Citation
Reduced cerebral blood flow and white matter hyperintensities predict poor sleep in heart failure

Material Information

Title:
Reduced cerebral blood flow and white matter hyperintensities predict poor sleep in heart failure
Creator:
Alosco, Michael L.
Brickman, Adam M.
Spitznagel, Mary Beth
Griffith, Erica Y.
Narkhede, Atul
Cohen, Ronald
Sweet, Lawrence H.
Publisher:
BioMed Central (BBF, Behavioral and Brain Functions)
Publication Date:
Language:
English

Notes

Abstract:
Background: Poor sleep is common in heart failure (HF), though mechanisms of sleep difficulties are not well understood. Adverse brain changes among regions important for sleep have been demonstrated in patients with HF. Cerebral hypoperfusion, a correlate of sleep quality, is also prevalent in HF and a likely contributor to white matter hyperintensities (WMH). However, no study to date has examined the effects of cerebral blood flow, WMH, and brain volume on sleep quality in HF. Methods: Fifty-three HF patients completed the Pittsburgh Sleep Quality Index and underwent brain magnetic resonance imaging to quantify brain and WMH volume. Transcranial Doppler ultrasonography assessed cerebral blood flow velocity of the middle cerebral artery (CBF-V of the MCA). Results: 75.5% of HF patients reported impaired sleep. Regression analyses adjusting for medical and demographic factors showed decreased CBF-V of the MCA and greater WMH volume were associated with poor sleep quality. No such pattern emerged on total brain or regional volume indices. Conclusions: Decreased cerebral perfusion and greater WMH may contribute to sleep difficulties in HF. Future studies are needed to confirm these findings and clarify the effects of cerebral blood flow and WMH on sleep in healthy and patient samples. Keywords: Sleep quality, Heart failure, MRI, Brain perfusion, White matter hyperintensity.
General Note:
Alosco et al. Behavioral and Brain Functions 2013, 9:42 http://www.behavioralandbrainfunctions.com/content/9/1/42; Pages 1-8
General Note:
doi:10.1186/1744-9081-9-42 Cite this article as: Alosco et al.: Reduced cerebral blood flow and white matter hyperintensities predict poor sleep in heart failure. Behavioral and Brain Functions 2013 9:42.

Record Information

Source Institution:
University of Florida
Holding Location:
University of Florida
Rights Management:
All rights reserved by the source institution.

UFDC Membership

Aggregations:
University of Florida Institutional Repository

Downloads

This item is only available as the following downloads:


Full Text
xml version 1.0 encoding UTF-8 standalone no
fcla fda yes
!-- Reduced cerebral blood flow and white matter hyperintensities predict poor sleep in heart failure ( Mixed Material ) --
METS:mets OBJID AA00019159_00001
xmlns:METS http:www.loc.govMETS
xmlns:xlink http:www.w3.org1999xlink
xmlns:xsi http:www.w3.org2001XMLSchema-instance
xmlns:daitss http:www.fcla.edudlsmddaitss
xmlns:mods http:www.loc.govmodsv3
xmlns:sobekcm http:digital.uflib.ufl.edumetadatasobekcm
xmlns:lom http:digital.uflib.ufl.edumetadatasobekcm_lom
xsi:schemaLocation
http:www.loc.govstandardsmetsmets.xsd
http:www.fcla.edudlsmddaitssdaitss.xsd
http:www.loc.govmodsv3mods-3-4.xsd
http:digital.uflib.ufl.edumetadatasobekcmsobekcm.xsd
METS:metsHdr CREATEDATE 2015-01-14T11:16:07Z ID LASTMODDATE 2013-11-12T08:17:51Z RECORDSTATUS COMPLETE
METS:agent ROLE CREATOR TYPE ORGANIZATION
METS:name UF,University of Florida
METS:note Created using template 'INTERNAL' and project 'NONE'.
OTHERTYPE SOFTWARE OTHER
Go UFDC FDA Preparation Tool
INDIVIDUAL
UFAD\renner
METS:dmdSec DMD1
METS:mdWrap MDTYPE MODS MIMETYPE textxml LABEL Metadata
METS:xmlData
mods:mods
mods:abstract Background: Poor sleep is common in heart failure (HF), though mechanisms of sleep difficulties are not well
understood. Adverse brain changes among regions important for sleep have been demonstrated in patients with
HF. Cerebral hypoperfusion, a correlate of sleep quality, is also prevalent in HF and a likely contributor to white
matter hyperintensities (WMH). However, no study to date has examined the effects of cerebral blood flow, WMH,
and brain volume on sleep quality in HF.
Methods: Fifty-three HF patients completed the Pittsburgh Sleep Quality Index and underwent brain magnetic
resonance imaging to quantify brain and WMH volume. Transcranial Doppler ultrasonography assessed cerebral
blood flow velocity of the middle cerebral artery (CBF-V of the MCA).
Results: 75.5% of HF patients reported impaired sleep. Regression analyses adjusting for medical and demographic
factors showed decreased CBF-V of the MCA and greater WMH volume were associated with poor sleep quality.
No such pattern emerged on total brain or regional volume indices.
Conclusions: Decreased cerebral perfusion and greater WMH may contribute to sleep difficulties in HF. Future
studies are needed to confirm these findings and clarify the effects of cerebral blood flow and WMH on sleep in
healthy and patient samples.
Keywords: Sleep quality, Heart failure, MRI, Brain perfusion, White matter hyperintensity.
mods:accessCondition type restrictions on use displayLabel Rights All rights reserved by the source institution.
mods:language
mods:languageTerm text English
code authority iso639-2b eng
mods:location
mods:physicalLocation University of Florida
UF
mods:name
mods:namePart Alosco, Michael L.
Brickman, Adam M.
Spitznagel, Mary Beth
Griffith, Erica Y.
Narkhede, Atul
Cohen, Ronald
Sweet, Lawrence H.
mods:note Alosco et al. Behavioral and Brain Functions 2013, 9:42
http://www.behavioralandbrainfunctions.com/content/9/1/42; Pages 1-8
doi:10.1186/1744-9081-9-42
Cite this article as: Alosco et al.: Reduced cerebral blood flow and white
matter hyperintensities predict poor sleep in heart failure. Behavioral and
Brain Functions 2013 9:42.
mods:originInfo
mods:publisher BioMed Central (BBF, Behavioral and Brain Functions)
mods:dateIssued 2013
mods:recordInfo
mods:recordIdentifier source sobekcm AA00019159_00001
mods:recordContentSource University of Florida
mods:titleInfo
mods:title Reduced cerebral blood flow and white matter hyperintensities predict poor sleep in heart failure
mods:typeOfResource mixed material
DMD2
OTHERMDTYPE SOBEKCM SobekCM Custom
sobekcm:procParam
sobekcm:Aggregation ALL
UFIRG
UFIR
IUF
sobekcm:Wordmark UFIR
sobekcm:bibDesc
sobekcm:BibID AA00019159
sobekcm:VID 00001
sobekcm:Publisher
sobekcm:Name BioMed Central (BBF, Behavioral and Brain Functions)
sobekcm:Source
sobekcm:statement UF University of Florida
sobekcm:SortDate 734868
METS:amdSec
METS:digiprovMD DIGIPROV1
DAITSS Archiving Information
daitss:daitss
daitss:AGREEMENT_INFO ACCOUNT PROJECT UFDC
METS:techMD TECH1
File Technical Details
sobekcm:FileInfo
METS:fileSec
METS:fileGrp USE reference
METS:file GROUPID G1 PDF1 applicationpdf CHECKSUM a549317afa561da89554afd0691e168b CHECKSUMTYPE MD5 SIZE 239429
METS:FLocat LOCTYPE OTHERLOCTYPE SYSTEM xlink:href 1744-9081-9-42.pdf
G2 METS2 unknownx-mets bf7e8822bb524e2c35cf0cb6b89fbb8c 5935
AA00019159_00001.mets
METS:structMap STRUCT2 other
METS:div DMDID ADMID ORDER 0 main
ODIV1 1 Main
FILES1 Page
METS:fptr FILEID
FILES2 2


