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Primary and secondary prevention interventions for cognitive decline and dementia
Overview of reviews
2016
2 Table of contents
Publishedby
Title
TheNorwegianInstituteofPublicHealthSectionforevidencesummariesintheKnowledgeCentrePrimaryandsecondarypreventioninterventionsforcognitivedeclineanddementia
Norwegiantitle Primær‐ogsekundærforebyggendetiltakforkognitivsviktogdemensResponsible CamillaStoltenberg,direktør
Authors GerdMFlodgren,projectleader,researcher,theKnowledgeCentreRigmorCBerg,HeadofUnit,forSocialWelfareResearchattheKnowledgeCentre
ISBN 978‐82‐8082‐745‐6
Projectnumber 798Typeofpublication Overviewofreviews
Noofpages 69(110inklusivvedlegg)Client Nasjonalforeningenforfolkehelsen
MeSHterms Alzheimer’sdisease,dementia,cognition,cognitiveimpairment,cognitivedisorders,memorycomplaints,primaryprevention,secondaryprevention
Citation
FlodgrenGM,BergRC.Primaryandsecondarypreventioninterventionsforcognitivedeclineanddementia.[Primær‐ogsekundærforebyggendetiltakforkognitivsviktogdemens]Rapport−2016.Oslo:Folkehelseinstituttet,2016.
3 Table of contents
Tableofcontents
TABLEOFCONTENTS 3
KEYMESSAGES 5
EXECUTIVESUMMARY 6 Background 6 Objectives 6 Methods 6 Results 6 Discussion 8 Conclusions 8
HOVEDFUNN(NORSK) 9
SAMMENDRAG(NORSK) 10 Bakgrunn 10 Problemstillinger 10 Metoder 10 Resultat 10 Diskusjon 12 Konklusjon 12
PREFACE 13
OBJECTIVES 15
BACKGROUND 16 Descriptionofthecondition 16 Howtheinterventionsmaywork 18 Whyisitimportanttodothisoverviewofreviews? 21
METHODS 22 Objectives 22 Inclusioncriteria 22 Exclusioncriteria 23 Literaturesearch 23 Selectionofreviews 24 Dataextraction 24 Datasynthesis 25 Gradingoftheevidence 25
4 Table of contents
Ethics 26
RESULTS 27 Descriptionofincludedreviews 27 Primarypreventioninterventions 31 Secondarypreventioninterventions 37 Certaintyoftheevidence 40 Effectsofinterventions 41 Ethics 50
DISCUSSION 52 Mainresults 52 Certaintyoftheevidence 52 Strengthsandweaknesses 53 Potentialbiasesintheoverviewprocess 54 Overallcompletenessandapplicabilityoftheevidence 54 Agreementsordisagreementswithotheroverviewsofreviews 57 Applicationsforpractice 57 Needforfurtherresearch 57
CONCLUSION 59
REFERENCES 60
APPENDICES 71 1Glossary 71 2Searchstrategy 77 3Excludedreviewsandreasonsforexclusion 88 4Assessmentofmethodologicalquality 90 5Ongoingreviews 92 6Descriptionofincludedreviews 93 7GRADEevidenceprofiles 97
5 Keymessages
Keymessages
Dementiaisasyndromecharacterisedbydeteriorationinmemory,thinking,behaviour,andtheabilitytoperformeverydayactivities,whichultimatelymayleadtototaldependenceanddeath.Sincetheworld’spopulationissteadilygrowingolder,thenumberofpeoplewithdementiaisalsoincreasing.Itisthereforeofutmostimportancetoidentifyeffectivestrategiestopreventordelayitsonset.Thekeyfindingsofthisoverviewofreviewsarebasedonevidencefromeightsystematicreviews.Theresultsforthesingleinterventionstargetingcognitivelyhealthypeoplesuggestthatcomparedtocontrol:
Antihypertensivedrugsmayleadtoaslightdecreaseinincidenceofdementiainpeoplewithhypertension(lowcertaintyofevidence).
Statintherapyprobablyleadstolittleornodifferenceonincidenceofdementiainpeoplewith,oratriskof,cardiovasculardisease(moderatecertainty).
Omega‐3FattyAcids(FAs)probablyleadtolittleornoeffectoncognitivetestscores(moderatetohighcertainty).
Computerisedcognitivetrainingprobablyleadstoaslightimprovementincognitivetestscoresdirectlyafterthetraining(moderatecertainty).
Aerobicexercisemayleadtolittleornoeffectoncognitivetestscores(lowcertainty).
Theresultsfortheinterventionstargetingpeoplewithmildcognitiveimpairmentsuggestthatcomparedtocontrol:
Cholinesteraseinhibitorsprobablyleadtoaslightdecreaseindementiaincidence,buttosignificantlymoreadverseevents(moderatecertainty).
VitaminEprobablyleadstolittleornodifferenceinincidenceofAlzheimer’sdementia(moderatecertainty).
Omega‐3FAsprobablyleadtolittleornodifferenceincognitivetestscores(moderatetohighcertainty).
Wedidnotfindanyreviewsthatevaluatedtheeffectsofinterventionstargetingmorethanoneriskfactor,andwecanthereforenotsayanythingaboutthecombinedeffectsoftheseinterventions.
Title:Primaryandsecondarypreventioninterventionsforcognitivedeclineanddementia‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Typeofpublication:
Overviewofreviews‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐Doesn’tanswereverything: Nointerventionstargetingpeoplewithdementia.
Nohealtheconomicevaluation.
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐Whoisresponsibleforthispublication?TheNorwegianInstituteofPublicHealthcompletedthisassignmentwhichwascom‐missionedbytheNationalAssociationofPublicHealth.‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐Whenweretheliteraturesearched?LiteraturesearcheswereconductedinJanuary2016.‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Peerreferees:ØyvindKirkevold,professorSeksjonforsykepleieAvdelingforhelse,omsorgogsykepleie,NorgesTeknisk‐Naturviten‐skapligeUniversitet.VeslemøyEgede‐Nissen,førs‐telektor,Instituttforsykepleieoghelsefremmendearbeid,HøgskoleniOsloogAkershus
6 Executivesummary
Executivesummary
Background
Dementiaisachronicsyndromecharacterisedbydeteriorationinmemory,thinking,behaviour,andtheabilitytoperformeverydayactivities,whichoftenleadstototalde‐pendenceanddeath.Theworld’spopulationissteadilygrowingolder,andasdementiaismoreprevalentinpeopleover70,andincreaseswithincreasingage,thenumberofpeoplewithdementiaisalsoincreasing.In2012,around71,000peopleinNorwayhadadementiadiagnosis,whichrepresents1.6%ofthetotalpopulation.
Objectives
Theaimofthisoverviewofreviewswastoanswerthefollowingtwoquestions:1)Whatisthedocumentedeffectivenessofinterventionstopreventcognitivedeclineorincidenceofdementiaincognitivelyhealthypeople(primaryprevention),2)Whatisthedocumentedeffectivenessofinterventionstoprevent(further)cognitivedeclineorprogressiontodementiainpeoplewithmildcognitiveimpairment(MCI)orotherearlysymptomsorsignsofdementia(secondaryprevention)?
Methods
WeconductedanoverviewofreviewsinaccordancewiththeKnowledgeCentre’shandbook.WesearchedineightdatabasesuptoFebruary2016forreviewsevaluatingtheeffectsofinterventionstopreventordelaycognitivedeclineordementiainpeoplewithorwithoutMCI.Twopeopleindependentlyscreenedalltitlesandabstracts,re‐viewedfulltexts,assessedreviewquality,andgradedthecertaintyoftheevidenceus‐ingtheGRADE(GradingofRecommendationsAssessment,DevelopmentandEvalua‐tion)tool.Oneauthorextracteddata,andanothercheckedthatitwascorrect.
Results
Weincludedeighthighqualityreviewspublishedbetween2009and2016.Fiveofthereviewsinvolvedprimarypreventioninterventionsforcognitivelyhealthypeople.ThreereviewsincludedsecondarypreventioninterventionsforpeoplewithMCIormemorycomplaints.Thereviewsevaluatedtheeffectsofpharmacologicaltherapies(3reviews),dietarysupplements(3reviews),aerobictraining(onereview),andcognitivetraining(onereview).Thecomparatorinthelattertwowaseitheranotheractiveinter‐ventionornointervention,andplaceboinalltheothers.
7 Executivesummary
Primarypreventioninterventions
Pharmacologicaltherapies
Antihypertensivedrugs.Weincludedonereview(4trials;n=15,936)concernedwiththeeffectsofantihypertensivedrugsondementiaincidenceinolderpeoplewithhyperten‐sion.TheparticipantswererecruitedinEurope,NorthAmerica,China,AustralasiaandTunisia.Thepooledresult(OddsRatio[OR]:0.89[0.74to1.07])indicatesthatantihy‐pertensivedrugsmayleadtoaslightdecreaseinincidenceofdementia,ascomparedtoplacebo,at1.8to4.5yearsfollowup.
Cholesterolloweringdrugs(Statins).Weincludedonereview(2trials;n=26,340)con‐cernedwiththeeffectsofstatinsonincidenceofdementiaincognitivelyhealthyolderpeoplewithevidenceof,orathighriskof,cerebrovasculardisease.ThestudieswereconductedintheUK,Ireland,andtheNetherlands.Theresultofonetrial(OR:1.00[0.61to1.65],n=20,536)indicatesthatstatintherapymayleadtolittleornodifferenceinincidenceofdementia,ascomparedtoplacebo.Theothertrial(n=5,804)reportednodifferenceincognitivetestscoresbetweengroupsatmean3.2yearsfollowup.
Dietarysupplements
Omega‐3FattyAcids(FAs).Weincludedonereview(3trials;n=4,080)whichevaluatedtheeffectsofOmega‐3FAsoncognitivedeclineincognitivelyhealthyparticipants.Thepooledresults(StandardisedMeanDifference[SMD][4tests]:0.06higherto0.04lowerscores;MeanDifference[MD][2tests]:0.12higherto0.07lowerscores)suggestthatOmega‐3FAsupplementationprobablyleadstolittleornodifferenceinoverallcognitivefunction,ascomparedtoplacebo,at6to40monthsfollowup.
Aerobicexercise
Weincludedonereview(12trials;n=754)whichevaluatedtheeffectsofsupervisedaerobicexerciseoncognitivefunctionincognitivelyhealthyolderpeople.ThestudieswereconductedintheUSA,CanadaandFrance.Thepooledresultssuggestthataerobicexercisemayleadtolittleornoeffectoncognitivetestscores(SMD:range0.09lowerto0.30higherscores;MD[2tests]:0.10to0.16ascomparedtonointerventionat8to24weeksfollowup).
Cognitivetraining
Weincludedonereview(52trials;n=4,885)whichevaluatedtheeffectsofcomputer‐isedcognitivetraining(CCT)oncognitivedeclineincognitivelyhealthypeople.TheparticipantswerefromtheUSA,Europe,Canada,Australia,Israel,China,Taiwan,SouthKorea,andJapan.Thepooledresultofthisreview(Hedge’sg:0.22[0.15to0.29])sug‐geststhatCCTprobablyleadstoasmallimprovementincognitivetestscoresdirectlyafterthetraining.Secondarypreventioninterventions
Pharmacologicaltherapies
Cholinesteraseinhibitors.Weincludedonereview(9trials;n=5,149)concernedwiththeeffectsofcholinesteraseinhibitorsforthepreventionofdementiainpeoplewithMCI.ThestudieswereconductedinUSA,Canada,Singapore,andGermany.Thepooled
8 Executivesummary
resultssuggestthatcholinesteraseinhibitorsmayleadtoaslightdecreaseinprogres‐siontodementia(RelativeRisk[RR]:0.84[0.70to1.02]),at3years,buttomoread‐verseeventsthanplacebo(RR:1.09[1.02to1.16]).
Dietarysupplements
VitaminE.Weincludedonereview(1trial;n=769)oftheeffectsofvitaminEonde‐mentiaincidenceinpeoplewithMCI.Theresultsofthissingletrial,conductedinUSAandCanada,suggestthatVitaminEsupplementationpossiblehaslittleeffectoninci‐denceofAD(HazardRatio:1.02[0.74to1.41])at36months,ascomparedtoplacebo.
Omega‐3FAs.Weincludedonereview(4trials;n=676)oftheeffectsofOmega‐3FAsoncognitivedeclineinpeoplewithMCI.ThestudieswereconductedintheNether‐lands,England,Wales,Japan,Israel,andtheUSA.ThepooledresultsshowthatOmega‐3FAsprobablyleadtolittleornodifferenceincognitivefunction(MD:0.16higherto0.05lowerscores)atmedian14.5to24weeks,ascomparedtoplacebo.
Discussion
Weincludedeighthighqualityreviews(86originalstudies)concernedwiththeeffectsofinterventionsaimedatpreventingcognitivedeclineanddementia.Resultsfromfourofthesereviewssuggestthatstatintherapy,Omega‐3FAsandvitaminEsupplementsprobablyleadtolittleornodifferenceincognitivefunctionorincidenceofdementia.Theresultsforcholinesteraseinhibitorsandantihypertensivedrugs,suggestthatthesedrugsmayleadtoaslightdecreaseinincidenceofdementia,butthatcholinesterasein‐hibitorsprobablyleadtomoreadverseeventsthanplacebo.CCTprobablyleadstoslightlyimprovedcognitivefunctiondirectlyafterthetraining,whileaerobicexercisemayleadtolittleornodifferenceincognitivefunction.
Wedidnotidentifyanyeligiblehighqualityreviewsconcernedwiththeeffectsofhealthylifestyles(otherthanaerobicexercise),e.g.changetoahealthydiet,decreasedalcoholuse,etc.,orotherriskfactors,e.g.depression,lackofsocialengagement,orloweducationalattainment.Wefoundnoreviewsassessingtheeffectsofinterventionstar‐getingmultipleriskfactorstopreventcognitivedeclineordementia.
Weunfortunatelystillhavelittleknowledgefromsystematicreviewsofeffectivepre‐ventiveinterventions,addressingsingleormultipleriskfactorsfordementia.
Conclusions
Wefoundnoconvincingevidencefortheeffectivenessoftheinterventionsincludedinthisoverviewofreviewsinpreventingcognitivedeclineordementia.Wideconfidenceintervalsandfeweventsinsomeoftheanalyseswarrantcautionwheninterpretingtheresults.Asprogressiontodementiaispartlydeterminedbyanumberofmodifiablefac‐torsrelatedtolifestyle,environment,depression,educationallevel,anddegreeofsocialinteraction,itispossiblethatpreventiveinterventionsmaybemoreeffectiveiftheytakeintoaccountthemultifacetedaetiologybehindthedisease,i.e.interventionsthattargetsmultipleriskfactors.
9 Hovedfunn(Norsk)
Hovedfunn(Norsk)
Demenserensykdomkjennetegnetvedsvekkethukommelse,tenkning,atferdogevnetilåutføredagligeaktiviteter,somtilsluttofteførertiltotalavhengighetogdød.Sidenverdensbefolk‐ningstadigblireldreforventesantallpersonermeddemensåøkedramatisk.Deterderforviktigåidentifisereeffektivestrate‐gierforåforebyggeellerutsettesykdomsdebuten.
Deviktigstefunneneidenneoversiktenoveroversiktererbasertpåevidensfraåtteoversikter.Forenkelt‐tiltakrettetmotkognitivtfriskeeldrepersonertyderresultatenepåatsammenlignetmedkontroll:• Blodtrykkssenkendelegemidlerførermuligenstilenliten
reduksjoniforekomstavdemenshoseldrepersonermedhøytblodtrykk(lavtillittileffektestimatene).
• Kolesterolsenkendelegemidler(statiner)førertroligtillitenelleringenforskjelliforekomstavdemenshoseldrepersonermedhjerte‐ogkarsykdommer(moderattillit).
• Omega‐3fettsyretilskuddførertillitenelleringenforskjellikognitivetestresultater(moderattilhøytillit).
• Datastyrtkognitivtreningførertroligtilenlitenbedringikognitivetestresultaterdirekteettertreningen(moderattillit).
• Aerobtreningførermuligenstillitenelleringenforskjellikognitivetestresultater(lavtillit).
Fortiltakrettetmotpersonermedmildkognitivsvikt,tyderresultatenepåatsammenlignetmedkontroll:
Kolinesterasehemmereførertroligtilenlitenreduksjoniforekomstavdemens,menførertilsignifikantflerebivirkninger(moderattillit).
VitaminEførertroligtillitenelleringengenerellforskjelliforekomstavAlzheimersdemens(moderattillit).
Omega‐3fettsyretilskuddførertroligtillitenelleringenforskjellikognitivetestresultater(moderattilhøytillit).
Vifantingenoversiktersomevaluerteeffektenavtiltakrettetmotmerennénrisikofaktor,ogvikandetderforikkesinoeomeffektenavåkombineredissetiltakene.
Tittel:Primær‐ogsekundærforebyggendetiltakforkognitivsviktogdemens‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Publikasjonstype:
Oversiktoveroversikter‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Svarerikkepåalt:•Ingentiltakrettetmotpersonermeddemensdiagnose.•Ingenhelseøkonomiskevaluering‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Hvemstårbakdenne
publikasjonen?
Folkehelseinstituttethargjennom‐
førtoppdragetetterforespørselfra
NasjonalforeningenforFolkehelsen‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Nårblelitteratursøketgjennom‐
ført:
Søketterstudierbleavslutteti
januar2016.‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Eksternefagfeller:ØyvindKirkevold,ProfessorSeksjonforsykepleieAvdelingforhelse,omsorgogsykepleie,NorgesTeknisk‐Naturviten‐skapligeUniversitetVeslemøyEgede‐Nissen,førstelektor,Instituttforsykepleiereoghelsefremmendearbeid,HøgskoleniOsloogAkershus
10 Sammendrag (Norsk)
Sammendrag(Norsk)
Bakgrunn
Demenserettilstandkarakterisertvedsvekkelseavhukommelsen,tenkning,adferdogevnentilåutføredagligeaktiviteter,somtilsluttførertiltotalavhengighetogdød.Si‐denverdensbefolkningstadigblireldre,ogdemensermerutbredthospersonerover70,forventesantalletpersonermeddemensogsååøke.I2012haddeomkring71000personeriNorgeendemensdiagnose,hvilketrepresenterer1,6prosentavdentotalebefolkningen.
Problemstillinger
Måletmeddenneoversiktoveroversiktervaråbesvarefølgendetospørsmål:1)Hvaerdendokumenterteeffektenavforebyggendetiltakforåforebyggekognitivsviktogdemens(primærforebygging)?2)Hvaerdendokumenterteeffektenavtiltakforåfore‐bygge(ytterligere)kognitivsviktogprogresjontildemenshospersonermedmildkog‐nitivsviktellerandretidligesymptomerellertegnpådemens(sekundærforebygging)?
Metoder
VigjennomførteenoversiktoveroversikterihenholdtilKunnskapssenteretshåndbok.Visøkteiåttedatabaseropptiljanuar2016foroversiktersomevaluerteeffektenavtiltakforåhindreellerforsinkekognitivsvikt,Alzheimerssykdomellerandreformerfordemenshospersonermedellerutenmildkognitivsvikt.Uavhengigavhverandregjennomgikktopersoneralletitlerogabstrakt,vurderterelevanteoversikterifulltekst,vurdertedenmetodiskekvalitetenogbedømtetillittileffektestimatenevedhjelpavGRADE(GradingofRecommendationsAssessment,DevelopmentandEvaluation).Enforfatterhentetutdata,ogenforfatterkontrollerteriktighetenavdata.
Resultat
Viinkluderteåtteoversikteravhøykvalitetpublisertmellom2009og2016.Femavoversikteneomhandletprimærforebyggendetiltakrettetmotkognitivtfriskepersoner.Treoversikteromhandletsekundærforebyggendetiltakrettetmotpersonermedmildkognitivsvikt.Oversikteneevaluerteeffektenavfarmakologisketiltak(3oversikter),kosttilskudd(3oversikter),aerobtrening(1oversikt),ogkognitivtrening(1oversikt).
11 Sammendrag (Norsk)
Detosistnevntesammenlignetmedentenenannenaktivtiltakelleringentiltak,ogalledeandresammenlignetmedplacebo.
Primærforebyggendetiltak
Farmakologiskbehandling
Blodtrykkssenkendelegemidler.Viinkluderteénoversikt(4studier;n=15936)omef‐fektenavblodtrykkssenkendemidlerpådemenshoseldrepersonermedhypertensjon.DeltakernevarrekruttertfraEuropa,Nord‐Amerika,Kina,AustralasiaogTunisia.Detsamlederesultatetfradenneoversikten(Oddsratio[OR]:0,89[0,74til1,07])tyderpåatblodtrykkssenkendemidlermuligensførertilenlitenreduksjoniforekomstavde‐mens,sammenlignetmedplaceboved1,8til4,5årsoppfølging.
Kolesterolsenkendelegemidler(statiner).Viinkluderteénoversikt(2studier;n=26340)omeffektenavstatinerpåforekomstavdemenshoskognitivtfriskeeldrepersonermedhøyrisikofor,ellerdokumentertcerebrovaskulærsykdom.StudienebleutførtiStorbritannia,IrlandogNederland.Resultatenefraenstudie(OR1,00[0,61til1,65];n=20536),tyderpåatstatinertroligførertillitenelleringenforskjellifore‐komstavdemens,sammenlignetmedplacebo.Denandreinkludertestudien(n=5804)rapporterteingenforskjellermellomgruppeneikognitivetestresultatervedgjennom‐snittlig3,2årsoppfølging.
Kosttilskudd
Omega‐3Fettsyrer(FAs).Viinkluderteénoversikt(3studier;n=4080)omeffektenavOmega‐3FAspåkognitivsvikthoskognitivtfriskepersoner.Desamlederesultatene(Standardisertgjennomsnittsforskjell[SMD][4tester]:0,06høyeretil0,04lavereskåre;Gjennomsnittsforskjell[MD][2tester]:0,12høyeretil0,07lavereskåre)tyderpåatOmega‐3FAsførertillitenelleringeneffektpåkognisjonved6til40månedersoppfølging.
AerobtreningViinkluderteénoversikt(12studier;n=754)omeffektenavaerobtreningpåkognitivfunksjonhoskognitivtfriskeeldrepersoner.StudienevarutførtiUSA,CanadaogFrankrike.Aerobtreningførermuligenstillitenelleringenforskjellikognitivetestre‐sultater(SMD[8tester]:0,09laveretil0,30høyereskåre;MD[2tester]:0,10til0,16,sammenlignetmedingentiltakved8til24ukersoppfølging).
KognitivtreningViinkluderteénoversikt(52studier;n=4885)omeffektenavuliketyperavdatastyrtkognitivtrening(CCT)forforebyggingavaldersrelatertkognitivsvikthoskognitivtfriskepersoner.Desamlederesultatenefradenneoversikten(Hedge’sg:0,22[0,15til0,29))tyderpåatCCTtroligførertilenlitenforbedringikognitivfunksjondirekteet‐tertreningen.
Sekundærforebyggendetiltak
Farmakologiskbehandling
Kolinesterasehemmere.Viinkluderteénoversikt(9studier;n=5149)omeffektenavkolinesterasehemmerepåforekomstavdemenshospersonermedmildkognitivsvikt.StudienevargjennomførtiUSA,Canada,Singapore,Tysklandogiflereikke‐navngitteland.Desamlederesultateneviseratkolinesterasehemmeretroligharenliteneffektpå
12 Sammendrag (Norsk)
progresjontildemens(datafra3studier;Riskratio[RR]:0,84[0,70til1,02])ved3årsoppfølging,menharflereskadevirkningerennplacebo(RR:1,09[1,02til1,16]).
Kosttilskudd
VitaminE.Viinkluderteénoversikt(1studie;n=769)omeffektenavvitaminEpåfore‐komstavdemenshospersonermedmildkognitivsvikt.Resultatenefradenneenkelt‐studien,utførtiUSAogCanada,tyderpåatvitaminEharliteneffektpåforekomstavmuligellertroligAlzheimer(Hazardratio:1,02[0,74til1,41])ved36månedersoppføl‐ging,sammenlignetmedplacebo.
Omega‐3Fettsyrer(FAs).Viinkluderteénoversikt(4studier;n=676)omeffektenavOmega‐3FAspåkognitivsvikthospersonermedmildkognitivtsvikt.StudieneblegjennomførtiNederland,England,Wales,Japan,IsraelogUSA.DesamlederesultateneviseratOmega‐3FAstroligharlitenelleringeneffektpåkognitivtestskåre(MD0,16høyeretil0,05lavereskåre)vedenmedianoppfølgingstidpå14,5til24ukeroppføl‐ging,sammenlignetmedplacebo.
Diskusjon
Viinkluderteåtteoversikteravhøymetodiskkvalitet(86originalestudier)somopp‐summerteeffektenavtiltakforåforebyggekognitivsviktogdemens.
Resultaterfrafireavdisseoversiktenetyderpåatkolesterolsenkendelegemidler,Omega‐3fettsyrerogvitaminEtilskuddtroligførertillitenelleringenforskjellikogni‐tivfunksjonellerforekomstavdemens.Resultateneforkolinesterasehemmereogblod‐trykkssenkendemedisinertyderpåatdissemedisinenekanføretilensvaknedgangiforekomstenavdemens,menatkolinesterasehemmeresannsynligvisførertilflerebi‐virkningerennplacebo.CCTførertroligtillittbedrekognitivfunksjonrettettertre‐ning,mensaerobtreningmuligensførertillitenelleringenforskjellikognitivfunksjon.
Vifantingenoversikteravhøymetodiskkvalitetsomomhandleteffektenavendringtilensunnlivsstil,annetennaerobtrening,f.eks.suntkosthold,røykeslutt,elleroversik‐teravtiltakrettetmotandrerisikofaktorer,f.eks.depresjon,lavtutdanningsnivåellermangelpåsosialtilknytning.Vifanthelleringenoversikteromsammensattetiltakret‐tetmotflererisikofaktorerforåforebyggekognitivsviktellerdemens.
Vihardessverrefortsattlitekunnskapfrasystematiskeoversikteromeffektivetiltak,bådenårdetgjelderénogflererisikofaktorer,foråforebyggekognitivsviktellerde‐mens.
