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REVIEWOpenAccessHIV-associatedneurocognitivedisordersMontserratSanmarti1,2*,LauraIbáez2,SoniaHuertas3,DolorsBadenes3,DavidDalmau1,2,MarkSlevin4,JerzyKrupinski2,3,4,AurelPopa-Wagner5andAngelesJaen2AbstractCurrently,neuropsychologicalimpairmentamongHIV+patientsonantiretroviraltherapyleadstoareductioninthequalityoflifeanditisanimportantchallengeduetothehighprevalenceofHIV-associatedneurocognitivedisordersanditsconcomitantconsequencesinrelationtomorbidityandmortality-includingthoseHIV+patientswithadequateimmunologicalandvirologicalstatus.
ThefactthatthevirusisestablishedinCNSintheearlystagesanditspersistencewithintheCNScanhelpustounderstandHIV-relatedbraininjuryevenwhenhighlyactiveantiretroviraltherapyiseffective.
TherisinginterestinHIVassociatedneurocognitivedisordershaslettodevelopmentnewdiagnostictools,improvementoftheneuropsychologicaltests,andtheuseofnewbiomarkersandnewneuroimagingtechniquesthatcanhelpthediagnosis.
Standardizationandhomogenizationofneurocognitivetestsaswellasnormalizingandsimplificationofeasilyaccessibletoolsthatcanidentifypatientswithincreasedriskofcognitiveimpairmentrepresentanurgentrequirement.
FutureeffortsshouldalsofocusondiagnostickeysandsearchingforusefulstrategiesinordertodecreaseHIVneurotoxicitywithintheCNS.
Keywords:HIV,Neurocognitivedisorders,HANDReviewDisruptionofneurocognitivefunctioningisoneofthemostfrequentcomplicationsinpatientsinfectedwithHIVnowadays.
ThisisacommonreasonforconsultationofHIVpatientsanditnegativelyaffectstheirqualityoflife,treatmentadherenceandlifespan.
SincetheintroductionofHighlyActiveAntiretroviralTherapy(HAART)thespectrumofHIV-associatedneurocognitivedisorders(HAND)hasbeenradicallychangedwithasignificantre-ductionindementiabutwithahighprevalenceofasymp-tomaticandmildneurocognitiveimpairments.
Currently,inclinicalpractice,patientswithHIVarestilladmittedtotheclinicformemory,concentrationorplanificationproblemsevenwhenvirologyisundercontrol.
Theseusu-allybeginwithsubtlechangesbutitcanleadtomorese-vereformsofneurocognitiveimpairment.
Theaimofthisreviewistodescribethedifferenttypesofneurocognitivedisorders,possiblemechanismsofdevelopment,epidemi-ologyandriskfactorsinHIVpatients,aswellastheclin-icalapproachandcurrenttreatmentofHAND.
ClassificationBefore1991,therewasonlyonekindofneurocognitivedisorderdefined,theHIV-associateddementia(HAD),whichwasknownasthecomplexAIDS-Dementia.
Itaf-fectedpatientswithsevereimmune-depressioncausingse-vereimpairmentofcognition,frequentlyaccompaniedbymotorandbehaviouralalterations.
Morerecently,theAmericanAcademyofNeurologyproposedanewclassifi-cationbydefiningtwolevelsofneurologicalimpairmentinpatientswithHIV:theclassicalHADandtheminorcognitivemotordisorder(MCMD)representingpatientsthatdidnotmeetdementiacriteriabutcomplainedofslightimpairmentsthatinterferedwiththeirdailylife[1].
In2007,afurtherrevisedclassificationsystemofHANDwasintroducedwhichisthoughttobemorepreciseandsensitive(FrascatiCriteria).
Itdescribes,besideHAD,othertwoneurocognitivedisorders:MildNeurocognitivedisorder(MND)andAsymptomaticNeurocognitiveim-pairment(ANI).
MNDisdefinedasmildtomoderateim-pairmentwithinatleasttwocognitiveareaswithatleastmildimpairmentofdailyfunction.