xml version 1.0 encoding UTF-8
REPORT xmlns http:www.fcla.edudlsmddaitss xmlns:xsi http:www.w3.org2001XMLSchema-instance xsi:schemaLocation http:www.fcla.edudlsmddaitssdaitssReport.xsd
INGEST IEID EGJL4YR8X_4NSMCT INGEST_TIME 2015-01-16T18:13:14Z PACKAGE AA00019159_00001
AGREEMENT_INFO ACCOUNT UF PROJECT UFDC
FILES



PAGE 1

RESEARCHOpenAccessReducedcerebralbloodflowandwhitematter hyperintensitiespredictpoorsleepinheartfailureMichaelLAlosco1,AdamMBrickman2,MaryBethSpitznagel1,EricaYGriffith2,AtulNarkhede2,RonaldCohen4, LawrenceHSweet5,JoelHughes1,3,JimRosneck3andJohnGunstad1*AbstractBackground: Poorsleepiscommoninheartfailure(HF),thoughmechanismsofsleepdifficultiesarenotwell understood.Adversebrainchangesamongregionsimportantforsleephavebeendemonstratedinpatientswith HF.Cerebralhypoperfusion,acorrelateofsleepquality,isalsoprevalentinHFandalikelycontributortowhite matterhyperintensities(WMH).However,nostudytodatehasexaminedtheeffectsofcerebralbloodflow,WMH, andbrainvolumeonsleepqualityinHF. Methods: Fifty-threeHFpatientscompletedthePittsburghSleepQualityIndexandunderwentbrainmagnetic resonanceimagingtoquantifybrainandWMHvolume.TranscranialDopplerultrasonographyassessedcerebral bloodflowvelocityofthemiddlecerebralartery(CBF-VoftheMCA). Results: 75.5%ofHFpatientsreportedimpairedsleep.Regressionanalysesadjustingformedicalanddemographic factorsshoweddecreasedCBF-VoftheMCAandgreaterWMHvolumewereassociatedwithpoorsleepquality. Nosuchpatternemergedontotalbrainorregionalvolumeindices. Conclusions: DecreasedcerebralperfusionandgreaterWMHmaycontributetosleepdifficultiesinHF.Future studiesareneededtoconfirmthesefindingsandclarifytheeffectsofcerebralbloodflowandWMHonsleepin healthyandpatientsamples. Keywords: Sleepquality,Heartfailure,MRI,Brainperfusion,WhitematterhyperintensityBackgroundHeartfailure(HF)affectsgreaterthan5millionAmerican adultsandisassociatedwithpooroutcomessuchas cognitiveimpairment,decreasedqualityoflife,rehospitalizations,andincreasedmorbidityandmortalityrisk[1-3]. Asmanyas80%ofHFpatientsalsoreportexperiencing sleepdifficulties[4]thataremultifacetedinnature,includingdifficultiesfallingasleep,insomnia,interruptedsleep atnight(e.g.,nocturia),restlesssleep,andbreathingdifficultyduringsleep[5-10].PoorsleepqualityinHF,in-turn, isassociatedwithdecreasedqualityoflife,depression,impairedself-care,anddecreasedparticipationinkeytreatmentrecommendations(e.g.,physicalactivity)[11,12]. Muchattentionhasbeenpaidtocorrelatesandmodifiers ofpoorsleepqualityinHF.SleepqualityinHFisaffected byanarrayofdemographic,med ical,andclinicalfactors. DemographicvariablesthatnegativelyinfluencesleepinHF includeolderageandbeingfemale[5,7,13].Intermsof medicalfactors,takingbeta -blockersandmedicalcomorbiditiessuchasrespiratorydisease,stroke,hypertension, andcoronaryarterydiseasehavebeenlinkedwithsleepdisturbances[5].Manyoftheseco morbiditiesaretheorizedto negativelyaffectcircadianrhythmssubsequenttoassociated disabilitiesandlimiteddaytimeactivity[14].KnownpsychosocialmodifiersofsleepinHFincludedepression,anxiety, andperceivedhealthstatus[5,13].Despitethesefindings, theliteratureonfactorsthatinfluencesleepqualityinHFis notentirelyconsistent[5,7,13 ],suggestingpoorsleepquality inHFmaybemorecomplicatedthantypicallybelieved. Althoughnotyetexamined,alikelymechanismofpoor sleepinHFmayinvolvestructuralandfunctionalbrainabnormalities.Adversebrainchangessuchasbrainatrophy, whitematterhyperintensities(WMH),andcerebralhypoperfusionarecommoninHFandbelievedtounderliecognitiveimpairmentinthispopulation[15,16].Interestingly, *Correspondence: jgunstad@kent.edu1DepartmentofPsychology,KentStateUniversity,Kent,OH,USA Fulllistofauthorinformationisavailableattheendofthearticle 2013Aloscoetal.;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.Alosco etal.BehavioralandBrainFunctions 2013, 9 :42 http://www.behavioralandbrainfunctions.com/content/9/1/42

