical biochemistry in MCI and Alzheimer disease: lack of correlation with clinical diagnosis
Neurology
Age but not diagnosis is the main predictor of plasma amyloid beta-protein levels
Arch. Neurol.
De novo genesis of neuropsychiatric symptoms in mild cognitive impairment (MCI)
Int. Psychogeriatr.
Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease
J. Neurosci.
Selective brain gray matter atrophy associated with APOE ε4 and MAPT H1 in subjects with mild cognitive impairment
J. Alzheimers Dis.
Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease
Arch. Neurol.
Areas 3a, 3b, and 1 of human primary somatosensory cortex
NeuroImage
Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer's disease
Cereb. Cortex
Volumes of lateral temporal and parietal structures distinguish between healthy aging, mild cognitive impairment, and Alzheimer's disease
J. Alzheimers Dis.
The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
Science
Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease
Arch. Neurol.
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