Claire André

Alice Laniepce

Gaël Chételat

PhD Géraldine Rauchs
email: geraldine.rauchs@inserm.fr

Brain changes associated with sleep disruption in cognitively unimpaired older adults: a short review of neuroimaging studies

Keywords: Sleep, Ageing, Alzheimer's disease, Neuroimaging, Amyloid, Tau

Brain changes associated with sleep disruption in cognitively unimpaired older adults: a short review of neuroimaging studies

Highlights:

• Sleep disruption is increasingly considered as a risk factor for Alzheimer's disease.

• Poor sleep is associated with diffuse frontal, temporal and parietal gray matter atrophy.

• Alzheimer's disease biomarkers are associated with several sleep parameters.

• However, the specificity, topography and causality of these links are unclear.

Introduction

As the worldwide population is ageing, preventing cognitive decline and the development of dementia represents an important challenge. Intense research aims at identifying modifiable lifestyle factors that might help to promote healthy ageing. Among them, sleep is receiving particular attention, as about 50% of older adults complain of poor sleep [START_REF] Foley | Sleep complaints among elderly persons: an epidemiologic study of three communities[END_REF].

Age-related changes consist, at the circadian level, in advanced sleep timing and reduced amplitude of the circadian rhythms [START_REF] Duffy | Aging and Circadian Rhythms[END_REF][START_REF] Kondratova | The circadian clock and pathology of the ageing brain[END_REF]. Sleep changes include longer sleep latency, decreased sleep duration, and increased number and duration of nocturnal awakenings, resulting in greater sleep fragmentation and lower sleep efficiency [START_REF] Li | Sleep in Normal Aging[END_REF][START_REF] Ohayon | Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan[END_REF]. Remarkably, the amount of slow wave sleep (SWS), the deepest non-rapid eye movement (NREM) sleep stage, linearly decreases across the adult lifespan, contrasting with the increase of lighter NREM sleep (especially stage N1).

Substantial changes in NREM sleep oscillations such as delta waves [START_REF] Carrier | The effects of age and gender on sleep EEG power spectral density in the middle years of life (ages 20-60 years old)[END_REF][START_REF] Landolt | Effect of age on the sleep EEG: Slowwave activity and spindle frequency activity in young and middle-aged men[END_REF][START_REF] Schwarz | Age affects sleep microstructure more than sleep macrostructure[END_REF] and sleep spindles, key features of N2 sleep [START_REF] Crowley | The effects of normal aging on sleep spindle and K-complex production[END_REF][START_REF] Schwarz | Age affects sleep microstructure more than sleep macrostructure[END_REF] are also reported. Rapid-eye movement (REM) sleep time is reduced with age, albeit to a lesser extent and later in life than SWS [START_REF] Floyd | Changes in REM-sleep percentage over the adult lifespan[END_REF][START_REF] Ohayon | Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan[END_REF]. Finally, 30 to 80% of older adults suffer from sleep-disordered breathing (SDB; [START_REF] Senaratna | Prevalence of obstructive sleep apnea in the general population: A systematic review[END_REF], a respiratory disorder defined by recurrent upper airway collapse during sleep, resulting in intermittent hypoxia episodes and sleep fragmentation, which may trigger neurodegenerative processes.

Sleep is essential for an optimal daytime cognitive functioning, notably for attention, executive functioning, memory, and synaptic plasticity [START_REF] Buzsáki | The Hippocampo-Neocortical Dialogue[END_REF][START_REF] Kang | Amyloid-β Dynamics are Regulated by Orexin and the Sleep-Wake Cycle[END_REF]Lowe et al., 2017;[START_REF] Tononi | Sleep function and synaptic homeostasis[END_REF]. In older adults, growing evidence show that sleep disturbances may represent a risk factor for cognitive decline and dementia. [START_REF] Bubu | Sleep, Cognitive impairment, and Alzheimer's disease: A Systematic Review and Meta-Analysis[END_REF][START_REF] Diem | Measures of Sleep-Wake Patterns and Risk of Mild Cognitive Impairment or Dementia in Older Women[END_REF][START_REF] Foley | Daytime sleepiness is associated with 3-year incident dementia and cognitive decline in older Japanese-American men[END_REF][START_REF] Gabelle | Excessive Sleepiness and Longer Nighttime in Bed Increase the Risk of Cognitive Decline in Frail Elderly Subjects: The MAPT-Sleep Study[END_REF][START_REF] Leng | Association of Sleep-Disordered Breathing With Cognitive Function and Risk of Cognitive Impairment: A Systematic Review and Meta-analysis[END_REF]Lim et al., 2013a;[START_REF] Pase | Sleep architecture and the risk of incident dementia in the community[END_REF][START_REF] Song | Relationships Between Sleep Stages and Changes in Cognitive Function in Older Men: The MrOS Sleep Study[END_REF][START_REF] Virta | Midlife sleep characteristics associated with late life cognitive function[END_REF]. As Alzheimer's disease (AD) pathology develops several years before the first clinical symptoms [START_REF] Jack | NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer[END_REF], it is crucial to better understand the associations between sleep disturbances and brain integrity (including AD biomarkers) in older adults who are still cognitively unimpaired.