Konklusjon
Ingenavdeprimær‐ellersekundærforebyggendetiltakeneoppsummertideinklu‐derteoversikteneviseroverbevisendeeffektpåforebyggingavkognitivsvikt,ADogandreformerfordemens.Bredekonfidensintervallerogfåhendelserinoenavanaly‐senetilsieratmanmåvisevarsomhetvedtolkningavresultatene.Progresjontilde‐menserknyttettilenrekkemodifiserbarefaktorer,sliksomlivsstil,miljø,depresjon,utdanningsnivåogsosialtilknytning.Derforerdetmuligatforebyggendetiltakkanhabedreeffekthvisdetarhensyntildensammensatteetiologienbaksykdommen,dvs.hvistiltakrettesmotflererisikofaktorersamtidig.
13 Preface
Preface
TheKnowledgeCentreattheNationalInstituteofPublicHealthwasintheautumn2013commissionedbytheNationalAssociationofPublicHealthtoconductanover‐viewofreviewsevaluatingtheeffectivenessofinterventionsaimedatpreventingorde‐layingtheonsetofdementiaincognitivelyhealthypeopleandinpeoplewithmildcog‐nitiveimpairmentwithoutadementiadiagnosis.Inthisoverviewofreviewswesummariseandevaluatetheevidencefromeightsys‐tematicreviews(SRs)oftheeffectofvariousprimaryandsecondaryinterventions(i.e.pharmacologicaltherapy,dietarysupplements,cognitivetrainingandaerobicexercise)oncognitivefunctionandprogressiontodementiainpatientswithoutadementiadiag‐nosis.TheKnowledgeCentrefollowsacommonapproachinsummarisingresearch,docu‐mentedinthemanual"Howwesummariseresearch."Itmeansthatwemayusestand‐ardformulationswhenwedescribethemethods,resultsanddiscussionofthefindings.Contributorstotheproject:Projectleaderandresearcher:GerdMFlodgren,theKnowledgeCentre,Headofunitandresearcher:RigmorCBerg,theKnowledgeCentre,Internalcontributors:RigmorCBergservedasprojectleaderduringthefirstphasesoftheproject.Shedevel‐opedtheprojectprotocol,andledtheworkrelatedtoscreeningandqualityassessmentofliterature.GerdMFlodgrenthereaftertookontheroleasprojectleader,andleddataextraction,analysis,andwriteupofthereportforpublication.RigmorCBergcom‐mentedonearlyversionsofthereportandapprovedthefinalversion.WewishtoacknowledgeKristinThuveDahmandThereseDalsbøwhocontributedattheinitialstage(i.e.toscreening,reviewselection/qualityassessmentfortheinitialsearch),re‐searchlibrarianGyriHvalStraumannwhoperformedthesystematicsearch,andre‐searchlibrarianIngridHarboeforpeerreviewingthesearchstrategy.WealsowishtoacknowledgeKjetilBrurbergforhelpfulcommentsonthereport,andGunnVist,LivMereteReinar,whopeerreviewedthereport.Externalcontributors:Wealsowishtoacknowledgetheexternalpeerreferees:ØyvindKirkevold,ProfessorvedSeksjonforsykepleieAvdelingforhelse,omsorgogsykepleie,NorgesTeknisk‐Na‐turvitenskapligeUniversitet,andførstelektorVeslemøyEgede‐Nissen,vedInstituttforsykepleiereoghelsefremmendearbeid,HøgskoleniOsloogAkershus.
14 Preface
Declarationofinterest:Neithertheauthorsnortheexternalpeerrefereesstateanyconflictsofinterest.Theaimofthisreportistosupportwell‐informedevidence‐baseddecisionsinhealthcarethatleadtoimprovedqualityofservices.Wesuggestthatwhenmeetingwiththeindividualpatient,theresultsofthisoverviewshouldbeconsideredinconjunctionwithotherrelevantfactors,patientneedsandclinicalexperience.
SigneFlottorpHeadofDepartment
RigmorCBergHeadofUnit
GerdMFlodgrenProjectleader
15 Objectives
Objectives
Theaimofthisprojectwastoconductanoverviewofreviewsthatanswersthefollow‐ingquestions:
1) Whatisthedocumentedeffectivenessofinterventionstopreventcognitivedeclineandincidenceofdementiaincognitivelyhealthypeople(primaryprevention)?
2) Whatisthedocumentedeffectivenessofinterventionstoprevent(further)cognitivedeclineandprogressiontodementiainpeoplewithmildcognitiveimpairmentorotherearlysymptomsorsignsofdementia(secondaryprevention)?
16 Background
Background
Descriptionofthecondition
Dementiaisasyndromeinwhichthereisdeteriorationinmemory,thinking,behav‐iour,andtheabilitytoperformeverydayactivities.Itisconsideredoneofthemajorcausesofdisabilityanddependencyintheworld(1).Dementiamainlyaffectspeopleover70yearsofage,butisnotapartofnormalageing.Thecauseofdementiaisdeathofbraincells,whichinturnmaybecausedbyvariousconditions.ThemostcommoncauseisAlzheimer’sdisease,aneurodegenerativedisease,whichmayaccountforasmuchas60‐70%ofalldementiacases(1).Othertypesofdementiaarevascularde‐mentia,Lewybodydementia,andfrontotemporaldementia.Otherlesscommonde‐mentiacausesaresubstanceabuse,headinjury,metabolicdisease,vitamindeficiencyandotherdiseases(2).Themostcommondementiatypesaredescribedinmoredetailbelow.AglossaryisfoundinAppendix1.Differenttypesofdementia
Alzheimer’sdisease
Alzheimer’sdisease(AD)ischaracterisedbyacomplexseriesofbrainchangesthatde‐velopovermanyyears.Itinvolvessocalledamyloidplaquesandneurofibrillarytangleswhichdevelopinbrainstructuresthathelptoencodememories,andinareasthatareusedinthinkingandmakingdecisions(3,4).Theseevolvingchangesresultinaslowdeclineinmemory,thinking,andreasoningskills,thatoftenleadstototaldependencyanddeath(3).Ithasbeensuggestedthatthecauseofthepathophysiologicalbrainchangesismultifactorial,i.e.acombinationofgenetic,environmental,andlifestylefac‐tors(3).ClinicallyitisonlypossibletomakeaprobableADdiagnosis,andadefinitedi‐agnosiscanonlybeachievedpostmortem.Researchisbeingconductedintothepatho‐physiologyofAD,inordertofindsensitivebiomarkerstoprovidebetterdiagnostictoolsandcriteriaforearlyidentificationofAD(4).
Vasculardementia
Vasculardementia(VAD)isthesecondmostcommontypeofdementiaafterAD,andaccountsforaround15%ofdementiacases(5).ItisgenerallyagreedthattheaetiologybehindVADinvolvesvariouscardiovascularconditionscausingdamagetothebloodvesselsofthebrain(e.g.stroke,highbloodpressure;hardeningofthearteries;diabe‐tes)(6).Thereishowevernoconsensusonexactlyhowthecerebrovascularpathologi‐calchangestranslateintocognitiveimpairmentordementia,andthereisalsono
17 Background
agreedschemeforstagingordiagnosingVAD(5).ThecognitivechangesinVADvariesmorethaninAD,butcommonlyincludedeficitsinattention,informationprocessing,andexecutivefunction(5).ThiseffectivelymeansthattoolsusedtodiagnoseADmaynotbeeffectiveindiagnosingVAD.Lewybodydementia
Lewybodydementia(LBD)isanumbrellatermthatincludesclinicallydiagnosedde‐mentiawithLewybodies(DLB)andParkinson’sdiseasedementia(PDD),which,ac‐cordingtomanyresearchers,sharethesamepathology.WhileDLBusuallydevelopsconcomitantlywithorbeforeanysignsofParkinsonism,PDDdevelopsinpatientswithanalreadywellestablishedPD.Thepathologicalchanges,whicharecharacterisedbyabnormalclumpsofaproteincalledalpha‐synuclein(Lewybodies)inneuronsinthebrain,whichresultsinaprogressivecognitivedecline(7).DespiteimprovedconsensuscriteriaforthediagnosisofDLB,diagnosticaccuracyisstillmoderateinresearchandpoorinclinicalsettings,andDLBisoftenmisdiagnosedasAD(7).Frontotemporaldementia
Frontotemporaldementia(FTD), isagroupofneurodegenerativediseasescharacter‐isedbydeficitsinbehaviour,executivefunction,orlanguage,andmayoftenbemis‐takenforapsychiatricdisorder(8).FTD,whichisparticularlycommoninpeopleyoungerthan65years,maybecausedbyanumberofdifferentneuropathologicalcon‐ditions,allofwhicharecharacterisedbytheselectivedegenerationofthefrontalandtemporalcorticesofthebrain.Improvedtoolsforclinicalimaging,andmolecularchar‐acterisationhavemadeiteasiertodiagnosethedifferentsubtypesofFTD,andalsotodifferentiateFTDfrompsychiatricdisorders(8).Mixedtypedementia
Therearedifferenttypesofmixeddementia,butinthemostcommonformtheabnor‐malplaquesassociatedwithADexisttogetherwithbloodvesselproblemslinkedtoVAD.BrainchangestypicalforADmayalsocoexistwithLewybodiesandsometimesallthreeconditionsmayco‐exist.Thereissomeevidencefromautopsystudiessuggestingthatmixeddementiamaybemorecommonthanwhatwaspreviouslythought(9).Ontheotherhand,recentresultsfromacross‐sectionalstudysuggestlowprevalenceofmixeddementiainlate‐onsetAD(10).Howmanypeopleareaffectedbydementia?
AccordingtorecentfiguresfromtheWorldHealthOrganisation(WHO),47.5millionpeoplearoundtheworldareafflictedbydementia,andeveryyearthereareapproxi‐mately7.7millionnewcases(11).Theestimatedagestandardiseddementiapreva‐lenceforpeoplemorethan60yearsoldliesbetween5and7percentinmostcountries(12).In2012itwasestimatedthat1.6percentofpeopleinNorwaylivedwithdemen‐tia,whichissimilartotheEUaverageof1.5percent(13).Howmanypeoplethatatpre‐sentareundiagnosedandwholivewiththepre‐stagesofADorotherdementiasinthegeneralpopulationisunknown.InNorwaythereareresearchindicatingthatonlyabouthalfofpeoplewithdementialivinginnursinghomeshaveadiagnosis(14)andinhomecaretheproportionmaybeevenlower(15).
18 Background
Whataretheriskfactorsfordementia?
Oldageisthestrongestnon‐modifiableriskfactorforthedevelopmentofdementia(16).Otherriskfactorsincludefemalesex,genes,andfamilialdisposition.Sincethereistodatenocurativetreatmentfordementia,itisonlynaturalthatthemodifiableriskfactorsareofgreatinterest.Ithasbeensuggestedthatriskfactorsforvascularandmixedtypedementiainparticular,butalsoforAD,maybethesameasforcardiovascu‐lardisease(17,18),i.e.hypertension,highcholesterol,diabetes,inflammation,recur‐rentinfections,andfactorsrelatedtoanunhealthylifestyle,e.g.physicalinactivity,smoking,excessivealcoholconsumption,unhealthydiet,andobesity.Otherriskfactorsaredepression,loweducationalattainment,lowsocioeconomicstatus,andlackofso‐cialinteraction(19,20).Mildcognitiveimpairment(MCI)isoftenthoughtofasapre‐stagetoADandotherde‐mentias.MCIischaracterisedbyacognitivedeterioration,includingmemoryproblems,butwhichisnotsevereenoughtohamperaperson’sdaytodayactivities,andthusdonotmeetthedementiacriteria(21).AreviewoftheliteraturesuggestsaprevalenceofMCIbetween16and20percentinpeopleovertheageof60,accordingtothenewercriteria(22).MCIdoesnotalwaysprogresstodementia.Inarecentsystematicreviewmostincludedstudiesreportedprogressionratesbetween20to40%(10‐15%peryear)(22).MCIduetoADisonlyoneofmanysuggestedsubtypes.AmnesticMCI,isasubtypethatprimarilyaffectsthememory.Itmaysometimesbedifficulttodifferenti‐atenormalage‐relatedcognitivedeclinefromdifferenttypesofMCI,andMCIfromde‐mentia(23).UntilfairlyrecentlytherehasbeenlittleconsensusaboutwhichtoolsandcriteriatousefordiagnosingMCI.Intworecentpapers(23,24),consensuscriteriafordiagnosingMCIhasbeenputforward.Resultsfromalongitudinalcohortstudyofpeo‐plewithParkinson’sdisease(25)suggestthattheprognosticaccuracyofMCImaybeincreased,ifneuropsychologicaltestsarerepeatedlyadministeredovertime.Cognitiveimpairmentnodementia(CIND)isatermthatalsodescribespeoplewithbelownor‐malcognitivefunctioningwhodonotmeetdementiacriteria,butthedefinitionisbroaderthanthatofMCI(22).
Howtheinterventionsmaywork
Sinceitatpresentisnotpossibletocuredementia,itisnaturalthatfocusofanti‐de‐mentiastrategies,inadditiontofindingacure,isonpreventingitsonset.ADisaslowlyprogressingcondition,andearlypathophysiologicalchangesmaybepresentmanyyearsorevendecadesbeforetheactualdiagnosis(26).IfpeopleatriskfordevelopingADanddementiacanbeidentifiedatearlypre‐clinicalstages,awindowforearlyinter‐ventionsopensup(27).Toaccomplishthis,furtherresearchregardingthepathophysi‐ologicalprocessesbehindAD,andtheidentificationofADsensitivebiomarkers,isneededtodeterminewhichfactorsbestpredicttheriskofprogressionfrom“normal”cognitiontomildcognitiveimpairmentandADdementia(27).
19 Background
Thereare,asmentionedearlier,severalmodifiableriskfactorsfordementia,ofwhichcardiovascularandlifestylemodificationshavereceivedgreatinterest.Thus,manydementiapreventionstrategiesfocusoncardiovascularrisk‐factors,e.g.statinsforhighcholesterol,antihypertensivedrugsforhighbloodpressure,andcholin‐esteraseinhibitorsforinflammation.Below,wedescribesomeofthetheoriesbehindwhythese,andotherinterventions,areconsideredforthepreventionofcognitivede‐clineanddementia.Pharmacologicaltreatment
Bloodpressureloweringinterventions
Anumberoflongitudinalstudieshaveconsistentlyshowedarelationshipbetweenmid‐lifehypertensionandthedevelopmentofcognitiveimpairmentlaterinlife,espe‐ciallyifuntreated.Fortherelationshipbetweenlate‐lifehypertensionanddementiaorcognitiveimpairmenthowever,theresultsareinconsistent(28).Inadditiontopharma‐cologicaltreatment,hypertensionmayalsobereducedbyinterventionsincludingsaltrestriction,weightreduction,physicalexercise,andreducedalcoholconsumption(29).Cholesterolloweringdrugs(statins)
IncreasedserumcholesterollevelhasbeensuggestedtocontributetothepathologicalprocessesleadingtoAD.Statinsarecholesterolloweringdrugsofprovenbenefitinvasculardisease(30,31).Resultsfromrecentsystematicreviews,includingmeta‐anal‐yses,mostlyofobservationaldata,suggestinconsistenteffectsofstatinsonincidenceofdementia(32).Theseresultsshouldbeinterpretedwithcautionduetothehighhetero‐geneityfoundinthemeta‐analyses.Thereareknownadverseeffectsofstatinuse,butitisdebatedhowfrequentlyoccurringtheseeventsareamongusers(33).Cholinesteraseinhibitors
PatientswithADhavereducedcerebralproductionofcholineacetyltransferaseinthebrain,whichleadstoadecreaseinacetylcholinesynthesisandimpairedcorticalcholin‐ergicfunction(34).Cholinesteraseinhibitors,whichincreasecholinergictransmissionbyinhibitingcholinesterase,havebeenshowntobeofsomebenefitinpatientswithADaswellasothernon‐ADdementias,eventhoughtheeffectsinmostcaseshavebeenmodest(35).Peoplewithamnesticmildcognitiveimpairmentarealsobelievedtohaveacentralcholinergicdeficit(36).Ithasthereforebeensuggestedthatcholinesterasein‐hibitorscouldbeusedtodelayorevenpreventtheprogressionfromamnesticMCItoAD.Dietarypatternsanddietarysupplements
Mediterraneandiet
Ithasbeensuggestedthatvariousdietarypatternswithdifferingfoodandnutrientcompositions,mayelicitdifferenteffectsontheageingbrain.ThetraditionalMediterra‐neandiet(MD)ischaracterisedbyhighconsumptionofvegetables,fruits,oliveoil,leg‐umes,fish,wholegraincereals,nutsandseeds,andmoderateredwineconsumption.Itislowinprocessedfoods,dairyproducts,redmeat,andvegetableoils(37).Arecentre‐viewoftheliterature(38)includingmostlycohort‐andobservationalstudies,suggests
20 Background
thatMDmaybeeffectiveinreducingcognitivedeclineinolderage.Theauthorshow‐ever,questionthefeasibilityofintroducingthistypeofdietaryinterventioninWesterncountriesduetoculturaldifferences.
Omega‐3FattyAcids
Fattyacids(FAs)areamongthemostcrucialmoleculesforthebrain'sabilitytoper‐form,andthereisevidenceforarelationshipbetweeninadequatedietaryintakeoffattyacidsandimpairedbrainperformanceanddiseases(39).AnumberofpossiblemechanismsforaprotectiveroleofOmega‐3FAsindementiahavebeenputforward,butresultsfromtrialsinvestigatingtheeffectsofOmega‐3FAsoncognitioninpeoplewithandwithoutcognitiveimpairmenthavebeenmixed(40).VitaminE
VitaminEisadietarycompoundknownforitsabilitytoprotectcellsfromthenegativeeffectsoffreeradicals.EvidencethatfreeradicalsmaybeinvolvedinthepathologicalprocessesofAD(andothercognitiveimpairments)hasledtointerestintheuseofvita‐minEinthetreatmentofMCIandAD.ThereisalsosomeevidencesuggestinglowerlevelsofVitaminEinplasmaofpeoplewithADandinMCI(41),butwhetherthelowervitaminElevelisacauseoraneffectofpoordietaryintakeisdebated(42).Physicalexercise
Evidencefromameta‐analysis(43),andamorerecentlongitudinalstudy(44),sug‐geststhatthehighertheamountofregularexercise,thelowertheriskfordevelopingAD.Theevidenceforthepossiblecellularandmolecularmechanismssuggestedtoliebehindtheneuroprotectiveeffectofaerobicexercise,isfromanimalstudies.Thesug‐gestedmechanismsincludeincreasedcerebralbloodflowwhichinturntriggersdiffer‐entneurobiologicaleventsthatmayincreasethelevelsofdifferentgrowthfactorsthatareofimportancetotheneuroplasticityofthebrain,andtheantioxidantenzymelevels(45)Cognitivetraining,education,andsocialengagement
ThecognitivereservehypothesisaimstoexplainwhythosewithhigherIQ,education,andmoresociallyactivepeoplewhoparticipateinleisureactivitiesexhibitlesssevereclinicalorcognitivechangeswhenafflictedbyage‐relatedorADpathology(46,47).Thehypothesisproposesthatdifferencesbetweenindividualsinhowtasksarepro‐cessedbyourbrainsprovideareserveagainstbrainneuropathology.Thisreservemayallowformoreflexibleusageofthebrain,greaterneuralefficiencyandcapacity,andgreaterabilitytocompensatefordegeneratedbrainareasthroughtherecruitmentofadditionalbrainregions,andthusimprovedbrainfunction.IthasbeensuggestedthatevencognitivetraininginterventionsdeliveredlateinlifemayhaveaprotectiveeffectagainstADandagerelatedcognitivedecline(48).Thisoverviewofreviewsislimitedtoeffectsofinterventionsoncognitivelyhealthyolderpeople,andpeoplewithcognitiveimpairment.PeoplewithdiagnosedADorothertypesofdementiaarenotincluded.
21 Background
Whyisitimportanttodothisoverviewofreviews?
TheprevalenceofADandothertypesofdementiaiscontinuouslyincreasingasthepopulationintheworldissteadilyageing,andthereforealsothesocietalcostsofcaringforpeoplewithdementiaareincreasing(12).Astheretodateisnocurefordementia,thereisagreatneedtoidentifyeffectiveinterventionstodelayorpreventdementiaatanearlystageofthediseaseprocess.Inthisoverviewofreviewswesummarisetheevi‐dencefromsystematicreviewsoftheeffectivenessofinterventionstodelayorpreventtheonsetofdementiaincognitivelyhealthypeopleandinpeoplewithmildcognitiveimpairment.Ifeffectiveinterventionscanbeidentified,alotcanbesavedintermsofpersonalsuffering,healthcareuseandcostsforthesocietyasawhole.Also,helpingolderpeopletostaycognitivehealthy,wouldenablethislargeandgrowinggroupofpeopletoliveanactiveandindependentlife,andtocontributetothesocietylongafterretirement.
22 Methods
Methods
Weconductedanoverviewofreviewsevaluatingtheeffectivenessofinterventionsaimedatpreventingordelayingcognitivedeclineand/ortheonsetofdementia.Wein‐cludedreviewsofinterventionsthattargetedcognitivelyhealthypeople(primarypre‐vention)andpeoplewithcognitiveimpairment(secondaryprevention).Weexcludedreviews/studiesofinterventionstargetingpeoplewithadementiadiagnosis.Thisover‐viewofreviewswasconductedinaccordancewiththeguidanceforsummarisingevi‐dencedescribedintheKnowledgeCentre’shandbook(49).
Objectives
Tosummariseandcriticallyappraisetheexistingevidencefromsystematicreviewsoftheeffectivenessofinterventionstopreventcognitivedeclineanddementia.Specifi‐cally,weaimedtoanswerthefollowingquestions:
1. Whatisthedocumentedeffectivenessofinterventionstopreventcognitivedeclineandincidenceofdementiaincognitivelyhealthypeople(primaryprevention)?
2. Whatisthedocumentedeffectivenessofinterventionstoprevent(further)cognitivedeclineanddementiainpeoplewithmildcognitiveimpairmentorotherearlysymptomsorsignsofdementia(secondaryprevention)?
Inclusioncriteria
Weusedthefollowingcriteriawhenconsideringreviewsforinclusion:
Population Cognitivelyhealthyolderpeople Peoplewithmildcognitiveimpairment
Intervention Weincludedsystematicreviewsofstudiesevaluatingtheeffec‐tivenessofanyinterventionaimedatdelayingorpreventingtheonsetofdementiaincludingthefollowing:
pharmacologicaltherapy psychosocial dietary/nutritionalsupplements lifestylemodificatione.g.changesrelatedtounhealthy
diet,physicalinactivity,useofalcoholortobacco
23 Methods
Comparison Usualcare,nointerventionorotherintervention.Outcomes Developmentofdementiaandsymptomsofmildcognitiveim‐
pairment.Symptomsincluded,butwerenotlimitedto,cogni‐tion,dailyfunction,neuropsychiatricsymptomsofdementia(e.g.agitation,depressionandanxiety).
Studydesign Weconsideredsystematicreviewsofhighquality,inanylan‐guage,andpublished2009orlaterforinclusion.
Otherinclusioncriteriaandspecifications:Weconsideredareviewasbeingsystematicifitcontainedadescriptionof1)arobustsearchstrategy,2)criteriaforinclusionand3)assessmentofthequalityofincludedstudies.WeassessedthemethodologicalqualityofpossiblyeligiblestudieswiththeKnowledgeCentre’schecklistforsystematicreviews,andincludedonlyreviewsofhighmethodologicalquality.Inaddition,weincludedonlyfinalisedsystematicreviewsthatwecouldfindinfulltext.Incaseswheretherewasoverlapbetweenreviews(thesameincludedindividualstudies,approximatelythesameresearchquestionsasked),weuseddatafromthemostrecentlyupdatedreview(orthelargerandmoredetailedre‐view)andexcludedtheotherreviews.
Exclusioncriteria
Weappliedthefollowingexclusioncriteria:•Systematicreviewsconcerningmeasuresdirectedtowardsindividualswithdementiadiagnosis.•Systematicreviewsconcerningmeasuresdirectedtowardsrelativesofdementiasuf‐ferers.•Systematicreviewsconcerningpreventivecomplementary/alternativemeasuresagainstdementia(e.g.Acupuncture,aromatherapy),andalternativemeasuresthatarenotinterventionsdescribedintheinclusioncriteria.•Systematicreviewsoflowormoderatemethodologicalquality.•Primarystudiesandotherstudiesthatdonotsummarisetheeffectofpreventivemeasuresagainstdementia.•Abstractsandotherpublicationformatsthatarenotavailableinfulltextormissingdetailsofacompletedsystematicreview.
Literaturesearch
WesearchedthefollowingdatabasesforsystematicreviewsuptoFebruary2016:
OvidMEDLINE(R)In‐Process&OtherNon‐IndexedCitations,OvidMEDLINE(R)
Daily,OvidMEDLINE(R)
EMBASE(Ovid)
PsycINFO(Ovid) Cinahl
24 Methods
TheCochraneDatabaseofSystematicReviews(CDSR) CRD
WebofScience
Pubmed
Thedatabasesearchstrategywasdesignedbyandsearchesexecutedbyresearchli‐brarianGyriHvalStraumann.Thesearchstrategywaspeer‐reviewedbyresearchli‐brarianIngridHarboe.Thesearchwasadaptedtoeachdatabase.Weusedacombina‐tionofsubjectterms,textwords,andwhenavailableinthedatabases,filtersforsys‐tematicreviews.ThecompletesearchstrategyisavailableinAppendix2.Wesupple‐mentedthedatabasesearchbysearchingliteraturelistsofrelevantreviewsandin‐cludedstudies.