PAGE 2

recentworkalsoshowspoorsleepisassociatedwithreducedcognitivefunctioninHF[11]andHFpatientsexhibitreducedstructural(e.g.,atrophy)andfunctional(e.g., impairedaxonalprojections)brainintegrityamongkey brainregionsthathelpregulatesleep(e.g.,raphemagnus, hypothalamus,medialtemporallobestructures)[17-20]. Cerebralhypoperfusioniscommonlyproposedtounderlie adversebrainchangesinHF,includingwhitematterhypertintensities,andmayalsoimpactsleepqualityinHF throughitsimpactonthebrainandsleepregulation [15,21].Indeed,alteredcereb ralhemodynamics,brain atrophy,andWMHhaveallbeenindependentlycorrelated withsleepdifficultiesandregulation(e.g.,excessivedaytimesleepiness,difficultieswithbreathingduringsleep, arousalsduringsleep)inotherpopulations[19,22-25]. Despitethesefindings,themechanismsofsleepdifficultiesinHFpatientsremainpoorlyunderstood.Thepurposeofthecurrentstudywastoexaminetheeffectsof cerebralbloodflow,WMH,andtotalbrainvolumeon sleepdisturbancesinolderadultswithHF.Thisstudyalso examinedthepossibleassociationbetweensleepquality andvolumesofregionalbrainstructuresbelievedto beimportantforsleep(e.g.,thalamusandbrainstem) [19,26].Basedonpastworkinothersamples,wehypothesizedthatadversestructuralbrainchanges(e.g.,greater WMH,smallertotalandregionalbrainvolume)wouldbe associatedwithgreatersleepdisturbancesinHFdueto theirknownroleinsleepregulation.Wealsohypothesized thatreducedcerebralbloodflowwouldpredictpoorer sleepqualityinHFinlightofitsknownassociationwith braininsult(e.g.,WMH)inthispopulation.MethodsParticipantsAtotalof77patientswithHFwererecruitedforaNIH fundedstudyexaminedcardiacrehabilitationandneurocognitiveoutcomesinHF.Allparticipantswererecruited fromprimarycareandcardiologypracticesatSumma HealthSysteminAkron,Ohio,andreflecttheHFpopulationreceivingtreatmentatthatfacility.Datacollectionfor thisstudyoccurredbetween2009and2012.Throughout thestudy,HFparticipantscompletedassessmentsovera one-yearperiod.Forthiscross-sectionalstudy,onlybaselineassessmentsamongasubsetofnon-cardiacrehabilitationcontrolsthatunderwentn euroimagingwereexamined. Theparticipantsamplesizeofthecurrentstudywas reducedto53duetomissingdataonstudyvariables andonindividualitemsofthePittsburghSleepQuality Index(PSQI)usedtocalculatetheglobalcomposite, and/orinvalidresponsesonthePSQI.Invalidresponses included>100%inthecalculationofcomponentnumber 4ofthePSQI(i.e.,percentoftimespentsleepingwhile inbed).Excludedparticipantsdidnotdifferinage ( t (75)= 1.50, p =0.14),gender( 2(df=1)=1.02, p = 0.31),education( t (75)= 1.19, p =0.24),cerebralblood flowvelocity( t (68)=0.01, p =0.99)orintermsofmedical comorbidhistory,includinghypertension( 2(df=1)= 3.84, p =0.05),sleepapnea( 2(df=1)=0.06, p =0.80), anddiabetes( 2(df=1)=2.32, p =0.13).However,excludedparticipantshadahigherleftventricularejection fraction( t (74)=2.45), p =0.02;M(SD)=49.43(14.34)vs. 40.98(13.57)). Strictinclusion/exclusioncriteriawerechosenforentry intothelargerNIHfundedstudy.Inclusioncriteriawere asfollows:agesof50 – 85years,Englishasaprimary language,andadiagnosisofNewYorkHeartAssociation (NYHA)classIIorIIIatthetimeofenrollment.Potential participantswereexcludedforanycontraindicationsto magneticresonanceimaging(MRI)(e.g.,pacemaker),historyofheadinjurywithmorethan10minuteslossofconsciousness,AxisIpsychiatricdisorders(e.g.schizophrenia, bipolardisorder),substanceabuseand/ordependence, andrenalfailure.Participantswerealsoexcludedforahistoryofsignificantneurologicaldisorder(e.g.,dementia) andthecurrentsampleexhibitedanaverageMiniMental StatusExaminationscoreof27.72(SD=1.96).Inclusion andexclusioncriteriaweredeterminedthroughselfreportandcorroboratedandsupplementedbyathorough medicalrecordreview.SeeTable1fordemographicand medicalinformation.Measures SleepqualityThePittsburghSleepQualityIndex(PSQI)wasusedto assesssleepqualityinthecurrentsample[27].ThePSQI Table1Demographic,medical,andclinicalcharacteristics of53olderadultswithheartfailureDemographiccharacteristics Age,mean(SD)69.81(8.79) Sex(%Women)37.7 Race(%Caucasian)( N =51)86.8 Education,meanyears(SD)14.17(2.87) Medicalandclinicalcharacteristics LVEF,mean(SD)40.98(13.57) SleepMedication(%)7.5 Diabetes(%)24.5 Hypertension(%)66.0 SleepApnea(%)26.4 Depression(%)17.0 2-minutesteptest,mean(SD)66.02(22.56) CBF-VMCA,cm/smean(SD)42.89(12.94) GlobalPSQI,mean(SD)8.42(3.57)Note LVEF leftventricularejectionfraction, CBF VMCA cerebralbloodflow velocityofthemiddlecerebralartery, PSQI Pittsburghsleepqualityindex.Alosco etal.BehavioralandBrainFunctions 2013, 9 :42 Page2of8 http://www.behavioralandbrainfunctions.com/content/9/1/42