Thus, our objective was to summarize existing data about these associations, with an emphasis on their topography and causality, and discuss the potential underlying mechanisms.

We focused the present short review on papers published during the last decade (i.e., between 2010 and November 2020), involving cognitively unimpaired older adults, with no history or current diagnosis of major neurological or psychiatric diseases, or any other major medical condition.

Sleep quality and gray matter volume changes

Cross-sectional studies show that lower grey matter (GM) volume within frontal areas is one of the brain changes most consistently associated with sleep quality in cognitively unimpaired older adults (Table 1). Sleep parameters associated with frontal atrophy include self-reported poor sleep quality [START_REF] Sexton | Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults[END_REF] and inadequate sleep duration [START_REF] Lo | Sleep Duration and Age-Related Changes in Brain Structure and Cognitive Performance[END_REF][START_REF] Westwood | Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia[END_REF], early-morning awakenings [START_REF] Stoffers | Orbitofrontal gray matter relates to early morning awakening: a neural correlate of insomnia complaints[END_REF], excessive daytime sleepiness [START_REF] Killgore | Voxel-based morphometric gray matter correlates of daytime sleepiness[END_REF], greater sleep fragmentation obtained from actigraphy [START_REF] Lim | Regional Neocortical Gray Matter Structure and Sleep Fragmentation in Older Adults[END_REF],

and decreased slow wave activity [START_REF] Dubé | Cortical Thinning Explains Changes in Sleep Slow Waves during Adulthood[END_REF][START_REF] Latreille | Age-related cortical signatures of human sleep electroencephalography[END_REF][START_REF] Mander | Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging[END_REF].

In addition, reduced GM volume in lateral and medial temporal regions (including the hippocampus and the amygdala), the thalamus, and parietal cortex, have been associated with poor self-reported sleep quality [START_REF] References Alperin | Effect of sleep quality on amnestic mild cognitive impairment vulnerable brain regions in cognitively normal elderly individuals[END_REF][START_REF] Liu | Sleep-related brain atrophy and disrupted functional connectivity in older adults[END_REF], inadequate sleep duration [START_REF] Lo | Sleep Duration and Age-Related Changes in Brain Structure and Cognitive Performance[END_REF][START_REF] Westwood | Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia[END_REF] and excessive daytime sleepiness [START_REF] Carvalho | Excessive daytime sleepiness and fatigue may indicate accelerated brain aging in cognitively normal late middleaged and older adults[END_REF]. [START_REF] Branger | Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood[END_REF] also found an association between a higher number of self-reported nocturnal awakenings and lower GM volume in the insula. Importantly, these findings are supported by studies using actigraphy or polysomnography. Indeed, SWS integrity has been associated with GM volume in parietal and insular cortices [START_REF] Dubé | Cortical Thinning Explains Changes in Sleep Slow Waves during Adulthood[END_REF], and reduced GM volume in medial temporal areas has been related to greater sleep-wake rhythm fragmentation [START_REF] Van Someren | Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk[END_REF]. GM volume changes associated with SDB in older adults vary importantly, some studies showing atrophy [START_REF] Huang | Structural and functional brain alterations in obstructive sleep apnea: a multimodal meta-analysis[END_REF][START_REF] Shi | A Metaanalysis of Voxel-based Brain Morphometry Studies in Obstructive Sleep Apnea[END_REF][START_REF] Tahmasian | Structural and functional neural adaptations in obstructive sleep apnea: An activation likelihood estimation meta-analysis[END_REF][START_REF] Weng | Mapping Gray Matter Reductions in Obstructive Sleep Apnea: An Activation Likelihood Estimation Meta-Analysis[END_REF] in frontal, temporal and parietal areas, while others rather report hypertrophy [START_REF] André | Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial[END_REF][START_REF] Baril | Gray Matter Hypertrophy and Thickening with Obstructive Sleep Apnea in Middle-aged and Older Adults[END_REF][START_REF] Cross | Structural brain correlates of obstructive sleep apnoea in older adults at risk for dementia[END_REF][START_REF] Rosenzweig | Hippocampal Hypertrophy and Sleep Apnea: A Role for the Ischemic Preconditioning[END_REF] in the same brain areas.