ANIisdefinedasanydegreeofneuropsychologicaltestingimpairmentinatleasttwocognitivedomainsbutwithoutcausinganob-servablefunctionalimpairment[2](Seethe"ClassificationofHAND"Section).
Finally,cognitiveneuropsychology*Correspondence:msanmarti@mutuaterrassa.
cat1ServeideMedicinaInterna,UnitatVIH/Sida,HospitalUniversitariMútuaTerrassa,Pl.
Dr.
Robert,5088221,Terrassa,Barcelona,Spain2FundacióDocènciaiRecercaMútuaTerrassa,Terrassa,Barcelona,SpainFulllistofauthorinformationisavailableattheendofthearticleJMP2014Sanmartietal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycredited.
TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
org/publicdomain/zero/1.
0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated.
Sanmartietal.
JournalofMolecularPsychiatry2014,2:2http://www.
jmolecularpsychiatry.
com/content/2/1/2aimstoelucidatethecomponentprocessesofHANDacrossthedomainsofexecutivefunctions,motorskills,speededinformationprocessing,episodicmemory,atten-tion/workingmemory,language,andvisuoperception[3].
ClassificationofHIV-associatedneurocognitivedisordersAsymptomaticneurocognitiveimpairment(ANI)1.
Noevidenceofpreexistingcause.
CognitiveimpairmentmustbeattributabletoHIVandnootheretiology(e.
g.
dementia,delirium).
2.
Thecognitiveimpairmentdoesnotinterferewithactivitiesofdailyliving.
3.
Involvesatleasttwocognitiveareas(memory,attention,language,processingspeed,sensory-perceptual,motorskills)documentedbyperform-anceof>1standarddeviationbelowthemeanofstandardizedneuropsychologicaltesting.
Mildneurocognitivedisorder(MND)1.
Noevidenceofpreexistingcause.
CognitiveimpairmentmustbeattributabletoHIVandnootheretiology(e.
g.
dementia,delirium).
2.
Atleastmildinterferencein>1activitiesofdailylivingincludingmentalacuity,inefficiencyatwork,homemakingorsocialfunctioning.
HIV-Associateddementia(HAD)1.
Noevidenceofanotherpreexistingcausefordementia(i.
e.
CNSinfections,CNSneoplasm,cerebrovasculardisease).
2.
Markedinterferenceinactivitiesofdailyliving.
3.
Markedcognitiveimpairmentinvolvingatleasttwocognitivedomainsbyperformanceof>twostandarddeviationbelowthemeanofstandarizedneuropsychologicaltests,especiallyinlearningofnewinformation,slowedinformationprocessinganddefectiveattentionorconcentration.
NeuropathogenesisThereasonforneurocognitivedisordersinHIV-patientsisstillunclear.
Itiswellknownthatthecentralnervoussys-tem(CNS)isoneofthetargetorganswhereHIVcanbedetectedsoonafterprimaryinfection.
Earlyneuro-invasionischaracterizedbymeasurablemarkersofCSFinflammation(eg,neopterinlevel)andbybrainparenchy-malinflammationdetectedbymagneticresonancespec-troscopy(MRS),althoughchangesinneurocognitivefunctioningareseenmoreclearlyinadvancedstages[2,4].
HIVentersthebraincarriedwithinmigratingmonocytesandlymphocytesthatcrossthebloodbrainbarrier(BBB)andpossiblyCD4+Tlymphocytesthatusethebrainasareservoirforviralreplication.
AftercrossingtheBBB,HIVinfectedmonocytesbecomeactiveperivascularmacro-phagesbeingabletoproduceHIVwithintheCNS,releasefreevirionsandfacilitateinfectionofmicroglialcells[5].
BothcellstypesallowHIVreplicationconcomitantwithex-pressionofneurotoxicmolecules-thoughttobetheonesin-volvedinthepathogenesisofHAND[6](eg.
solubleimmunemediators).
AstrocytesmayalsoharbourHIVandcontributetoHIV-relatedbraindiseasethroughmechanismsofastrogliosisinducedbylocalchemokinesandcytokinesleadingtoincreasedBBBpermeabilityandconsequently,monocyteandlymphocytemigration.