Selectionofreviews
Tworeviewersindependentlyreadallrecordsresultingfromthesearches.Weusedpre‐designedinclusion/exclusionformsforeachscreeninglevel:(i)thereviewti‐tle/abstract,(ii)thecompletefulltextofthereview,and(iii)thereview’smethodologi‐calquality(seedetailsbelow).Weresolveddisagreementsthroughdiscussionandsub‐sequentconsensus.Iftherewascompleteoverlapintermsofincludedstudiesbetweentwoormoreofthereviews,wereportedtheresultsfromthemostrecentreviewand/orthereviewwiththelargestnumberofincludedstudiesorthemostdetailedde‐scription.Itwasnotnecessarytocontacttheauthorsofanyreviewstoaidthedecisionprocess.Welistthereviewsconsideredinfull‐text,butsubsequentlyexcluded,inAp‐pendix3alongwiththereasonsforexclusion.Qualityassessmentaspartoftheselectionprocess:Tworeviewersindependentlyassessedthemethodologicalqualityofeachpossibleeli‐giblesystematicreviewusingtheKnowledgeCentre’schecklistforsystematicreviews(49).Thechecklistevaluatesthemethodsusedinareviewagainst10criteriatodeter‐minethedegreetowhichthereviewmethodsareunbiased.Areviewthatadequatelymet“allormostofthecriteria”wasconsideredtobeofhighquality,orifanyofthecri‐teriawerenotmet,ithadtobejudgedveryunlikelythatthiswouldaffectthereview’sconclusions.Weincludedonlysystematicreviewsofhighqualityandexcludedreviewsofmoderateorlowquality.Wedescribetheresultsofthequalityassessment,aswellasthechecklistitemsinAppendix4.
Dataextraction
Alldatawerereviewedandextractedbyonereviewer(GF)intoastandardiseddataex‐tractionform,whichwasthencheckedforaccuracybyanotherreviewer(RB).Thefol‐lowingdatawereextractedfromeachreview:citation,aimofthereview,theoryused/evidencebaseofintervention,numberofrelevantandnon‐relevantincludedstudies,studydesignoforiginalstudies,totalnumberofparticipants,baselinecharac‐teristicsofparticipants(age,gender,cognitivestatus,educationallevel,andethnicity),
25 Methods
country,typeandcomponentsofintervention,durationofinterventionandfollowup,comparators,methodsusedtoassessoutcomes(e.g.toolstoassesscognitivestatus,ortodiagnosedementia),effectsizesreported(andmeasuresofdispersion),statisticalmethodsusedandadjustmentsforconfoundingfactorsinmultivariatemodels,lossestofollowup,conflictofinterestofreviewauthorsandofauthorsoforiginalstudies(ifavailable),andtypeofreview(Cochraneornon‐Cochranereview).
Datasynthesis
Wepresenttheresultsseparatelyforprimarypreventioninterventionstargetingcog‐nitivelyhealthypeople,andsecondarypreventioninterventionstargetingpeoplewithcognitiveimpairmentand/ormemorycomplaints.Weorganisedthedatawithineachofthetwogroupsaccordingto:i)typeofinterven‐tionbeingevaluated(pharmacologicalinterventions,dietaryinterventions,cognitivetrainingandaerobicexercise),andii)typeofoutcomes(incidenceofdementia,cogni‐tivetestscores,adverseeffects,andotherclinicaloutcomes).Wereporttheresultsforthemainoutcomesintextandintables.Ifacombinedmeasureofperformanceonabatteryofcognitivetestswasreportedbythereviewauthors,weusedthissummaryestimatewhenreportingtheresults.Ifnosummaryofeffectestimatewasprovided,wereportedtherangeofeffects.Weconductednooverarchingmeta‐analysisoftheresultreportedintheincludedreviews,astheyallevaluateddifferenttypesofinterventions.
Gradingoftheevidence
Tworeviewauthors(GFandRB)usedtheGRADEtool(GradingofRecommendationsAssessment,DevelopmentandEvaluation)developedbytheGRADEworkinggroup(50)todeterminethecertaintyoftheestimatesofeffectsofinterventionsreportedintheincludedreviews,i.e.towhatdegreewecouldtrusttheresults.Weconsideredthecompileddocumentationforeachofthemainoutcomes(i.e.progressiontodementia,performanceofcognitivetests)usingGRADE.EvidencefromrandomisedcontrolledtrialsstartashighcertaintyevidencebutmaybedowngradeddependingonfivecriteriainGRADEthatareusedtodeterminethecer‐taintyoftheevidence:i)methodologicalstudyqualityasassessedbyreviewauthors,ii)degreeofinconsistency,iii)indirectness,iv)imprecision,andv)publicationbias.Up‐gradingofresultsfromobservationalstudiesispossibleaccordingtoGRADEifthereisalargeeffectestimate,oradose‐responsegradient,orifallpossibleconfounderswouldonlydiminishtheobservedeffectandthatthereforetheactualeffectmostlikelyislargerthanwhatissuggestedbythedata.InaccordancewiththeGRADEtool,wegradedthecertaintyoftheevidenceashigh,moderate,low,andverylow.ThesegradesofevidencearedefinedbytheGRADEWorkingGroupinthefollowingway:Highquality:Weareveryconfidentthatthetrueeffectliesclosetothatoftheestimateoftheeffect
26 Methods
Moderatequality:Wearemoderatelyconfidentintheeffectestimate:Thetrueeffectislikelytobeclosetotheestimateoftheeffect,butthereisapossibilitythatitissubstantiallydifferentLowquality:Ourconfidenceintheeffectestimateislimited:ThetrueeffectmaybesubstantiallydifferentfromtheestimateoftheeffectVerylowquality:Wehaveverylittleconfidenceintheeffectestimate:Thetrueeffectislikelytobesubstantiallydifferentfromtheestimateofeffect
Ethics
Inthisoverviewofreviewsweassessedwhetherandhowauthorsofincludedreviewsaddressedissuespertainingtoequity,benefitsandharms,andfinancialdisclosuresre‐portedintheoriginalstudies.Inaddition,wealsotooknotesonanyreportingofpa‐tientinvolvementindecisionsregardingthetrialdesign.
27 Results
Results
Descriptionofincludedreviews
Searchresults
Theliteraturesearchesandsearchingothersourcesyielded4,349uniquecitations(see
Figure1).Oftheseweexcluded4,247irrelevantcitationsonthebasisoftitleandab‐
stract.Weretrievedandevaluated102reviewsinfulltext.Forty‐oneofthe102re‐
viewswerepromotedtofurtherevaluationofmethodologicalquality(28,40,42,51‐
87),andtheotherswereeitherexcludedwithreasons(seeAppendix3),orlistedunder
ongoingstudies(seeAppendix5;73‐79).Wejudged10ofthe41reviewstobeofhigh
methodologicalqualityandeligibleforinclusioninthisoverviewofreviews(28,40,42,
51,57,65‐67,71‐73,78,85).Afterfurtherscrutinywefoundthattwoofthereviews
(52,57),whichevaluatedtheeffectsofcholinesteraseinhibitors,overlappedinterms
ofincludedstudieswiththereviewbyRussandcolleagues(78).Asthelatterreview
wasmoredetailedandincludedadditionalstudieswedecidedtoreporttheresults
fromthisreview.Twootherreviews(40,71)thatevaluatedtheeffectsofOmega3fatty
acidsupplements,hadtwooutofthreeincludedstudiestargetingcognitivelyhealthy
peopleincommon,andreportedresultsforoneuniquestudyeach.Sincetheunique
studyreportedinoneofthereviews(71)wassmall(49participants)andoflowqual‐
ity,andthestudyintheotherreview(40)waslarge(2,911participants),wedecidedto
includetheresultsforcognitivelyhealthypeoplereportedintheSydenhamreview
(40).Wereporttheresultsforpeoplewithmildcognitiveimpairment(MCI)fromthe
reviewbyMazereeuwandcolleagues(71).SeelistofexcludedreviewsinAppendix3.Characteristicsofincludedreviews
Weidentifiedeighthighqualityreviews(40,42,65,71‐73,78,85)thatweincludedinthisoverviewofreviews.Allthereviewsincludedrandomisedcontrolledtrialsonly.SixwereCochranereviews(40,42,72,73,78,85),andtwowerenon‐Cochranere‐views(65,71).Forfurtherdetailsseetable1andAppendix6.Populations
Fiveofthereviewsincludedstudiesthattargetedcognitivelyhealthypeople(40,65,72,73,85).Tworeviews(42,78)includedstudiesofpeoplewithmildcognitiveimpair‐ment(MCI).Inoneofthestudies(42)peoplewithMCIofamnestictypewereincludedwhiletheotherstudy(78)includedpeoplewithanytypeofMCI(howeverdefined).
28 Results
Onereview(71)includedbothcognitivelyhealthypeopleandthosewithcognitiveim‐pairment.Thelattergroupconstitutedpeoplewithmemorycomplaintsandobjectivecognitivedecline.Interventions
Threereviewsfocusedonpharmacologicalinterventions(72,73,78),andthreeevalu‐
atedtheeffectsofdietarysupplements(40,42,71).Onereviewwasconcernedwith
theeffectsofcognitivetraining(65),andonewiththeeffectsofaerobicexercise(85).
Noneoftheincludedreviewsevaluatedtheeffectsofotherlifestylechanges,e.g.change
toahealthydiet,reduceduseofalcoholortobacco,orinterventionstargetingother
riskfactorsfordementia,e.g.depression,lowlevelofeducation,orlackofsocialinter‐
action.
Comparators
Thecomparatorinterventionwasplaceboinallbuttworeviews(65,85),inwhichthe
activeinterventions(i.e.cognitivetrainingandaerobicexercise)werecomparedwith
eitheranotheractiveinterventionornointervention.Outcomes
Fouroftheincludedreviews(42,72,73,78)reportedondementiaincidence/progres‐siontodementia.Threeofthesealsoreportedcognitivetestscores(72,73,78).Theotherfourreviewsreportedonlycognitivetestscores(intotal>350differentcognitiveoutcomes).Oneofthereviews,however,didnotreportanybetween‐groupcompari‐sonsforthecognitivetestsscores(42).Fourreviews(40,72,73,78)reportedadverseeffectsofinterventions.Threereviews(72,73,85)reportedotherclinicaloutcomes(i.e.cholesterollevel,bloodpressure,andmeasuresofaerobiccapacity).Onereview(72)alsoreportedactivitylevelandinstrumentalactivitiesofdailyliving.
29 Results
Figure1PRISMAstudyflowdiagram(88)describingthereviewselectionprocess.
Toolsusedbyreviewauthorstodetermineriskofbiasandqualityoftheevidence
AllfiveincludedCochranereviewsusedtheCochraneriskofbiastool(89)toassesstheriskofbiasoftheincludedstudies.Inaddition,oneofthereviews(85)alsousedtheCLEARNPTtoolfornon‐pharmacologicalinterventions(90).Oneofthetwonon‐CochranereviewsusedthePEDroscale(91)andtheothernon‐CochranereviewusedboththeCochranetoolandthePEDroscale(65).NoneoftheincludedreviewsusedtheGRADEtool(50)toassessthecertaintyoftheincludedevidenceforaneffect,nordidtheyprovideasummaryoffindingstable.Toolsusedinoriginalstudiestodefineparticipantsascognitivelyimpaired
Theoriginalstudiessummarisedinthreeoftheincludedreviews(42,71,78)useddif‐ferenttestsandcriteriatodeterminethedegreeofcognitiveimpairmentofpartici‐pantsatbaseline.ThemostcommonlyusedtestswereClinicalDementiaRating(CDR)scale(92),themodifiedHachinskiIschemicScore(93)andtheMiniMentalStateExam‐ination(MMSE)(94).
Records screened (n =4, 349)
Records identified through database searching
(n = 5, 824)
Additional records identified through other sources
(n = 3)
Records after removal of duplicates (n =4, 349)
Excluded records (n = 4, 247)
Full text reviews assessed for eligibility (n = 102 )
Reviews directly excluded (n=36)
Full text reviews excluded with reasons
(n = 49) Review protocols (n=9)
Included reviews (n = 8)
30 Results
Toolsusedinoriginalstudiestoassesseffectsoncognitivefunction
Around400differentcognitivetestswereusedtoassesstheeffectsoncognitivefunc‐tion,ofwhichtheMMSE(94)wasoneofthemostcommonlyusedtests.OthertestswereforexampletheADAS‐Cog,CDRSumofboxes,andtheSymbolDigitModalitiestest.Thenumberofdifferenttestsusedbysinglestudiesrangedfromonetomorethan10.Inoneofthereviews(65)onlythetotalnumberoftests(n=396)usedinthe52in‐cludedstudieswasreported,butnoinformationonthetypeandnumberoftestsusedinindividualstudieswasprovided.Littleinformationwasprovidedaboutthescalingandinterpretationofthedifferenttests(e.g.thedesireddirectionofeffect).ToolsusedinoriginalstudiestodetermineeffectsonincidenceADanddementia
Fouroftheincludedreviews(42,72,73,78)reportedonincidenceofdementia.Crite‐riathatwereused,withtheverificationofthediagnosisbyablindedexpertpanel,weretheDiagnosticandStatisticalManualofMentalDisorderscriteria(DSM‐IIIR)(95)theInternationalStatisticalClassificationofDiseasesandRelatedHealthProblemscrite‐ria(ICD10)(96),andtheNationalInstituteofNeurologicalandCommunicativeDisor‐dersandStrokeandtheAlzheimer'sDiseaseandRelatedDisordersAssociationcriteria(NINCSD‐ADRDA)(26).ThesecriteriaweresometimesusedtogetherwiththeDSM‐IVcriteria(97).Table1.Descriptionofthereviews(n=8)includedinthisoverviewofreviews.
Review Search date No of studies1 Population Intervention
Farina 2012(42) June 2012 3 (1) Cognitively im-paired
Vitamin E
Lampit 2014 (65) July 2014 52 (52) Cognitively healthy
Cognitive training
Mazereeuw 2012 (71)
September 2011 10 (7)2 Cognitively im-paired (and cog-nitively healthy)
Omega 3 Fatty Acids
McGuinness 2009 (73)
February 2008 4 (4) Cognitively healthy
Hypertensive drugs
McGuinness 2016 (72)
November 2015 2 (2) Cognitively healthy
Cholesterol lower-ing drugs (statins)
Russ 2012 (78) Not reported 8 (8) Cognitively im-paired
Cholinesterase in-hibitors
Sydenham 2012 (40)
April 2012 3 (3) Cognitively healthy
Omega 3 Fatty Acids
Young 2015 (85) August 2013 12 (12) Cognitively healthy
Aerobic exercise
1Fromtheincludedreviewsweonlyusedstudieswithpopulationsandinterventionsthatwererelevantforourresearchquestion.Thenumberswithinparenthesisgiveinformationonhowmanystudiesintheincludedreviewthatmetourinclusioncriteria.2FromthisreviewonlythreestudiestargetingpeoplewithMCIwasincludedinthisoverviewofreview,astheincludedstudiestargetinghealthypeopleoverlappedalmostentirelywiththeSydenhamreview.
Theeighthighqualitysystematicreviewsincludedintotal86uniqueoriginalstudies
(range1to52studies)thatwererelevantforourresearchquestion.
31 Results
Wefoundnoreviewsconcernedwiththeeffectsoflifestylechanges(otherthanaerobic
exercisetraining),i.e.healthyeating,reducedalcoholconsumption,smokingcessation,
orinterventionstargetingotherriskfactorsfordementia,likeforexamplemid‐life
depression,loweducationalattainment.Wealsodidnotfindanyreviewsconcerned
withmultifacetedinterventionstodelayorpreventcognitivedecline,ADorothertypes
ofdementia.
Primarypreventioninterventions
Sixreviews(fourCochranereviews(40,72,73,85)andtwonon‐Cochranereviews(65,
71)),evaluatedtheeffectivenessofinterventionsaimedatpreventingcognitivedecline
and/ordementiaincognitivelyhealthypeople.Thefocusofthreeofthereviews(72,
73,78)wasonpharmacologicalinterventions(i.e.antihypertensivedrugs,cholesterol
loweringdrugs,andcholinesteraseinhibitors).Onefocusedontheeffectsofdietary
supplements(40),oneontheeffectsofaerobicexercise(85),andonereviewwascon‐
cernedwiththeeffectsofcognitivetraining(65).
Thecharacteristicsoftheincludedreviewsaredescribedbelow.
Pharmacologicaltherapies
Antihypertensivedrugs
OnereviewbyMcGuinnessetalfrom2009(73)evaluatedtheeffectsofantihyperten‐
sivedrugtherapyforthepreventionofcognitivedeclineandincidenceofdementia.
ThereviewincludedfourRCTsofcognitivelyhealthyolderpeoplewithhypertension
withnoapparentpriorcerebrovasculardisease.Allfourtrialsmettheinclusioncriteria
ofouroverviewofreviews.Thereviewauthorsjudgedthetrialstobeofhighmethodo‐
logicalquality.Theincludedoriginalstudieswerepublishedbetween1991and2008.
Participants
Theaverageageofparticipants(n=15,936)was75.4years.MeanMMSEscoreatbase‐
linerangedfrom26to29acrossstudies.InoneofthetrialsbaselineMMSEscorewas
notreported,onlytheMMSEcut‐offforinclusion(>24).Theaveragelengthofeduca‐
tionintwoofthestudieswas11.7and12.3yearsrespectively,whileinonestudymore
than50%ofparticipantshadeithernoeducationorprimaryschooleducationonly.
Onestudydidnotreporteducationallevel.Meanbloodpressurelevelatbaselinewas
171/86mmHgacrossstudies.Theparticipantswererecruitedfromanumberofcoun‐
triesandgeographicregions:WesternandEasternEurope,NorthAmerica,China,anda
smallerproportionofparticipantsfromAustralasiaandTunisia.Themajorityweream‐
bulatorypatients,recruitedinthecommunityorinprimarycaresettings.
Intervention
32 Results
Allfourincludedstudiesreportedasteppedcareapproachtohypertensiontreatment,
andevaluatedtheeffectsofdifferentfirstlinedrugtherapies(calcium‐channelblock‐
ers,thiazidediuretics,orangiotensinIItypeIreceptorblockers).Thesecondlinedrugs
includeddiuretics,beta‐blockers,centrallyactingagents,andACEinhibitors.Forfur‐
therdetailsonthedrugregimenpleaseseethefulltextreview(73).Themeanduration
offollowuprangedfrom1.8to4.5yearsacrossstudies(median2.8years).
Comparison
Thecomparatorinterventionwasplacebo.Itshouldhoweverbenotedthatmanyofthe
participantsinthecontrolgroupwereprescribedothernon‐studyantihypertensive
drugsduringthestudyperiodastheirbloodpressureexceededpre‐setvalues.Inone
ofthetrials84percentofthecontrolgroupparticipantsand75percentofthetreat‐
mentgroupwerenotonassignedtherapyatstudyend.Inanothertrial44percentof
theplacebogroupparticipantsascomparedwith10%oftheinterventionparticipants
werenotonassignedtherapyatstudyend.
Outcomes
Theprimaryoutcomesinthisreviewwereincidenceofdementiaandchangeincogni‐
tivetestscores(onetest;MMSE),forwhichpooledresultswerereportedbythereview
authors.Secondaryoutcomeswerebloodpressurelevel,adverseeffectsrequiringdis‐
continuationoftreatment,andqualityoflife.Pooledeffectestimateswereprovidedfor
thefirsttwo,whilethequalityoflifedatacouldnotbeanalysed.Incidenceofdementia
wasasecondaryoutcomeinalltrialsincludedinthereview.
Table2.Characteristicsofthereviewonantihypertensivedrugtherapy(McGuinness2009).
No of studies Population Intervention Comparison Outcomes 4 trials N=15,936 cognitively
healthy hypertensive participants; mean age 75.4 years (range 70.3 to 83.6); mean BP 171/86 mmHg
Antihypertensive drug therapy1,2
Follow up: range 1.8 to 4.5 years (median 2.8 years)
Placebo3
Incidence of dementia, change in cognitive test scores,4 blood pressure level, incidence and se-verity of adverse effects requiring discontinuation of treatment5
1 The studies used different first-line drugs, and a number of different second-line drugs. 2 McGuinness and colleagues intended to include also non-pharmacological blood pressure lowering interventions, e.g. salt restriction, weight reduction, exercise, alcohol restriction, smoking cessation, but failed to find any eligible studies evaluating non-drug interventions for inclusion. 3 A large proportion of control group participants received other antihypertensive medication during the study. 4 Incidence of dementia and cognitive test scores were secondary outcomes in all four included studies. Only one test, the Mini Mental State examination (MMSE) were used to assess cognitive change. No information about the tests i.e. scaling or interpretation of the MMSE scores, was provided by the review authors.5Type of adverse effects that required discontinuation of treatment not further described.
Cholesterolloweringdrugs
OnereviewbyMcGuinnessetalfrom2016(72)summarisedtheeffectsofstatins(cho‐
lesterolloweringdrugs)forthepreventionofdementiaandcognitivedecline.There‐
viewincludedtwotrialsinvolvingcognitivelyhealthypeoplewithahistoryof,orat
33 Results
highriskforcerebrovasculardisease.Bothtrialswererelevantforourresearchques‐
tions.Thereviewauthorsjudgedthetrialstobeofhighmethodologicalquality.Both
trialswerepublishedin2002.
Participants
Theageofparticipants(n=26,340)inthetwotrialsrangedfrom40to82years.Oneof
thetrialsrecruitedpeoplewithcoronaryheartdisease,otherocclusivearterialdisease,
anddiabetesorhypertension(n=20,536patients40to80yearsold,n=5,806wereat
least70yearsold),andtheothertrialrecruitedpeople(n=5,804;age70‐82years)with
ahistoryof,oratriskofvasculardisease.Oneofthetrialsdidnotprovidebaseline
measuresofcognitivefunction,andtheothertrialreportedameanMMSEscoreof28
acrossgroups.Educationallevelorsocioeconomicclasswerenotreportedineither
study.Totalcholesterollevelrangedfrommean5.7to5.9mMol/Latstudyentry.One
ofthetrialswasconductedintheUK,andtheotherinScotland,Ireland,andtheNeth‐
erlands.Mostoftheparticipantswereambulatorypatients,recruitedeitherinacom‐
munityorinaprimarycaresetting.Intervention
Differenttypesofstatinswereusedinthetwotrials:inonetrialparticipantsreceived
simvastatin40mgdaily,andintheothertheparticipantsreceivedpravastatin40mg
daily.Meanfollowupwas3.2yearsinonestudyand5yearsintheother.
Comparison
Thecomparatorinterventionwasplacebo
Outcomes
Theoutcomesreportedinthereviewwere:incidenceofdementia,changeincognitive
testscores(4tests;MMSE;StroopColourWordTest;Picture‐WordLearningtest;Let‐
terDigitCodingtest)orininterviewassessedcognitivefunction(TICS‐m),cholesterol
level,andincidenceandseverityofadverseeffects.
Table3.Characteristicsofthereviewoncholesterolloweringtherapy(McGuinness2016).
No of studies Population Intervention Comparison Outcomes 2 trials N=26,340 cognitively
healthy people with a history of, or risk fac-tors for, vascular dis-ease, age between 40 and 82 years
Cholesterol lowering drugs (Statins1)
Follow up: 3.2 years and 5 years
Placebo Incidence of dementia2, change in cognitive test scores2; cholesterol level; incidence and se-verity of adverse effects
1 The two trials used different types of Statins (simvastatin and pravastatin) 2 Incidence of dementia was a secondary outcome in the trial reporting this outcome .No information was provided on what criteria that was used to diagnose dementia. 3 A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an improvement) was not provided for all tests: Mini Mental State Examination (MMSE) Score: Score out of 30 (higher score better) (measures global cognitive function); Stroop Colour Word Test: Total number of seconds required to complete the third Stroop card containing 40 items (Measures atten-tion); Picture-Word Learning Test 15 Picture Learning Test (measures immediate and delayed recall); Letter Digit Coding Test. Total number of correct entries completed in 60 seconds (measures processing speed); Modified Telephone Interview for Cognitive Status Score (Score out of 39) A TICS-m score below 22 out of 39 was pre-specified as indicative of some cognitive impairment..
34 Results
Dietarysupplements
Omega‐3FAs
OnereviewbySydenhametalfrom2012(40)evaluatedtheeffectsofOmega‐3FAsup‐
plementsoncognitivedeclineincognitivelyhealthypeople.Thereviewincludedinto‐
talthreetrialsthatwererelevantforourresearchquestion.Thereviewauthorsjudged
thetrialstobeatlowriskofbias.Thetrialswerepublishedbetween2008and2011.
Population
Thethreetrialsrecruitedintotal4,080cognitivelyhealthyparticipantsagedbetween
60and80years.PerformanceontheMMSEwasusedtodeterminetheeligibilityof
participants.ThestudieswereconductedintheNetherlands,England,andWales,and
inonestudythecountryoforiginwasunclear.Inoneofthestudiestheparticipants
wererecruitedusingadatabasewithvolunteers,inonestudyparticipantsweredrawn
frompatientlistsof20generalpractices,andinthethirdstudyparticipantswithprevi‐
ousmyocardialinfarctionwererecruitedthroughcardiologists.
Intervention
IntwostudiesinterventionparticipantsreceivedgelcapsulescontainingOmega‐3FAs.
Inonestudy,participantsreceivedmargarinespreadcontainingOmega‐3FAs.Forde‐
tailsondosespleaseseethefulltextreview.Thefollowuprangedfrom6to40months
(median24months).
Comparison
Thecomparisoninterventionwasmatchedplaceboinalltrials:capsuledwithhigh‐
oleicsunfloweroil(onestudy),withOmega‐9richoliveoil(onestudy),andplacebo
margarineinthethirdstudy.
Outcomes
ThisreviewaimedtoinvestigatetheeffectofOmega‐3FAsonincidenceofdementia
butnoneoftheincludedstudiesreportedthisoutcome.Thereportedoutcomeswere
cognitivetestscores,adverseeffects,andadherence.Theauthorscategorisedthecog‐
nitivetestsintosixsub‐categories(MMSE,immediateanddelayedrecall,verbalflu‐
ency,andexecutivefunction)andpooledtheseseparately.
Table4.CharacteristicsofthereviewontheeffectsofOmega‐3FAs(Sydenham2012).
No of studies Population Intervention Comparison Outcomes 3 trials1 N=4,080 cognitively
healthy people aged 60 years or more
Omega 3 FAs (sup-plements or pro-vided meals) Follow up: range 6 to 40 months
Placebo or usual diet
Cognitive tests scores2, adverse effects, and ad-herence to supplementa-tion
1 Two trials were included in both Mazareeuw 2012 and Sydenham 2012, and both reviews reported results from one unique study each. As the unique study reported in Mazereeuw 2012 was very small compared to the one reported in Sydenham 2012, it was excluded, and we here present the results reported in the review by Sydenham 2012. 2 A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an improvement) was not provided.
