Sleep,
rest-activity
fragmentation
and
structural
brain
changes
related
to
the
ageing
process
Marion
Baillet
1and
Christina
Schmidt
1,2Increasingevidencesuggestsanassociationbetweentypical age-relatedchangesinsleepandbrainstructure.Herewe reviewstudiesexploringtheassociationbetweenhuman histo-pathologicalandinvivoneuroimagingmarkersofbrain structureandsleep-wakeparametersinhealthyolderadults. Evidencefrombothlarge-scaleepidemiologicalstudiesand in-labquantificationofspecificsleepsignaturesarereviewedand advantagesandpitfallshighlighted.Overall,theresultspointto anassociationbetweensleep-wakedisruptionandbothlocal anddiffusechangesinbrainstructure.Theassociativestrength largelyvariesbetweenstudiesandseemstopartiallydepend onthesleeptraitunderinvestigation.Theroleofspecific sleep-wakeregulatingmechanismsonhumancognitiveandbrain fitnessandmoreparticularlytheircausalrelationshipremains tobedisentangled.
Addresses
1GIGA-Institute,CyclotronResearchCenter/InVivoImaging,Sleepand ChronobiologyLab,UniversityofLie`ge,Lie`ge,Belgium
2PsychologyandNeuroscienceofCognitionResearchUnit,Facultyof PsychologyandEducationalSciences,UniversityofLie`ge,Lie`ge, Belgium
Correspondingauthor:Schmidt,Christina(christina.schmidt@uliege.be)
CurrentOpinioninBehavioralSciences2019,33:8–16
ThisreviewcomesfromathemedissueonCognitionandperception –*sleepandcognition*
EditedbyMichaelCheeandPhilippePeigneux
https://doi.org/10.1016/j.cobeha.2019.11.003
2352-1546/ã2019ElsevierLtd.Allrightsreserved.
Introduction
Overthelastfew years,growinginterest isobserved in
understanding theprotective effects of sleep onhealth
andqualityoflife,especiallyinthecontextoftheageing
population.Inhumans,thegrossframeworktosleepand
wakefulness alternation is provided by the interaction
betweenasleep-dependenthomeostaticprocessandthe
circadiantimingsystemresponsibleforendogenous
mod-ulationsof sleep and wakepropensity over the24-hour
day [1]. Those regulating processes act as important
modulators for brain and behavior (e.g. [2]) and their
potential implication in cognitive and brain ageing is
increasinglyconsidered([3–5];seealso[6]for areview).
Here we review studies exploring the association
betweenhuman post-mortemand in vivomagnetic
reso-nance imaging (MRI) markers of brain structure and
sleep-wakeparameters in healthyolder adults.As
sum-marized in Table 1, brain structural measures include
quantificationofgreymatteraswellaswhitematterfrom
cross-sectional and longitudinal designs, using
whole-brainorregionsofinterestapproaches.Wewill
differen-tiate studies investigating sleep-wake parameters
collected through (1) self-reported questionnaires, (2)
polysomnography(sleep architectureand
electrophysio-logicalsignatures),and(3)actimetryrecordings(integrity
of the temporal distribution of rest-activity cycles and
estimatedsleepfragmentationin real-lifesettings).
Association
between
brain
structure
and
self-reported
sleep
Sleep complaints are increasing while getting older
including altered sleep perception, changes in sleep
architecture or increased variability in the timing and
duration of sleep [7]. Sleep questionnaires have been
developedtoprovideageneraloverviewofthesubjective
quality of sleep. While they are often used as a first
diagnostictoolinclinicalpractice,qualitativeassessments
of sleep perception donot inform about specific
sleep-regulating mechanisms and are the consequence of an
amalgamofvariousbiologicalandenvironmentalfactors,
varyingover time.However,they remain costeffective
andeasytouseallowingthereforethegenerationoflarge
andrepresentativesamplesbyadoptingepidemiological
approaches.