Neuronsarenotpro-ductivelyinfected.
AutopsystudiesofAIDSpatientswithHADshowscharacteristicwhitematterchangesanddemyelination,microglialnodules,multinucleatedgiantcellsandperivas-cularinfiltrates[7].
Avarietyofproteinsencodedbytheviralgenomewereidentifiedasneurotoxicagents,includ-inggp120,thevirus'senvelopeprotein,andtransactivatoroftranscription(Tat).
Gp120isnecessaryforinfectivity,butalsointeractswithhostcellularreceptorstoalterglu-tamatepathwaysignalingandinducecytokineproductionthatcaninjureneuronsandaffecttheactivationstateofmicrogliaandastrocytes.
Tatproteinwhichisproducedbyinfectedastrocytes[8]hasbothneurotoxicandproinflammatoryfeatures.
Insev-eralstudieswhereTat-expressingastrocyteswereinjectedintotheratdentategyrusitcauseddendriticlossandneur-onalcelldeath[9].
Furthermore,itisknownthatthevirusisnotevenlydistributedintheCNS.
DifferentareasofthebrainaremoresusceptibletoHIVduetothepresenceofin-dividualviralgeneticconditionsandcharacteristicsofthehost[10].
TheregionsinwhichHIVismostprevalentarebasalgangliaandthehippocampus,andtoalesserextentinthecortexandcerebellargreymatterofthemid-frontalcor-tex.
Thesefindingscorrespondwithneuropsychologicalim-pairmentofthefronto-subcortical-regionanddysfunction,correspondingtofrontalandsubcorticalareas[11].
PatientsinfectedwithHIVfrequentlyhaveco-morbidconditionsthatmaycontributetooramplifythepathogenicityofHIV,thushavinganimportantroleinthedevelopmentofneuro-cognitiveimpairment(e.
g.
drugabuseandalcoholorinfec-tionwithviralco-pathogenssuchashepatitisCvirus)[12].
OtherfactorsthatmaycontributetoHANDarethepro-longedsurvivalofHIV-infectedpatients,therebyextendingthebrain'sexposuretoHIVvirionsandproteins,theuseofincreasinglytoxiccombinationsofpoorlypenetratingdrugsinhighlyantiretroviral-experiencedAIDSpatients,andse-lectionofmorevirulentHIVstrainswithhigherreplica-tionratesandgreatervirulenceinneuraltissues.
Edenandcolleaguesfoundthatasubstantialnumberofpa-tientsstillshowsignsofmacrophage/microgliaactiva-tionevenafter4yearsofviralsuppressionwithHAART[13].
Allthesefactorsconvergeinproducingdamagetodendritesandsynapsesleadingtothedisruptionofthehighlyintegratedfunctioningofneuralsystemsthatisrequiredtoprocessinformation,leadingtoHIV-associatedneurocognitivedisorders.
Sanmartietal.
JournalofMolecularPsychiatry2014,2:2Page2of10http://www.
jmolecularpsychiatry.
com/content/2/1/2EpidemiologySeveralstudiesdemonstratedthatneurocognitivedeficitsaremorecommoninHIV+patientsthantheHIV-popu-lation,andthesedeficitswereindependentofeitherART,ordiseasestate[14,15].
However,onerecentstudydem-onstratedsimilarratesofcognitiveimpairmentbetweenasubgroupofHIV+patients,withahighCD4levelandHIVviralsuppressionascomparedwithHIV-controls[16].
AhighprevalenceofHIV-associatedneurocognitivedisorders(HAND)isassociatedwithachangeinthepat-ternofHANDandwithanincreasedprevalenceofmilddiseasevsdementia[17,18].
BeforetheintroductionofHAART,theHIV-associatedneurocognitiveimpairmentwascategorizedasAIDS-dementiacomplex,HIVenceph-alitisorencephalopathy,withanestimatedprevalenceof16%inpatientswithadiagnosisofAIDS[19].
However,inthepost-HAARTera,theprevalenceofdementiaisesti-matedtobelessthan5%[17,20].
Incontrast,itappearsthatmildcognitivedisordersareverycommondespitetreatment[17].