A few longitudinal studies reported that self-estimated poor sleep quality [START_REF] Fjell | Selfreported sleep relates to hippocampal atrophy across the adult lifespan -results from the Lifebrain consortium[END_REF][START_REF] Sexton | Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults[END_REF] and short sleep duration [START_REF] Lo | Sleep Duration and Age-Related Changes in Brain Structure and Cognitive Performance[END_REF][START_REF] Spira | Sleep Duration and Subsequent Cortical Thinning in Cognitively Normal Older Adults[END_REF] are associated with an increased rate of atrophy within frontal, temporal (including the hippocampus) and parietal areas. However, long self-reported sleep duration (> 7h) has also been related to a higher rate of frontal GM atrophy [START_REF] Spira | Sleep Duration and Subsequent Cortical Thinning in Cognitively Normal Older Adults[END_REF].

Sleep, brain glucose metabolism and perfusion changes

Only a few studies have explored the associations between sleep quality and resting-state glucose metabolism using 18 F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET), or perfusion, using Arterial Spin Labeling (ASL) or Single Photon Emission Computed Tomography (SPECT) imaging (see Table 1).

In cognitively unimpaired older adults, if self-reported sleep measures were not associated to glucose metabolism [START_REF] Branger | Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood[END_REF], greater sleep fragmentation obtained from actigraphy was related to lower glucose metabolism within the ventromedial prefrontal cortex and the hippocampi [START_REF] André | Brain and cognitive correlates of sleep fragmentation in elderly subjects with and without cognitive deficits[END_REF]. In addition, as for GM volume, SDB has been related

to both lower [START_REF] Baril | Obstructive sleep apnea during REM sleep and daytime cerebral functioning: A regional cerebral blood flow study using high-resolution SPECT[END_REF][START_REF] Baril | Regional Cerebral Blood Flow during Wakeful Rest in Older Subjects with Mild to Severe Obstructive Sleep Apnea[END_REF][START_REF] Innes | Decreased Regional Cerebral Perfusion in Moderate-Severe Obstructive Sleep Apnoea during Wakefulness[END_REF][START_REF] Kim | Effect of continuous positive airway pressure on regional cerebral blood flow in patients with severe obstructive sleep apnea syndrome[END_REF][START_REF] Nie | Resting cerebral blood flow alteration in severe obstructive sleep apnoea: an arterial spin labelling perfusion fMRI study[END_REF] and greater [START_REF] André | Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial[END_REF][START_REF] Baril | Regional Cerebral Blood Flow during Wakeful Rest in Older Subjects with Mild to Severe Obstructive Sleep Apnea[END_REF][START_REF] Nie | Resting cerebral blood flow alteration in severe obstructive sleep apnoea: an arterial spin labelling perfusion fMRI study[END_REF] metabolism and/or perfusion mainly in frontal, temporal and parietal areas, including the precuneus and posterior cingulate cortex (Table 1).

Sleep and amyloid pathology

In animal models of Alzheimer's disease and in humans, amyloid-ß peptide (Aß) levels fluctuate following a circadian pattern, increasing with wakefulness and decreasing during NREM sleep [START_REF] Kang | Amyloid-β Dynamics are Regulated by Orexin and the Sleep-Wake Cycle[END_REF]. Whether this effect is mainly attributable to decreased metabolic activity during SWS, and/or increased metabolites clearance through the "glymphatic system" (Tarasoff-Conway et al., 2015a;[START_REF] Xie | Sleep Drives Metabolite Clearance from the Adult Brain[END_REF] is still debated.

Nevertheless, the circadian fluctuations of Aß levels in the cerebrospinal fluid (CSF) are attenuated with ageing and with increased Aß deposition [START_REF] Huang | Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System[END_REF][START_REF] Roh | Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology[END_REF].