Cross-sectionalstudiesdetectedan associationbetween
poorself-reportedsleepqualityandreducedgreymatter
volumeincludingorbitofrontalregions[8],insula[9],and
age-related thalamic and hippocampal atrophy [10]. A
longitudinalapproach reportedthatgreymatteratrophy
of frontal, parietal and temporal, but not hippocampal
regionswaspredictivefor poorsleepqualityat3.5years
follow up [11]. Compared to sleep quality, reports on
sleepdurationhaveproducedmore mixedresults. Most
cross-sectionalstudiesfailedtoobserveasignificant
asso-ciation between self-reported sleep duration and grey
mattervolume [9,12,13]. A longitudinal study reported
that both short (<7hours) and long (>7hours) sleep
durations were associated with higher rates of cortical
Table1
Crosssectionalandlongitudinalstudiesofsleep-wakestatesandstructuralbrainimaging
Paper Design n,meanageSD Project
Brainmeasures Mainfindings
Sleepquestionnairestudies Stoffers[8] Crosssectional n=65,40.59.7
Netherlandsstudyof depressionandanxiety
GMvolume–VBM8,voxel wiseanalysis
EMAwasassociatedwithlow volumewithintheleftOFC.No associationwithDIS,DMS Branger[9] Crosssectional n=51,64.110.6
Multimodalimagingofearly stageAlzheimer’sdisease
GMvolume–VBM5,voxel wiseanalysis
Highnumberofnocturnal awakeningswasrelatedtolow insularvolume.Noassociationwith sleeplatency,durationandquality Liu[10] Crosssectional n=54young,21.61.6
n=94older,66.25.1 Independentsample
GM,WM,hippocampaland thalamicvolumes–VBM8
Poorsleepqualitywasassociated withage-relatedGM,hippocampal andthalamicatrophy
Sexton[11] Longitudinal3.5years n=147,53.915.5 Cognitionandplasticity throughthelifespan
Corticalvolume–Freesurfer, vertexwiseanalysis Hippocampalvolumes– Freesurfer
Lowvolumewithintherightsuperior frontalcortex(crosssectional)and increasedrateofatrophywithin frontal,temporal,andparietal regions(longitudinal)waspredictive forpoorsleepquality.No associationwithhippocampal volumeoratrophy
Lo[12] Longitudinal2years n=66,67.45.8
Singapore-longitudinalaging brainstudy
GM,WM,hippocampal, ventricles,inferiorand superiorfrontalgyrivolumes –Freesurfer
Shortsleepdurationwasrelatedto increasedventricularexpansion.No associationwithotherbrainvolumes andsleepquality
Lutsey[13] Crosssectional n=312,61.75 Theatherosclerosisriskin communitiesstudy
Frontal,temporal,parietal andoccipitalcortical volume.Hippocampal,and deepgreymattervolume– Freesurfer
WMHvolumeandbrain infarcts
Noassociationbetweensleep durationandMRImeasures
Spira[14] Longitudinal8years n=122,66.68
Baltimorelongitudinalstudy ofaging
Corticalthickness– Freesurfer,vertexwise analysis
Longsleepdurationwasassociated withlowcorticalthicknessinthe inferioroccipitalgyrusandsulcusof thelefthemisphere(crosssectional). Longandshortsleepdurationwere associatedwithincreasedrateof corticalthinninginfronto-temporal area(longitudinal)
Carvalho[15] Crosssectional n=1374,>50
Mayoclinicstudyofaging
Frontal,parietal,temporal andoccipitalcortical thicknessandhippocampal volume–Freesurfer
Excessivedaytimesleepinesswas associatedwithlowcortical thicknessinfrontal,parietal, temporalandoccipitalregionsand hippocampalvolume
DelBrutto[16] Crosssectional n=237,708 Atahualpaproject
WMHvolume,lacunar infarctsanddeep microbleeds
Poorsleepqualitywasassociated withWMHpresenceandseverity. Noassociationwithsilentlacunar infarctordeepmicrobleeds Kocevska[17] Longitudinal5years n=2,529,55.86.0
Rotterdamstudy
FA,MD–tractography Sleepcomplaintswererelatedto decreasedFAinthemiddle cerebellarpeduncleandmedial lemniscusovertime.Shortsleep durationwasrelatedtoincreased WMHburdenovertimeandhigh sleepefficiencywithhighWMH volumeatfollowup.Noassociation betweenWMmeasuresatbaseline andchangesinsleepcomplaints Sexton[19] Crosssectional n=448,69.25.1