TheprevalenceofHANDisestimatedinapproximately40-50%ofallcases.
Mildneurocognitivedisorder(MND)andAsymptomaticNeurocognitiveImpairment(ANI)arenowmorecommonthanHAD.
Inacross-sectionalstudyconductedinSwitzerland,therewasaprevalenceofHANDin85%ofpatientswithevidenceofcognitivede-cline,and64%amongthosewhodidnotdemonstrateanydeterioration.
Inthefirstgroup,24%hadANI,52%MNDand8%HAD,whileinthesecondgroup60%hadANI,4%MNDand0%HAD.
Subclinicalalterationsthatdonotaffectthefunctionalityofthepatientsoraltertheirdailylivesarethemostfrequentinbothgroups[17].
Inacross-sectionalstudyconductedon1555HIVinfectedpatientstheCNSHIVAnti-RetroviralTherapyEffectsResearch(CHARTER)foundthat52%hadHAND,ofwhich33%hadANI,12%MNDand2%HAD.
Theprevalenceofim-pairmentscorrelatedwiththenumberofpatientcomor-bidities[20].
Anotherstudyshoweda48%rateofoccurrenceofcognitivedeclineinHIV-infectedpatients[21],whilsttheAquitainecohortfoundaprevalenceof58.
5%TNAVs,20.
8%ANI,31%MND,and6.
7%HAD[18].
InSpain,averyrecentmulticenterstudyconductedbyquestionnaire,foundthat50%oftheHIV+populationcomplainedofcognitiveimpairments.
Ahighproportionofthem(72.
1%)believedthattheircognitiveimpairmentsinterferedwithdailylifeactivity[22].
ProgressionandimplicationTherealclinicalrelevanceofANIisnotclear.
Itdoesnotinterferewithdailylifeandinaddition,itisnotproventhatANIpatientsareatincreasedriskofprogressiontomoreadvancedstagesofdeterioration.
Moreover,therearenosatisfactorybiomarkersorclinicalprognostic/diag-nosticindicatorsassociatedwiththissubgroupofpatientsthatcandetermineevolutionandend-point.
TheCHAR-TERstudyreportedpreliminaryresultsofmonitoringat18and42months.
Theproportionofpatientswithwors-eningneurocognitivefunctionaccordingtotheirbasalHANDclassificationwasdifferentineachgroup(ANI-23%,MND-30%,notTNAV-13%),howevertherewasnostatisticallysignificantdifferenceinmeandeclineinneu-rocognitivefunctionbetweenANIandMNDgroups[23].
Fromaprospectivecohort,ACTGLongitudinalLinkedRandomizedTrials(ALLRT)of1160patientsfromclinicaltrials,921wereexaminedusingneuropsychologicaltests,andweresubsequentlyfollowedfor48weeks.
Thepreva-lenceofHANDwas39%atinclusion,ofthem44%im-provedafteroneyear.
Incontrast,ofthosepatienswithoutHAND,21%developedworsecognitivefunction[24].
RiskfactorsTheriskfactorsassociatedwithneurocognitivedisordersarenotwellestablishedinthepostHAARTera.
Theymayincludehostfactors(e.
g.
geneticpredisposition,metabolicdisorders,cardiovascularriskfactororaging),HIV-relatedfactors(AIDS,immuneactivation,drugresistance)andco-morbiditiessuchashepatitisCvirusco-infectionordepres-sion.
Poorimmunologicalstatus,reflectedbylowernadirCD4cellcount,hasbeenassociatedwithneurocognitiveimpairmentbeforeandafterHAART[20,24,25].
However,otherstudiesdidnotfindthisassociationwiththeCD4levels[17,18,26].
ThecorrelationwithvirologicalstatusisevenlessclearintheHAARTera[17,18,26].
Olderagewasassociatedwithneurocognitiveimpairment[18,21,25]andHAD[27].
Valcourandcollaborators[27]foundabout3-foldincreasedriskofHADinpatient>50yearscomparedwiththosebetween20to39yearsold,independentlyofotherfactors.