In cognitively unimpaired older adults, various sleep parameters have been associated with greater global Aß levels measured in the CSF or using PET, including poorer self-reported sleep quality, both cross-sectionally [START_REF] Sprecher | Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults[END_REF] and longitudinally [START_REF] Fjell | Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy[END_REF], longer subjective [START_REF] Brown | The Relationship between Sleep Quality and Brain Amyloid Burden[END_REF] and objective [START_REF] Ettore | Relationships between objectives sleep parameters and brain amyloid load in subjects at risk to Alzheimer's disease: the INSIGHT-preAD Study[END_REF] sleep latency, both insufficient and long self-reported sleep duration [START_REF] Spira | Self-reported sleep and β-amyloid deposition in community-dwelling older adults[END_REF][START_REF] Xu | Sleep characteristics and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: The CABLE study[END_REF], lower sleep efficiency [START_REF] Ettore | Relationships between objectives sleep parameters and brain amyloid load in subjects at risk to Alzheimer's disease: the INSIGHT-preAD Study[END_REF][START_REF] Ju | Sleep Quality and Preclinical Alzheimer Disease[END_REF][START_REF] Molano | The interaction of sleep and amyloid deposition on cognitive performance[END_REF], increased sleep fragmentation [START_REF] Ettore | Relationships between objectives sleep parameters and brain amyloid load in subjects at risk to Alzheimer's disease: the INSIGHT-preAD Study[END_REF][START_REF] Lucey | Reduced nonrapid eye movement sleep is associated with tau pathology in early Alzheimer's disease[END_REF][START_REF] Wilckens | Sleep moderates the relationship between amyloid beta and memory recall[END_REF], excessive daytime sleepiness [START_REF] Xu | Sleep characteristics and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: The CABLE study[END_REF], and altered slow wave activity (SWA) [START_REF] Ju | Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels[END_REF][START_REF] Varga | Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly[END_REF][START_REF] Winer | Sleep as a potential biomarker of tau and β-amyloid burden in the human brain[END_REF] (Table 1). Furthermore, [START_REF] Mander | β-amyloid disrupts human NREM slow waves and related hippocampusdependent memory consolidation[END_REF] showed that amyloid burden in medial prefrontal areas disrupts SWA, negatively affecting sleep-dependent memory consolidation. In addition, [START_REF] Winer | Sleep Disturbance Forecasts β-Amyloid Accumulation across Subsequent Years[END_REF] showed that decreased SWA and sleep efficiency significantly predicted the subsequent Aß accumulation over several years. Studies using regional approaches have revealed that greater amyloid deposition in frontal and/or parietal areas, including the precuneus and posterior cingulate cortex, is associated with lower self-reported sleep quality [START_REF] Sprecher | Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults[END_REF], longer self-reported sleep latency [START_REF] Branger | Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood[END_REF], lower subjective sleep adequacy [START_REF] Sprecher | Amyloid burden is associated with self-reported sleep in nondemented late middle-aged adults[END_REF], corresponding to insufficient sleep quality and duration, and excessive daytime sleepiness, both crosssectionally [START_REF] Sprecher | Amyloid burden is associated with self-reported sleep in nondemented late middle-aged adults[END_REF] and longitudinally [START_REF] Carvalho | Association of Excessive Daytime Sleepiness With Longitudinal β-Amyloid Accumulation in Elderly Persons Without Dementia[END_REF]. Short sleep duration has been associated with greater amyloid deposition in the precuneus [START_REF] Spira | Self-reported sleep and β-amyloid deposition in community-dwelling older adults[END_REF], but this result failed replication by [START_REF] Gabelle | Absence of Relationship Between Self-Reported Sleep Measures and Amyloid Load in Elderly Subjects[END_REF].

Lastly, SBD has also been related to higher amyloid levels measured in the CSF or using PET imaging (both cross-sectionally and longitudinally) [START_REF] Bu | Serum amyloid-beta levels are increased in patients with obstructive sleep apnea syndrome[END_REF][START_REF] Bubu | Obstructive sleep apnea and longitudinal Alzheimer's disease biomarker changes[END_REF][START_REF][END_REF][START_REF] Kong | Biomarkers of Alzheimer's disease in severe obstructive sleep apnea-hypopnea syndrome in the Chinese population[END_REF][START_REF] Liguori | Obstructive Sleep Apnea is Associated With Early but Possibly Modifiable Alzheimer's Disease Biomarkers Changes[END_REF][START_REF] Sharma | Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study[END_REF][START_REF] Ylä-Herttuala | Severe Obstructive Sleep Apnea and Increased Cortical Amyloid-β Deposition[END_REF], and specifically in the posterior cingulate cortex and the precuneus [START_REF] André | Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial[END_REF][START_REF] Ylä-Herttuala | Severe Obstructive Sleep Apnea and Increased Cortical Amyloid-β Deposition[END_REF][START_REF] Yun | Amyloid Burden in Obstructive Sleep Apnea[END_REF].

Sleep and tau pathology

Besides Aß deposition, sleep disruption may also exacerbate tau pathology in older adults without cognitive deficits, the second pathophysiological hallmark of AD [START_REF] Holth | The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans[END_REF].

Self-estimated poor sleep quality and excessive daytime sleepiness have been associated with higher t-tau and p-tau/Aβ42 ratios [START_REF] Sprecher | Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults[END_REF]. In addition, [START_REF] Fjell | Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy[END_REF] showed that CSF tau levels predict poor sleep quality in amyloid-positive older adults. Moreover, CSF tau levels increased after one night of sleep deprivation [START_REF] Holth | The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans[END_REF], and are associated with greater sleep fragmentation (Lim et al., 2013b) and lower sleep efficiency [START_REF] Ju | Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels[END_REF].