WhitehallIIimaging substudy
FA,AD,RD-FSL,TBSS, voxelwiseanalysis WMHvolume
Poorsleepqualitywasrelatedtolow FA,highADandRDvaluesinfrontal lobe.Noassociationwithsleep duration,sleepefficiency,WMH volumeandpersistenceofpoor sleep16yearspriorbrainimaging
Table1 (Continued)
Paper Design n,meanageSD Project
Brainmeasures Mainfindings
Yaffe[21] Crosssectional n=613,45.4 Coronaryarteryrisk developmentinyoungadults
Frontal,parietal,temporal andoccipitalFA,MD WMHvolume
Shortsleepdurationwasassociated withhighMDvaluesinfrontal, parietalandtemporalregionsand highparietalWMHvolume Ramos[22] Crosssectional n=1,244,70.09.0
NorthernManhattanstudy
WMHvolume Longsleepdurationwasassociated withhighWMHvolumeonlyinolder adultssufferingfromdiabetes Polysomnographicstudies
Gelber[28] Crosssectional n=167,83.7(79–95) Honolulu-Asiaagingstudy
Brainautopsy GreaterSWSdurationwas associatedwithlessbrainatrophy Dube´ [29] Crosssectional n=30young,23.492.79
n=33older,60.355.71 Independentsample
Corticalthickness–CIVET, voxelwiseanalysis
HigherSWdensitywasassociated withage-relatedinsular,superior temporal,parietalandmiddlefrontal thickness.HigherSWamplitude wasassociatedwithage-related middlefrontal,medialprefrontal, andmedialposteriorthinning Mander[30] Crosssectional n=18young,20.42.1
n=18older,72.46.1 Independentsample
mPFCvolume–VBM8 ReducedSWAwasassociatedwith age-relatedmPFCatrophy
Varga[31] Crosssectional n=18young,18–23 n=13older,51–85 Independentsample
mPFCvolume–Freesurfer ReducedfrontalSWAwasassociatd withage-relatedmPFCatrophy
Helfrich[32] Crosssectional n=20young,20.42.0 n=32older,73.75.3 Independentsample
mPFC,dlPFC,lateral orbitofrontalcortex,thalamic andhippocampalvolumes– VBM8
Impairedslowwave-spindle couplingwasrelatedtoage-related mPFCatrophy.Noassociationwith hippocampus,thalamus,lateral OFCanddlPFC
Fogel[33] Crosssectional n=13young,24.13.5 n=15older,62.23.8 Independentsample
GMvolume–FSL,voxelwise analysis
Sleepspindleswererelatedtogrey mattervolumewithinthe
hippocampus,cerebellum, cingulateandparietalcortexin youngbutnotolderadults Mander[34] Crosssectional n=20young,20.42.0
n=31older,73.55.2 Independentsample
MD-FSL,TBSS,voxelwise analysis
Decreasedinfastspindledensity wasassociatedwithage-related increasedMDvaluesin commissuralandprojectingfiber tracts
Gaudreault[35] Crosssectional n=30young,22.92.7 n=31older,59.85.4 Independentsample
FA,MD,AD,RD-FSL,TBSS, voxelwiseanalysis
SleepspindleswererelatedtoWM modificationsoverfrontalregionsin youngbutnotolderadults
Actigraphicstudies Lim[37] Crosssectional n=45,33healthyolderand
12AD,89.4(85.2–93.5) Rushmemoryandaging project
Brainautopsy Highfragmentationofsleepand activestateswasrelatedtolow galanin-immunoreactiveneuronsin theintermediatenucleus.No associationwithself-reportedsleep duration,DIS,DMS
Lim[38] Crosssectional n=315older,90.46.1 Rushmemoryandaging project
Brainautopsy Highsleepfragmentationwas associatedwithsevere
arteriolosclerosisandsubcortical macroscopicinfarcts
Wang[39] Crosssectional n=17,10healthyolderand 7AD,90.45.5
Rushmemoryandaging project
Brainautopsy Lowrest-activityamplitudewas associatedwithlow VIP-immunoreactiveneuronsinthe suprachiasmaticnucleus
while an association between short sleep duration and
ventricular expansion over two years was detected in
anotherstudy[12].Besidesleep,Carvalhoetal.reported
that excessive daytime sleepiness was associated with
reducedhippocampalvolumeandcorticalthickness,
par-ticularly in temporal regions, suggesting that not only
alteredsleepbutalsoresultingdaytimesleepinessmaybe
related tobrainstructure [15].