Harezlakandco-workersfoundanassoci-ationbetweenageandmarkersofbraininjuryinHIVin-fectedpatientsascomparedwiththosebeingHIVnegative[21].
However,inotherstudiestherewasnotahigherage-relatedimpairmentofneuropsychologicalfunctionbetweenHIV+andHIV-populations[28].
Comorbidities,suchascoinfectionwithhepatitisCvirus(HCV),werefoundtobeariskfactorforthepresenceofHAND[25,29]thatcouldbeexplainedbyanindependentneurotoxiceffectofHCV.
Othercomorbiditiesasobesityanddiabeteswereassociatedwithneurocognitiveimpairment,especiallyinolderpatients[30].
Dataonneuropsychiatricsymptomsincoinfectedper-sonsareinconclusiveatthistime.
Withregardofdepres-sionwasthemostcommondisorderbyfar,reachingratesof71%and62%forpastdepressionincoinfectedandHIV-infectedpersons,respectively,and42%forcurrentratesinbothgroups.
Pastdysthymia,pastposttraumaticstressdisorder,andchildhoodconductdisorderwerethenextmostprevalent,withratesforeachrangingbetween16%and19%inbothgroups[31].
OthercardiovascularSanmartietal.
JournalofMolecularPsychiatry2014,2:2Page3of10http://www.
jmolecularpsychiatry.
com/content/2/1/2riskfactorsanddiseaseswereassociatedwithlowercogni-tiveperformance[18,32].
Hostgeneticfactorssuchasapo-lipoproteinE4havebeensuggestedaspossibleriskfactorsforneurocognitiveimpairment[33].
Whilstinthegeneralpopulation,sub-groupswiththeApoE4allelehaveaworseprognosisforneurodegeneration[34],thisriskislessclearintheHIV+population[35,36].
ClinicalfeaturesThelandmarkofneuropsychologicalimpairmentinpa-tientsinfectedwithHIVhaschangedinrecentyearspar-ticularlyaftertheintroductionofHAART.
Currently,mostpatientswithalterationsinneurocognitivetestshavenoevidentsymptomsordysfunctionintheirdailylives(ANI).
Ithasbeendemonstratedthattheneurocognitiveimpair-mentinearlystagesofinfectionshowsasubcorticalpatternandinmoreadvancedstagesimplicatesmorecorticalareas.
Themaincognitivecomplaintsofthepatientswithmildcognitivedysfunctioninvolvesubtlechangesinworkingmemoryandattention,speedofinformationalprocessing,executivefunctioning(includingorganizing,planningandproblem-solving)ordifficultiesinverbalfluency.
Motorsymptomsarelesscommonbutcanincludelegweakness,tremororunsteadygait.
HAD,however,isoftencharacter-izedbyaprogressingsubcorticaldementiawithclassicallyseverememorylossandalteredexecutivefunction.
Moreadvancedstagesalsoshowaphasia,agnosiaandapraxia,thataremoretypicalofcorticaldementiassuchasAlzhei-mer'sdisease.
OtherneurobehavioraldisturbancesresultingfromHIV-mediatedneuraldamageincludeemotionalandotherbehaviouraldisturbances(e.
g.
depression,anxiety,sleepdisorders,maniaandpsychosis)[37].
DiagnosisAnyindividualwithHIVinfectioncouldbeatriskofdevelopingHAND[38].
Therefore,theneedforasys-tematicstudyofcognitiveHIVinfectedindividualsseemsincreasinglyevident.
AlthoughmanydifferentstudiesassessingneurocognitiveimpairmentinHIVin-fectionhavebeenpublished,astandardapproachtoop-timallyassessingneuropsychologicaldeficitsdoesnotcurrentlyexist.
Multipleclinicaltestsareavailableforuseinordertoevaluateneurocognitivefunctional-thoughthereiscurrentlynosingleanduniversalneuro-psychologicalbatterytoassessspecificallypeoplewithHIV.
Evaluationofthedifferentcognitivefunctionsre-quiresaconcertedeffort(2–4hours)withtheneedforexpertstaffspecializedinclinicalneuropsychologywhohastoevaluateatleastfiveofthefollowingcognitiveabilities:verbal/language,attention/workingmemory,abstraction/executivefunctioning,learning/recall,speedofinformationalprocessing,andsensory-perceptualandmotorskills.