35 Results
Physicalexercise
Aerobicexercise
OneCochranereviewbyYoungandcolleaguesfrom2015(85)evaluatedtheeffectsofaerobicexerciseoncognitivefunctionincognitivelyhealthyolderpeople.There‐viewincludedintotal11trials(n=754),whichallwererelevantforourresearchquestion.Thereviewauthorsjudgedthemethodologicalqualityoftheincludedstud‐iestobeathightomoderateriskofbias,asassessedwiththeCochraneriskofbiastoolandtheCLEARNRTtool(meanscore:33;IQR:29to37;thescalegoesfrom14to48points,lowerscoresbetter).Thetrialswerepublishedbetween1990and2012.Participants
The11trialsrecruitedintotal754cognitivelyhealthyparticipants,withameanagerangingfrom60to91yearsacrossstudies.Themediannumberofparticipantsintheincludedstudieswas49(IQR:30to101participants).ThetrialswereconductedintheUSA,CanadaandFrance.Baselineaerobicandcognitivecapacityofparticipantswasnotreported. InterventionTheaerobicexercisewaseitherbriskwalking,jogging,orcycling,oracombination.Thefrequencyanddurationofsupervisedtrainingrangedfrom1to3one‐hourses‐sionsperweek,withamajorityofstudiesproviding3X60minutestrainingperweek.Thedurationoffollowuprangedfrom8to24weeks(median16weeks).ComparisonThecomparatorwaseithernointervention,oranactiveintervention(aflexibil‐ity/balanceprogramme,astrengthtrainingprogramme,orasocial/cognitivepro‐gramme).Inamajorityofstudiesthefrequencyand/ordurationofsessionswerenotmatchedtothoseoftheinterventionprogramme.
OutcomesTheoutcomesreportedinthisreviewwerecognitivetestscores(oneto14testsacrossstudies),measuresofaerobiccapacity(i.e.VO2max,steptests,differentwalk‐ingtestsorratepressureproduct),anddropoutrate.Thecognitivetestswerecatego‐risedinto11subdomainsandpooled.
36 Results
Table5.Characteristicsofthereviewontheeffectsofaerobicexerciseoncognition(Young2015).
No of studies Population Intervention Comparator Outcomes 11 trials1
N= 754 cognitively healthy participants; mean age ranged from 61 to 91 years
Aerobic exercise (i.e. brisk walking, jogging or cycling) Follow up: range 8 to 24 weeks (me-dian 16 weeks)
No intervention or other active intervention (i.e. strength training, flexibil-ity/balance training, or social/cognitive training).
Cognitive tests scores2, measures of aerobic capacity, and dropout rate.
1 One additional study reported a secondary analysis of a subgroup of participants from one of the included trials, but these results were not used in the review. 2 A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an improvement) was not provided for the cognitive tests:
Cognitivetraining
Weincludedonenon‐Cochranereview(65)thatevaluatedtheeffectivenessofcomput‐
erisedcognitivetraining(CCT)inattenuatingage‐relatedcognitivedeclineincogni‐
tivelyhealthyolderpeople.Thisreviewincludedintotal51randomisedstudies(52in‐
dependentcomparisons).Thereviewauthorsjudgedthemethodologicalqualityofthe
includedstudiestobemixed:34of51studieswerejudgedtobeathighriskofbias,as
assessedwiththeCochrane’sriskofbiastool.ThemeanPEDroscorewas6.2/9(SD
1.35),andaccordingtothistool35studieswerejudgedtobeathighriskofbias.The
trialswerepublishedbetween1997and2013.
Participants
Thetrialsrecruitedintotal4,885participants,withmeanagesrangingfrom60.7to
81.9yearsacrossstudies.Accordingtothereviewauthorstheparticipantslackedany
majorcognitive,neurological,psychiatric,and/orsensoryimpairment. The MMSE
scoresatbaselinerangedfrom>24to29.3acrossstudiesthatreportedabaseline
measureofcognitivefunction(39of51studies).Themediannumberofparticipantsin
theincludedstudieswas44(IQR:30to67participants).Theparticipantsweremainly
fromtheUSAandEurope,butalsotoalesserextentfromCanada.Australia,Israel,
China,TaiwanSpecialAdministrativeRegion,RepublicofKorea,andJapan.
Intervention
TheCCTprogramswerestandardized,computerisedtasksorvideogames.Thetotal
durationofthetrainingvariedfrom4to60hours,thenumberofsessionsvariedfrom
3to50(of15to120minutesduration),andtheintensityofintervention(frequencyof
sessionsperweek)rangedfromonetoseventimesperweek.Variouselectronicde‐
vices,e.g.personalcomputers,mobiledevices,orgamingconsoles,wereusedtodeliver
thetraining.ThereviewauthorscategorizedtheCCTprogramsinto5groups:multi‐do‐
maintraining(24studies),speedofprocessingtraining(ninestudies),working
memorytraining(ninestudies),attentiontraining(sixstudies),andinfourstudies
video‐gameswereused.Fifteenstudiesused‘in‐house’programs,andtheremaining36
studiesusedcommercialcognitivetrainingprograms,orvideo‐games.Theintervention
wasdeliveredeitherascenter‐basedgrouptraining(32studies;61.5%),orasunsuper‐
visedtrainingintheparticipant’shome(19studies;36.5%).Nodataonadherenceto
theinterventionwasprovided.
37 Results
Comparison
Thecomparisoninterventionswereeitheractive,i.e.anotherintervention(26studies;
50%),orpassive(nointervention).Theactivecontrolconditionswerenotfurtherde‐
scribed.Outcomes
Theprimaryoutcomeofthisreviewwaschangeincognitivetestscoresfrombaseline
toimmediatelypost‐training.Nolong‐termeffectswereevaluated.Intotal,396cogni‐
tiveoutcomeswerereported.Noinformationwasprovidedonwhattestshadbeen
usedinthedifferentstudies.
Table6.Characteristicsofthereviewontheeffectsofcognitivetraining(Lampit2009).
No of studies Population Intervention Comparator Outcomes 51 trials (52 com-parisons)
N=4,885 cognitively healthy participants; mean age ranged from 60 to 82 years
Computerized cognitive training (CCT);> 4 duration; home-based (unsupervised) or centre-based (group) training; 5 different types of CCT Follow up: 40 to 60 hours total duration (unclear number of weeks)
Active or pas-sive interven-tions
Cognitive tests scores1
1 The names of the cognitive tests, details on the scaling and how to interpret the test scores were not provided in the review, neither was the number of tests used in the included studies.
Secondarypreventioninterventions
Threereviews(twoCochranereviews(42,78)andonenon‐Cochranereview(71)),
evaluatedtheeffectsofsecondarypreventioninterventions,i.e.pharmacologicalther‐
apy(78),dietarysupplements(71),todelayorpreventtheonsetofdementiainpeople
withMCIorearlysymptomsandsignsofdementia.
Pharmacologicaltherapy
Cholinesteraseinhibitors
OneCochranereviewbyRussetalfrom2012(78)evaluatedtheeffectivenessofcho‐
linesteraseinhibitorsinpreventingordelayingprogressiontodementiainpeoplewith
MCI.Thereviewincludedninetrials(8publishedreports)whichallwererelevantfor
ourresearchquestions.Thereviewauthorsjudgedallincludedstudiestobe“wellcon‐
ductedandrobustRCTs”.Thetrialswerepublishedbetween2004and2012.
Participants
Theeightincludedstudiesrecruitedintotal5,149participantswithMCI(anywayde‐
fined)withameanagerangingfrom45to90years.Threeofthestudieswerecon‐
ductedintheUSA,oneinUSAandCanada,oneinGermany,oneinSingapore,andin
38 Results
twomultisitestudiestheparticipantswerefrom16and14countriesrespectively.The
mediannumberofparticipantsperstudywas769(range19to2,037participants).
Intervention
Threedifferentcholinesteraseinhibitorswereusedintheincludedstudies:donepezil
(threestudies),rivastigmine(twostudies),andgalantamine(fourstudies).Onetrial,
whichreportedontwodifferentdosages,wasreportedintwostudies.Inamajorityof
studies,theend‐dose(afterescalationfromalowerdose),was10‐12mg/day.
Comparator
Thecomparatorinterventionwasplacebo.Inonestudybothinterventionandcontrol
groupsalsoreceivedmultivitamins.Themedianfollowupwas76weeks(range16
weeksto48months).
Outcomes
Thereviewreportedonprogressiontodementia(primaryoutcome)andadverseef‐
fectsofthedrugtherapy.Otheroutcomeswerechangeinperformanceoncognitive
tests(5tests;MMSE,ADAS‐Cog,CDR‐sumofboxes,SymbolDigitModalities,ADCS‐
ADL)andmortality.Thereviewauthorsreportthepooledeffectsofincidenceofde‐
mentiaat3years,andpooledeffectsofadverseevents(anyadverseevent,seriousad‐
verseevents,mortality,andotheradverseevents)thatoccurredduringthestudy.
Table7.Characteristicsofthereviewontheeffectsofcholinesteraseinhibitors(Russ2012).
No of studies Population Intervention Comparator Outcomes 9 trials N= 5,149 participants
with MCI; age 45 to 90 years
Cholinesterase inhibi-tors1(end-dose typi-cally 10-12 mg/day) Follow up: range 16 weeks to 48 months (median 76 weeks)
Placebo Progression to dementia, side effects, change in cognitive test scores2 and mortality
1 Three different cholinesterase inhibitors were used in the included studies (Donepezil, Rivastigmine and Galantamine) 2 A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an improvement) was not provided for the cognitive tests:
Dietarysupplements
VitaminE
OneCochrane‐reviewbyFarinaetal(42)evaluatedtheeffectivenessofvitaminEsup‐
plementationinpreventingprogressiontodementiainpeoplewithMCI.Thisreview
includedthreetrials,ofwhichonethatrecruitedparticipantswithMCI,wasrelevant
forouroverviewofreviews.Thereviewauthorsjudgedthetrialtobeatlowriskof
bias.Theincludedstudywaspublishedin2005.
Population
Inthismulti‐centretrial,people(n=516)withamnestictypeofMCIandanaverageage
of73yearsparticipated.ThetrialwasconductedintheUSAandinCanada.
39 Results
Intervention
TheincludedtrialhadthreetreatmentgroupsbutonlydatafortheVitaminE(alpha‐
tocopherol;2000IU/day)groupandtheplacebogroupwereevaluated.Bothinterven‐
tionandcontrolgroupparticipantsalsoreceivedmultivitamins.Thedurationoffollow
upwas3years.
Comparator
Thecomparatorinterventionwasplacebo.
Outcomes
TheoutcomesreportedinthereviewwereprogressionfromMCItopossibleorproba‐
bleAD(primaryoutcome),adverseeventsanddeath.
Table8.CharacteristicsofthereviewontheeffectsofvitaminEonADincidence(Farina2012).
No of studies Population Intervention Comparator Outcomes
3 trials (of which one
was included in this
overview of reviews)
N=5161 participants
with amnestic MCI;
mean age 73 years,
46% females
Vitamin E (alpha-to-
copherol; 2000
IU/day)+ multivita-
mins
Follow up: 3 years
Placebo + multivita-
mins
Time to progression
from MCI to possible
or probable AD; cog-
nitive test scores2
1 Total number of participants, including the third study arm (n= 769). The third study arm was not included in Farina 2012.. 2 The authors of the original trial did not report any between group comparisons for any of the cognitive (secondary)outcomes. Nor did they
provide information on the cognitive tests i.e. scaling and interpretation.
Omega3FAs
OnereviewbyMazereeuwandcolleaguesfrom2012(71)evaluatedtheeffectsof
Omega‐3FAssupplementsoncognitivefunctioninpeoplewithcognitiveimpairment
butnodementia(CIND).Thereviewincludedfourtrials,encompassing650partici‐
pantswithMCIormemorycomplaints,whichwerealleligibleforinclusioninourover‐
viewofreviews.Thereviewauthorsjudgedthemethodologicalqualityoftheincluded
studiestobehigh.Thetrialswerepublishedbetween2006and2011.
Population
Participants(n=650)withCINDand/ormemorycomplaintswererecruited.Meanage
oftheparticipantsrangedfrom68.5to74.5acrossstudies.Twoofthestudiesrecruited
peoplewithCIND(inonestudythiswasnotconfirmedwithanycognitivetests).The
othertwostudiesrecruitedpeoplewithmemorycomplaints.MeanMMSEscoreranged
from27.6to28.2acrossstudies.Inonestudyparticipantsscored>25onmemoryCom‐
plaintQuestionnaireScale).ThestudieswereconductedintheNetherlands,England
andWales,Japan,Australia,Israel,andUSA.Themediannumberofparticipantsinthe
includedstudieswas86(range:21to487).
Intervention
40 Results
TheinterventionconsistedintheprovisionofOmega‐3FAsupplementstopeoplewith
cognitiveimpairment.Thedurationoffollowuprangedfrom12.8to27weeks(median
19.5weeks).
Comparator
Thecomparatorinterventionwasplacebo.Outcomes
Themainoutcomeswerechangeinperformanceonanumberofcognitivetestswhich
werecategorisedintosevencognitivesubdomains(MMSE,compositememory;imme‐
diaterecall;delayedrecall,recognition,attentionandprocessingspeed,working
memory,andexecutivefunction).
Table9.CharacteristicsofthereviewontheeffectsofOmega‐3FAs(Mazereeuw2012).
No of studies Population Intervention Comparator Outcomes 4 trials N= 650 participants
with CIND; mean age 65.7 to 74.6; MMSE 27.6-28.2. One study did not report MMSE scores
Omega-3 FAs. Dura-tion: 12.8 to 27 weeks (median 19.5 weeks) Follow up::range 12.8 to 27 weeks (median 19.5 weeks)
Placebo Cognitive test scores1.
1 A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an im-provement) was not provided for the cognitive tests.
Certaintyoftheevidence
Allstudiesintheincludedreviewswererandomisedcontrolledtrialswhichareconsid‐eredthehighestlevelofevidence.Insixoftheincludedreviews,theauthorsjudgedtheriskofbiasofincludedstudiestobelow.Inonereviewtheauthorsjudgedtherisktobemoderatetohigh(85),andinonereviewamajorityofstudieswerejudgedtobeathighrisk(65),whichresultedindowngradingoftheevidence.Thecertaintyoftheincludedevidenceforthemainoutcomes(dementiaandpossibleorprobableAD)asassessedusingtheGRADEtool,wasmoderateinthreeofthere‐viewsthatreportedthisoutcome(72,78,42),andlowinone(73).Forcognitivetestscores(whichwerereportedinallbutoneofthereviews)thecertaintyoftheevidencerangedfromlowinonereview,duetoriskofbiasandimprecision(85),topredomi‐nantlymoderatetohighcertaintyofevidence,intheotherincludedreviews.Inonere‐view(78),however,thecertaintyofevidencefortheeffectoncognitivetestscoresrangedfromverylowtohigh.Regardingtheresultsforadverseeffects(threereviewsreportedpooledresults)(72,73,78),thecertaintyofevidencewasmoderatetohigh.ForfurtherdetailsseeAppendix7Evidenceprofiles.
41 Results
Effectsofinterventions
Primarypreventioninterventions
Pharmacologicaltherapies
Antihypertensivedrugs
PooledresultsofincidenceofdementiafromthereviewbyMcGuinnessandcolleagues
(73)(4studies;n=15,427participants),suggestaslightdifferencebetweenpartici‐
pantswhoreceivedantihypertensivedrugsandthosewhoreceivedplacebo(OR:0.89
[0.74to1.07],p=0.21)at1.8to4.5yearsfollowup.Belowwereporttherangeofeffect
sizesforcognitivetestscores(MMSE),adverseeffects,andchangeinbloodpressure
levelacrossstudies,ratherthanthepooledeffectestimatesreportedbythereviewau‐
thors,intable10(allp<0.00001),astheheterogeneitywasveryhigh(I2=97‐98%).The
meandifferenceforthechangeinMMSEscores(3trials;n=10,640)rangedfrom1.80
to0.07;adverseeffects(3trials;n=12,091)rangedfromOR0.92to1.11.Themeande‐
creaseinbloodpressurerangedfrom3.2to15.0mmHgandfrom1.6to5.9mmHgfor
systolicanddiastolicbloodpressurerespectively.
Inconclusion,lowcertaintyofevidencesuggestthatantihypertensivedrugsmaylead
toaslightdecreaseinincidenceofdementiaascomparedwithplacebo.Theresults
shouldbeinterpretedwithcaution,duetothewideCI,andlargelossestofollowupin
someoftheincludedstudies.
Table10.Summaryoffindingstableoftheeffectsofantihypertensivedrugsoncognitiveimpair‐mentanddementiaincidence(McGuinness2009).
Antihypertensive drugs vs. placebo for prevention of cognitive impairment and dementia in patients without prior cerebrovascular disease
Patient or population: cognitively healthy participants without prior cerebrovascular disease Setting: Western and Eastern Europe, North America, China, Australasia and Tunisia Intervention: antihypertensive drugs Comparison: placebo
Outcomes Anticipated absolute effects* (95% CI) Relative ef-fect (95% CI)
№ of parti-cipants (studies)
Quality of the evi-dence (GRADE) Risk with placebo Risk with antihypertensive drugs
Dementia inci-dence1
Study population OR 0.89 (0.74 to 1.07)
15, 427 (4 RCT)
⨁⨁◯◯
LOW 2,3
34 per 1000 30 per 1000 (25 to 36)
Change in cog-nitive test score (MMSE)4
The mean cogni-tive test scores (MMSE) was 0
The mean change in cognitive test scores from baseline (MMSE) in the in-tervention group was 0.42 higher (0.3 higher to 0.53 higher)
- 10, 640 (3 RCT)
⨁⨁◯◯
LOW 5
Study population
42 Results
Antihypertensive drugs vs. placebo for prevention of cognitive impairment and dementia in patients without prior cerebrovascular disease
Patient or population: cognitively healthy participants without prior cerebrovascular disease Setting: Western and Eastern Europe, North America, China, Australasia and Tunisia Intervention: antihypertensive drugs Comparison: placebo
Outcomes Anticipated absolute effects* (95% CI) Relative ef-fect (95% CI)
№ of parti-cipants (studies)
Quality of the evi-dence (GRADE) Risk with placebo Risk with antihypertensive drugs
Adverse events6 186 per 1000
187 per 1000 (174 to 202)
OR 1.01 (0.92 to 1.11)
12, 091 (3 RCT)
⨁⨁◯◯
LOW 5,6
The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio; MD: Mean difference Note: The results on dementia incidence can be compared with the 80 per 1000 dementia incidence in Norway for people over the age of 80.
1. Follow up ranged from mean 2 to 4.5 years across three studies, and was average 1.8 years in one study. 2. Relatively wide CI. 3. Indirectness as many of the people in the control group also received non-study antihypertensive drugs. 4. MMSE: Mini Mental State Examination. Scaling and interpretation of scale not further described. 5. Very high heterogeneity (I2=97-98%).* 6. Adverse events that required a discontinuation of treatment. No further description of the adverse events provided.
Cholesterolloweringdrugs(statins)
TheresultsfromthereviewbyMcGuinnessandcolleaguesfrom2016(72)indicateno
differenceindementiaincidence(1study;n=20,536participants)betweenpartici‐
pantsreceivingstatinsandthosereceivingplacebo(OR:1.00(0.61to1.65))atmean5
yearsfollowup(SeeTable11).Further,theauthorsreportednobetweengroupdiffer‐
encesincognitivetestscores(MMSE,SCWT,Pictureword,Letterdigittests;rangeof
meandifferences:0.8higherto0.01lowerthancontrol),andnodifferencesfortele‐
phoneinterviewassessedcognitivestatus(TICS;meandifference0.02).Inaddition,
thereweresimilareffectsonadverseeffects(2trials;OR:0.94[0.83to1.05}).TheLDL
cholesterollevel(2trials;1.2mmol/L[‐1.24to‐1.15])waslowerintheintervention
groupascomparedtocontrol.
Adherencetothedrugtherapyintheinterventiongrouprangedfrom82to94%across
studies.Between3and5%ofinterventionparticipantswereonnon‐studystatins
aloneand2%onboth,andbetween10and17%ofcontrolpatientsreceivednon‐study
statins.Inonetrialapproximately25%oftheparticipantswerelosttofollowup,while
intheothertrialthelossestofollowupwereverysmall.Inbothtrialsanalysiswasby
intentiontotreat.
Inconclusion,thereismoderatecertaintyofevidenceindicatingthatstatintherapy
giventoolderpeoplewith,oratriskof,vasculardisease,probablyleadstolittleorno
differenceinincidenceofdementiaascomparedtoplacebo.Therewereveryfew
events(andwideCI),whytheresultsshouldbeinterpretedwithcaution.
43 Results
Table11.Summaryoffindingstableoftheeffectsofcholesterolloweringtherapyonincidenceofdementiaandcognitivedecline(McGuinness2016).
Cholesterol lowering therapy (statins) vs. placebo for the prevention of dementia and cognitive de-cline in cognitively healthy people
Patient or population: cognitively healthy people Setting: UK, Ireland and the Netherlands Intervention: statins (cholesterol lowering drugs) Comparison: placebo
Outcomes Anticipated absolute effects* (95% CI) Relative ef-fect (95% CI)
№ of partic-ipants (studies)
Quality of the evidence (GRADE)
Risk with pla-cebo
Risk with statins
Dementia incidence; mean follow up: 5 years
Study population OR 1.00 (0.61 to 1.65)
20, 536 (1 RCT)
⨁⨁⨁◯
MODERATE1
3 per 1000 3 per 1000 (2 to 5)
Cognitive test scores (MMSE); mean follow up: 3.2 years1
The mean cogni-tive test scores (MMSE) was 0
The mean change in cognitive test scores (MMSE) in the in-tervention group was 0.06 higher (0.04 lower to 0.16 higher)
- 5, 804 (1 RCT)
⨁⨁⨁⨁ HIGH
Cognitive test scores (Stroop, Picture world test, Letter Digit test)
The mean cogni-tive test scores was 0
The mean change in cognitive test scores in the intervention group ranged from 0.8 higher to 0.01 lower
- 5, 804 (1 RCT)
⨁⨁⨁◯
MODERATE 2
TICS-m2 scores at mean 5 years (final visit)
The mean TICS-m scores at final visit was 0
The mean TICS-m scores at fi-nal visit in the intervention group was 0.02 higher (0.12 lower to 0.16 higher)
- 20, 536 (1 RCT)
⨁⨁⨁⨁ HIGH
Adverse effect; at 3.2 to 5 years follow up
The mean adverse effects was 0
The mean adverse effects in the intervention group was 0.94 higher (0.83 higher to 1.05 higher)
- 26, 340 (2 RCT)
⨁⨁⨁⨁ HIGH
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio; MD: Mean difference
1 We downgraded the evidence due to few events and wide CI. 2 Change from second baseline visit to last, on treatment for MMSE (Score out of 30 (higher score better), Stroop test (Total number of sec-onds required to complete the third Stroop card containing 40 items; lower is better), Picture word (15 Picture Learning Test; unclear scaling), and Letter digit tests scores (Total number of correct entries completed in 60 seconds, higher is better). Mean follow up 3.2 years. Moderate quality for Stroop test, but high for the other three tests. 3 TICS-m: The modified Telephone Interview of Cognitive Status. Score out of 39. No further information on interpretation of test. 4 Adverse effects requiring discontinuation of treatment i.e. Rhabdomyolysis; creatinine kinase levels >10 times upper limit of normal values, a liver aminotransferase levels>3 times upper limits of normal values.
Dietarysupplements
Omega‐3FAs
ThereviewbySydenhamandcolleaguesfrom2012(40)reportednodifferencesfor
thepooledresults(3studies;n=4,080)ofeightcognitivetestscores(SeeTable12)be‐
tweenparticipantsreceivingOmega‐3FAsandthosereceivingplaceboat6to40
monthsfollowup.Inadditiontherewerelittleornodifferencesinadverseeffectsbe‐
tweengroups.
44 Results
Treatmentcompliancewasreportedtobehigh(81%and99%)acrosstreatmentandplacebogroup.
Inconclusion,hightomoderatecertaintyofevidencesuggestthatOmega‐3FAsproba‐blyleadlittleornodifferenceincognitivedecline,ascomparedwithplacebo,whengiventocognitivelyhealthyolderpeople.
Table12.SummaryoffindingstableoftheeffectsofOmega‐3FAsoncognitivedeclineanddementia(Sydenham2012).
Omega-3 FAs vs. placebo for prevention of cognitive decline and dementia in cognitively healthy older people
Patient or population: cognitively healthy older people Setting: England and Wales Intervention: omega-3 fatty acids Comparison: placebo
Outcomes Anticipated absolute effects* (95% CI) Rela-tive effect (95% CI)
№ of participants (studies)
Quality of the evidence (GRADE)
Risk with placebo
Risk with Omega-3 fatty acids
Cognitive test scores1 (MMSE). Follow up: range 24 to 40 months
The mean cognitive test scores - was 0
The mean MMSE scores in the intervention group was 0.07 lower (0.25 lower to 0.1 higher)
- 3, 221 (2 RCT)
⨁⨁⨁◯ MODERATE 2
Cognitive test scores1(Imme-diate recall, Delayed recall, Word recognition, Number of animals named). Follow up: range 6 to 24 months
The mean cognitive test scores was 0
The mean cognitive test scores3 in the intervention group was 0.06 standard deviations higher to 0.04 standard deviations lower
- 1, 043 (3 RCT)
⨁⨁⨁⨁ HIGH
Cognitive test score1 (Digit span forward and backward). Follow up: range 6 to 24 months
The mean cognitive test score was 0
The mean cognitive test score4 in the intervention group was 0.12 to 0.03 higher
- 1, 018 (3 RCT)
⨁⨁⨁⨁ HIGH
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
1. A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an improve-ment) was not provided for the cognitive tests.
2. High I2=53% 3. We have reported the range of effects (SMD) since none of the individual test scores showed an effect of the inter-
vention. 4. We have reported the range of effects (MD) for two tests here.