PAGE 3

isa19-itemself-reportmeasurethatgenerates7componentsofsleepquality,includingsubjectivesleepquality, sleeplatency,sleepduration,habitualsleepefficiency, sleepdisturbances,useofsleepingmedication,anddaytimedysfunction.Thesumofthesecomponentsyieldsa globalPSQIscorethatrangefrom0to21.Higherscores reflectpoorersleepqualityandascore>5isasensitive andspecificpredictorofimpairedsleep[27];thiscutscore wasusedtohelpcharacterizethesampleandthecontinuousglobalPSQIservedasthedependentvariable.The PSQIdemonstratesstrongpsychometricproperties,includinginternalconsistency,test-retestreliability,andis widelyusedinmedicalpopulationsincludingHF[5,11].NeuroimagingWhole-brain,high-resolution3DT1-weightedimages (MagnetizationPreparedRapidGradient-Echo,MPRAGE) wereacquiredonaSiemensSymphony1.5Teslamagnetic resonanceimagingscannerformorphologicanalysis. Twenty-sixsliceswereacquiredinthesagittalplanewitha 230100mmfieldofview.Theacquisitionparameters wereasfollows:Echotime(TE)=17,repetitiontime (TR)=360,acquisitionmatrix=256100,andslice thickness=5mm.Whole-brainFLAIRimageswere alsoacquiredtoquantifyWMH.FortheFLAIRimages, twenty-one5-mmsliceswereacquiredwithTR=8500, TI=2500,FlipAngle=150degrees,TE=115,and FOV=22075. MorphometricanalysisofbrainstructurewascompletedwithFreeSurferVersion5.1(http://surfer.nmr.mgh. harvard.edu).Detailedmethodologyforregionalandtotal volumederivationhasbeendescribedindetailpreviously [28-30].FreeSurferwasusedtoperformimagepreprocessing(e.g.intensitynormalization,skullstripping),then toprovidebothcorticalandsubcorticalvolumemeasures usingthesurfacestreamandthesubcorticalsegmentation streamrespectively.FreeSurferperformssuchparcellationsbyregisteringimagestoaprobabilisticbrainatlas, builtfromamanuallylabeledtrainingset,andthenusing thisprobabilisticatlastoassignaneuroanatomicallabelto eachvoxelinanMRIvolume.Totalbrainvolume,total graymattervolume,andvolumeofthethalamusand brainstemwereallautomaticallyderivedwiththesubcorticalprocessingstream(i.e., “ aseg.stats ” ).Intracranialvolumewasalsoautomaticallyderivedandservedasa covariateinanalysesexaminingMRIindicesinorderto controlforinterindividualdifferencesinheadsize.Asummarycompositewascomputedfortheleftandrighthemispherevolumesofthethalamus. TotalWMHvolumewasderivedbyathree-step operator-drivenprotocolthathasbeendescribedindetailpreviously[31].Briefly,inStep1,athresholdwasappliedtoeachFLAIRimagetolabelallvoxelsthatfell withintheintensitydistributionofhyperintensesignal. InStep2,grossregions-of-interest(ROI)weredrawn manuallytoincludeWMHbuttoexcludeotherregions (e.g.,dermalfat)thathavesimilarintensityvalues.In Step3,anewimageisgeneratedthatcontainstheintersectionofvoxelslabeledinStep1andthoselabeledin Step2.Theresultingimagecontainslabeledvoxelsthat arecommoninStep1andStep2.Thenumberofresultingvoxelsissummedandmultipliedbyvoxeldimensionstoderiveatotalvolumescore.Thevalidityand reliabilityofthisapproachhasbeendemonstratedpreviously[31].CerebralbloodflowTranscranialDoppler(TCD)ultrasonographywasperformedthroughanexpandedStrokePreventionTrialin SickleCellAnemia(STOP)protocol[32]andusedto quantifymeancerebralbloodflowvelocity(CBF-V)ofthe MiddleCerebralArtery(MCA).TheMCAwaschosento operationalizecerebralbloodflowinthisstudyforseveral reasons.First,itirrigatesthefrontal,temporal,andthe parietalcerebrumandreliablyreflectschangesincerebral bloodflow.CBF-VoftheMCAalsoexhibitshigherblood flowvelocitycomparedtootherTCDmeasuredarteries (e.g.,ACA,PCA)[33,34].Furthermore,personswithHF demonstratesignificantreductionsinCBF-VoftheMCA [35]andsuchreductionshavebeenlinkedwithWMHin olderadultswithHF[15].Lastly,CBF-VoftheMCAwas alsochosenbecauseofitsknownsensitivitytosleepdisturbancesinhealthypopulations[36].EstimateofHFseverity/physicalfitnessThe2-minutesteptest(2MST)wasusedtoassessphysicalfitnesslevelsandtoserveasaproxyofHFseverity inthecurrentsample[37].The2MSTisabriefassessmentthatrequiresparticipantstomarchinplacelifting his/herkneestoamarkedtargetsetonthewallsetat themidpointbetweenthekneecapandcrestoftheiliac fora2-minuteperiod.Greaterstepcountisassociated withbetterphysicalfitnessandhasbeencorrelatedwith metabolicequivalentsderivedfromstresstesting[38]. The2MSTwasincludedasacovariateinthecurrent analysestocontrolfortheeffectsofphysicalfitnesson thebraininHF[39]andonsleepquality[40].DemographicandmedicalhistoryParticipants ’ medicalanddemographichistorywas ascertainedthroughself-reportandcorroboratedand supplementedbymedicalrecordreview.Throughthese methods,informationregardingparticipants ’ physician diagnostichistoryofdiabetes,sleepapnea,hypertension, anddepressionaswellasprescribedmedicationswere obtained.LVEFofthecurrentsamplewasobtained throughmedicalchartreview.MedicalrecordreviewAlosco etal.BehavioralandBrainFunctions 2013, 9 :42 Page3of8 http://www.behavioralandbrainfunctions.com/content/9/1/42

PAGE 4

tookprecedenceinthecaseofdiscrepancyfromselfreport.RefertoTable1.ProceduresTheKentStateUniversityandSummaHealthSystem InstitutionalReviewBoard(IRB)approvedthestudyproceduresandallparticipantsprovidedwritteninformed consentpriortostudyenrollment.Atabaselineassessment,allparticipantscompleteddemographic,medical history,andpsychosocialself-reportmeasures,including thePSQI.Amedicalrecordreviewwasalsocompleted atthisbaselineassessmenttocorroborateself-report andalsoascertainLVEFofthesample;allparticipants completedanechocardiographaspartoftheirstandard clinicalcarepriortostudyentry.Ataseparatestudyvisit, butwithin2-weeksofthebaselineassessment,allparticipantsalsounderwentMRIandTCDultrasonography.StatisticalmethodsAllanalyseswereperformedusingSPSSsoftware.Alog transformationofWMHwasperformedtocorrectfor thepositivelyskeweddistributionofthisvariable.A seriesofmultivariablehierarchicalregressionanalyses wasconductedtoexaminetheeffectsofadversebrain changesonsleepqualityinHF.Forallanalyses,theglobalPSQIservedasthecontinuousdependentvariable. Todeterminetheindependenteffectsofbrainindices onsleepquality,demographicandmedicalcovariates thatareknowntoinfluenceneurocognitiveoutcomes and/orsleepqualityinHFwereenteredintoblock1of allregressionmodelstoaccountfortheirvariance. Thesecovariatesincludedage,LVEF,2MST,intracranial volume,anddiagnostichistoryofdiabetes,sleepapnea, hypertension,anddepression(1=positivediagnostichistory;0=negativediagnostichistory).Aseparateregressionmodelwasperformedforeachofthefollowing continuousbrainpredictorsthatwereenteredinblock 2,yieldingsixseparateregressionmodels:WMH,total brainvolume,totalgraymattervolume,thalamus,and brainstemvolume,andCBF-VoftheMCA.Intracranial volumewasnotcontrolledforintheregressionmodel examiningCBF-VoftheMCAasthepredictorvariable, asheadsizedoesnotrepresentapossibleconfoundin thisanalysis.Follow-uppartialcorrelationsadjustingfor age,LVEF,2MST,intracranialvolume,anddiagnostic historyofdiabetes,sleepapnea,hypertension,anddepressionwereconductedtoexaminethecorrelations amongWMH,cerebralbloodflow,specificitem-level sleepdifficultiesofthePSQI. Lastly,bivariatecorrelationsexaminedtheassociation betweenCBF-VoftheMCAandWMH.Aregression modelwiththeabovelistedcovariates(but,notintracranialvolume)enteredinblock1andCBF-VoftheMCA andWMHenteredinblock2wasthenperformedto determinewhetherthecombinationofcerebralhypoperfusionandincreasedWMHindependentlypredicted poorsleepquality.ResultsSleepqualityRefertoTable2forsleepcharacteristicsofthe currentsample.ThesamplehadanaverageglobalPSQI scoreof8.41(SD=3.57)with75.5%classifiedasimpairedsleepers(i.e.,PSQI>5).Themostcommonly reportedsleepdifficultiesinthesampleincludedinterruptedsleep,nocturia,snoringorcoughingfits,and pain.Intermsofoverallqualityofsleep,5.7%ratedtheir qualityofsleeptobeverybadand22.6%reportedtheir sleepqualitytobefairlybad.Neuroimaging,cerebralbloodflow,andoverallsleep qualitySeeTable3forafullsummaryofdemographicand medicalpredictorsofsleepquality.Afteradjustment formedicalanddemographicvariablesandintracranial volume,WMHwasassociatedwiththeglobalPSQI( = 0.28, p =0.046).IncreasedWMHvolumewasassociatedwithgreatersleepdifficulties.CBF-VoftheMCA alsoemergedasasignificantpredictorofglobalPSQI ( = 0.28, p =0.04),evenaftercontrollingformedical anddemographicvariables.SeeTable4.DecreasedCBF-V oftheMCAwasassociatedwithpoorersleepquality. Therewerenosignificanteffectsonsleepqualityfortotal brain,totalgraymattervolumeorforanyoftheregional volumetricindices(i.e.,thalamusorbrainstemvolume) ( p >.05forall).Sleepdifficulties,WMH,cerebralbloodflowPartialcorrelationsadjustingforage,LVEF,2MST,intracranialvolume,anddiagnostichistoryofdiabetes,sleep apnea,hypertension,anddepressionshowedincreased WMHwasassociatedwithgreaterdifficultyfalling asleep( r (43)=0.31, p =0.04),feelingtoohot( r (43)= 0.32, p =0.03),anddecreasedoverallsleepquality( r (43)= 0.39, p =.01).LowerCBF-Vwasalsoassociatedwith havingbaddreams( r (43)= 0.39, p =0.01),decreased enthusiasmtogetthingsdone( r (43)= 0.40, p =0.01), andpooreroverallqualityofsleep( r (43)= 0.40, p = 0.01).Interestingly,greaterCBF-VoftheMCAwasassociatedwithincreasedsleepmedicationuse( r (43)= 0.33, p =0.03).AssociationbetweenWMHandcerebralbloodflowBivariatecorrelationsshowedthatCBF-VoftheMCA demonstratedasignificantassociationwithWMH ( r (51)= 0.31, p =0.03).Decreasedcerebralbloodflowwas associatedwithgreaterWMH.Regressionanalysescontrollingformedicalanddemograph icvariablesrevealedthatAlosco etal.BehavioralandBrainFunctions 2013, 9 :42 Page4of8 http://www.behavioralandbrainfunctions.com/content/9/1/42