Interestingly, in this latter study, the association between sleep and tau was mainly driven by increased neuronal activity during sleep. Moreover, patients with SDB also exhibit increased CSF tau levels, both cross-sectionally [START_REF] Bu | Serum amyloid-beta levels are increased in patients with obstructive sleep apnea syndrome[END_REF][START_REF] Kong | Biomarkers of Alzheimer's disease in severe obstructive sleep apnea-hypopnea syndrome in the Chinese population[END_REF][START_REF] Liguori | Obstructive Sleep Apnea is Associated With Early but Possibly Modifiable Alzheimer's Disease Biomarkers Changes[END_REF] and longitudinally [START_REF] Bubu | Obstructive sleep apnea and longitudinal Alzheimer's disease biomarker changes[END_REF].

Recent studies using tau-PET imaging have provided mixed results (Table 1). [START_REF] Lucey | Reduced nonrapid eye movement sleep is associated with tau pathology in early Alzheimer's disease[END_REF] reported that both amyloid and tau pathologies are associated with decreased SWA, with a stronger link for tau. In contrast, [START_REF] Winer | Sleep as a potential biomarker of tau and β-amyloid burden in the human brain[END_REF] did not report any direct association between tau in the medial temporal lobe and prefrontal SWA, but rather a relationship between medial temporal tau burden and altered coupling between slow waves and sleep spindles. However, research using tau-PET imaging is still in their infancy, and further studies are needed to unravel the associations between tau pathology and sleep quality.

Discussion

Poor sleep quality in cognitively unimpaired older adults is associated with diffuse and heterogeneous structural, functional and molecular brain changes in frontal, temporal and parietal areas. While some of these brain substrates are consistent with early pathological changes observed in AD, other sleep-associated brain changes seem less suggestive of AD, both in terms of topography and nature of brain alterations involved.

Indeed, frontal amyloid burden is associated with self-reported sleep difficulties [START_REF] Branger | Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood[END_REF][START_REF] Sprecher | Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults[END_REF][START_REF] Sprecher | Amyloid burden is associated with self-reported sleep in nondemented late middle-aged adults[END_REF]. Moreover, SWS disruption appears to be robustly associated with amyloid pathology [START_REF] Ju | Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels[END_REF][START_REF] Varga | Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly[END_REF], notably in medial prefrontal areas [START_REF] Mander | β-amyloid disrupts human NREM slow waves and related hippocampusdependent memory consolidation[END_REF]. Interestingly, AD is defined by the presence of amyloid deposition [START_REF] Jack | NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer[END_REF] spreading from frontal areas, before the appearance of cognitive deficits.

Moreover, self-reported sleep difficulties [START_REF] References Alperin | Effect of sleep quality on amnestic mild cognitive impairment vulnerable brain regions in cognitively normal elderly individuals[END_REF][START_REF] Carvalho | Excessive daytime sleepiness and fatigue may indicate accelerated brain aging in cognitively normal late middleaged and older adults[END_REF][START_REF] Fjell | Selfreported sleep relates to hippocampal atrophy across the adult lifespan -results from the Lifebrain consortium[END_REF] and greater fragmentation of the sleep/wake rhythm [START_REF] Van Someren | Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk[END_REF] have been linked to medial temporal lobe (MTL) atrophy. Of note, SDB has been related to both reduced [START_REF] Huang | Structural and functional brain alterations in obstructive sleep apnea: a multimodal meta-analysis[END_REF][START_REF] Tahmasian | Structural and functional neural adaptations in obstructive sleep apnea: An activation likelihood estimation meta-analysis[END_REF][START_REF] Weng | Mapping Gray Matter Reductions in Obstructive Sleep Apnea: An Activation Likelihood Estimation Meta-Analysis[END_REF] and greater [START_REF] Cross | Structural brain correlates of obstructive sleep apnoea in older adults at risk for dementia[END_REF][START_REF] Rosenzweig | Hippocampal Hypertrophy and Sleep Apnea: A Role for the Ischemic Preconditioning[END_REF] MTL volume. It seems crucial to better characterize sleep parameters associated with MTL atrophy, as medial temporal areas are known to be affected by tau pathology and atrophied since AD pre-dementia stages [START_REF] Braak | Neuropathological stageing of Alzheimer-related changes[END_REF][START_REF] Villemagne | Neuroimaging biomarkers in Alzheimer's disease and other dementias[END_REF]. In addition, beyond the MTL, tau pathology also affects the brainstem, which is involved in sleep-wake regulation and REM sleep generation [START_REF] Horner | Brain Circuitry Controlling Sleep and Wakefulness[END_REF].