Aerobictraining
ThereviewbyYoungetal.from2015(85),reportednodifferencesbetweengroupsfortheindividuallypooledtestscoresfor10cognitivecategories(11trials;n=754)forthecomparisonaerobicexercisevs.nointervention(SDM[8outcomes]:0.09lowerto0.30higher;MD[2outcomes],0.10to0.16).SeeTable13below.Theresultsforthecompar‐isonaerobicexerciseversusanyactiveintervention(SDM[10outcomes],range:0.26lowerto0.38higher;MD[1outcome]:0.15)(resultsnotshowninTable12).Forall
45 Results
outcomestheconfidenceintervalincludedthepointofnoeffect.FormoredetailsseeevidenceprofileinAppendix6.
Inconclusion,aerobicexercisemayleadtolittleornoeffectontheperformanceoncognitivetests.
Table13.Summaryoffindingstableoftheeffectsofaerobicexerciseoncognitivedecline(Young2015).
Aerobic exercise vs. no intervention for the prevention of cognitive decline
Patient or population: cognitively healthy older people Setting: USA, France and Canada Intervention: Aerobic exercise Comparison: no intervention
Outcomes3 Anticipated absolute effects* (95% CI) Rela-tive ef-fect (95% CI)
№ of participants (studies)
Quality of the evidence (GRADE)
Risk with no inter-vention
Risk with Aerobic exercise
Cognitive speed 1 - SMD 0.12 higher ( 0.16 lower to 0.41 higher) - 260 (5 RCTs)
⨁⨁◯◯
LOW 2,3
Verbal memory func-tions (immediate) 1
- SMD 0.09 higher ( 0.24 lower to 0.43 higher) - 137 (2 RCTs)
⨁⨁◯◯
LOW 2,3
Visual mamory func-tions (immediate) 1
- SMD 0.09 lower ( 0.57 lower to 0.40 higher) - 65 (1 RCT)
⨁⨁◯◯
LOW 2,3
Working memory 1 The mean working memory was 0
The mean working memory in the interven-tion group was 0,3 higher (0.54 lower to 1.15 higher)
- 137 (2 RCTs)
⨁⨁◯◯
LOW 2,3
Memory functions (delayed) 1
- SMD 0.09 higher ( 0.23 lower to 0.41 higher) - 152 (2 RCTs)
⨁⨁◯◯
LOW 2,3
Executive functions 1 - SMD 0.18 higher ( 0.16 lower to 0.53 higher) - 217 (3 RCTs)
⨁⨁◯◯
LOW 2,3
Cognitive inhibition1 - SMD 0.20 higher ( 0.06 lower to 0.47 higher) - 217 (3 RCTs)
⨁⨁◯◯
LOW 2,3
Visual attention 1 - SMD 0.05 higher (0.26 lower to 0.37 higher) - 155 (3 RCTs)
⨁⨁◯◯
LOW 2,3
Auditory attention1 The mean auditory at-tention was 0
The mean auditory attention in the interven-tion group was 0,16 higher (0.01 lower to 1.33 higher)
- 65 (1 RCT)
⨁⨁◯◯
LOW 2,3
Motor function 1 The mean motor func-tion was 0
The mean motor function in the intervention group was 0,1 higher (7.87 lower to 8.08 higher)
- 65 (1 RCT)
⨁⨁◯◯
LOW 2,3
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; SMD: Standardised mean difference; MD: Mean difference
46 Results
Table13.Summaryoffindingstableoftheeffectsofaerobicexerciseoncognitivedecline(Young2015).
Aerobic exercise vs. no intervention for the prevention of cognitive decline
Patient or population: cognitively healthy older people Setting: USA, France and Canada Intervention: Aerobic exercise Comparison: no intervention
Outcomes3 Anticipated absolute effects* (95% CI) Rela-tive ef-fect (95% CI)
№ of participants (studies)
Quality of the evidence (GRADE)
Risk with no inter-vention
Risk with Aerobic exercise
1. A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an improvement) was not provided for the cognitive tests.
2. High to moderate risk of bias in at least one domain. 3. Fewer than 300 participants (imprecision).
Computerisedcognitivetraining
ThereviewbyLampitetalfrom2014(65),reportedasmalleffectofcomputerised
cognitivetraining(CCT)oncognitivetestscores(52studies;n=4,445participants)in
cognitivelyhealthyolderpeople(Hedge’sg;95%CI:0.22[0.15to0.29],p<0.001).
Therewaslowtomoderateheterogeneity(I2=29.92,p=0.03).Cognitivefunctionwas
measureddirectlyafterthetraining,whichvariedindurationfrom4to60hoursinto‐
tal.Seetable14.
Insummary,thereismoderatecertaintyofevidenceofasmallbeneficialeffectofCCT
oncognitivetestscores,directlyafterthetraining.
Table14.Summaryoffindingstableoftheeffectsofcomputerisedcognitivetrainingonage‐re‐latedcognitivedecline(Lampit2014).
Computerised cognitive training vs. active or passive intervention for prevention of age-related cog-nitive decline in cognitively healthy older people
Patient or population: cognitively healthy older people Setting: USA, Europe, Canada, Australia, Israel, China, Taiwan, Republic of Korea and Japan Intervention: Computerised cognitive training Comparison: active or passive intervention
Outcomes Anticipated absolute effects* (95% CI) Rela-tive ef-fect (95% CI)
№ of participants (studies)
Quality of the evidence (GRADE)
Risk with ac-tive or pas-sive interven-tion
Risk with Computerised cog-nitive training
Cognitive test scores1
The mean cog-nitive test scores was 0
The mean cognitive test scores in the intervention group was 0.22 higher (0.15 higher to 0.29 higher)
- 4, 885 (52 RCT)
⨁⨁⨁◯ MODERATE2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference
1. No information was provided on the type and number of cognitive tests used in the 51 included studies. No information on scaling and interpretation of test scores. Only short-term effects were evaluated.
2. Thirty-three of 51 included studies were at high risk of bias. Eighteen studies were at low risk.
47 Results
Secondarypreventioninterventions
Pharmacologicaltherapy
CholinesteraseinhibitorsThereviewbyRussetalfrom2012(78)reportedaslightdifferenceinprogressiontodementia(9studies;n=4,207)betweengroupsreceivingcholinesteraseinhibitorsandthosereceivingplaceboat3years(RR:0.84[0.70to1.02]).Further,thereviewauthorsreportnoeffectofcholinesteraseinhibitorsoncognitivetestscores,apartfromasmallandmostlikelyclinicallyinsignificantbeneficialeffectonasingletest.Thereweresig‐nificantlymoreadverseeventsinthecholinesteraseinhibitorgroups(RR:1.09[1.02to1.16]),butnomoreseriousadverseeventsordeaths.Resultsforanyadverseeventwereasfollows:gastrointestinalsideeffects:diarrhea(RR2.10[1.30to3.39]),nausea(RR2.97[2.57to3.42]),vomiting(RR4.42[3.23to6.05]);musclespasmsorlegcramps(RR7.52[4.34to13.02]);abnormaldreams(RR4.25[2.57to7.04]);insomnia(RR1.66[1.36to2.02]);syncopeordizziness(RR1.62[1.36to1.93]);andheadache(RR1.34[1.05to1.71]).Insummary,cholinesteraseinhibitorsprobablyleadtoaslightdecreaseinincidenceofdementia,ascomparedtoplacebo(moderatecertainty).However,moderatecertaintyofevidenceindicatehigherincidenceofanyadverseeventsinthecholinesterasegroup,butasimilareffectonseriousadverseevents.TheresultsforincidenceofdementiaandseriousadverseeffectsshouldbothbeinterpretedwithcautionduetothewideCI.Evidenceofmixedcertaintysuggestlittleornoeffectofcholinesteraseinhibitorsoncognitivetestscores.
Table15.Summaryoffindingstableoftheeffectsofcholinesteraseinhibitorsondementiain‐cidenceandcognitivedecline(Russ2012).
Cholinesterase inhibitors vs. placebo for prevention of dementia and cognitive decline in people with cognitive impairment no dementia (CIND)
Patient or population: people with mild cognitive impairment Setting: USA, Canada, Singapore and a number of other countries Intervention: Cholinesterase inhibitors Comparison: placebo
Outcomes Anticipated absolute effects* (95% CI) Relative effect (95% CI)
№ of par-ticipants (studies)
Quality of the evidence (GRADE)
Risk with placebo
Risk with Cholines-terase inhibitors
Conversion to dementia Follow up: mean 3 years
Study population RR 0.84 (0.70 to 1.02)
1, 530 (2 RCT)
⨁⨁⨁◯
MODERATE1
237 per 1000 199 per 1000 (166 to 241)
Cognitive test scores (ADAS-Cog1). Follow up: mean 2 years
The mean cognitive test scores was 0
The mean cognitive test scores in the intervention group was 0.78 lower (1.92 lower to 0.35 higher)
- 2, 675 (4 RCT)
⨁⨁◯◯
LOW 2,3
48 Results
Table15.Summaryoffindingstableoftheeffectsofcholinesteraseinhibitorsondementiain‐cidenceandcognitivedecline(Russ2012).
Cholinesterase inhibitors vs. placebo for prevention of dementia and cognitive decline in people with cognitive impairment no dementia (CIND)
Patient or population: people with mild cognitive impairment Setting: USA, Canada, Singapore and a number of other countries Intervention: Cholinesterase inhibitors Comparison: placebo
Outcomes Anticipated absolute effects* (95% CI) Relative effect (95% CI)
№ of par-ticipants (studies)
Quality of the evidence (GRADE)
Risk with placebo
Risk with Cholines-terase inhibitors
Cognitive test scores (CDR Sum of boxes1). Follow up: mean 1 years
The mean cognitive test scores was 0
The mean cognitive test scores in the intervention group was 0.1 lower (0.11 lower to 0.09 lower)
- 1, 269 (2 RCT)
⨁⨁⨁⨁ HIGH
Cognitive test scores- (Symbol digit modalities1). Follow up: mean 6 months
The mean cognitive test scores was 0
The mean cognitive test scores in the intervention group was 0.17 higher (2.87 lower to 3.21 higher)
- 312 (2 RCT)
⨁◯◯◯
VERY LOW2,3,
Cognitive test scores (MMSE); scale from 0 to 30. Follow up: mean 1 years
The mean cognitive test scores was 0
The mean cognitive test scores in the intervention group was 0.24 higher (0.13 lower to 0.61 higher)
- 1, 269 (2 RCT)
⨁⨁◯◯
LOW 2,3
Cognitive test scores 1(ADCS-ADL); scale from 0 to 78. Fol-low up: mean 1 years
The mean cognitive test scores was 0
The mean cognitive test scores in the intervention group was 0.15 higher (0.27 lower to 0.57 higher)
- 2, 408 (3 RCT)
⨁⨁⨁◯
MODERATE2
Serious adverse events4 Study population RR 0.97 (0.86 to 1.10)
4, 207 (5 RCT)
⨁⨁⨁◯
MODERATE3
190 per 1000 185 per 1000 (164 to 209)
Any adverse events5 Study population RR 1.09 (1.02 to 1.16)
4, 207 (5 RCT)
⨁⨁⨁◯
MODERATE3
825 per 1000 899 per 1000 (841 to 957)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; MD: Mean difference
1. A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an improve-ment) was not provided for the cognitive tests. 2. Wide CI. 3. I2=79-98% and thus very high heterogeneity. 4. Serious adverse events (not further described) and death. 5. Any adverse events including gastrointestinal side effects (diarrhoea, vomiting and nausea), cardiac problems, muscle spasms or leg cramps, headache, syncope or dizziness, insomnia and abnormal dreams.
49 Results
Dietarysupplements
VitaminE
ThereviewbyFarinaetalfrom2012(42)reportedlittleornodifferenceinthepro‐gressiontopossibleorprobableADbetweentheVitaminEandtheplacebogroup.Atstudyendpoint(36months),76outof257participants(29.6%)inthevitaminEgroupand73outof259participants(28.2%)intheplacebogrouphadprogressedtoAD(HR:1.02:95%CI0.74to1.41,p=0.91)(seeTable16).Nobetween‐groupcomparisonswerereportedforthecognitivetestscores.Sixty‐sixparticipantsfromthetreatmentgroupand72fromtheplacebogroupdroppedoutduringthestudy,withthemainreasonsbeingdeath,adverseeffects,andwithdrawalofconsent.Noinformationwasprovidedregardingthedistributionofthereasonsfordiscontinuingtreatmentacrossgroups,oronadverseeffectsoftheintervention.
Insummary,thereismoderatecertaintyofevidencethatvitaminEprobablyleadstolittleornodifferenceinincidenceofpossibleorprobableAD,ascomparedtoplacebo.However,duetothewideCI,theresultsshouldbeinterpretedwithcaution.
Table16.SummaryoffindingstableoftheeffectsofvitaminEonprogressiontoAD(Farina2012)
Vitamin E vs. placebo for prevention of Alzheimer’s disease in people with MCI
Population: people with mild cognitive impairment Setting: USA and Canada Intervention: Vitamin E Comparison: Placebo
Outcomes Anticipated absolute effects* (95% CI)
Relative effect (95% CI)
№ of participants (studies)
Quality of the evidence (GRADE)
Risk with pla-cebo
Risk with Vita-min E
Possible or probable Alzheimer's disease. Follow up: mean 3 years
Study population HR 1.02 (0.74 to 1.41)
516 (1 RCT)
⨁⨁⨁◯
MODERATE 1,2
282 per 1000
287 per 1000 (217 to 373)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the rela-tive effect of the intervention (and its 95% CI).
CI: Confidence interval; HR: hazard ratio
1. Only one study. Relatively small groups. 2. Wide CI overlapping no effect. *As noted by the review authors, measures were taken at 6, 12, 18, 24, 30 and 36 months, but results were only reported for 12 and 36 months, and for the remainder only changes from baseline were provided.
Omega‐3FAs
ThepooledresultsfromthereviewbyMazereeuwetalfrom2011(68)suggestlittleornoeffectsofOmega‐3FAsoncognitivetestscores(4studies;n=650)atmedian14.5to24weeksfollowup.Onlyfortwoofthesevencognitivesubdomainswasthereabenefi‐cialeffectoftheintervention:immediaterecall(Hedge’sg(95%CI):0.16(0.01to0.32)),andattentionandprocessingspeed(Hedge’sg(95%CI):0.32(0.03to0.61).Seetable17.Therewerenodifferencesindropoutrateoradverseeventsbetweengroups.
50 Results
Insummary,evidence,mainlyofhighcertainty,suggestthatOmega‐3FAsprobablyleadtolittleornodifferenceincognitivetestscores,ascomparedtoplacebo.
Table17.SummaryoffindingstableontheeffectsofOmeaga‐3FAsoncognitivetestscores(Ma‐zereeuw2012).
Omega-3 FAs vs. placebo for improved cognitive function in people with CIND
Population: people with cognitive impairment no dementia (CIND) Setting: the Netherlands, England, Wales, Japan, Australia, Israel, and USA Intervention: omega-3 FAs Comparison: placebo
Outcomes Anticipated absolute effects* (95% CI) Rela-
tive ef-fect (95% CI)
№ of parti-cipants (studies)
Quality of the evidence (GRADE)
Risk with placebo Risk with Omega-3 fatty acids
Cognitive test scores (Composite memory1). Follow up: median 14.5 weeks
The mean Compo-site memory score was 0
The mean cognitive test scores in the intervention group was 0.1 higher (0.06 lower to 0.25 higher)
- 676 (4 RCT)
⨁⨁⨁⨁ HIGH
Cognitive test scores (Immediate and delayed recall1). Follow up: me-dian 19.5 weeks
The mean Immediate recall test score was 0
The mean cognitive test scores in the intervention group was 0.16 to 0.03 higher
- 676 (4 RCT)
⨁⨁⨁⨁ HIGH
Cognitive test scores (Recognition1)
The mean Recogni-tion test score was 0
The mean cognitive test in the intervention group was 0.03 lower (0.18 lower to 0.13 higher)
- 655 (3 RCT)
⨁⨁⨁⨁ HIGH
Cognitive test scores (At-tention and processing speed1)
The mean Attention and processing speed test scores were 0
The mean cognitive test in the intervention group was 0.32 higher (0.03 higher to 0.61 higher)
- 193 (3 RCT)
⨁⨁⨁◯
MODERATE2
Cognitive test scores (Working memory and executive function1)
The mean Working memory and execu-tive function test scores was 0
The mean cognitive test scores - in the intervention group was 0.04 higher (0.13 lower to 0.21 higher)
- 533 (2 RCT)
⨁⨁⨁⨁ HIGH
Cognitive test scores – (MMSE). Follow up: mean 24 weeks
The mean MMSE score was 0
The mean cognitive test scores in the intervention group was 0.06 lower (0.23 lower to 0.12 higher)
- 483 (1 RCT)
⨁⨁⨁⨁ HIGH
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference
1 A description of the cognitive tests i.e. scaling and how to interpret them (i.e. if higher or lower score would indicate an improvement) was not provided for the cognitive tests 2 Downgraded due to imprecision (wide CI).
Ethics
Noneoftheincludedreviewsdiscussedequity,orthelackofadiscussionofequityis‐sues,inthestudiesincludedinthereviews.Nordidtheyattempttodiscussthebalance
51 Results
betweenbenefitsandharms,takingintoaccountthecostsandcost‐effectivenessofin‐terventions.Inamajorityoftheincludedreviews,possiblefinancialinterestsandcon‐flictsofinterestrelatedtotheinterventionunderstudywerenotdiscussed.Forexam‐ple,inthereviewbyLampitandcolleagues(65),inwhichcommercialandsocalled‘in‐house’computerprogramswereusedtodeliverthecognitivetraining,noinformationonpossiblefinancialconflictsofinterestwasprovided(i.e.ifpeopleconductingthetri‐alswereinanywayassociatedwith,orfundedby,thepeopleproducingtheCCTpro‐grams).Noneoftheincludedreviewsdiscussedanyconsumerinvolvementintrialde‐sign,orthelackofit.
52 Discussion
Discussion
Mainresults
Inthisoverviewofreviewsweincludedeighthighqualityreviewssummarisingtheef‐fectsofinterventionsaimedatpreventingcognitivedecline,AD,andotherdementiasincognitivelyhealthypeople(primaryprevention),andinpeoplewithmildcognitiveim‐pairment(secondaryprevention).Moderatetohighcertaintyofevidencefromfourofthesereviewssuggeststhatstatintherapy(72)andthedietarysupplementsevaluated(40,42,71)probablyleadtolittleornodifferenceincognitivedeclineandincidenceofdementiaascomparedtoplacebo.Moderatecertaintyofevidenceforcholinesterasein‐hibitors(78),andlowcertaintyofevidenceforantihypertensivedrugs(73)indicatethatthesedrugsmayleadtoslightlydecreasedincidenceofdementia,ascomparedtoplacebo.WideCIsandfeweventsinsomeoftheanalyseswarrantcautionwheninter‐pretingtheresults.Moderatecertaintyofevidencefromonereview(65)suggeststhatcomputerisedcognitivetraining(CCT)probablyleadstoasmallimprovementincogni‐tivetestscoresdirectlyafterthetraining,butthelong‐termeffectsareunknown.Lowcertaintyofevidencefromonereview(85)indicatethataerobictrainingpossiblyleadstolittleornodifferenceincognitivefunction.Threeoftheincludedreviews(42,72,73)reportedsimilarratesofadverseeventsininterventionandcontrolgroups.Onereview(78)reportedhigherincidenceofadverseeventinthetreatment(cholinesterase)groupascomparedtoplacebo,andforseriousadverseeventstheinterventioneffectvaried.
Certaintyoftheevidence
Alloriginalstudiesincludedinthereviewswererandomisedcontrolledtrials,whichconstitutethehighestlevelofevidence.Thecertaintyoftheevidencefortheoutcomedementiaincidence,asassessedusingtheGRADEtool,wasmoderateinthreeofthefourreviewsthatreportedthisoutcome,andlowinonereview,Moderatecertainty,meansthatthetrueeffectislikelytobeclosetotheestimateoftheeffect,butthereisalsoapossibility(bothfortheinterventionssupportedbylowandmoderatecertaintyofevidence)thattheeffectsoftheevaluateddrugsandthedietarysupplementsmaybesubstantiallydifferent.Somecautionwheninterpretingtheresultsonincidenceofde‐mentia,isinorder,astheincidenceratewasratherlow(around3%),forsomeoftheanalysesand/ortheCIsrelativelywide.Forthecognitivetestscoresthequalityofevi‐dencerangedfromhightolow(duetoimprecision,inconsistencyand/orhighriskofbiasforsomeofthecognitiveoutcomes).
53 Discussion
Strengthsandweaknesses
Weconductedacomprehensivesearchforsystematicreviewsofinterventionstodelayorpreventcognitivedeclineanddementia,whichwasupdatedinFebruary2016.Therewerenolanguagerestrictions.Wesearchedthereferencelistsofincludedreviews,andthereferencelistsofotherrelevantpublicationsidentified.Thesearchstrategywasde‐velopedbyanexperiencedinformationscientist,whoalsoconductedthesearch.Inad‐dition,twoauthorsindependentlyscreenedallthereferencesforinclusion,whichmakesitlesslikelythatwemissedanyrelevantreviews.Wealsogradedthecertaintyoftheevidenceinduplicate.Weincludedonlyreviewsthatwejudgedtobeofhighquality,andtheyinturnincludedonlyRCTs.SixoftheeightincludedreviewswereCochranereviews.Allreviewswerepublishedbetween2009and2016.Therearesomelimitationswithouroverviewofreviews.Oneisthatweonlyincludedhighqualitysystematicreviews,asitcanbearguedthattheexclusionofmoderate‐tolowqualityreviewsmayhaveexcludeddatarelevantforthepresentwork.Anotherlimitationisthatwereliedentirelyonthedescriptionoftheoriginalpapersprovidedintheincludedsystematicreviews,whenconductingouroverviewofreviews.Athirdlimitation,relatedtotheoldsearchdateinoneoftheincludedreviews(literaturesearchin2008),isthatwemayhavemissedtoincludemorerecentlypublishedstudiesontheeffectsofantihypertensivedrugs.Alimitationwiththeavailableevidenceisthattherearenostudieswithlongerfollowuptimethan5years.Itmaybedoubtedthatthisissufficienttimeforchangetotakeplacegiventhenatureofthecondition(i.e.dementia)andtheeffectsoftheinterven‐tionsunderstudy.Evenifsomereviewsincludedstudiesofpeoplewithdementia,whichwasagroupofpeoplenotwithinthescopeofouroverviewofreviews,thisdidnotconstituteaprob‐lemaslongasresultsforeachgroup(cognitivelyhealthy,MCIanddementia)werere‐portedseparately.WehadtoexcludeonereviewtargetingpeoplewithParkinson’sdis‐ease(67),andfourotherreviews(58,63,66,77)ascognitivelyhealthypeopleandcog‐nitivelyimpairedpeoplewerenotanalysedseparately.Wecould,ifitisjudgedim‐portant,includeathirdmixedgroup,ifwedecidetoupdatethisoverviewofreviews.
Ethics
ThenumberofpeoplelivingwithADisexpectedtoincreasedramaticallyoverthenextdecades.Mostofthisincreasewillbeinlow‐andmiddleincomecountries,wheretheprevalencealreadyisthehighest(12).Despitethis,issuespertainingtoequitywerenotaddressedinanyoftheincludedreviews.Themajorityoftheincludedstudieswerefromhighincomecountries,whileinsomecasesitwasnotclearwherethestudieshadbeenconducted.
54 Discussion
Introducingandimplementingnewinterventions/treatmentscanbecostly,andpayingforanewtreatmentforonediseasegroupmaytakeawaymoneyfromothertreatmentalternatives,orfromotherpatientgroups.Ensuringthataninterventioniscost‐effec‐tive,andthatthebeneficialeffectsexceedsharms,isthereforeveryimportanttopre‐ventwasteofhealthcareresources(99).Noneoftheincludedreviewsreportedordis‐cussedthelackofdataoncostsandcost‐effectivenessoftheinterventionsevaluatedintheoriginalstudies.Therearehugefinancialinterestsinvolvedindruginterventionstopreventcognitivedecline,AD,anddementia.Ithasbeensuggestedthatresearchthatisfundedbydrugcompaniesismorelikelytoyieldpositiveoutcomesthanresearchwithothertypeoffunding.Thisbiascanbeintroducedinanumberofways(100).Itisthereforeim‐portanttodisclosethefundingsourcesforincludedstudies,andpossiblerelationshipsbetweenthoseconductingtheresearchandthepharmaceuticalcompanies(101).Onlyoneofthereviews(78)reportedthefinancialdisclosuresoftheoriginalstudies,whichallweresupportedbydrugcompanies.Whendesigningatrial,itisimportanttoensurethatoutcomesthatareofimportancetothepatientsaremeasured(102).Qualityoflifeisoneexampleofanimportantpa‐tient‐centredoutcome,whichwasonlyreportedintwooftheincludedreviews(72,73),functioninactivitiesofdailylivingisanother.Noneofthereviewsreportedonpa‐tientinvolvementinthetrialdevelopment,ordiscussedthelackofit.Involvingpa‐tientsinrefininganinterventionmayleadtoclinicaltrialendpointsthatbettercomplywiththeneedsandconcernsofpatientsandcaregivers(103).
Potentialbiasesintheoverviewprocess
Atleasttwopeopleindependentlyappliedeligibilitycriteriaandassessedthereviewsforinclusion.Oneauthorextracteddataintoastandardiseddataextractionsform,andanotherauthorcheckedtheaccuracyoftheextracteddata,whichshouldreducebiasintheoverviewprocess.Atleasttwoauthorsassessedthescientificqualityofreviewsac‐cordingtothetoolusedbytheKnowledgeCentre.However,excludingreviewsofmod‐eratetolowqualitymayhaveinducedbias.