Regarding white matter, poor sleep quality has been
associatedwiththepresenceofwhitematter
hyperinten-sities(WMH)incross-sectional andlongitudinalstudies
[16,17].WMHarecommonlyobservedduringageingand
reflectwhitemattertissue injurysuchasdemyelination,
axonallossandgliosis[18].Importantly,WMHhavebeen
related to cognitive decline, especially executive
dys-function, and incident dementia [18]. Another study
Table1 (Continued)
Paper Design n,meanageSD Project
Brainmeasures Mainfindings
Lim[40] Crosssectional n=141,82.9(median,IQR 77.4–87.4)
Rushmemoryandaging project
Volume,surfaceandareaof Desikan-Killianyatlas regions–Freesurfer
Highsleepfragmentationwas relatedtolowvolumeswithinthe lateralorbitofrontalandinferior frontalparsorbitalisandthickness withintherightinferiorfrontalpars orbitalis.Noassociationwith corticalarea,subcorticalandWM volume,self-reportedsleepduration andnocturnalawakenings Andre´ [41] Crosssectional n=30cognitively
unimpaired,73.37 n=36SCDand/orMCI, 71.58.2 IMPAP+study GMvolume–SPM12,voxel wiseanalysis
Highvariabilityofsleep
fragmentationduringthefirstpartof thenightwasrelatedtolowvolume withinthethalamusincognitively unimpairedolderadults.No associationwithsleep fragmentationintensity vanSomeren[42] Crosssectional n=138,69.18.5
Independentsample
Medialtemporallobeand globalcorticalatrophy– visualrattingscales
Highrest-activityfragmentationwas associatedwithmedialtemporal lobeatrophy
Baillet[43] Crosssectional n=58,76.10.5(SEM) AMImagestudy
GMvolume–VBM8,voxel wiseanalysis
FA,MD,RD,AD-FSL,TBSS, voxelwiseanalysis WMHvolume
Lowrest-activityamplitudeandhigh sleepfragmentationwererelatedto lowFA,highMDandRDvaluesin thewholeWM.Thisassociationwas partlyassociatedwithWMH.No associationwithrest-activity fragmentation,stabilityofactivity rhythms,sleepdurationandGM volume
Kocevska[44] Longitudinal5.8years n=1,201,59.37.9 Rotterdamstudy
FA,MD–tractography Shortsleepduration,highWASO andlowsleepefficiencywere relatedtoWMmodificationsin severalWMtractsuptosevenyears afterbrainimaging.Noassociation withsleeplatencyandwithWM modificationchangesovertime Oosterman[45] Crosssectional n=162,69.18.6
Independentsample
WMHvolume–visualrating scale
Lowrest-activityamplitudeand unstableactivityrhythmswere associatedwithfrontaldeepWMH. Noassociationwithperiventricular WMHandrest-activity
fragmentation Zuurbier[47] Crosssectional n=970,59.27.5
Rotterdamstudy
WMHvolume,lacunar infarctsandcerebral microbleeds
Rest-activityfragmentationwas associatedwithhighWMHvolume andcerebralmicrobleeds.No associationwithstabilityofactivity rhythms,sleepduration,WASO, self-reportedsleepqualityand lacunarinfarcts
Abbreviations:GM=greymatter,WM=whitematter,OFC=orbitofrontalcortex,mPFC=medialprefrontalcortex,dlPFC=dorsolateralprefrontal cortex,VIP=vasoactiveintestinalpolypeptideneurons,WMH=whitematterhyperintensities,VBM=voxelbasedmorphometry,FA=fractional anisotropy,MD=meandiffusivity,RD=radialdiffusivity,AD=axialdiffusivity,TBSS=tractbasedspatialstatistics;EMA=earlymorning awaken-ings,DIS=difficultyinitiatingsleep,DMS=difficultymaintainingsleep,SWS=slow-wavesleep,SWA=slow-waveactivity,WASO=wakeafter sleeponset.