PAGE 5

thecombinationofbothreducedCBF-VoftheMCAand increasedWMHdemonstratedsignificantpredictivepropertiesofpoorersleepquality( F (10,42)=2.93, p =0.03),suggestingapossibleinteractio nbetweenthesevariableson sleepquality.DiscussionConsistentwiththeextantliterature,thecurrentstudy showsthatreportedsleepdifficultiesareprevalentinolder adultswithHF.Pastworkhasdemonstratedthataseries ofdemographic(e.g.,olderage)andmedicalfactors(e.g., HFseverity)arecorrelatedwithpoorsleepqualityinHF [5],thoughfindingsarenotentirelyconsistentacross studies[7].Thecurrentfindingsextendpastworkby showingthatadversestructuralandfunctionalbrain changesmaybeimportantcontributorstosleepdisturbancesinpatientswithHF. ThecurrentstudyshowsthatgreaterWMHvolumeis associatedwithpoorersleepqualityinolderadultswith HF.Theexactmechanismsunderlyingthisassociation areunclear,thoughthereareseveralpossibleexplanations.Disruptedcircadianrhythmshavebeenshownto occurinvasculardementiapatients,believedtobethe resultofdeafferentation[41,42],andWMHmayleadto similarcircadianrhythmdisturbancesinHFbyinterferingwithcorticalandsubcorticalneuronalconnections tokeybrainregionsthathelpregulatesleep(e.g.,brain Table2Reportedsleepdifficultiesin53olderadultswithheartfailureOnceortwiceperweek(%)Threeormoretimesperweek(%) CannotGettoSleepwithin30Minutes26.417.0 WakeUpintheMiddleoftheNightorEarlyMorning30.241.5 GetUptoUsetheBathroom26.458.5 CannotBreatheComfortably7.511.3 CoughorSnoreLoudly7.526.4 FeelToocold1.913.2 FeelTooHot13.25.7 BadDreams9.43.8 Pain13.220.8 OtherReasons11.39.4 Table3WMHpredictsleepqualityinolderadultswith heartfailure( N =53)VariableGlobalPSQI ( SEb ) Block1 Age-.03(.06) 2MST-.36(.02)* LVEF-.10(.03) Depression-.06(1.25) Hypertension-.17(1.04) Diabetes.12(1.09) SleepApnea-.18(.00) ICV-.18(.00) R2.30 F 2.41* Block2 WMH.28(1.36)* R2.37 F for R24.22*Note .*denotesp<0.05. Abbreviations : standardizedregressioncoefficients, SE standarderror,2 MST 2-minutesteptest, LVEF leftventricularejectionfraction, ICV Intracranialvolume, WMH Whitematterhyperintensities, PSQI Pittsburghsleepqualityindex. Table4Cerebralbloodflowpredictssleepqualityin olderadultswithheartfailure( N =53)VariableGlobalPSQI ( SEb ) Block1 Age.06(.06) 2MST.43(.02)* LVEF-.10(.03) Depression-.04(1.24) Hypertension-.15(1.03) Diabetes.14(1.08) SleepApnea.21(1.12) R2.28 F 2.53* Block2 CBF-VMCA-.28(.04)* R2.35 F for R24.41*Note .*denotesp<0.05. Abbreviations : standardizedregressioncoefficients, SE standarderror,2 MST 2-minutesteptest, LVEF leftventricularejectionfraction, CBF VMCA cerebral bloodflowvelocityofthemiddlecerebralartery, PSQI Pittsburghsleep qualityindex.Alosco etal.BehavioralandBrainFunctions 2013, 9 :42 Page5of8 http://www.behavioralandbrainfunctions.com/content/9/1/42