Overallcompletenessandapplicabilityoftheevidence
OnlyfouroftheincludedreviewsreportedonAD(42)orincidenceofothertypesofde‐mentia(72,73,78),whileallreviewsreportedoncognitivetestscores.Itcanbeques‐tionedifcognitivetestscoresisagoodproxyforprogressiontodementia.Qualityoflifewasonlyreportedintworeviews(72,73),andADLfunctioninonereviewonly(72).Adverseeffectswerereportedinfourreviews(42,72,73,78).Eventhoughthepharmacologicalinterventions(antihypertensivedrugsandstatins)evaluatedintwooftheincludedreviews(72,73),showedbeneficialeffectsonthetar‐getedriskfactorsfordementia(i.e.bloodpressureandcholesterollevelrespectively),
55 Discussion
incidenceofdementiaandcognitivefunctiondidnotchangesignificantly.Theconfi‐denceintervals(forincidenceofdementia)wererelativelywideinbothstudies,whytheresultsshouldbeinterpretedwithcaution.McGuinnessandcolleagues(73),aimedtoincludealsonon‐pharmacologicalbloodpressureloweringinterventions(e.g.saltrestriction,weightreduction,exercise,re‐ducedalcoholintake),butcouldnotidentifyanysuchstudiesforinclusion.Someoftheincludedtrialssufferedfromlargelossestofollowup,andalargeproportionofcontrolparticipantsreceivingnon‐studyantihypertensivedrugs.Anotherlimitationwiththereviewonantihypertensivedrugswasthatonlyasingletest(MMSE)wasusedtoas‐sesstheeffectsoncognitivefunction.Alimitationwiththestatinreview(72)wastheunclearmethodsusedtodiagnosede‐mentiainsomeoftheincludedstudies,andthatonlypeopledeemedtobeatmoderatetohighriskofacardiovasculardiseasewereincluded.Alimitationwithboththereviewonantihypertensivedrugsandthereviewonstatins,isthatincidenceofdementiawasasecondaryoutcomeinallincludedstudiesInthereviewthatevaluatedtheeffectofaerobicexerciseoncognitivefunction(85),notalloftheincludedstudiesreportedimprovedaerobicfitnessasaresultoftheinter‐vention,andnonereportedabeneficialeffectoncognition.Inamajorityofstudies,thefrequency/durationofthecomparatorinterventions,werenotmatchedtothoseintheinterventiongroup.Inaddition,neithercognitivefunctionnoraerobicfitnessatbase‐linewerereported,whichmakesitdifficulttofullyappreciatetheresults.Itmaybedoubtedwhetherthefollowuptimewassufficientforchangetotakeplace(from8to26weeks),andwhetherthestudiesweresufficientlypowered(median49partici‐pants).Itmayalsobequestionedwhetherthetargetedpopulationwasoptimalforthistypeofinterventiontoshowaneffect,asitincludedveryoldpeopleupto92yearsofage.Itispossiblethatinterventionsaddressinglifestylerelatedriskfactorslikephysi‐calinactivity,aremorelikelytobeeffectiveinconservingcognitivefunctioniftheyaredeliveredearlierinlife.Thereisofcoursethentheproblemwithverylonginterventiontimes,astheoptimalageforoutcomeassessmentislaterinlife(104).Theonereview(65),whichsummarisedtheeffectsofCCToncognitivetestscoresfromanumberofsmallstudies(mediann=44participants),didnotreportanylong‐termef‐fectsonperformanceoncognitivetests.Inaddition,thereviewauthorsdidnotprovideanyinformationonwhattypeofcognitiveteststhathadbeenusedintheincludedstudies,nordidtheyprovideanydetailsontheactivecomparisoninterventionortheadherencetotheintervention,whichmakeinterpretationoftheresultsdifficult.Wedidnotfindanyhighqualityreviewsconcernedwiththeeffectsofhealthylifestylechangesoncognitivefunctionanddementiaincidence(apartfromthereviewonaero‐bicexercise),e.g.conversiontoahealthydiet,decreasedalcoholintake,smokingcessa‐tion,weightlossetc.Threeexcludedreviews(includingmostlycohortandcross‐sec‐tionalstudies)reportsomeevidenceofaneffectofincreasedfruitandvegetableintakeand/oradherencetoaMediterraneandiet(69,70,75).Wealsodidnotfindanyhigh
56 Discussion
qualityreviewsconcernedwiththeeffectsofinterventionstargetingotherriskfactorsfordementialikeforexamplemid‐lifedepression,lackofsocialinteraction,orlowedu‐cationalattainment.Oneexcludedreviewoflowquality(105)reportedoninterven‐tionstotreatdepressioninpeoplewithMCIanddementia,andtwoexcludedreviews(79,80)ofmoderatequalitywereconcernedwithcognitiveandphysicalleisureactivi‐ties.Ithasbeensuggestedthatloweducationalattainmentistheriskfactorcontrib‐utingmosttotheburdenofdementiaworldwide,andthatphysicalinactivityistheriskfactorthatcontributesthemosttothediseaseburdeninUSAandEurope(17).Thereisthereforeanurgentneedtoevaluateeffectiveinterventionstargetingthese,andotherriskfactors,inRCTsandlargescalepopulationbasedstudies,withlongfollowuptimes.Dementiasaresyndromesthatmostlikelyareofamultifactorialorigin(16).Itispossi‐blethatpreventiveinterventionsmaybemoreeffectiveiftheytakeintoaccountthemultifacetedaetiologybehindthedisease,i.e.interventionsthattargetmultipleriskfactorsmaybemoreeffective.However,allofthereviewsincludedinthisoverviewofreviews,evaluatedtheeffectivenessofasingleitemintervention,targetingonlyoneriskfactor.WeareawareoffourlargeEuropeantrialsofsocalledmultidimensionalin‐terventions(includingforexamplediet,exercise,cognitivetraining,andvascularriskmonitoring)forpeopleatriskfordementia.Threeofthesetrialsareongoing(106).Re‐sultsfromoneofthetrials,recentlypublished(107),suggestbeneficialeffectsofthemultidimensionalinterventiononcognitivefunction.Untilfairlyrecently(23,26)therehasbeenlittleornoconsensusonwhatcriteriaandtoolstouseforthediagnosisofMCI,ADandothertypesofdementia.Intheoriginalstudiesincludedinthereviewsnowunderconsideration,ofwhich54.6percentwerepublishedbeforethepublicationoftheconsensuscriteriaand45.4percentafter,differ‐entcriteriawereusedtodeterminetheonsetofdementiaandtodiagnoseMCI.Inaddi‐tion,morethan396differentcognitivetestswereusedtoassesstheeffectsofinterven‐tionsoncognitivefunction.Mostcommonlythetestswerenotwelldescribed,i.e.infor‐mationaboutthescaling,thedesireddirectionofeffect,andwhatwouldbeconsideredaclinicallyimportanteffectwasnotprovided.InonereviewallstudiesusedonlytheMiniMentalStateExamination(MMSE)toassesscognitivefunction,whileotherstudiesuseduptotendifferenttestsortestbatteriestoassesscognition.Achangein2pointsontheMMSEscalehasbeensuggestedtobeaclinicallysignificanteffect(108).ThechangeintheMMSErangedfrom0.07lowerto0.42higheracrosssixoftheincludedreviews.Resultsfromarecentsystematicreview(109)donotsupporttheuseoftheMMSEasasingleadministeredstand‐alonetesttoassessprogressiontodementia.Thereviewauthorsinsteadsuggesttouseasetoftestsadministeredovertime.Tofacili‐tatefutureevaluationsofthecomparativeeffectivenessofinterventions,researchersshouldattempttocometoaconsensusonwhattestbatteriestouseforassessmentofcognitivefunction,andtousepublishedconsensuscriteriaandmethodsfordiagnosingMCIanddementia.
57 Discussion
Agreementsordisagreementswithotheroverviewsofreviews
Weidentifiedoneoverviewofreviewsofinterventionstopreventcognitivedeclineanddementia(110).Thisoverviewwaspublishedin2010andwithaliteraturesearchfrom2009,andthusitisbecomingoutdated.Incontrasttoouroverviewofreviewsithadwiderinclusioncriteria,andalsolookedatfactorsassociatedwithriskreduction,andnotonlyeffectsofinterventionstodelayorpreventcognitivedeclineanddemen‐tia.Insomerespecttheireligibilitycriteriawerestricter,astheyincludedonlyoriginalstudieswithafollowupofatleast6monthsduration,whileweappliednorestrictionstothelengthoffollowup.Ourresultsofnon‐significanteffectsofvitaminE,antihyper‐tensivedrugs,andcholinesteraseinhibitorsondementiaincidence,ascomparedtopla‐cebo,areinagreementwiththeresultsreportedinthisotheroverviewofreviews.ItdidnotidentifyanystudiesevaluatingtheeffectivenessofOmega‐3FAsforinclusion,thereforecomparisonwithourresultcouldnotbemade.
Applicationsforpractice
Physicians,patients,andcarersshouldbemadeawareofthelackofconvincingevi‐denceforaneffectofOmega‐3FAs,antihypertensivedrugs,andstatinsondementiaincidenceandcognitivefunction,whendeliveredtocognitivelyhealthyolderpeople.Thisofcoursehavenobearingontheeffectsofantihypertensivedrugsandstatinsonotherconditions(e.g.cardiovasculardisease).ThepractitionershouldalsobemadeawareoftheevidenceoflittleornoeffectofOmega‐3FAs,vitaminE,andcholinester‐aseinhibitorsinpreventingcognitivedecline,ADorothertypesofdementia,inpeoplewithmildcognitiveimpairment.ThereissomeevidenceforasmalleffectofCCTontheperformanceincognitivetestsincognitivelyhealthypeople,butfurtherresearchofthelongtermeffectsisneeded.
Needforfurtherresearch
Furtherresearchisneededtoidentifyeffectiveinterventionstopreventcognitivede‐clineanddementia,whilewaitingforresearcherstodiscoveracurativetreatmentfordementia.Toincreasethecertaintyoftheresultsofthisreview,trialswithmorepre‐ciseeffectestimatesandnarrowerCIsareneeded.Sincesofaronlyeffectsofsinglefac‐etedinterventionshavebeenevaluatedandsummarisedinreviews,interventionsin‐volvingacombinationofhealthylifestylechanges,e.g.conversiontoahealthydiet,de‐creasedalcoholconsumption,smokingcessation,weightloss,cognitivetrainingetc.,areneeded.Alsostudiesevaluatingtheeffectivenessofinterventionstargetingotherriskfactorsfordementia,likeforexampleinterventionsforearlyidentificationandtreatmentofmid‐lifedepression,forincreasedsocialinteraction,andinterventionstoencourageeducationinpopulationswithloweducationalattainment.Physicalinactiv‐ityandloweducationalattainmentshouldbeaddressedinlargescalestudies,sincetheseriskfactorsareestimatedtocontributemosttotheburdenofdisease.
58 Discussion
ResearchersshouldaimtouseconsensusmethodsandcriteriatodiagnoseMCI,ADanddementia,andforassessingcognitivefunction,toenableeffectcomparisonsbetweenstudies.Theyshouldalsoaimtoimprovethereporting(describethetests/scalesusedtoassesscognitivefunction,givedetailsontheinterventionandthecomparatorinter‐vention),soastoprovidesufficientdetailtoenablereplication.Preferablyallstudiesshouldreportincidenceofdementia(asaprimaryoutcome),andnotonlyperformanceoncognitivetests.
59 Conclusion
Conclusion
Giventheevidencefromtheincludedsystematicreviews,thereisatpresentstillsomeuncertaintyabouttheeffectivenessoftheevaluatedinterventionsforpreventionofcognitivedeclineanddementia.Onlysingleiteminterventionshavesofarbeenevalu‐ated.However,sincetheaetiologybehinddementiamostlikelyismultifactorial,inter‐ventionsaddressingmorethanonemodifiableriskfactormaybeneeded.Thereisanurgentneedtoevaluateinterventionstargetingimportantriskfactors,usingRCTsandlargescalepopulationbasedstudies,withlongfollowuptimes.
60
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Appendices
1Glossary
Term Explanation
AD Alzheimer'sdisease(AD)isaprogressive,degenerativedisor‐derthatattacksthebrain'snervecells,orneurons,resultinginlossofmemory,thinkingandlanguageskills,andbehaviouralchanges.
ADAS‐Cog Alzheimer'sDiseaseAssessmentScale‐Cognitivesubscale(ADAS‐cog).
ADCS‐ADL ActivitiesofDailyLivingInventory.Aninventoryofinformantbaseditemstoassessactivitiesofdailylivingandinstrumentalactivitiesofdailyliving,i.e.functionalperformance,ofAlz‐heimer’sdisease(AD).
ADL Activitiesofdailyliving(ADL)scale.
Aerobictraining Aerobictraininginphysicalexerciseoflowtohighinten‐sitythatdependsprimarilyontheaerobicenergy‐generatingprocessi.e.thatthereissufficientamountofoxygentomeetthebody’senergydemands.
Alpha‐tocopherol α‐TocopherolisaformofvitaminEthatispreferentiallyab‐sorbedandaccumulatedinhumans.
AmnesticMCI MildCognitiveImpairmentthatprimarilyaffectsmemory.
Bias Abiasisasystematicerror,ordeviationfromthetruth,inre‐sultsorinferences.Biasescanoperateineitherdirection:differ‐entbiasescanleadtounderestimationoroverestimationofthetrueinterventioneffect.Biasescanvaryinmagnitude:somearesmall(andtrivialcomparedwiththeobservedeffect)andsomearesubstantial(sothatanapparentfindingmaybeentirelyduetobias).Evenaparticularsourceofbiasmayvaryindirection:biasduetoaparticulardesignflaw(e.g.lackofallocationcon‐cealment)mayleadtounderestimationofaneffectinonestudybutoverestimationinanotherstudy.Itisusuallyimpossibleto
72
knowtowhatextentbiaseshaveaffectedtheresultsofapartic‐ularstudy,althoughthereisgoodempiricalevidencethatpar‐ticularflawsinthedesign,conductandanalysisofrandomizedclinicaltrialsleadtobias.
CDR‐SumofBoxes TheClinicalDementiaRatingScaleSumofBoxes.
CI ConfidenceInterval
CIND Cognitiveimpairmentnodementia(CIND)describesindividualswhosecognitivefunctioningfallsbelownormalbutwhodonotmeetdementiacriteria.AcriterialessrestrictivethanMCI,asitdoesnotexcludepeoplebasedontheaetiologyoftheircogni‐tiveimpairment.
Cognitivefunction Anintellectualprocessbywhichonebecomesawareof,per‐ceives,orcomprehendsideas.Itinvolvesallaspectsofpercep‐tion,thinking,reasoning,andremembering.
Delayedrecall Theabilitytoremembersomethingafteraperiodofrestordis‐tractionranginganywherefromminutestodays.
Dementia Dementiaisalossofmentalabilitysevereenoughtointer‐ferewithnormalactivitiesofdailyliving,last‐ingmorethansixmonths,notpresentsincebirth,andnotasso‐ciatedwithalossoralterationofconsciousness.Therearedif‐ferenttypesofdementia,ofwhichthemostcommonlyoccur‐ringisAlzheimer’sdisease.
Dietarysupplement Adietarysupplementprovidenutrientsthatmayotherwisenotbeconsumedinsufficientquantitiesandincludevitamins,min‐erals,fiber,fattyacids,oraminoacids,amongothersubstances.
Digitspanforwardandbackward
Digit‐spantaskisusedtomeasureworkingmemory’snumberstoragecapacity.Participantsarepresentedwithaseriesofdig‐its(e.g.,'8,2,4')andmustimmediatelyrepeatthemback.Thelengthofthelongestlistapersoncanrememberisthatperson'sdigitspan.Whiletheparticipantisaskedtoenterthedigitsinthegivenorderintheforwarddigit‐spantask,inthebackwarddigit‐spantasktheparticipantneedstoreversetheorderofthenumbers.
Executivefunction Cognitivecontrolandsupervisoryattentionalsystem.Anum‐brellatermforthemanagement(regulation,control)ofcogni‐tiveprocesses,includingworkingmemory,reasoning,flexibil‐ity,andproblemsolvingaswellasplanningandexecution.
Frontotemporalde‐mentia
Frontotemporallobardegenerationisanumbrellatermforadi‐versegroupofuncommondisordersthatprimarilyaffectthe
73
frontalandtemporallobesofthebraini.e.theareasgenerallyassociatedwithpersonality,behaviourandlanguage.
GRADE GradingofRecommendations,Assessment,DevelopmentandEvaluation.Atoolthatisusedtoassessthecertaintyoftheevi‐denceinasystematicreview.
Hedge’sg Hedges'gpoolvariancesontheassumptionofequalpopulationvariances,usingn‐1foreachsampleinsteadofn(asinCohen’sd),whichprovidesabetterestimate,especiallythesmallerthesamplesizes.Providesthedifferencebetweenthetwomeans.
Heterogeneity Anykindofvariabilityamongstudiesinasystematicreviewmaybetermedheterogeneity.Variabilityintheparticipants,in‐terventionsandoutcomesstudiedmaybedescribedasclinicalheterogeneity,andvariabilityinstudydesignandriskofbiasmaybedescribedasmethodologicalheterogeneity.Variabilityintheinterventioneffectsbeingevaluatedinthedifferentstud‐iesisknownasstatisticalheterogeneity,andisaconsequenceofclinicalormethodologicaldiversity,orboth,amongthestud‐ies.Statisticalheterogeneitymanifestsitselfintheobservedin‐terventioneffectsbeingmoredifferentfromeachotherthanonewouldexpectduetorandomerror(chance)alone.
HR Hazardratio.Theinstantaneoushazardrateisthelimitofthenumberofeventsperunittimedividedbythenumberatrisk,asthetimeintervalapproaches0.
Hypertension Hypertension,alsoknownashighbloodpressureorarterialhy‐pertension,isachronicmedicalconditioninwhichthebloodpressureinthearteriesispersistentlyelevated.
Immediaterecall Theabilitytoremembereventsoccurringwithinthepastfewminutes.
Imprecision Imprecisioningeneral,iswhenstudiesincluderelativelyfewparticipants,andfewevents,andthereforehavewideconfi‐denceintervalsaroundtheestimateofeffect.
Indirectness Indirectnessofevidenceiswhenevidencecomesfromresearchthateitherdoesnotdirectlycomparetheinterventionsofinter‐estwithcontrol,orwhentheinterventionisnotappliedtothepopulationsofinterestorifastudymeasuresoutcomesthatarenotdirectmeasuresimportanttopatientsbutproxymeasuresorprocessmeasures.
Inconsistency Inconsistencyofrelative(ratherthanabsolute)treatmentef‐fectsinbinary/dichotomousoutcomesmaybedeterminedby
74
lookingatthe(dis)similarityofpointestimates,extentofover‐lapofconfidenceintervals,andstatisticalcriteriaincludingtestsofheterogeneity(I2).
Letterdigitsubstitu‐tiontest
Digitsymbolsubstitutiontest(DSST)isaneuropsychological‐testsensitivetobraindamage,dementia,ageanddepression.Itconsistsof(e.g.nine)digit‐symbolpairs(e.g.1/‐,2/┴...7/Λ,8/X,9/=)followedbyalistofdigits.Undereachdigitthesubjectshouldwritedownthecorrespondingsymbolasfastaspossible.Thenumberofcorrectsymbolswithintheallowedtime(e.g.90or120sec)ismeasured.
Levybodydementias LBDisanumbrellatermfortworelateddiagnoses.LBDreferstobothParkinson’sdiseasedementiaanddementiawithLewybodies.Theearliestsymptomsofthesetwodiseasesdiffer,butreflectthesameunderlyingbiologicalchangesinthebrain.Overtime,peoplewithbothdiagnoseswilldevelopverysimilarcog‐nitive,physical,sleep,andbehavioralsymptoms.
MCI Mildcognitiveimpairment.MCIcausescognitivechangesthatareseriousenoughtobenoticedbytheindividualsexperienc‐ingthemortootherpeople,butthechangesarenotsevereenoughtointerferewithdailylifeorindependentfunction.
MMSE TheMiniMentalStateExamination(MMSE)isthemostcom‐monlyusedtestforcomplaintsofproblemswithmemoryorothermentalabilities.Itcanbeusedbyclinicianstohelpdiag‐nosedementiaandtohelpassessitsprogressionandseverity.Itconsistsofaseriesofquestionsandtests,eachofwhichscorespointsifansweredcorrectly.TheMMSEtestsanumberofdif‐ferentmentalabilities,includingaperson'smemory,attentionandlanguage.
Omega‐3FattyAcids Omega‐3fattyacids(FAs)arepoly‐saturatedfattyac‐ids(PUFAs)withadouble‐bond(C=C)atthethirdcarbonatomfromtheendofthecarbonchain.Omega‐3fattyacidsaeim‐portantfornormalmetabolism.
OR Anoddsratio(OR)isameasureofassociationbetweenanexpo‐sureandanoutcome.Itrepresentstheoddsthatanoutcomewilloccurgivenaparticularexposure,comparedtotheoddsoftheoutcomeoccurringintheabsenceofthatexposure(i.e.inthecontrolgroup).
Primaryprevention Primarypreventionseekstopreventtheonsetofspecificdis‐easesviariskreduction:byalteringbehavioursorexposuresthatcanleadtodisease,orbyenhancingresistancetotheef‐fectsofexposuretoadiseaseagent.
75
Processingspeed Thepaceatwhichapersontakeininformation,makesenseofitandbegintorespond.
RR Riskratioorrelativerisk.Relativeriskisthera‐tiooftheriskofdiseaseamongthoseexposedtoariskfac‐tortotheriskamongthosenotexposed.
SMD Thestandardizedmeandifferenceisusedasasummarystatis‐ticinmeta‐analysiswhenthestudiesallassessthesameout‐comebutmeasureitinavarietyofways(forexample,allstud‐iesmeasuredepressionbuttheyusedifferentpsychometricscales).Inthiscircumstanceitisnecessarytostandardizetheresultsofthestudiestoauniformscalebeforetheycanbecom‐bined.Thestandardizedmeandifferenceexpressesthesizeoftheinterventioneffectineachstudyrelativetothevariabilityobservedinthatstudy.
Secondaryprevention Secondarypreventionincludesproceduresthatdetectandtreatpre‐clinicalpathologicalchangesandtherebycontroldiseaseprogression.
SD Thestandarddeviation(SD)isameasureusedtoquantifytheamountofvariationofasetofdatavalues.Ifcloseto‘0’itindicatesthatthedatapointstendtobeveryclosetothemeanofthedataset,whileahighstandarddeviationindicatesthatthedatapointsarespreadoutoverawiderrangeofvalues.
SDMT TheSymbolDigitModalitiestest(SDMT)involvesasimplesubsti‐tutiontask.Usingareferencekey,theexamineehas90secondstopairspecificnumberswithgivengeometricfigures.
Statins Statins(orHMG‐CoAreductaseinhibitors)areaclassofcholes‐terolloweringdrugsthatinhibittheenzymeHMG‐CoAreduc‐tasewhichplaysacentralroleintheproductionofcholesterol.
Strooptest TheStroopeffectisthefindingthatnamingthecolourofthefirstsetofwordsiseasierandquickerthanthesecond.Inpsychology,theStroopeffectisademonstrationofinterferenceinthereactiontimeofatask.
TICS‐m TheModifiedTelephoneInterviewforCognitiveStatus.
VAD Vasculardementiaiscausedbyreducedbloodsupplytothebrainduetodiseasedbloodvessels.Itisthesecondmostcom‐montypeofdementiaafterAD.ThereareseveraldifferenttypesofVADthatdifferinthecauseofthedamageandthepartofthebrainthatisaffected.ThedifferenttypesofVADhavesomesymptomsincommonandsomesymptomsthatdiffer.Theirsymptomstendtoprogressindifferentways.
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Verbalfluencytest Verbalfluencytestsareakindofcognitivetestinwhichpartici‐pantsareaskedtosayasmanywordsaspossiblefromacate‐gory(e.g.animals,fruitsorwordsthatbeginwithaspecificlet‐ter)inagiventime(usually60seconds).
Workingmemory Thepartofshort‐termmemorywhichisconcernedwithimme‐diateconsciousperceptualandlinguisticprocessing.
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2Searchstrategy
OvidMEDLINE(R)In‐Process&OtherNon‐IndexedCitations,OvidMEDLINE(R)Daily,OvidMEDLINE(R)
# Searches Results
1 expDementia/ 128933
2 LewyBodies/ 1591
3 alzheim$.mp. 111287
4 binswanger$.mp. 555
5 cadasil.mp. 996
6 cerad.tw. 501
7 dement$.mp. 98538
8 (ftldorftd$).tw. 3680
9 ((fronto?temporalorcortico?basalorfrontotemporalorcorticobasalorfrontallobe)adj5(degenerat$4ordysfunction$)).tw.
4266
10 (kluveradj5(bucyorbusy)).mp. 249
11 ((lew$2adj5bod$3)ordlbd).mp. 7187
12 (lobaradj5atroph$3adj5(brainorcerebr$2)).tw. 17
13 (mesulamadj5syndrome$).tw. 3
14 (pick$2adj5(disease$1orcomplex)).mp. 3987
15 posteriorcortic$atroph$.tw. 236
16 ((primaryorprogressive)adj5aphasi$).tw. 1311
17 sdat.tw. 648
18 sivd.tw. 118
19 ((subcortic$3orsub?cortic$3)adj5(encephalopath$3orleukoencephalo‐path$3)).tw.
988
20 (dement$oralzheim$).jw. 11541
21 (mesulamorhuntington*).tw. 13555
22 mesulamm.au. 86
23 amentia.tw. 72
24 or/1‐23[demens] 201139
25 Cognition/ 70348
26 expCognitionDisorders/ 68645
27 expMemoryDisorders/ 24068
28 ((cognit$ormemor$ormental$)adj5(disabil$ordisabl$ordeclin$ordefect$orimpair$orlos$ordeteriorat$)).tw.
93040
29 (memoryadj(deficitordisorder$)).tw. 3200
30 ((cognit$orbehavio?r$)adj5symptom$).tw. 20537
78
31 (cognit$adj2(abnormal$ordisorder$)).tw. 5387
32 (mci$1orcind$1).tw. 12363
33 or/25‐32[mildkognitivsvikt] 227065
34 PrimaryPrevention/orSecondaryPrevention/ 16433
35 pc.fs. 1077475
36 prevent*.ti,ab. 1016676
37 (earlyadj3(intervention*ortherap*ortreatment*)).ti,ab. 80321
38 or/34‐37[forebygging] 1855764
39 (24or33)and38 34224
40 systematicreview.kw. 1529
41 (((systematic*orliteratureorintegrative)adj3(overvieworreview*orsearch*))ormeta‐analys*).ti,ab.