observedthatpoorsleepquality,andespeciallylongsleep
latency, was associated with modifications of Diffusion
Tensor Imaging (DTI) parameters, particularly radial
diffusivity(RD),butnotwithWMHvolume.Persistence
ofpoorsleepqualitysixteenyearspriorMRIwashowever
notassociatedwithwhitemattermeasures[19].Ofnote,
ageingisrelatedtoreducedfractionalanisotropy(FA)and
increased diffusivity parameters (mean diffusivity,MD
andRD;lessprominentforaxialdiffusivity,AD)
reflect-ingimpairedfiberintegrityduetoalossofcoherenceona
preferred direction and an increase of diffusion rate.
Changes in RD are assumed to reflect myelin damage
whilechangesinAD presumablyreflectaxonaldamage
[20]. Kocevskaet al. revealed no significant association
betweenwhitemattermeasuresatbaselineandchanges
in sleep complaints over time, but observed that sleep
complaintsatbaselinewereassociatedwithdecreasedFA
values in brainstem tracts over a five-year longitudinal
design; thereby suggesting that sleep complaints may
predict future age-related white matter modifications
[17]. With respect to sleep duration, shorter durations
(<6hours)havebeenassociatedwithhighWMHvolume
in parietalareas [21] and increased WMHburden over
time [17]. Short self-reported sleepers presented also
higherMDvaluesmainlyinfrontal,parietalandtemporal
whitematterregionsand,higherprevalenceof vascular
risk factors compared to moderate sleepers [21]. Other
studiesdidnotobserveasignificantassociationbetween
self-reported sleep duration and WMH in older adults
[13,22]; note that Ramos et al. reported an association
betweenlongsleep duration(>9hours)andWMH
vol-umeonlyin olderadultssuffering fromdiabetes[22].
Association
between
brain
structure
and
electrophysiological
signatures
of
sleep
Sleeparchitectureischaracterizedbytheultradian
alter-nation between rapid eye movement (REM) and
non-REM (NREM) sleep as assessed by polysomnographic
(PSG) recordings. Standard PSG-assessed variables and
moreparticularlyfrequency-bandspecificspectralpower
exhibits stable and trait-like-interindividual differences
(e.g. [23]) which make them interesting candidates for
brain-behaviorcorrelations.Sleepspindleshavefor
exam-ple been proposed to reflect featuresof trait and
time-varyingpropertiesofneuroplasticity[24]andhavebeen
associatedwithgeneralintelligence(e.g.[25]).
Compro-mised generation and propagation of sleep oscillations
(spindlesandslowwaves)havebeenlinkedtoage-related
corticalthinning[26].
Post-mortem assessments from theHonolulu-Asia Aging
Study [27] revealed that short slow-wave sleep (SWS)
duration was associated with more global grey matter
atrophy at death [28]. In vivo MRI studies similarly
revealed that during adulthood,changes in slow waves
densityandamplitudewereassociated withage-related
corticalthinninginfrontal,temporal,parietalandinsular
regions[29].Importantly,age-relatedgreymatteratrophy
within the medial prefrontal cortex (mPFC) has been
relatedtodecreasedslow-waveactivity[30,31]andslow
wave—sleepspindlecoupling[32],bothassociatedwith
overnight sleep-dependent memory impairment. Note
howeverthatanotherstudyreported significant
associa-tionsbetweensleepspindlecharacteristicsandgrey
mat-tervolume in younger adultsonly [33].Withrespectto
white matter, Mander et al. observed that age-related
increase of MD values in several white matter tracts,
suchasthecorpuscallosum,wasassociatedwithalossof
frontalfastsleepspindles.Thiswhitemattermodification
moderated the impairment of overnight sleep
spindle-dependent motor memory consolidation [34]. Another
study failed to observe such association in a younger
agerange[35].