PAGE 6

stem,suprachiasmaticnucleus)[43-47].Supportingthis possibilityisthecurrentassociationbetweenWMHand alteredcorebodytemperature(i.e.,feelingtoohotas assessedbyitem5gonthePSQI)andpastworkthat demonstratesHFpatientsexhibitimpairedintegrityof axonalprojectionsamongbrainstructuresimportantfor sleep,includingconnectionsamongthebasalforebrain, hypothalamus,raphemagnus,andbrainstem[20,48]. WMHarealsocloselylinkedwithamyloidbetadeposition[49]andamyloidbetaisasignificantcontributorto poorsleepqualityinpre-clinicalAlzheimer Â’ sdisease (AD)patients[50].Thisisnoteworthy,asHFpatients areatriskforADanddecliningsleepqualitymaybeindicativeofADpathogenesisinthispopulation[50,51]. Lastly,theknowninfluenceofWMHonpsychiatric symptoms(e.g.,depression)inHFmayalsocontribute todecreasedsleepquality[13,52]. Reducedcerebralbloodflowalsoemergedasasignificantpredictorofsleepqualityinthecurrentsampleof HFpatients,andmayinteractwithincreasedWMHto exacerbatesleepdisturbances.Cerebralhypoperfusion andsubsequentischemiaiscommonlyproposedto underlieWMHinHF[15,21]andthecurrentfindings showedaninverseassociationbetweencerebralperfusionandWMH.Thus,itislikelythatchronicdisruptionsincerebralhemodynamicsaffectssleepinHF throughitsassociationwithWMH,thoughthecrosssectionaldesignofthecurrentstudyprecludesempirical testofsuchmediation.Ourfindingsareintheopposite directionofpastworkexaminingcerebralbloodflow andsleepqualityinADpatients[24].Similarly,sleep spindleshelptopreventarousalduringsleep,andin contrasttothesuggesteddirectionofourfindings,past workshowsthatcerebralbloodflowandspindleactivity arenegativelycorrelated[25,53-56].Theexactreason forthedirectionalityofourfindingsisnotclear,butitis plausiblethatdecreasedcerebralbloodflowinHFmay reflectgreaterHFseveritysuchasincreasednumberof medicalcomorbiditiesandcardiacdysfunction,which areallsignificantcorrelatesofpoorsleepqualityinthis population[5].Interestingly,pastworkshowsthatcerebralbloodflowcanbeimprovedthroughphysicalactivityinterventions[57].Thisisnoteworthy,asimproved systemicperfusioninHFhasbeenlinkedwithbetter neurocognitiveoutcomes[58].Becausephysicalactivity isakeytreatmentrecommendationinthemanagement ofHF,futurestudiesshouldexaminewhethergreater physicalactivityresultsinbettersleepqualityamongHF patientsduetoimprovedcerebralcirculation. Thecurrentstudyfoundnoassociationbetweentotal andregionalbrainvolumeandsleepquality.Thesefindingsfurthersuggestinterferencewithcortico-cortical andcortico-subcorticalconnectionsasalikelyunderpinningforpoorsleepqualityinHFgiventheobserved impactofWMHonreducedsleepqualityinthecurrent study.Althoughbrainatrophyhasbeenlinkedwithreducedsleepqualityinothermedicalpopulations[19], itislikelythatatrophyinthecurrentsampledidnot reachthresholdtoproduceclinicalmanifestations.For instance,brainvolumelosshasbeenshownamongpatientswithgreaterHFseverity(i.e.,LVEF<30)[20]while LVEFinthissamplefellwithintheaveragerange(i.e., meanLVEF=40).Longitudinalstudiesthatexaminethe effectsofbrainatrophyonsleepinHFareneeded,particularlyasitinvolvesWMH. Thecurrentfindingsarelimitedinseveralways.The cross-sectionaldesigndoesnotpermitcausalinferences andprospectivestudiesareneededtoconfirmourfindings.Forinstance,itispossiblethatinsufficientsleepin HFmayleadtoreducedcerebralperfusion[23],though thisisunlikelyinthispopulationinlightofthenegative effectsofcerebralhypoperfusiononthebrain[15].In addition,self-reportofsleepqualityislimitedbybiases [59]andfutureworkshoulduseobjectiveassessments ofsleepquality(e.g.,polysomnography).Similarly,futurestudiesthatemployimagingtechniquesexamining axonaltractographywouldalsohelpelucidatetheunderlyingmechanismsbetweenWMHandsleepquality throughdirectexaminationofneuronalpathwaysthat maybeoccludedbythepresenceofWMH.Wealso foundaninverseassociationbetweenphysicalfitness andsleepquality.PastworkshowsthatexerciseinterventionsinHFleadtoimprovedsleepquality[60]and futureworkshouldexaminewhethersuchfindingsarea resultofthepositivebenefitsofexerciseonthebrain. Lastly,althoughitisnotablethatthecurrentstudy controlledfortheeffectsofdiagnosedsleepapnea,such historywasobtainedthroughself-reportandmedical recordreviewandinformationregardingduration,treatment,andseverityofsleepapneaisunknown.Consequently,itispossiblethatundiagnosedsleepapneaor sleepdisorderedbreathingwaspresentinmanyofthe HFparticipants[10],whichmayhaveintroducedpossibleconfounds.Futureworkthatemploysmoreobjectiveassessmentsofsleepqualityisneededtoclarifyand confirmthecurrentfindings.Likewise,casecontrolled studieswithlargersamplesthataremorediversein diseaseseverityandutilizedirectmeasurementsofcomorbidconditionsaremuchneededtobetterunderstandtheindependenteffectsofbrainabnormalitieson sleepinHF.ConclusionsInbriefsummary,thecurrentstudyshowsthatWMH anddecreasedcerebralbloodflowareassociatedwith poorsleepqualityinolderadultswithHF.Prospective studiesareneededtoconfirmthesefindings,clarify mechanismsbywhichWMHandreducedcerebralbloodAlosco etal.BehavioralandBrainFunctions 2013, 9 :42 Page6of8 http://www.behavioralandbrainfunctions.com/content/9/1/42