REM sleep is reduced in AD patients [START_REF] Brayet | Quantitative EEG of Rapid-Eye-Movement Sleep: A Marker of Amnestic Mild Cognitive Impairment[END_REF][START_REF] Hassainia | Quantitative EEG and Statistical Mapping of Wakefulness and REM Sleep in the Evaluation of Mild to Moderate Alzheimer's Disease[END_REF][START_REF] Hita-Yañez | Disturbed sleep patterns in elders with mild cognitive impairment: the role of memory decline and ApoE ε4 genotype[END_REF][START_REF] Montplaisir | Sleep in Alzheimer's disease: further considerations on the role of brainstem and forebrain cholinergic populations in sleepwake mechanisms[END_REF] and this alteration is predictive of cognitive decline in older adults [START_REF] Pase | Sleep architecture and the risk of incident dementia in the community[END_REF]. [START_REF] Liguori | Sleep dysregulation, memory impairment, and CSF biomarkers during different levels of neurocognitive functioning in Alzheimer's disease course[END_REF] have recently demonstrated that REM sleep reduction is associated with increased CSF tau levels, in a cohort of cognitively healthy older adults and patients with subjective cognitive decline, mild cognitive impairment and AD.

However, due to the relatively recent emergence of tau-PET neuroimaging, the relationships between REM sleep changes and tau pathology in the brainstem and medial temporal areas remains to be clarified, specifically in cognitively normal older populations.

Lastly, the associations between sleep changes and glucose metabolism have been much less investigated. SDB has been associated with decreased metabolism and/or perfusion in posterior parietal areas [START_REF] Baril | Regional Cerebral Blood Flow during Wakeful Rest in Older Subjects with Mild to Severe Obstructive Sleep Apnea[END_REF][START_REF] Yaouhi | A combined neuropsychological and brain imaging study of obstructive sleep apnea[END_REF], but increases have also been reported [START_REF] André | Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial[END_REF]. Taken together, it is unclear whether sleep quality is associated with the marked hypometabolism in posterior cingulate and precuneus areas observed in AD and mild cognitive impairment patients [START_REF] Chételat | Mild cognitive impairment: Can FDG-PET predict who is to rapidly convert to Alzheimer's disease?[END_REF][START_REF] Minoshima | Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease[END_REF][START_REF] Schroeter | Neural correlates of Alzheimer's disease and mild cognitive impairment: A systematic and quantitative meta-analysis involving 1351 patients[END_REF].

Besides, sleep modifications have been linked to other brain changes which seem less directly suggestive of early AD pathological processes, and could rather reflect normal ageing processes. Indeed, GM atrophy in frontal and parietal areas is robustly associated with SWS disruption, in particular decreased slow wave activity [START_REF] Dubé | Cortical Thinning Explains Changes in Sleep Slow Waves during Adulthood[END_REF][START_REF] Latreille | Age-related cortical signatures of human sleep electroencephalography[END_REF][START_REF] Mander | Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging[END_REF]. These results are consistent with the fact that these regions are involved in sleep physiology and the generation of slow waves [START_REF] Massimini | The Sleep Slow Oscillation as a Traveling Wave[END_REF][START_REF] Murphy | Source modeling sleep slow waves[END_REF]. Moreover, greater sleep fragmentation is related to lower frontal GM volume [START_REF] Lim | Regional Neocortical Gray Matter Structure and Sleep Fragmentation in Older Adults[END_REF] and fronto-hippocampal metabolism [START_REF] André | Brain and cognitive correlates of sleep fragmentation in elderly subjects with and without cognitive deficits[END_REF], two areas critical for sleepdependent memory consolidation [START_REF] Buzsáki | The Hippocampo-Neocortical Dialogue[END_REF][START_REF] Maingret | Hippocampo-cortical coupling mediates memory consolidation during sleep[END_REF]. The brain correlates of SDB appear however still conflicting, with both positive and negative associations with frontal GM volume and metabolism, MTL metabolism, and parietal GM volume (see Table 1). The pattern of SDB-related neuronal hyperactivity (i.e., greater GM volume, metabolism and perfusion) reported in some studies could reflect acute and early reactive processes, likely due to neuroinflammation in response to hypoxia. This neuronal hyperactivity may also reflect compensatory mechanisms due to greater individual brain reserve, which may help to maintain cognitive performance in the normal range by increasing brain activity. Importantly, these acute changes may only be temporary and may trigger neurodegeneration (i.e., GM atrophy and hypometabolism) and the development of cognitive deficits over time.

Longitudinal studies combining several neuroimaging modalities on large cohorts with various levels of SDB severity will be necessary to confirm this hypothesis.