Association
between
brain
structure
and
rest-activity
cycles
The application of in-lab approaches allow to uncover
processesunderlyingdifferentsleepphenotypes.At
con-trast,fieldactigraphyenablesmonitoringof masked
24-hourrest-activitycyclesoverdays,weeksorevenmonths.
Difficulty however remains in the inference of
physio-logicallymeaningful sleep phenotypes.Strength of this
approach is that, unlike single-night polysomnographic
recordings, it allows a rather unique assessment of the
temporalprofilesofrest-activitypatternsandtherebythe
inferencesabout putative temporaldisruption of
sleep-wakestates.Assuch,notonlysleep,butalsothetemporal
organization of rest-activity cycles has been associated
withcognitivefunctioning(e.g. [3–5]).
Knowledgeonhistopathological changesrelatedto
rest-activity cycles in ageing mainly arises from actigraphic
studiesoftheRushMemory andAging Project[36].In
the latter, Lim et al. observed that higher rest-activity
fragmentationwasrelatedtoalowernumberof
galanin-immunoreactiveneuronswithintheintermediatenucleus
ofthehypothalamus(homologueofthesleep-promoting
ventrolateralpreopticnucleusinrodents;[37]).
Further-more, higher sleep fragmentation was associated with
more severe arteriolosclerosis and subcortical
macro-scopic infarcts at autopsy (27% and 31% higher odds
foreach1standarddeviationincreaseof sleep
fragmen-tation;[38]).Finally,Wangetal.reportedthatalower
24-hour cycle amplitude (i.e. less differentiation between
day-time activity and night-time rest) was related to a
lowernumber of vasoactiveintestinal polypeptide
neu-rons of the suprachiasmatic nucleus implicated in the
maintainance of a high-amplitude circadian output and
photicresetting[39].
Fewstudiesevaluatedtheassociationbetween
actigra-phy-derivedrest-activityparametersandgreymatterin
older adults. Highsleep fragmentation has been
and inferior frontal regions [40], and its variability
during the first part of the night with low thalamic
volume[41].Recently,vanSomerenetal.reportedthat
rest-activity fragmentation accounted for 19% of the
variance in medial temporal lobe atrophy, evaluated
withavisualratingscale[42].Incontrast,anotherstudy
did not observe any significant association between
actigraphic measures of rest-activity cycles and grey
matter volume[43].
Regarding white matter, a population-based study
reportedthatactigraphic derivedpoorsleepquality and
short sleep duration wererelated to whitematter
mod-ifications(highFAandlowMD)uptosevenyearslater
butnotwiththeevolutionofDTIparametersovertime.
Howeverasactigraphicrecordingswerenotperformedat
baseline, causality between sleep and brain structure
remains difficulttoinferatthis stage[44].Threecross
sectionalactigraphicstudiesprovidedfirstevidencethat
rest-activity disturbances observed in older adults are
related to cerebral small vessel disease manifestations.
Oosterman et al. observed that a lower 24-hour
rest-activityamplitude,especiallydecreaseindaytime
activ-ity,andunstableactivityrhythmswererelatedtohigher
deepWMHvolumesinfrontalregions[45].Inmorethan
900participantsoftheRotterdamStudy[46],rest-activity
fragmentation has been associated with WMH volume
and cerebral microbleeds but not with the number of
lacunarinfarcts[47].IntheonlystudyusingDTI,Baillet
et al. observed that low 24-hour rest-activity amplitude
andhigh sleepfragmentationwerebothassociatedwith
diffusewhitemattermodifications(lowFA,highMDand
RD) and WMH volume. Interestingly, rest-activity
amplituderemained associatedwith whitematter
prop-ertieswhenaccountingforsleepfragmentation,
suggest-ing aspecific effectof the temporaldistributionofrest
andactivityover the24-hourday[43].