312951
42 meta‐analysis.pt. 54768
43 or/40‐42 324678
44 39and43 1198
45 limit44toyr="2009‐Current" 687Embase1974to2014November20
# Searches Results
1 expdementia/ 234963
2 expprimaryprogressiveaphasia/ 1783
3 Binswangerencephalopathy/ 411
4 corticobasaldegeneration/ 1655
5 Lewybody/ 5429
6 alzheim$.mp. 152189
7 binswanger$.mp. 845
8 cadasil.mp. 1640
9 cerad.tw. 861
10 cerad.tw. 861
11 dement$.mp. 127933
12 (ftldorftd$).tw. 5250
13 ((fronto?temporalorcortico?basalorfrontotemporalorcorticobasalorfrontallobe)adj5(degenerat$4ordysfunction$)).tw.
5337
14 (kluveradj5(bucyorbusy)).mp. 311
15 ((lew$2adj5bod$3)ordlbd).mp. 10861
16 (lobaradj5atroph$3adj5(brainorcerebr$2)).tw. 24
17 (mesulamadj5syndrome$).tw. 2
18 (pick$2adj5(disease$1orcomplex)).mp. 5211
19 posteriorcortic$atroph$.tw. 348
79
20 ((primaryorprogressive)adj5aphasi$).tw. 1799
21 sdat.tw. 745
22 sivd.tw. 128
23 ((subcortic$3orsub?cortic$3)adj5(encephalopath$3orleukoencephalo‐path$3)).tw.
1202
24 (dement$oralzheim$).jw. 23003
25 (mesulamorhuntington*).tw. 15654
26 mesulamm.au. 85
27 amentia.tw. 81
28 or/1‐27[demens] 280278
29 cognition/ 161153
30 cognitivedefect/ 99835
31 expmemorydisorder/ 52627
32 ((cognit$ormemor$ormental$)adj5(disabil$ordisable$ordeclin$ordefect$orimpair$orlos$ordeteriorat$)).tw.
119465
33 ((cognit$orbehavio?r$)adj5symptom$).tw. 27113
34 (memoryadj(deficitordisorder$)).tw. 4021
35 (cognit$adj2(abnormal$ordisorder$)).tw. 7696
36 (mci$1orcind$1).tw. 19492
37 or/29‐36[mildkognitivsvikt] 341074
38 primaryprevention/ 28363
39 prophylaxis/ 71282
40 secondaryprevention/ 17234
41 pc.fs. 977503
42 prevent*.ti,ab. 1207917
43 (earlyadj3(intervention*ortherap*ortreatment*)).ti,ab. 107582
44 or/38‐43[forebygging] 2005544
45 (28or37)and44 51079
46 systematicreview.kw. 8906
47 (((systematic*orliteratureorintegrative)adj3(overvieworreview*orsearch*))ormeta‐analys*).ti,ab.
363376
48 “systematicreview”/ 81429
49 metaanalysis/ 84604
50 or/46‐49[SR] 404522
51 45and50 1960
52 limit51toyr="2009‐Current" 1161
53 limit52toembase 1157PsycINFO1806toNovemberWeek32014
# Searches Results
80
1 expdementia/ 54112
2 alzheimer'sdisease/ 32737
3 corticobasaldegeneration/ 230
4 kluverbucysyndrome/ 52
5 alzheim$.mp. 43337
6 binswanger$.mp. 425
7 cadasil.mp. 216
8 cerad.tw. 300
9 dement$.mp. 51846
10 (ftldorftd$).tw. 1988
11 ((fronto?temporalorcortico?basalorfrontotemporalorcorticobasalorfrontallobe)adj5(degenerat$4ordysfunction$)).tw.
2368
12 (kluveradj5(bucyorbusy)).mp. 127
13 ((lew$2adj5bod$3)ordlbd).mp. 2583
14 (lobaradj5atroph$3adj5(brainorcerebr$2)).tw. 5
15 (mesulamadj5syndrome$).tw. 2
16 (pick$2adj5(disease$1orcomplex)).mp. 651
17 posteriorcortic$atroph$.tw. 162
18 ((primaryorprogressive)adj5aphasi$).tw. 915
19 sdat.tw. 325
20 sivd.tw. 55
21 ((subcortic$3orsub?cortic$3)adj5(encephalopath$3orleukoencephalo‐path$3)).tw.
231
22 (dement$oralzheim$).jw. 9968
23 (mesulamorhuntington*).tw. 3665
24 mesulamm.au. 3
25 amentia.tw. 194
26 or/1‐25[demens] 79799
27 cognition/ 21672
28 cognitiveimpairment/ 23622
29 expmemorydisorders/ 8217
30 ((cognit$ormemor$ormental$)adj5(disabil$ordisable$ordeclin$ordefect$orimpair$orlos$ordeteriorat$)).ti,ab.
65797
31 ((cognit$orbehavio?r$)adj5symptom$).ti,ab. 20101
32 (memoryadj(deficitordisorder$)).tw. 2843
33 (cognit$adj2(abnormal$ordisorder$)).ti,ab. 4073
34 (mci$1orcind$1).ti,ab. 4157
35 or/27‐34[mildkognitivsvikt] 118087
36 Prevention/ 21979
37 preventivemedicine/ 1763
81
38 prevent*.ti,ab. 150008
39 earlyintervention/ 8704
40 (earlyadj3(intervention*ortherap*ortreatment*)).ti,ab. 18624
41 or/36‐40[forebygging] 169892
42 (26or35)and41 9685
43 "literaturereview"/ 21991
44 metaanalysis/ 3473
45 (((systematic*orliteratureorintegrative)adj3(overvieworreview*orsearch*))ormeta‐analys*).ti,ab.
80629
46 or/43‐45[SR] 96129
47 42and46 429
48 limit47toyr="2009‐Current" 236CinahlS48
S41ANDS45 Limiters‐ExcludeMEDLINErecords;PublishedDate:20100101‐20141231
2
S47
S41ANDS45 Limiters‐PublishedDate:20090101‐20141231 14
S46
S41ANDS45 16
S45
S42ANDS43ANDS44 3,411
S44
TI((((systematic*orliteratureorintegrative)N3(review*orovervieworsearch*))ormeta‐analys*))ORAB((((systematic*orliteratureorintegra‐tive)N3(review*orovervieworsearch*))ormeta‐analys*))
66,155
S43
(MH"MetaAnalysis") 15,067
S42
(MH"SystematicReview") 19,946
S41
S34ANDS40 12,594
S40
S35ORS36ORS37ORS38ORS39 462,399
S3
(MH"PreventiveHealthCare+") 139,635
S38
(MH"EarlyIntervention") 5,908
S37
TI((earlyN3(intervention*ortherap*ortreatment*)))ORAB((earlyN3(in‐tervention*ortherap*ortreatment*)))
14,242
S36
TIprevent*ORABprevent* 136,404
S35
MWpcORMJpc 283,361
82
S34
S24ORS33 90,993
S33
S25ORS26ORS27ORS28ORS29ORS30ORS31ORS32 57,280
S32
TI(mci*orcind*)ORAB(mci*orcind*) 1,848
S31
TI((cognit*N2(abnormal*ordisorder*)))ORAB((cognit*N2(abnormal*ordisorder*)))
876
S30
TI(((cognit*orbehavio?r*)N5symptom*))ORAB(((cognit*orbehavio?r*)N5symptom*))
2,665
S29
TI(((cognit*ormemor*ormental*)N5(disabil*ordisable*ordeclin*orde‐fect*orimpair*orlos*ordeteriorat*))or(memoryW0(deficitordisorder*)))ORAB(((cognit*ormemor*ormental*)N5(disabil*ordisabel*ordeclin*ordefect*orimpair*orlos*ordeteriorat*))or(memoryW0(deficitordisor‐der*)))
16,642
S28
(MH"Memory+") 12,749
S27
(MH"MemoryDisorders+") Searchmodes‐Boolean/Phrase Interface‐EBSCOhostResearchDatabases
3,484
S26
(MH"CognitionDisorders+") 13,114
S25
(MH"Cognition+") 24,111
S24
S1ORS2ORS3ORS4ORS5ORS6ORS7ORS8ORS9ORS10ORS11ORS12ORS13ORS14ORS15ORS16ORS17ORS18ORS19ORS20ORS21ORS22ORS23
43,984
S23
TIamentiaORABamentia 1
S22
AUmesulam 40
S21
TI((mesulamorhuntington*))ORAB((mesulamorhuntington*)) 719
S20
SOdement*oralzheim* 5,022
S19
TI(((subcortic*orsub?cortic*)N5(encephalopath*orleukoencephalopath*)))ORAB(((subcortic*orsub?cortic*)N5(encephalopath*orleukoencephalo‐path*)))
102
S18
TIsivdORABsivd 19
S17
TIsdatORABsdat 17
S16
TI(((primaryorprogressive)N5aphasi*))ORAB(((primaryorprogressive)N5aphasi*))
331
83
S15
TIposteriorcortic*atroph*ORABposteriorcortic*atroph* 51
S14
TI((pick*N5(diseasesorcomplex)))ORAB((pick*N5(diseasesorcom‐plex)))
10
S13
TI(mesulamN5syndrome*)ORAB(mesulamN5syndrome*) 0
S12
TI((lobarN5atroph*N5(brainorcerebr*)))ORAB((lobarN5atroph*N5(brainorcerebr*)))
1
S11
TI(((lew*N5(bodyorbodies))ordlbd))ORAB(((lew*N5(bodyorbodies))ordlbd))
615
S10
TI((kluverN5(bucyorbusy)))ORAB((kluverN5(bucyorbusy))) 6
S9
TI(((frontotemporalorcorticobasalorfrontotemporalorcorticobasalorfrontallobe)N5(degenerat*ordysfunction*)))ORAB(((frontotemporalorcorticobasalorfrontotemporalorcorticobasalorfrontallobe)N5(degenerat*ordysfunction*)))
398
S8 TI(ftldorftd*)ORAB(ftldorftd*) 380S7 TIdement*ORABdement* 21,186S6 TIceradORABcerad 78S5 TIcadasilORABcadasil 120S4 TIbinswanger*ORABbinswanger* 26S3 TIalzheim*ORABalzheim* 12,136S2 (MH"Aphasia+") 3,300S1 (MH"Dementia+") 35,097CDSR#1 MeSHdescriptor:[Dementia]explodealltrees 3863#2 MeSHdescriptor:[LewyBodies]thistermonly 6#3 alzheim*:ti,ab,kw 5076#4 binswanger*:ti,ab,kw 6#5 cadasil:ti,ab,kw 15#6 cerad:ti,ab,kw 16#7 dement*:ti,ab,kw 5327#8 ftldorftd*:ti,ab,kw 53#9 ((frontotemporalorcorticobasalorfrontotemporalorcorticobasalorfrontal
lobe)near/5(degenerat*ordysfunction$*)):ti,ab,kw50
#10 (kluvernear/5(bucyorbusy)):ti,ab,kw 1#11 ((lew*near/5bod*)ordlbd):ti,ab,kw 128#12 (lobarnear/5atroph*near/5(brainorcerebr*)):ti,ab,kw 0#13 mesulamnear/5syndrome*:ti,ab,kw 0#14 pick*near/5(disease*orcomplex):ti,ab,kw 38#15 posteriornextcortic*nextatroph*:ti,ab,kw 1#16 ((primaryorprogressive)near/5aphasi*):ti,ab,kw 11
84
#17 sdat:ti,ab,kw 42#18 sivd:ti,ab,kw 5#19 (subcortic*near/5(encephalopath*orleukoencephalopath*)):ti,ab,kw 15#20 mesulamorhuntington*:ti,ab,kw 184#21 amentia:ti,ab,kw 1#22 #1or#2or#3or#4or#5or#6or#7or#8or#9or#10or#11or#12or
#13or#14or#15or#16or#17or#18or#19or#20or#218991
#23 MeSHdescriptor:[Cognition]thistermonly 4956#24 MeSHdescriptor:[CognitionDisorders]explodealltrees 2823#25 MeSHdescriptor:[MemoryDisorders]explodealltrees 909#26 ((cognit*ormemor*ormental*)near/5(disabil*ordisable*ordeclin*orde‐
fect*orimpair*orlos*ordeteriorat*))or(memorynext(deficitordisor‐der*)):ti,ab,kw
7836
#27 ((cognit*orbehavio*)near/5symptom*):ti,ab,kw 2359#28 (cognit*near/2(abnormal*ordisorder*)):ti,ab,kw 3315#29 mci*orcind*:ti,ab,kw 2920#30 #23or#24or#25or#26or#27or#28or#29 20294#31 MeSHdescriptor:[PrimaryPrevention]explodealltrees 3506#32 MeSHdescriptor:[SecondaryPrevention]explodealltrees 257#33 AnyMeSHdescriptorwithqualifier(s):[Prevention&control‐PC] 77444#34 prevent*:ti,ab,kw 73266#35 (earlynear/3(intervention*ortherap*ortreatment*)):ti,ab,kw 8571#36 #31or#32or#33or#34or#35 131591#37 (#22or#30)and#36PublicationYearfrom2009to2014,inCochraneRe‐
views(ReviewsandProtocols),OtherReviewsandTechnologyAssessments410
CRD
Line Searchfor Hits
1 MeSHDESCRIPTORDementiaEXPLODEALLTREES 612
2 MeSHDESCRIPTORLewyBodiesEXPLODEALLTREES 0
3 (alzheim*) 523
4 (binswanger*) 4
5 (cadasil) 1
6 (cerad) 6
7 (dement*) 825
8 (ftldorftd*) 4
9 ((frontotemporalorcorticobasalorfrontotemporalorcorticobasalorfrontallobe)near5(degenerat*ordysfunction$*))
4
10 (kluvernear5(bucyorbusy)) 0
11 ((lew*near5bod*)ordlbd) 19
12 (lobarnear5atroph*NEAR5(brainorcerebr*)) 0
13 (mesulamnear5syndrome*) 0
85
Line Searchfor Hits
14 (pick*near5(disease*orcomplex)) 5
15 (posteriornextcortic*nextatroph*) 0
16 ((primaryorprogressive)near5aphasi*) 0
17 (sdat) 2
18 (sivd) 2
19 (subcortic*near5(encephalopath*orleukoencephalopath*)) 1
20 (mesulamorhuntington*) 24
21 (amentia) 0
22 #1OR#2OR#3OR#4OR#5OR#6OR#7OR#8OR#9OR#10OR#11OR#12OR#13OR#14OR#15OR#16OR#17OR#18OR#19OR#20OR#21
1083
23 MeSHDESCRIPTORCognitionEXPLODEALLTREES 221
24 MeSHDESCRIPTORCognitionDisordersEXPLODEALLTREES 254
25 MeSHDESCRIPTORMemoryDisordersEXPLODEALLTREES 36
26 ((cognit*ormemor*ormental*)near5(disabil*irdisable*ordeclin*ordefect*orim‐pair*orlos*ordeteriorat*))or((memorynear0(deficitordisorder*))
1392
27 ((cognit*orbehavio*)near5symptom*) 171
28 (cognit*near2(abnormal*ordisorder*)) 297
29 (mci*orcind*) 327
30 #23OR#24OR#25OR#26OR#27OR#28OR#29 2122
31 MeSHDESCRIPTORPrimaryPreventionEXPLODEALLTREES 812
32 MeSHDESCRIPTORSecondaryPreventionEXPLODEALLTREES 89
33 (prevent*) 16401
34 (earlynear3(intervention*ortherap*ortreatment*)) 0
35 #31OR#32OR#33OR#34 16515
36 #22OR#30 2756
37 #35AND#36 649
38 *INDARE,HTAFROM2009TO2014 34131
39 #37AND#38 186
Pubmed241114Search((((((prevent*OR(earlyAND(intervention*ORtherap*ORtreatment*)))))AND((((sys‐tematic*ORintegrativeORliterature)AND(review*ORoverview*ORsearch*))ORmeta‐analys*ORmedlineORpubmedORembase)))AND(((alzheim*ORdement*OR"lewybody"OR"lewybodies"ORbinswanger*ORcadasilORcerdaORftldORftd*OR((frontotemporalORcor‐ticobasal)AND(degenerat*ORdysfunction*))OR(kluverAND(bucyORbusy))ORdlbdOR(lo‐barANDatroph*AND(brainORcerebral*))ORmesulam*OR(pick*AND(disease*ORcom‐plex))OR(posteriorANDcortic*ANDatroph*)ORaphasi*ORsdatORsivdOR(subcortic*AND(encephalopath*ORleukoencephalopath*))ORhuntington*ORamentia))OR((((cognit*or
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memor*ormental*)and(disable*ordisabil*ordeclin*ordefect*orimpair*orlos*ordeterio‐rat*))OR(memorydisorder*ormemorydeficit)or((cognit*orbehavio*)ANDsymptom*)OR(cognit*AND(abnormal*ordisorder*))ORmci*ORcind*)))))ANDpublisher[sb]
SearchHistory:WebofScienceTMCoreCollection
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1,686 #6AND#5Indexes=SCI‐EXPANDED,SSCITimespan=2009‐2014
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TOPIC:(((systematic*ORintegrativeORlitera‐ture)AND(review*ORoverview*ORsearch*)))Indexes=SCI‐EXPANDED,SSCITimespan=2009‐2014
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TOPIC:((((cognit*ormemor*ormental*)and(disabil*ordisable*ordeclin*ordefect*orim‐pair*orlos*ordeteriorat*))OR(memoryand(disorder*ordeficit))or((cognit*orbehavio*)ANDsymptom*)OR(cognit*AND(abnormal*ordisorder*))ORmci*ORcind*))Indexes=SCI‐EXPANDED,SSCITimespan=2009‐2014
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#194,246 TOPIC:((alzheim*ORdement*or"lewybody"
OR"lewybodies"ORbinswanger*ORcadasilORceradORftldORftd*or((frontotemporalORcorticobasal)AND(degenerat*ORdysfunc‐tion*))OR(kluvyAND(bucyORbusy))ORdlbdOR(lobarANDatroph*AND(brainORcerebral*))ORmesulam*OR(pick*AND(dis‐ease*ORcomplex))OR(posteriorANDcortic*ANDatroph*)ORaphasi*ORsdatORsivdOR
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(subcortic*AND(encephalopath*orleu‐koencephalopath*))ORhuntington*ORamen‐tia))Indexes=SCI‐EXPANDED,SSCITimespan=2009‐2014
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3Excludedreviewsandreasonsforexclusion
Table18.Excludedreviewsandreasonsforexclusion.
Firstauthor(refno.)
Reasonforexclusion
Aarsland2010(111) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Barnes2012(112) Notapopulationwithoutdementiadiagnosis
Blondell2014(53) Notasystematicreviewofhighmethodologicalquality(moderate)
Cheng2015(54) Notasystematicreviewofhighquality(moderate)
Cooper2013(55) Notasystematicreviewofhighmethodologicalquality(moderate)
Dangour2010(56) Notasystematicreviewofhighmethodologicalquality(moderate)
Etgen2012(113) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Faucounau2010(114) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Forbes2015(58) Notasystematicreviewofhighmethodologicalquality(lowtomoderatequality).Alsocognitivelyhealthypeopleandcognitivelyimpairedpeoplearenotanalysedseparately.
Fotuhi2009(115) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Franco‐Martin2013(116)
Notasystematicreview(noassessmentofstudies’methodologicalquality)
Gizachew2012(117) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Jiao2014(63) Mixedgroups.Datafrompeoplewithmildtomoderatecognitiveimpairment,werenotseparatelyanalysed.
Kim2014(118) Thereisnofulldescriptionofthesystematicreview(abstractonly)
Kueider2012(119) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Kuiper2015(64) Notaninterventionreview
Law2014(66) Mixedgroups.Datafrompeoplewithcognitiveimpairmentanddementiawerenotseparatelyanalysed
Leung2014(67) Notapopulationwithoutdementiadiagnosis
Li2014(68) Notasystematicreviewofhighmthodologicalquality(moderate).
Ligthart2010(120) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Loef2012(69) Notasystematicreviewofhighmethodologicalquality(moderate)
Lopez‐Leon2013(121)
Thereisnofulldescriptionofthesystematicreview(abstractonly)
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Lourida2013(70) Notaninterventionreview
Maidment2013(122) Notaninterventiontopreventdementia
Martin2011(87) Notasystematicreviewofhighmethodologicalquality(moderatetolowquality)
Mauer2014(123) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Muangpaisan2010(74)
Notasystematicreviewofhighmethodologicalquality(moderate)
Naqvi2013(124) Notasystematicreview(noassessmentofstudies’methodologicalquality)
OoiCheow2011(125) Notapreventioninterventionfordementia
Opie2013(75) Notasystematicreviewofhighmethodologicalquality(moderate)
Ott2015(126) Notapreventioninterventionfordementia
Regan2013(76) Notasystematicreviewofhighmethodologicalquality(low)
Rouch2015(77) Notasystematicreviewofhighmethodologicalquality(moderatequality).Also,cognitivelyhealthyandcognitivelyimpaired(andpeoplewithdementia)arenotreportedseparately
RuizAragon2010(127)
Notapopulationwithoutdementiadiagnosis
Santos2010(128) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Simon2012(129) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Sofi2011(130) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Stern2010(79) Notasystematicreviewofhighmethodologicalquality(moderate)
Stern2009(80) Notasystematicreviewofhighmethodologicalquality(moderate)
Swiger2013(81) Notasystematicreviewofhighmethodologicalquality(moderate)
Tseng2011(82) Notasystematicreviewofhighmethodologicalquality(moderate)
Valenzuela2009(83,131)
Notasystematicreviewofhighmethodologicalquality(moderate)
VanderSchaft2013(132)
Notasystematicreview(noassessmentofstudies’methodologicalquality)
Wald2010(133) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Weih2010(134) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Wong2013(32) Notasystematicreview(noassessmentofstudies’methodologicalquality)
Yang2014(135) Notapopulationwithoutdementiadiagnosis
Zheng2015(86) Notasystematicreviewofhighmethodologicalquality(moderate)
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4Assessmentofmethodologicalquality
WeusedtheKnowledgeCentre’schecklistforsystematicreviewsforassessingthesys‐tematicreviewsincludedinoutoverviewofreviews.Thechecklistconsistsof9questionswhichallanswerswitha‘yes’,‘unclear’or‘no’.1.Didtheauthorsofthereviewclearlydescribewhatmethodstheyusedtoidentifyprimarystudies?2.Wasacomprehensiveliteraturesearchconducted?3.Didthereviewauthorsdescribewhatcriteriatheyusedtoassesstheeligibilityofstudiesforinclusion(studydesign,participants,intervention,andend‐points)?4.Didtheauthorsattempttopreventbiaswhenselectingstudiesbyusingexpliciteligi‐bilitycriteria,andbyindependenteligibilityassessmentofstudiesbyatleasttwopeo‐ple?5.Wasasetofcriteriatoassessinternvalidityoforiginalstudiesdescribed?6.Wasthevalidityofincludedstudiesassessed(eitheratinclusionofprimarystudiesorintheanalysisofprimarystudies)usingrelevantcriteria?7.Werethemethodsusedwhensummarizingtheresultsclearlydescribed?8.Weretheresultssummarizedinanappropriateway?9.Aretheauthors’conclusionssupportedbythedataand/ortheanalysisreportedinthereview?Overallassessmentofeachreview(Question10.Howwillyourankthemethodologicalqualityofthisreview?)isitjudgedasbeing‘high’,‘moderate’or‘unclear’onthebasisofthefollowing: Highquality:Usedifallormostofthechecklistcriteriaareansweredwitha
‘yes’(adequate).Ifsomeofthecriteriaarenotfulfilled,itmustbeclearthatthiswillnothaveaneffectontheconclusionofthereview.
Moderatequality:Usedifsomeofthechecklistcriteriaarenotfulfilledornotsatisfactorydescribed.Theoverallassessmentindicatesthatthelikelihoodthatthiswouldhaveaneffectonthereviewconclusionsisverysmall.
Unclearquality:Usediffewornocriteriafromthechecklistarefulfilled,and/ornotadequatelydescribed.Overallassessmentindicatesthatitislikelythatthereview'sconclusionmaychangeduetothis.
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Table19.Resultsoftheassessmentofthemethodologicalqualityofincludedreviews(n=8).Review 1 2 3 4 5 6 7 8 9
Farina2009 Yes Yes Yes Yes Yes Yes Yes Yes Yes
Lampit2009 Yes Yes Yes Yes Yes Yes Yes Un‐clear
Yes
Mazereeuw2012
Yes Yes Yes Un‐clear
Yes Yes Yes Yes Yes
McGuinness2009
Yes Yes Yes Yes Yes Yes Yes Yes Yes
McGuinness2016
Yes Yes Yes Yes Yes Un‐clear
Yes Yes Yes
Russ2012 Yes Un‐clear
Yes Yes Yes Yes Yes Yes Yes
Sydenham2012
Yes Yes Yes Yes Yes Yes Yes Yes Yes
Young2015 Yes Yes Yes Yes Yes Yes Yes Un‐clear
Yes
Note:NoneoftheincludedreviewshadusedtheGRADEtooltogradethecertaintyoftheevidence,orreportedtheirmainresultsinaSummaryoffindingstable.
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5Ongoingreviews
Table20.Ongoingreviewsandoverviewsofreviews.AuthorYear ProtocoltitleAbraham2015(136) Vitaminandmineralsupplementation
forpreventionofdementiaordelayingcognitivedeclineinpeoplewithmildcognitiveimpairment
Forbes2015(137) Exerciseinterventionsformaintainingcognitivefunctionincognitivelyhealthypeopleinlatelife
Forbes2015(138) Exerciseinterventionsforpreventingde‐mentiaordelayingcognitivedeclineinpeoplewithmildcognitiveimpairment
Forbes2015 Exerciseinterventionsformaintainingcognitivefunctionincognitivelyhealthypeopleinmidlife
Harrison2015(139) Dietaryinterventionsformaintainingcognitivefunctionincognitivelyhealthypeopleinmidlife
Jordan2015(140) Aspirinandanti‐inflammatorydrugsforthepreventionofdementia
Krause2015(141) Dietaryinterventionsasaneuroprotec‐tivetherapyforthedelayoftheonsetofcognitivedeclineinolderadults:anum‐brellareviewprotocol
Siervo2015(142) Dietaryinterventionsformaintainingcognitivefunctionincognitivelyhealthypeopleinlatelife.