Frontal, temporal and posterior parietal regions thus constitute common brain substrates between sleep physiology and AD pathology, but a critical question is whether sleep disturbances are causal and/or consecutive to brain alterations. First, AD pathology located in frontal, medial temporal and brainstem areas, involved in sleep rhythms, could disrupt sleep quality, eventually impairing cognitive performance. Supporting this hypothesis, atrophy and amyloid burden within medial prefrontal areas have been shown to disrupt SWS [START_REF] Mander | [END_REF][START_REF] Mander | Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging[END_REF], ultimately impairing sleep-dependent memory consolidation. Moreover, sleep disruption may also mediate or moderate the association between brain alterations and cognitive performance. Indeed, poor self-estimated sleep quality [START_REF] Molano | The interaction of sleep and amyloid deposition on cognitive performance[END_REF] and increased nocturnal wakefulness [START_REF] Wilckens | Sleep moderates the relationship between amyloid beta and memory recall[END_REF] moderate the association between amyloid burden and memory performance. Lastly, greater sleep fragmentation mediates the association between fronto-hippocampal hypometabolism and poorer executive functioning [START_REF] André | Brain and cognitive correlates of sleep fragmentation in elderly subjects with and without cognitive deficits[END_REF].

However, it is likely that the links between sleep and brain alterations are bidirectional [START_REF] Ju | Sleep and Alzheimer disease pathology--a bidirectional relationship[END_REF]. Indeed, the consequence of disrupted sleep is to increase the amount of wakefulness during sleep and to decrease the amount of sleep per se. Subsequently, greater neuronal activity and reduced brain clearance function may result in greater amyloid and tau release (Fig. 1). If increased activity and reduced clearance are likely to co-exist, their respective contributions are unclear. A pilot study in humans showed that these links are mainly driven by increased Aβ secretion, and not by decreased clearance [START_REF] Lucey | Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics[END_REF]. However, the study of brain clearance mechanisms is a recent area of research. In mice, clearance through the blood brain barrier and interstitial fluid bulk-flow seem to be both implicated in amyloid clearance and related to sleep quality [START_REF] Rasmussen | The glymphatic pathway in neurological disorders[END_REF]Tarasoff-Conway et al., 2015b;[START_REF] Xie | Sleep Drives Metabolite Clearance from the Adult Brain[END_REF]. Notably, the glymphatic system hypothesis proposes that arterial pulsations drive waste clearance through a directional convective flow of CSF, from periarterial areas in the deep brain parenchyma to the perivenous spaces. This process implicates water channels, like aquaporin-4, located in glial cells [START_REF] Iliff | Cerebral Arterial Pulsation Drives Paravascular CSF-Interstitial Fluid Exchange in the Murine Brain[END_REF][START_REF] Iliff | A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid[END_REF][START_REF] Nedergaard | Garbage Truck of the Brain[END_REF], and is facilitated during sleep [START_REF] Xie | Sleep Drives Metabolite Clearance from the Adult Brain[END_REF]. Nevertheless, several aspects of this model are currently debated [START_REF] Mestre | The Brain's Glymphatic System: Current Controversies[END_REF], and most findings in mice are pending replication in humans, as noninvasive neuroimaging tools of clearance mechanisms are still under development. Moreover, the associations with AD pathology remain to be confirmed. In healthy young subjects, a promising recent study demonstrated that slow waves during NREM sleep are followed by hemodynamic oscillations, which are in turn coherent with large waves of CSF [START_REF] Fultz | Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep[END_REF].

Conclusion

Age-related sleep disruption is associated with brain changes mainly in frontal, temporal and parietal areas, some of them being suggestive of early AD pathological changes. These links may explain why sleep disruption is related to lower cognitive performance and steeper cognitive decline. However, the specific aspects of sleep disruption involved in these associations, the impact on tau pathology, and the associations with disrupted brain clearance mechanisms during sleep remain to be further explored. In addition, if we only discussed the associations between sleep disruption and regional GM integrity and functioning, sleeprelated changes in structural and functional connectivity specifically in cognitively unimpaired older adults are a promising area of research. From a clinical perspective, it is crucial to screen for sleep problems in older adults, as they may exacerbate AD pathophysiological mechanisms and may represent a modifiable lifestyle factor contributing to healthy ageing.

Competing interests

None declared.

Figure 1 Figure 1 .

 11 Figure 1

Table 1 . Summary of the associations between sleep parameters and brain integrity in older adults.

 1 Positrons Emission Tomography, PFC: prefrontal cortex, SDB: sleep-disordered breathing, SPECT: Single Photon Emission Computed Tomography. When meta-analyses (in bold) were available, original studies showing the same results were not mentioned. Objective sleep measures encompass actigraphy and polysomnography measures. Longitudinal studies are indicated in italics.