Discussion
Ageing is associated with modifications of brain
struc-ture,sleep-wakeregulationandcognitionbuthowthese
factors are related to each other remains to be
deter-mined.Atthisstage,itmightappearprematuretodraw
firm conclusions regarding region-specific implications
(see also Figure 1a for a conceptual representation).
Regions of interest based approaches mainly targeted
on frontal, temporal, hippocampal, and thalamic grey
mattervolume,consideringthepredominantimplication
of those regions in brain ageing trajectory but also in
sleep-wakeregulationormorespecifically,inthe
gener-ation and/or coupling of slow oscillations and sleep
spindles.OfthirteenMRIstudiesincludingsubcortical
structures[8–13,15,32,33,40–42,43],onlyfourreported
apositiveassociationbetween sleep-wakepatternsand
hippocampal [10,15,42]orthalamicvolumes[10,41]. In
contrast, all polysomnographic studies included inthis
Figure1
(a)
(b) Self-reported sleep Actigraphy Polysomnography
Brain
ageing
Trait-like sleep phenotyping
Effect size
Sample size
Representativity
Duration Quality Night-time rest Rest-activity cycles SWS REM Spindles Cortical thinning White matter changesCSVD manifestations Sleep perception
Sleep macro- and microstructure Rest-activity cycles
(e.g. mPFC, hypothalamus)
Sleep-wake states Diffuse process
Local process
Current Opinion in Behavioral Sciences
Conceptualrepresentationof(a)resultsfromstudiesreportinganassociationbetweensleep-wakestatesandMRI-derivedbrainstructureand(b) methodologicalconsiderations.
reviewsuggestthatadecreaseinslowwavesparameters
isassociatedwithcorticalatrophy,includingthemedial
prefrontal cortex [29–31,32] suggesting a possible
neuroanatomicalsubstratetoexplain sleep-related
cog-nitive impairment. Rather consistent results were
observed regarding white matter, and especially with
actigraphicrest-activitypatternsandcerebralsmall
ves-sel disease manifestations as WMH, cerebral
micro-bleeds and related cerebrovascular pathologies
[38,43,45,47]. Actingas adiffuse process,these
man-ifestationsdisruptnotonlythenormalappearingwhite
matterbutalso connected corticalregionsthrough
sec-ondaryneurodegeneration disrupting efficient
informa-tiontransferinbrainnetworks[48].Cerebralsmallvessel
diseaseisunderlinedbyreducedcerebralbloodflowand
blood-braindysfunctionandassociatedwithvascularrisk
factors [48], suggesting that rest-activity disturbances
mayberelatedtovascularabnormalities.
Mostofthestudiesexploringtheassociationbetweensleep
andstructuralbrainchangesatolder agereliedon
ques-tionnaire-basedsubjectiveassessments ofsleep duration
andquality.Thismightatleastpartiallyexplainthe
vari-abilityinobservedresultswithrespecttobrainstructural
changesovertheageingprocess.Itmightbeassumedthat
replicabilityofstructuralbrain-behaviorassociations
criti-callyreliesuponthedefinitionandprecisionofthesleep
traitunderinvestigation(e.g.[49]).Itisthusimportantto
completepopulation-basedsampleswithin-lab
measure-mentsofmoreunmaskedsleepphenotypeswhile
control-lingforpriorsleep-wakehistory.Withinthiscontext,
trait-likeand thusreplicable characteristics havebeen attributed
forexampletoelectrophysiological-derivedsleep
charac-teristics(e.g.[50]).Thosestudies,testingforanassociation
betweenelectroencephalographic-derivedspectralpower
measures(mainlyslow-waveactivity,spindledensityand
theircoupling)andbrainstructuremostlyrevealedstrong
effectsizes([29–31,34]butsee[33,35]).Addingcomplexity
tosuchphenotypes,asforinstancetakingintoaccountthe
dynamic interaction between REM and NREM sleep
whentestingfor putativeassociations will completethe
pictureabouttheimportanceofsleeponbrainageing[51].