Thishasledtotheneedforscreeninginstrumentsthat,althoughmaybeusefulintheinitialscreening,areinsufficienttomakeagoodneuropsycho-logicaldiagnosiswithinclinics.
Theclassictests-mini-mentalstateexamination(MMSE)orMontrealcognitiveassessment(MoCA)arenotsufficientlysensitivetoscreenforHANDunlessthepatientsaresymptomatic[39].
TherearespecificscreeninginstrumentsforassessingtheHIVDementiaScaleHAND(HDS)[40],TheInter-nationalHIVDementiaScale(IHDS)[41]ortheMon-trealcognitiveassessment(MoCA)[42].
Allthesetestscanbeperformedinlessthantenminutes.
OthertestsoftenusedinconjunctionwiththeseincludetheBriefNeurocognitiveScreen(BNC)[43],screeningbatteryofHNRC[44],computedCOGSTATE[45]orNeuScreen-ing[46].
ThediagnosisofHANDisconfirmedbytheclinicaldetectionofcognitiveimpairmentthroughneuropsychologicaltestingandtheevidenceofneuro-cognitiveimpairment.
Cognitiveimpairmentmustbeat-tributabletoHIVafterexcludingothercausesthatcanjustifythedisorder(Figure1).
DifferentialdiagnosisThedifferentialdiagnosisofneurocognitivedisordersas-sociatedwithHIVinfectionspresentswithtwodifficulties:1)todiscardallthepathologiesthatcanleadtoneurocog-nitivedisordersinthegeneralpopulation,associatedornotwithHIV;2)todeterminethedegreeofcontributionofcertaincomorbiditiesassociatedwithHIVinfection,be-foreattributingneurologicaldamagetoHIVitself.
Thisgroupmayactastruecomorbidityconfounderswhileattemptingtodiagnoseaneurocognitivedisorderinpa-tientsassociatedwithHIVinfection[47].
Whenthepres-enceofneurocognitiveimpairmentissuspected,anexhaustivestudyhastobedoneinordertodetectotherpotentialcausesofneurocognitiveimpairment,includinglaboratorytestingofvitaminB12,folatelevel,TSH,syph-ilis,hepatitisC,glucoseandvitaminB1aswellasscreen-ingfordyslipidaemia.
Sometimes,itisnecessarytoexamineCFSespeciallywhenthereareothersignsofCNSinfection,fever,CD4cellcountsbelow200cells/mm3orpositiveserologyforsyphilis.
Othertestingshouldincludescreeningformajordepres-sionandanxiety,prescriptionofpsycho-pharmacologictreatmentsandidentificationofself-abuseofothersub-stances.
Frequently,patientspresentothercomorbiditiessuchaspsychiatricillness,vascularcerebraldisease,oppor-tunisticinfections,alcoholanddrugsabuse.
Allthesefac-torscancauseneurocognitivedisordersorcontributetoHANDprogression[2].
Itisarequirementtoknowtherealimpactofcomorbiditiesinordertofindnewpreventionandtreatmentstrategies.
ThereisagrowinginterestinfindingbiomarkersthataresensitiveandspecificforHAND.
Oneofthemostreliablebiomarkercurrentlyusedformonitoringdiseaseprogres-sionandHAARTeffectivenessisCD4cellcount.
CountsSanmartietal.
JournalofMolecularPsychiatry2014,2:2Page4of10http://www.
jmolecularpsychiatry.
com/content/2/1/2above200cells/mLarerarelyassociatedwithdementia[48,49].
DetectionofHIVRNAconcentrationintheCSFcanalsobedetermined.
ThepresenceofHIVRNAinCSF,evenathighconcentrations,isnotdiagnosticforHANDandcognitivelyasymptomaticsubjectsmayhavehighViralLoad(VL).
IntheCHARTERstudy,pa-tientswithCSFVL4yearsofeffectivehighlyactiveantirretroviraltherapy.
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