Abbreviations: ASL: Arterial Spin Labeling, CSF: cerebrospinal fluid, FDG: 18 F-fluorodeoxyglucose, MTL: medial temporal lobe, OFC: orbitofrontal cortex, PET:

Tau levels were measured in the CSF[START_REF] Osorio | [END_REF] Ju et al., 2016;[START_REF] Liguori | Obstructive Sleep Apnea is Associated With Early but Possibly Modifiable Alzheimer's Disease Biomarkers Changes[END_REF][START_REF] Sprecher | Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults[END_REF][START_REF] Ju | Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels[END_REF][START_REF] Fjell | Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy[END_REF][START_REF] Bubu | Obstructive sleep apnea and longitudinal Alzheimer's disease biomarker changes[END_REF] Ju et al., 2019;[START_REF] Holth | The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans[END_REF][START_REF] Bubu | Obstructive sleep apnea and longitudinal Alzheimer's disease biomarker changes[END_REF][START_REF] Liguori | Sleep dysregulation, memory impairment, and CSF biomarkers during different levels of neurocognitive functioning in Alzheimer's disease course[END_REF][START_REF] Kong | Biomarkers of Alzheimer's disease in severe obstructive sleep apnea-hypopnea syndrome in the Chinese population[END_REF], the blood[START_REF] Bu | Serum amyloid-beta levels are increased in patients with obstructive sleep apnea syndrome[END_REF][START_REF] Baril | temporo-parietal (: Weng 2014, Shi 2017), parieto-occipital (: Baril 2017, Cross 2018, André 2020[END_REF], using PET imaging[START_REF] Lucey | Reduced nonrapid eye movement sleep is associated with tau pathology in early Alzheimer's disease[END_REF][START_REF] Winer | Sleep as a potential biomarker of tau and β-amyloid burden in the human brain[END_REF], or at autopsy(Lim et al., 2013b).

Sleep parameter

Method Grey matter volume Perfusion and glucose metabolism 1 Amyloid pathology 2 Tau pathology 3

Sleep deprivation

Objective Global levels [START_REF] Ooms | [END_REF] Global levels [START_REF] Holth | The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans[END_REF]  Global sleep quality

Selfreported

Frontal [START_REF] Sexton | Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults[END_REF]), hippocampus (Alperin 2018, Liu 2018), thalamus (Liu 2018), parietal and amygdala (Alperin 2018). Longitudinal: frontal, temporal and parietal [START_REF] Sexton | Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults[END_REF], hippocampus [START_REF] Fjell | Selfreported sleep relates to hippocampal atrophy across the adult lifespan -results from the Lifebrain consortium[END_REF] Global levels [START_REF] Sprecher | [END_REF], frontal & parietal [START_REF] Sprecher | [END_REF] Longitudinal: global levels [START_REF] Fjell | Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy[END_REF] Global levels [START_REF] Sprecher | [END_REF] Longitudinal: global levels [START_REF] Fjell | Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy[END_REF]  Excessive daytime sleepiness

Selfreported MTL, frontal, parietal and occipital [START_REF] Carvalho | Excessive daytime sleepiness and fatigue may indicate accelerated brain aging in cognitively normal late middleaged and older adults[END_REF] Global levels [START_REF] Xu | or using PET imaging[END_REF], frontal & parietal [START_REF] Sprecher | [END_REF]. Longitudinal: global levels [START_REF] Wilckens | [END_REF], anterior and posterior cingulate & precuneus [START_REF] Carvalho | [END_REF] Global levels [START_REF] Sprecher | [END_REF]  Sleep latency

Selfreported

Global levels [START_REF] Brown | [END_REF] Global levels (Ju 2017)

Short sleep duration

Selfreported

Global atrophy [START_REF] Lo | Sleep Duration and Age-Related Changes in Brain Structure and Cognitive Performance[END_REF]. Longitudinal: fronto-temporal (Spira 2016: <7h) Global levels [START_REF] Spira | Self-reported sleep and β-amyloid deposition in community-dwelling older adults[END_REF], Xu 2020: 6h) & precuneus (Spira 2013: 6h)

Long sleep duration

Selfreported Global atrophy (Westwood 2017: ≥9h), occipital (Spira 2016: >7h). Longitudinal: frontal (Spira 2016: >7h) Global levels (Xu 2020: ≥6h)

 Nocturnal awakenings & sleep fragmentation

Selfreported OFC (Stoffers 2012, early awakenings), insula (Branger 2016, nocturnal awakenings) Objective Frontal [START_REF] Lim | Regional Neocortical Gray Matter Structure and Sleep Fragmentation in Older Adults[END_REF] Frontal & hippocampus (André 2019) Global levels [START_REF] Wilckens | [END_REF]