It wasrecently observed forexamplethatNREMand REM
sleepstagesdifferentlyaffectcognitiveoutputslinkedto
theageing process(e.g.[52])therebyre-emphasizingon
REMsleepasanimportantcontributortobrainfunction.
Finally,theroleofthecircadianclockonshapinghuman
brain ageing has been widely underestimated. This
appearssurprisingbecauseofitswidespreadimplication
and regulation of cognitive brain function [2]. Even
thoughnotassessingtheinternalclock,actigraphyallows
toinfer abouttemporalprofiles of rest-activitypatterns.
Note that most studies have focused on sleep and its
disturbanceswithoutconsideringitasapartofa24-hour
cycle.Ofseven[40,41,42,43,44,45,47]studiesusingMRI
andactigraphy,onlyfourdescribedrest-activitypatterns
[42,43,45,47]andmostof thememphasizedan
associa-tion with white matter properties. Furthermore,
post-mortem studies provide evidence that actigraphic
rest-activity patterns are associated with degeneration of
hypothalamic neurons implicated in circadian timing
and sleep-wake regulation, regionsnot easilyreachable
withconventionalMRI[37,39].Thesestudieshinttothe
importance of the temporal framework given to sleep
regulation for brain fitness at older age. Older adults
present an advanced phase of circadian rhythms (e.g.
classicalendocrinemarkerssuchasmelatoninsecretion),
leadingtoearliersleeptimesandareducedamplitudein
bothcircadian sleepand wake consolidation [53],
puta-tivelyleadingtomorefragmentedactiveandsleepstates
(i.e. intrusion of sleep into daytime activities and
frag-mentationofnight-timesleepbywakeperiodsor
noctur-nalarousals;e.g. [54]).Note that atool regrouping
cur-rentlyavailableanalysismethodswasrecentlydeveloped
inourlabinordertocatchsuchtemporalspecificitiesin
actigraphy-derivedrest-activitydata,makingthistypeof
analysisopenlyavailableforfuturestudies(Pyactigraphy,
doi:https://doi.org/10.5281/zenodo.2537921).
Assummarizedin Figure1b,bothlarge-scale
epidemio-logicalstudiesbutalsocontrolledin-labquantificationof
specific sleep phenotypes present strengths and pitfalls
suchthattheirrespectiveoutputsshouldnotbetakenas
equalbutratherusedinacomplementarymanner.Inthe
samevein,inferencesweremostlybasedoncross-sectional
correlationsbetweenbrainandsleepvariables.
Longitudi-naldesignsaredecisivetodifferentiatebetween
intraindi-vidualandinter-individualvariabilityandtherebyofferthe
possibilitytodeterminewhethersleep-wakedisturbances
haveapredictivevalueoncognitiveandbrainchanges.In
subjectivecognitivedeclinepopulation,definedas
preclin-icalstageofAD,poorsleepqualityhasforexamplebeen
reportedtoprecedemedialtemporallobeatrophy[55].
Notethatourreviewfocusesonpossiblecontributionsof
sleep-wake states on non-symptomatic age-related
changesin brainstructure. Insights frompositron
emis-sion tomography imaging studies, not included in this
review, revealed for example that poor sleep and
frag-mented rest-activity cycles are related to Ab and Tau
burden(e.g. [56];seealso [57]for areview). The latter
might partially account for the modification in brain
structure,openingnewavenuestoexploretheassociation
betweensleepandage-relatedchangesinbrainintegrity.
Conflict
of
interest
statement
Nothingdeclared.
Acknowledgements
TheresearchersarefundedbyanERCStartingGrant(GA757763)andby theFondsdelaRechercheScientifiquedeBelgique(F.R.S.-FNRS).
References
and
recommended
reading
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