PAGE 7

flowdisruptsleep,andexaminewhethersleepdifficulties aremodifiablethroughinterventionsthattargetimproved cerebralbloodflow(e.g.,cardiacrehabilitation).Abbreviations HF: Heartfailure;WMH:Whitematterhyperintensities;LVEF:Leftventricular ejectionfraction;CBF-VoftheMCA:Cerebralbloodflowvelocityofthe middlecerebralartery;2MST:2-minutesteptest. Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authors ’ contributions MA,AMB,MBS,JG,RC,andLSparticipatedinthedesignofthestudy, acquisitionofdata,andanalysisandinterpretationofdata.MA,MBS,JG,EYG, AN,JH,JRparticipatedinacquisitionofdataandanalysisandinterpretation ofdata.Allauthorswereinvolvedindraftingthemanuscriptandrevisingit forintellectualcontent.Allauthorsalsoprovidedfinalapprovalofthe versiontobepublished. Acknowledgements SupportforthisworkincludedNationalInstitutesofHealth(NIH)grants DK075119andHLO89311.Theauthorshavenocompetingintereststo report. Authordetails1DepartmentofPsychology,KentStateUniversity,Kent,OH,USA.2DepartmentofNeurology,TaubInstituteforResearchonAlzheimer ’ s DiseaseandtheAgingBrain,CollegeofPhysiciansandSurgeons,Columbia University,NewYork,NY,USA.3DepartmentofPsychiatry,SummaHealth SystemAkronCityHospital,Akron,OH,USA.4DepartmentsofNeurology PsychiatryandtheInstituteonAging,CenterforCognitiveAgingand Memory,UniversityofFlorida,Florida,Gainesville,USA.5Departmentof Psychology,UniversityofGeorgia,Athens,USA. Received:21August2013Accepted:27October2013 Published:30October2013 References1.PresslerSJ,SubramanianU,KarekenD,PerkinsSM,Gradus-PizloI,SuaveMJ, DingY,KimJ,SloanR,JaynesH,ShawRM: Cognitivedeficitsinchronic heartfailure. NursRes 2010, 59: 127 – 139. 2.GoAS,MozaffarianD,RogerVL: Heartdiseaseandstrokestatistics — 2013 update. Circulation 2013, 127: e6 – e245. 3.BennettSJ,OldridgeNB,EckertG,EmbreeJL,BrowningS,HouN,HouN, ChuiM,DeerM,MurrayMD: Comparisonofqualityoflifemeasuresin heartfailure. NursRes 2003, 52: 207 – 216. 4.TremelF,PepinJL,VealeD, etal : Highprevalenceandpersistenceof sleepapnoeainpatientsreferredforacuteleftventricularfailureand medicallytreatedover2months. EurHeartJ 1999, 20: 1201 – 1209. 5.WangTJ,LeeSC,TsaySL, etal : Factorsinfluencingheartfailurepatients sleepquality. JAdvNurs 2010, 66: 1730 – 1740. 6.DosSantosMA,GuedesEdeS,BarbosaRL,DaCruzDdeA: Sleeping difficuliesreportedbypatientswithheartfailure. RevLatAmEnfermagem 2012, 20: 644 – 650. 7.EricksonVS,WestlakeCA,DracupKA,WooMA,HageA: Sleepdisturbance symptomsinpatientswithheartfailure. AACNClinIssures 2003, 14: 477 – 487. 8.RedekerNS: Sleepdisturbanceinpeoplewithheartfailure:implications forself-care. JCardiovascNurs 2008, 23: 231 – 238. 9.RedekerNS,SteinS: Characteristicsofsleepinpatientswithstableheart failureversusacomparisongroup. HeartLung 2006, 35: 252 – 261. 10.RedekerNS,MuenchU,ZuckerMJ, etal : Sleepdisorderedbreathing, daytimesymptoms,andfunctionalperformanceinstableheartfailure. Sleep 2010, 33: 551 – 560. 11.GarciaS,AloscoML,SpitznagelMB,etal : Poorsleepqualityandreduced cognitivefunctioninpersonswithheartfailure. IntJCardiol 2012, 156: 248 – 249. 12.IzawaKP,WatanabeS,OkaK,HirakiK, etal : Relationbetweensleepquality andphysicalactivityinchronicheartfailurepatients. RecentPat CardiovascDrugDiscov 2011, 6: 161 – 167. 13.ParkerKP,DunbarSB: Sleepandheartfailure. JCardiovascNurs 2002, 17: 30 – 41. 14.FoleyDJ,MonjanA,SimonsickEM, etal : Incidenceandremissionof insomniaamongelderlyadults:anepidemiologicstudyof6,800persons overthreeyears. Sleep 1999, 22: S366 – S372. 15.AloscoML,BrickmanAM,SpitznagelMB, etal : Cerebralperfusionis associatedwithwhitematterhyperintensitiesinolderadultswithheart failure. CongestHeartFail 2013.epubaheadofprint. 16.BeerC,EbenezerE,FennerS, etal : Contributortocognitiveimpairmentin congestiveheartfailure:apilotcase – controlstudy. InternMedJ 2009, 39: 600 – 605. 17.VogelsRL,vanderFlierWM,vanHartenB, etal : Brainmagneticresonance imagingabnormalitiesinpatientswithheartfailure. EurJHeartFail 2007, 9: 1003 – 1009. 18.WooMA,KumarR,MaceyPM, etal : Braininjuryinautonomic,emotional, andcognitiveregulatoryareasinpatientswithheartfailure. JCardFail 2009, 15: 214 – 223. 19.GamaRL,TavoraDG,BomfirmRC,SilvaCE,DeBruinVM,DeBruinPF: Sleep disturbancesandbrainMRImorphometryinParkinsonsdisease, multiplesystematrophyandprogressivesupranuclearpalsy-a comparativestudy. ParkinsonismRelatDisord 2010, 16: 275 – 279. 20.KumarR,WooMA,MaceyPM, etal : Brainaxonalandmyelinevaluationin heartfailure. JNeurolSci2011, 307: 106 – 113. 21.GruhnN,LarsenFS,BoesgaardS,KnudsenGM,MortensenSA,ThomsenG, AldershvilleJ: Cerebralbloodflowinpatientswithchronicheartfailure beforeandafterhearttransplantation. Stroke 2001, 32: 2530 – 2533. 22.CelleS,PeyronR,FaillenotI, etal : Undiagnosedsleep-relatedbreathing disordersareassociatedwithfocalbrainstematrophyintheelderly. HumBrainMapp 2009, 30: 2090 – 2097. 23.MiyataS,NodaA,OzakiN, etal : Insufficientsleepimpairsdriving performanceandcognitivefunction. NeurosciLett 2010, 469: 229 – 233. 24.IsmailZ,HerrmannN,FrancisPL, etal : ASPECTstudyofsleep disturbanceandAlzheimer ’ sdisease. DementGeriatrCognDisord 2009, 27: 254 – 259. 25.HofleN,PausT,ReutensD,FisetP, etal : Regionalcerebralbloodflow changesasafunctionofdeltaandspindleactivityduringslowwave sleepinhumans. JNeurosci 1997, 17: 4800 – 4808. 26.GviliaI: Underlyingbrainmechanismsthatregulatesleep-wakefulness cycles. IntRevNeurbiol 2010, 93: 1 – 21. 27.BuysseDJ,ReynoldsCFIII,MonkTH, etal : ThePittsburghSleepQuality Index:Anewinstrumentforpsychiatricpracticeandresearch. Psychiatry Res 1989, 28: 193 – 213. 28.FischlB,SalatDH,BusaE,AlbertM,DieterichM,HaselgroveC, etal : Whole brainsegmentation:automatedlabelingofneuroanatomicalstructures inthehumanbrain. Neuron 2002, 33: 341 – 355. 29.FischlB,SerenoMI,DaleAM: Corticalsurface-basedanalysis.II:Inflation, flattening,andasurface-basedcoordinatesystem. Neuroimage 1999, 9: 195 –207. 30.FischlB,vanderKouweA,DestrieuxC,HalgrenE,SegonneF,SalatDH, etal : Automaticallyparcellatingthehumancerebralcortex. CerebCortex 2004, 14: 11 – 22. 31.BrickmanAM,SneedJR,ProvenzanoFA,GarconE,JohnertL,MuraskinJ, etal : Quantitativeapproachesforassessmentofwhitematter hyperintensitiesinelderlypopulations. PsychiatryRes 2011, 193: 101 – 106. 32.BulasD,JonesA,SeibertJ,DriscollC,O ’ DonnellR,AdamsRJ: Transcranial Doppler(TCD)screeningforstrokepreventionIsicklecellanemia: pitfallsintechniquevariation. PediatrRadiol 2000, 30: 733 – 738. 33.BishopCC,PowellS,RuttD,BrowseNL: TranscranialDoppler measurementofmiddlecerebralarterybloodflowvelocity:avalidation study. Stroke 1986, 17: 913 – 915. 34.MacchiC,CatiniC: Themeasuremntofthecalibersandblood-flow velocitiesofthearterieisofthecircleofwillis:astatisticalinvestigation of120livingsubjectsusingtranscrnialcolo-Dopplerultrasonogrpahy. ItalJAnatEmbryol 1994, 99: 9 – 16. 35.VogelsRL,OostermanJM,LamanDM, etal : TranscrandialDopplerblood flowassessmentinpatientswithmildheartfailure:correlateswith neuroimagingandcognitiveperformance. CongestHeartFail 2008, 14: 61 – 65. 36.NetzerN,WernerP,JochumsI, etal : Bloodflowofthemiddlecerebral arterywithsleep-disorderedbreathing:Correlationwithobstructive hypneas. Stroke 1998, 29: 87 – 93. 37.JonesCJ,RikliRE: Measuringfunctionalfitnessofolderadults. TheJournal onActiveAging 2002 : 24 – 30.Alosco etal.BehavioralandBrainFunctions 2013, 9 :42 Page7of8 http://www.behavioralandbrainfunctions.com/content/9/1/42