Tang2015(143) Dietaryinterventionsforpreventionofdementiainpeoplewithmildcognitiveimpairment
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6Descriptionofincludedreviews
Table21.Descriptionofincludedreviews(listedinalphabeticalorder;n=8).
Farina2009(42) DescriptionofreviewPopulation: People(n=569)withmildcognitiveimpairmentfromtheUSA
andCanadaIntervention: VitaminEsupplements(2000IUperday)for3yearsComparator: PlaceboOutcomes: TimetoprogressiontopossibleorprobableADIncludedstudies: 3RCTs(Lloret2009,Petersen2005*,Sano1996)
*Includedinthisoverviewofreviews(onestudyoutof3). Lampit2014(65) DescriptionofreviewPopulation: Cognitivelyhealthyolderpeople(n=4,885)largelyfromthe
USAorEurope,butalsofromCanada,Australia,Israel,China,TaiwanSpecialAdministrativeRegion,RepublicofKorea,Ja‐panandAustralia
Intervention: >4hourscomputerizedcognitivetrainingComparator: In50%ofstudiesthecomparatorwaspassive(nointerven‐
tion)andintheremainingstudiesthecontrolconditionwasanotheractiveintervention.
Outcomes: Performanceinneuropsychologicaltests(notfurtherde‐scribed).
Includedstudies: 52trials(Ackerman2010;Anderson2013;Anguera2013;Ball2002;Barnes2013;Basak2008;Belchierstudy12013;Belchiorstudy22013;Berry2010;Boot2013;Bottiroli2009;Bozoki2013;Brehmer2012;Burki2014;Buschkuehl2008;Casutt2014;Colzato2011;Dahlin2008;Dustman1992;Ed‐wards2002;Edwards2005,Edwards2013;Garcia‐Campu‐zano2013;Goldstein1997;Heinzel2013;Lampit2014;Lee2012;Legault2011;Li2010;Lussier2012;Mahncke2006;Maillot2012;Mayas2014;McAvinue2013;Miller2013;Nou‐chi2012;O’Brien2013;Peng2012;Peretz2011;Rasmusson1999;Richmond2011;Sandberg2014;Shatil2013;Shatil2014;Simpson2012;Smith2009;Stern2011;Vance2007;VanMuijden2012;vonBastian2013;Wang2011,Wolinski2011).All52trialswereincludedinouroverviewofreviews.
Mazereeuw2012(71)
Descriptionofreview
Population: Cognitivelyhealthypeople(n=1,218),andcognitivelyIm‐pairedpeople(n=670),withnodementiadiagnosisfromthe
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Netherlands,England,Wales,Japan,Australia,IsraelandtheUSA
Intervention: Omega‐3FattyAcidsComparator: PlaceboOutcomes: Changeincognitivetestscores(Immediaterecall;delayedre‐
call,recognition,workingmemoryandexecutivefunction,at‐tentionandprocessingspeed).
Includedstudies: 10trials(3trialsthatincludedcognitivelyhealthypeople:Dangour2010*;Johnson2008*;VandeRest2008*;4RCTsthatincludedpeoplewithCIND(Kotani2006*;Sinn2011*;Vakhapora2010*;Yurko‐Mauro2010*)andthreestudiestar‐getingpeoplewithAD(Chiu2008;Freund‐Levi2006;Quinn2010).Includedinthisoverview(4outof10trials,i.e.thetri‐alsofcognitivelyimpairedpeople).
McGuinness2016(72)
Descriptionofreview
Population: Cognitivelyhealthypeople(n=26,340)aged40to82yearsofwhom11,610wereaged70orolder,andwithevidenceofcer‐ebrovasculardiseaseorathighriskofcerebrovasculardis‐easefromUK,Scotland,IrelandandtheNetherlands
Intervention: Cholesterolloweringdrugsi.e.anymemberofthestatinfam‐ily.Dose:40mgperday.
Comparator: Placebo
Outcomes: Primaryoutcomes:objectivediagnosisofdementia,ADorVADaccordingtostandardcriteria,changeincognitivetestscores(MMSE,ADAS‐cogorotheracceptedobjectiveandstandardizedtests).
Secondaryoutcomes:cholesterollevel;incidenceandseverityofadverseeffects,changeincognitivestatusinpatientsatriskofdementiaontreatmentwithstatinsaccountingforpriorcholesterollevel,APOEgenotypeandcognitivelevel,qualityoflife,changeinActivitiesofDailyLiving(ADL),andchangeinbehaviour
Includedstudies: 2RCTs(HPS2002andPROSPER2002)ofwhichbothwererelevantforthisoverviewofreviews
McGuinness2009(73)
Descriptionofreview
Population: Cognitivelyhealthypeople(n=15,936)withadiagnosisofhy‐pertensionandanaverageageof75.4years(range60to89),
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fromEurope(EastandWest),NorthAmerica,China,andtoalesserextentfromAustralasiaandTunisia.
Intervention: Antihypertensivedrugs
Note:Thereviewauthorsaimedtoincludealsostudiesevalu‐atingnon‐pharmacologicalhypertensiontreatmentinthere‐view,butfoundonlystudiesevaluatingpharmacologicalther‐apy
Comparator: Placebo
Outcomes: Primaryoutcomes:Incidenceofdementia(diagnosedaccord‐ingtostandarddiagnosticcriteriaorthoseappropriateatthetime),changeincognitivetestscores
Secondaryoutcomes:Bloodpressurelevel,incidenceandse‐verityofadverseeffects,andqualityoflife
Includedstudies: 4RCTs(HYVET2008;SCOPE2003;SHEP1991,SystEur1997)Allstudieswereeligibleforinclusioninouroverviewofre‐views.
Russ2012(78) Descriptionofreview
Population: Peoplewithmildcognitiveimpairment(n=5,149)fromtheUSA,Canada,Germany,Singapore,andfromanumberofcountriesthatwerenotnamed
Intervention: Cholinesteraseinhibitors(ofanydosebutatleastonemonths’duration)
Comparator: Placebo
Outcomes: Progressiontodementia,eitheringeneralorspecificsub‐types,sideeffects,
Secondaryoutcomes:changeincognitivetestscores
Includedstudies: 8RCTs(Doody2009,Petersen2005a;Salloway2004;Feld‐man2007,Koontz2005;Narasimhalu2010,Winblad2008(combined)).All8studieswereincludedinthisoverviewofreviews.
Sydenham2012(40)
Descriptionofreview
Population: Cognitivelyhealthypeople(n=4,080),60yearsandolderfromtheNetherlands,EnglandandWales.Inonestudythelocationwasunknown.
Intervention: VitaminEsupplements(capsulesorenrichedmargarine)
Comparator: Placeboorusualmargarine
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Outcomes: Measuresofcognitivefunction,adverseeffectsandadherencetotherapy.
Includedstudies: 3RCTs,ofwhichonetrialincludedtwointerventions(Dangour2010;Geleijnse2011;VandeRest2008highandmediumdose).Allstudieswererelevantforthisoverviewofreviews.
Young2015(85) Descriptionofreview
Population: Cognitivelyhealthypeople(N=754);meanagerangedfrom61to91yearsacrossthestudieswhichwerefromUSA,FranceandCanada
Intervention: Aerobicexercisetraining
Comparator: Nointerventionorotheractiveintervention
Outcomes: Measuresofcognitivefunction,adverseeffectsanddrop‐out.Inaddition,anobjectivemeasureofcardiorespiratoryfitnesswasrequired.
Includedstudies: 11RCTS(Bakken2001,Blumenthal1989,Emery1990a,Fa‐bre2002,Kramer2001,Langlois2012,Legault2011,Madden1989,Moul1995,Oken2006, Panton1990,Whitehurst1991)ofwhichallwererelevantforouroverviewofreviews.
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7GRADEevidenceprofiles
GRADEevidenceprofilesfortheeightincludedreviewsarefoundbeloworganisedinalphabeticalorder.
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Author(s): Flodgren G, Berg R Date: 11.12.15 Question: Vitamin E compared to placebo for prevention of Alzheimer's disease in people with mild cognitive impairment Setting: USA and Canada Bibliography: Farina N, Isaac MG, Clark AR, Rusted J, Tabet N. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD002854. DOI:10.1002/14651858.CD002854.pub3.
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Vitamin E Placebo Relative (95% CI)
Absolute (95% CI)
Possible or probable Alzheimer's disease (follow up: mean 3 years; assessed with: no information)
1 randomised trials not serious not serious not serious serious 1,2 none 76/257 (29.6%) 73/259 (28.2%) HR 1.02 (0.74 to 1.41)
5 more per 1000 (from 65 fewer to 91 more) ⨁⨁⨁◯
MODERATE
HR – hazard ratio; CI: confidence interval 1. Only one study. Relatively small groups. 2. Wide CI overlapping no effec
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Author(s): Flodgren G, Berg R Date: 17.12.15 Question: Computerised cognitive training compared to active or passive intervention for prevention of age-related cognitive decline in cognitively healthy older people Setting: the participants’ homes (unsupervised training) and in other facilities (centre-based group training). Trials mainly from the USA or Europe, with the addition of studies from Canada, Australia, Israel, China, Taiwan Special Administrative region, Republic of Korea and Japan Bibliography: Lampit A, Hallock H, Valenzuela M (2014) Computerized Cognitive Training in Cognitively Healthy Older Adults: A Systematic Review and Meta-Analysis of Effect Modifiers. PLoS Med 11(11): e1001756. doi:10.1371/journal.pmed.1001756
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Computerised cognitive training Active or passive intervention Relative (95% CI)
Absolute (95% CI)
Cognitive test scores (assessed with: no information)
52 randomised trials serious 1 not serious not serious not serious none 2527 2358 - MD 0.22 higher (0.15 higher to 0.29 higher) ⨁⨁⨁◯
MODERATE
CI: Confidence interval; MD: Mean difference 1. Thirty-three of 52 studies at high risk of bias. Eighteen studies were at low risk.
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Author(s): Flodgren G, Berg R Date: 17.12.15 Question: Omega-3 fatty acids to improve cognitive function as compared to placebo for people with cognitive impairment no dementia (CIND) Setting: the Netherlands, England, Wales, japan, Israel and the US Bibliography: Mazereeuw G, Lanctot KL, Chau SA, Swardfager W, Herrmann N. Effects of omega-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol Aging 2012. Jul;33 (7):1482.e17-29.
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Omega-3 fatty acids Placebo Relative (95% CI)
Absolute (95% CI)
Cognitive test scores - Composite memory (follow up: median 14.5 weeks; assessed with: unclear)
4 randomised trials not serious not serious not serious not serious none 349 327 - MD 0.1 higher (0.06 lower to 0.25 higher)
⨁⨁⨁⨁
HIGH
Cognitive test scores - Immediate recall (follow up: median 19.5 weeks; assessed with: unclear)
4 randomised trials not serious not serious not serious not serious none 349 327 - MD 0.16 higher (0.01 higher to 0.32 higher)
⨁⨁⨁⨁
HIGH
Cognitive test scores - Delayed recall (follow up: median 19.5 weeks; assessed with: unclear)
4 randomised trials not serious not serious not serious not serious none 349 327 - MD 0.03 higher (0.12 lower to 0.18 higher)
⨁⨁⨁⨁ HIGH
Cognitive test scores - Recognition (assessed with: unclear)
3 randomised trials not serious not serious not serious not serious none 337 318 - MD 0.03 lower (0.18 lower to 0.13 higher)
⨁⨁⨁⨁
HIGH
Cognitive test scores - Attention and processing speed (assessed with: unclear)
3 randomised trials not serious not serious not serious not serious none 107 86 - MD 0.32 higher (0.03 higher to 0.61 higher)
⨁⨁⨁⨁ HIGH
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Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Omega-3 fatty acids Placebo Relative (95% CI)
Absolute (95% CI)
Cognitive test scores - Working memory and executive function (assessed with: unclear)
2 randomised trials not serious not serious not serious not serious none 277 256 - MD 0.04 higher (0.13 lower to 0.21 higher)
⨁⨁⨁⨁ HIGH
Cognitive test scores - MMSE (follow up: mean 24 weeks; assessed with: MMSE)
1 randomised trials not serious not serious not serious not serious none 242 241 - MD 0.06 lower (0.23 lower to 0.12 higher)
⨁⨁⨁⨁
HIGH
CI: Confidence interval; MD: Mean difference
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Author(s): Flodgren G, Berg R Date: 11.12.15 Question: Blood pressure lowering drugs compared to placebo for the prevention of dementia in cognitively healthy people with hypertension Setting: Western and Eastern Europe, North America, China and to a lesser extent Australasia and Tunisia Bibliography: McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD004034. DOI: 10.1002/14651858.CD004034.pub3.
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Antihypertensive drugs Placebo Relative (95% CI)
Absolute (95% CI)
Incidence of dementia (follow up: median 2.8 years; assessed with: DSM III-R, DSM-IV, ICD 10, MMSE)
4 randomised trials not serious not serious not serious serious 1 none 236/7767 (3.0%) 259/7660 (3.4%) OR 0.89 (0.74 to 1.07)
4 fewer per 1000 (from 2 more to 9 fewer)
⨁⨁◯◯ LOW
Change in cognitive test scores from baseline (MMSE) (follow up: range 1.8 years to 4.5 years; Scale from: 0 to 30)
3 randomised trials not serious serious 2 not serious not serious none 5402 5238 - MD 0.42 higher (0.3 higher to 0.53 higher) ⨁⨁⨁◯
MODERATE
Adverse events (follow up: range 2 years to 4.5 years)
3 randomised trials not serious Serious2 not serious not serious none 1138/6080 (18.7%) 1117/6011 (18.6%) OR 1.01 (0.92 to 1.11)
2 more per 1000 (from 12 fewer to 16 more) ⨁⨁⨁◯
MODERATE
MD – mean difference, OR – odds ratio 1. Wide CI. 2. High heterogeneity: I2=98%.
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Author(s): Flodgren G, berg R Date: 17.12.15 Question: Statins compared to placebo for prevention of dementia in cognitively healthy people Setting: UK, Ireland and the Netherlands Bibliography: McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD003160. DOI: 10.1002/14651858.CD003160.pub3
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Statins Placebo Relative (95% CI)
Absolute (95% CI)
Dementia incidence (follow up: range 3.2 years to 5 years)
1 randomised trials not serious not serious not serious serious 1 none 31/10269 (0.3%) 31/10267 (0.3%) OR 1.00 (0.61 to 1.65)
0 fewer per 1000 (from 1 fewer to 2 more) ⨁⨁⨁◯1
MODERATE
Change in cognitive test scores from baseline (MMSE) (follow up: range 3.2 years to 5 years)
1 randomised trials not serious not serious not serious not serious none 2891 2913 - MD 0.06 higher (0.04 lower to 0.16 higher)
⨁⨁⨁⨁ HIGH
Change in cognitive test scores from baseline (Stroop) (follow up: range 3.2 years to 5 years)
1 randomised trials not serious not serious not serious serious 1 none 2891 2913 - MD 0.8 higher (0.38 lower to 1.98 higher) ⨁⨁⨁◯1
MODERATE
Change in cognitive test scores from baseline (Picture world) (follow up: range 3.2 years to 5 years)
1 randomised trials not serious not serious not serious not serious none 2891 2913 - MD 0.02 higher (0.12 lower to 0.16 higher)
⨁⨁⨁⨁
HIGH
Change in cognitive test scores from baseline (Letter digit test) (follow up: range 3.2 years to 5 years)
1 randomised trials not serious not serious not serious not serious none 2891 2913 - MD 0.01 lower (0.25 lower to 0.23 higher)
⨁⨁⨁⨁ HIGH
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Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Statins Placebo Relative (95% CI)
Absolute (95% CI)
Cognitive test scores- TICS-m at final visit (follow up: range 3.2 years to 5 years)
1 randomised trials not serious not serious not serious not serious none 10269 10267 - MD 0.02 higher (0.12 lower to 0.16 higher)
⨁⨁⨁⨁ HIGH
Adverse effects requiring discontinuation of treatment (follow up: range 3.2 years to 5 years)
2 randomised trials not serious not serious not serious not serious none 13160 13180 - OR 0.94 higher (0.83 higher to 1.05 higher)
⨁⨁⨁⨁
HIGH
CI: Confidence interval; OR: Odds ratio; MD: Mean difference 1. Wide CI.
105
Author(s): Flodgren G, Berg R Date: 11.12.15 Question: Cholinesterase inhibitors compared to placebo for people with mild cognitive impairment no dementia Setting: USA, Canada, Singapore and a number of other countries Bibliography: Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev [Internet]. 2012 [cited CDSR 211114; (9).
Quality assessment № of patients Effect
Quality № of stu-dies Study design Risk of
bias Inconsistency Indirectness Imprecision Other considerations Cholinesterase inhibi-tors Placebo Relative
(95% CI) Absolute (95% CI)
Conversion to dementia (follow up: mean 3 years; assessed with: NINCDS-ADRDA with or without DSM-IV, and without explicit criteria in one study)
2 randomised tri-als
not serious not serious 2 not serious serious none 151/761 (19.8%) 182/769 (23.7%) RR 0.84 (0.70 to 1.02)
38 fewer per 1000 (from 5 more to 71 fewer)
⨁⨁⨁◯ MODERATE
Cognitive test scores - ADAS-Cog (follow up: mean 2 years; assessed with: ADAS-Cog (modified))
4 randomised tri-als
not serious serious 1 not serious serious 2 none 1321 1354 - MD 0.78 lower (1.92 lower to 0.35 higher)
⨁⨁◯◯ LOW
Any adverse event
5 randomised tri-als
not serious serious 3 not serious not serious none 1849/2101 (88.0%) 1737/2106 (82.5%)
RR 1.09 (1.02 to 1.16)
74 more per 1000 (from 16 more to 132 more)
⨁⨁⨁◯ MODERATE
Cognitive test scores - CDR Sum of boxes (follow up: mean 1 years)
2 randomised tri-als
not serious not serious not serious not serious none 632 637 - MD 0.1 lower (0.11 lower to 0.09 lower)
⨁⨁⨁⨁ HIGH
Cognitive test scores- Symbol digit modalities (follow up: mean 6 months)
2 randomised tri-als
not serious serious 4 not serious very serious 5
none 155 157 - MD 0.17 higher (2.87 lower to 3.21 higher)
⨁◯◯◯ VERY LOW
Cognitive test scores -Mini Mental State Examination (follow up: mean 1 years; Scale from: 0 to 30)
2 randomised tri-als
not serious serious 3 not serious serious 6 none 632 637 - MD 0.24 higher (0.13 lower to 0.61 higher)
⨁⨁◯◯ LOW
Cognitive test scores - ADCS-ADL (follow up: mean 1 years; Scale from: 0 to 78)
3 randomised tri-als
not serious not serious not serious serious 5 none 1191 1217 - MD 0.15 higher (0.27 lower to 0.57 higher)
⨁⨁⨁◯ MODERATE
Serious adverse events
106
Quality assessment № of patients Effect
Quality № of stu-dies Study design Risk of
bias Inconsistency Indirectness Imprecision Other considerations Cholinesterase inhibi-tors Placebo Relative
(95% CI) Absolute (95% CI)
5 randomised tri-als
not serious not serious not serious serious 2 none 391/2101 (18.6%) 401/2106 (19.0%) RR 0.97 (0.86 to 1.10)
6 fewer per 1000 (from 19 more to 27 fewer)
⨁⨁⨁◯ MODERATE
MD – mean difference, RR – risk ratio
1. High heterogeneity: I2=98%. 2. Wide CI overlapping no effect. 3. High heterogeneity: I2=79%. 4. High heterogeneity: I2=99% 5. Wide CI overlapping no effect. 6. Wide CI overlapping no effect.
107
Author(s): Flodgren G, Berg R Date: 17.12.15 Question: Omega-3 fatty acids compared to placebo for prevention of cognitive decline and dementia in cognitively healthy older people Setting: England and Wales Bibliography: Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev 2012;6:CD005379. (NB! Also published in Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Sao Paulo Med J 2012;130(6):419.)
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Omega-3 fatty acids placebo Relative (95% CI)
Absolute (95% CI)
Cognitive test scores - MMSE (follow up: range 24 months to 40 months)
2 randomised trials not serious serious 1 not serious not serious none 990 2231 - MD 0.07 lower (0.25 lower to 0.1 higher) ⨁⨁⨁◯
MODERATE
Cognitive test scores -Immediate recall (follow up: range 6 months to 24 months)
3 randomised trials not serious not serious not serious not serious none 472 571 - SMD 0.01 higher (0.11 lower to 0.14 higher)
⨁⨁⨁⨁ HIGH
Cognitive test scores - Delayed recall (follow up: range 6 months to 24 months)
3 randomised trials not serious not serious not serious not serious none 472 571 - SMD 0.04 lower (0.16 lower to 0.09 higher)
⨁⨁⨁⨁
HIGH
Cognitive test scores - Word recognition (follow up: range 6 months to 24 months)
3 randomised trials not serious not serious not serious not serious none 472 571 - SMD 0.04 higher (0.08 lower to 0.16 higher)
⨁⨁⨁⨁ HIGH
Cognitive test scores- Number of animals named (follow up: range 6 months to 24 months)
108
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Omega-3 fatty acids placebo Relative (95% CI)
Absolute (95% CI)
3 randomised trials not serious not serious not serious not serious none 472 570 - SMD 0.06 higher (0.06 lower to 0.18 higher)
⨁⨁⨁⨁ HIGH
Cognitive test scores - Digit span forward (follow up: range 6 months to 24 months)
3 randomised trials not serious not serious not serious not serious none 458 560 - MD 0.03 higher (0.25 lower to 0.31 higher)
⨁⨁⨁⨁
HIGH
Cognitive test scores - Digit span backwards (follow up: range 6 months to 24 months)
3 randomised trials not serious not serious not serious not serious none 458 557 - MD 0.12 higher (0.12 lower to 0.36 higher)
⨁⨁⨁⨁ HIGH
CI: Confidence interval; MD: Mean difference; SMD: Standardised mean difference 1. High I2.
109
Author(s): Flodgren GM, Berg R Date: 27.04.16 Question: Aerobic exercise compared to active or passive control for cognitive decline Setting: USA, France and Canada Bibliography: Young J, Angevaren M, Rusted J, Tabet N. Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database of Systematic Reviews 2015, Issue 4. Art. No.: CD005381. DOI: 10.1002/14651858.CD005381.pub4.
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations primary and secondary prevention interventions control Relative (95% CI)
Absolute (95% CI)
Cognitive test scortes
6 randomised trials serious 1 not serious not serious serious 2 none 389 - - SMD 0.12 SD higher (0.08 lower to 0.33 higher) ⨁⨁◯◯
LOW
Verbal memory function (immediate)
2 randomised trials serious 1 serious not serious serious 2 none 299 - - SMD 0.08 SD higher (0.38 lower to 0.55 higher) ⨁◯◯◯
VERY LOW
Visual memory functions (immediate)
2 randomised trials serious 1 serious not serious serious 3 none 89 - - SMD 0.26 SD lower (0.97 lower to 0.44 higher) ⨁◯◯◯
VERY LOW
Woorking memory
3 randomised trials serious 1 not serious not serious serious 2 none 238 - - SMD 0.1 SD higher (0.16 lower to 0.36 higher) ⨁⨁◯◯
LOW
Memory function (delayed)
110
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations primary and secondary prevention interventions control Relative (95% CI)
Absolute (95% CI)
3 randomised trials serious 1 not serious not serious serious 2 none 249 - - SMD 0.1 SD higher (0.16 lower to 0.35 higher) ⨁⨁◯◯
LOW
Executive functions
6 randomised trials serious 1 serious 4 not serious serious 2 none 367 - - SMD 0.38 SD higher (0.14 lower to 0.9 higher) ⨁◯◯◯
VERY LOW
Perception
3 randomised trials serious 1 not serious not serious serious 2 none 178 - - SMD 0.01 SD lower (0.5 lower to 0.48 higher) ⨁⨁◯◯
LOW
Cognitive inhibition
4 randomised trials serious 1 not serious not serious serious 2 none 314 - - SMD 0.06 SD lower (0.28 lower to 0.17 higher) ⨁⨁◯◯
LOW
Visual attention
3 randomised trials serious 1 not serious not serious serious 2 none 265 - - SMD 0.22 SD higher (0.03 lower to 0.46 higher) ⨁⨁◯◯
LOW
Auditory attention
111
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations primary and secondary prevention interventions control Relative (95% CI)
Absolute (95% CI)
4 randomised trials serious 1 not serious not serious serious 2 none 251 - MD 0.15 higher (0.38 lower to 0.69 higher) ⨁⨁◯◯
LOW
Motor function
2 randomised trials serious 1 not serious not serious serious 2 none 189 - - SMD 0.08 SD higher (0.2 lower to 0.37 higher) ⨁⨁◯◯
LOW
CI: Confidence interval; SMD: Standardised mean difference; MD: Mean difference 1. High to moderate risk of bias in one or more domains., 2. Fewer than 400 particpants., 3.No explanation was provided, 4. High heterogeneity I2=80%
112
Quality assessment № of patients Effect
Quality
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations primary and secondary prevention interventions control Relative (95% CI)
Absolute (95% CI)
4 randomised trials serious 1 not serious not serious serious 2 none 251 - MD 0.15 higher (0.38 lower to 0.69 higher) ⨁⨁◯◯
LOW
Motor function
2 randomised trials serious 1 not serious not serious serious 2 none 189 - - SMD 0.08 SD higher (0.2 lower to 0.37 higher) ⨁⨁◯◯
LOW
CI: Confidence interval; SMD: Standardised mean difference; MD: Mean difference 1. High to moderate risk of bias in one or more domains., 2. Fewer than 400 particpants., 3.No explanation was provided, 4. High heterogeneity I2=80%
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