PAGE 8

38.GarciaS,AloscoML,SpitznagelMB, etal : Cardiovascularfitnessassociated withcognitiveperformanceinheartfailurepatientsenrolledincardiac rehabilitation. BMCCardiovascDisord 2013, 13: 29. 39.AloscoML,BrickmanAM,SpitznagelMB, etal : Poorerphysicalfitnessis associatedwithreducedstructuralbrainintegrityinheartfailure. JNeurolSci 2013.epubaheadofprint. 40.LoprinziPD,CardinalBJ: Associationbetweenobjectively-easuredphysical activityandsleep,NHANES2005 – 2006. MentalHealthandPhysicalActivity 2011, 4: 65 – 69. 41.Aharon-PeretzJ,MasiahA,PillarT,EpsteinR,TzischinskyO,LavieP: Sleep – wakecyclesinmulti-infarctdementiaanddementiaoftheAlzheimer type. Neurology 1991, 41: 1616 – 1619. 42.MishimaK,OkawaM,SatohK,ShimizuT,HozumiS,HishikawaY: Different manifestationsofcircadianrhythmsinseniledementiaofAlzheimer ’ s typeandmulti-infarctdementia. NeurobiolAging 1997, 18: 105 – 109. 43.OostermanJ,vanHartenB,VogelsR,GouwA,WeinsteinH,ScheltensP, ScherderE: Distortionsinrest-activityrhythminagingrelatetowhite matterhyperintensities. NeurobiolAging 2008, 29: 1265 – 1271. 44.KandaA,MatsuiT,EbiharaS,AraiH,SasakiH: Periventricularwhitematter lesionsandsleepalterationinolderpeople. JAmGeriatrSoc 2003, 51: 432 – 433. 45.MeguroK,UedaM,KobayashiI,YamaguchiS,YamazakiH,OikawaY,Kikuchi Y,SasakiH: Sleepdisturbanceinelderlypatientswithcognitive impairment,decreaseddailyactivityandperiventricularwhitematter lesions. Sleep 1995, 18: 109 – 114. 46.MooreRY,SpehJC,LezakRK: Suprachiasmaticnucleusorganization. CellTissueRes 2002, 309: 89 – 98. 47.Pace-SchottEF,HobsonJA: Theneurobiologyofsleep:genetics,cellular physiologyandsubcorticalnetworks. NatRevNeurosci 2002, 3: 591 – 605. 48.WeldemichaelDA,GrossbergGT: Circadianrhythm-distrubancesinpatients withAlzheimer ’ sdisease:Areview.IntJAlzeimersDis 2010, 2: 716453. 49.GurolME,IrizarryMC,SmithEE, etal : Plasmabeta-amyloidandwhite matterlesionsinAD,MCI,andcerebralamyloidangiopathy. Neurology 2006, 66: 23 – 29. 50.JuYS,McLelandJS,ToedebuschCD, etal : Sleepqualityandpreclinical Alzheimerdisease. JAMANeurol 2013, 11: 1 – 7. 51.QiuC,WinbladB,MarengoniA, etal : Heartfailureandriskofdementia andAlzheimerdisease:apopulation-basedcohortstudy. ArchInternMed 2006, 166: 1003 – 1008. 52.AlmeidaJR,AlvesTC,WajngartenM, etal : Late-lifedepression,heart failureandfrontalwhitematterhyperintensities:astructuralmagnetic resonanceimagingstudy. BrazJMedBiolRes 2005, 38: 431 – 436. 53.CoenenAM: Neuronalactivitiesunderlyingtheelectroencephalogram andevokedpotentialsofsleepingandwaking:implicationsfor informationprocessing. NeurosciBiobehavRev 1995, 19: 447 – 463. 54.EltonM,WinterO,HeslenfeldD,LoewyD,CampbellK,KokA: Event-related potentialstotonesintheabsenceandpresenceofsleepspindles. JSleepRes 1997, 6: 78 – 83. 55.LopesDaSilvaF: Neuralmechanismsunderlyingbrainwaves:fromneural membranestonetworks. ElectroencaphalogrClinNeurophysiol 1991, 79: 81 – 93. 56.SteriadeM,AmzicaF: Coalescenceofsleeprhytmsandtheirchronology incorticothalamicnetworks. SleepResOnline 1998, 1: 1 – 10. 57.BaileyDM,MarleyCJ,BrugniauxJV, etal : Elevatedaerobicfitness sustainedthroughouttheadultlifespanisassociatedwithimproved cerebralhemodynamics. Stroke 2013.epubaheadofprint. 58.BornsteinRA,StarlingRC,MyerowitzPD, etal : Neuropsychologicalfunction inpatientswithend-stageheartfailurebeforeandaftercardiac transplantation. ActaNeurolScand 1995, 91:260 – 265. 59.PerilsML,GilesDE,MendelsonWB,BootzinRR,WyattJK: Psychophysiologicalinsomnia.Thebehaviouralmodelanda neurocognitiveperspective. JSleepRes 1997, 6: 179 – 188. 60.GaryR,LeeSY: Physicalfunctionandqualityoflifeinolderwomenwith diastolicheartfailure:effectsofaprogressivewalkingprogramonsleep patterns. ProgCardiovascNurs 2007, 22: 72 – 80.doi:10.1186/1744-9081-9-42 Citethisarticleas: Alosco etal. : Reducedcerebralbloodflowandwhite matterhyperintensitiespredictpoorsleepinheartfailure. Behavioraland BrainFunctions 2013 9 :42. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Alosco etal.BehavioralandBrainFunctions 2013, 9 :42 Page8of8 http://www.behavioralandbrainfunctions.com/content/9/1/42