Review of Dementia.ppt

ReviewofDementia,Introduction,DEMENTIAISALARMINGLYREVALENTintheelderlypopulation65+:5%,85+:50%Itisessentialtodiagnosedementiaaccurately,sothatappropriateinterventionscanbeimplementedCurrently,theunderdiagnosisrateofdementiainprimarycaresettingsisashighas75%Severalcausesofdementiaaretotallyreversible,althoughthevastmajorityofdementiasarenotreversible,DiagnosingDementia,Dementiavs.MildCognitiveImpairmentvs.NormalAgingTheDifferentialDiagnosisofDementia,Memoryimpairment,Clinicalhistorymemory,language,orientationactivitiesofdailylivingsocial,community,andintellectualfunctionsjudgmentproblemsolvingabilitiesbehavioralchangespsychiatricsymptomsCourseofdeterioration,Memoryimpairmentisanecessarybutnotsufficientcriterionforthediagnosisofdementiaaphasiaapraxiaagnosiaimpairmentofexecutivefunctioning,Moreover,thesedeficitsmustresultinimpairmentofsocialoroccupationalfunctioningandrepresentasignificantdeclinefromapersonspreviousleveloffunctioning,Toaverylimitedextent,somecognitivechangesobservedinADoccurinnormalagingNeuropsychologicaltestingreliablydistinguishesamongchangesassociatedwithnormalaging,mildcognitiveimpairment(MCI)andearlyAD,MCIIncontrasttodementia,MCIisdefinedasimpairmentinmemoryonly,withothercognitivefunctionssparedMCIisasyndromethatinasubgrouprepresentstheearlieststagesofADApproximately15%ofpatientswithMCIwillprogresstoADwithinayear,orupto70%in45years,TheDifferentialDiagnosisofDementia,ComprehensivehistoryPhysicalexaminationincludingneurologicalevaluationLaboratorytestsCognitivetestingNeuroimagingtoruleoutvascularlesions,tumors,subduralhematomasandnormalpressurehydrocephalus,Typesofdementiainpopulation65+,Alzheimersdisease(AD),ADandvasculardementiaarethemostcommonillnessesinthedifferentialdiagnosisofaprogressive,irreversibledementiaADaccountsfor55%ofalldementiasandvasculardementiaforapproximately15%Otherimportantetiologiesforirreversibledementia:LewybodydementiafrontotemporaldementiaParkinsonsdisease(PD),AD,Contrarytopriorthinking,ADisadiagnosisofinclusion,notexclusion,AIDSdementia,ItisimportanttoincludeHIVinfectionandAIDSdementia,whicharenotrev-ersibleandarefoundintheelderlyThemajorityofthesediagnosesaccountfor510%ofdementias,Vasculardementia,FollowingAD,vasculardementiaisthemostcommondementiainthegeriatricpopulationintheU.S.andWesternEuropeThecriteriafordiagnosingischemicvasculardementiarequireevidenceofatleastoneinfarct(corticalorthalamic)thathasatemporalrelationshiptotheonsetofdementia,Mixeddementia,ThereisapreexistingdiagnosisofADthatiscomplicatedbyastroke,withasubsequentdeclineincognitivefunctioningAnADcoursedevelopsaftertheevidenceofasinglestrokethatcausedacognitivedecline,PathophysiologyofAD,NeuriticplaquesTanglesNeuronallossNeurochemicalabnormalities,Amyloidprecursorprotein(APP),ExtracellularamyloidplaquesareformedfromAPPAPPisatransmembraneproteinAPPiscleavedbysecretasestoformeithera1-40or42basepairA,orasolubleproductofanotherlength3secretases:,andA1-40orA1-42aggregatetoforminsoluble-pleatedsheetfibrils,whichformthenidusofplaque,Amyloid-plaque,Amyloid-plaque-relatedneurotoxicityleadstocelldeathbyattractinginflammatoryproductsSomeplaqueisseeninnormalagingbrain,butitisthedensityoftheplaqueandnotthenumberthatcorrelateswithcognitiveimpairmentanddiseaseseverityinAD,Neurofibrillarytangles,AbnormaltauproteinproductionTauisusedtostabilizemicrotubulesWhentauisabnormallyhyperphosphor-ylated,itformspairedhelicalfilaments,whichdistortthearchitectureofmicrotubulesintotanglesTheseneurofibrillarytanglesimpedethedeliveryofneurotransmittersalongtheaxonsandcontributetocelldeath,Neuronalloss,Attributedto:neurotoxicityofplaques,tangles,degenerationofthecholinergicsystemNucleusbasalisofMeynert(nbM)Affects:corticalandsub-corticalstructuresAtrophyisdemonstratedonimagingandautopsyEarly:PETandSPECTshowreducedmetabolisminthehippocampusandentorhinalcortexProgress:medialtemporalstructuresandthetemporoparietalassociationcortex,Neurochemicalabnormalities,Neurotransmittersacetylcholine,norepinephrine,dopamineNeuropeptidessomatostatin,corticotropin-releasingfactorModerate-to-advancedcasesAch,NERapidlyprogressiveorlessthan65yearsNE,serotoninThecholinergicdeficithasbeenfoundtocorrelatewithsymptomseverityinAD,Genes,AccountsforonlyasmallpercentageofcasesGenetictestingisnotroutinelydoneChromosomes21,19,14,and1ApointmutationintheAPPgeneisassociatedwithfamilialearlyonsetAD-chromosome21Thepresenilingenesaretransmittedasautosomaldominantwithvariablepenetrance,andhavebeenimplicatedinfamilialAD-chromosome14,1ApoEisacholesterol-carryingproteinthatmaybeinvolvedinplaquemetabolism-chromosome19,Presenilin,Presenilin1chromosome14Presenilin2chromosome1Membrane-boundproteinsofunclearfunctionMayalterAPPprocessingbypromotingamyloidogenicAPresenilin1mutationsaccountforapproximately50%ofearlyonsetfamilialADPresenilinsmayprovetobeassociatedwiththeandsecretasesThesecretase,alsocalledBACE(forbeta-siteAPP-cleavingenzyme),hasbeenclonedandprovideshopeforthedevelopmentofinhibitorstotheproductionofamyloidogenicA,APOE,APOEgenotypeisrelatedtoplaquedensityandtoincreaseinamyloiddepositioninADAPOE1,2,3,4,5APOE1and5APOE2allelemayconferprotectionfromamyloiddepositionTheAPOE3allele:doesnotseemtoconferriskorbenefit,mostcommonTheAPOE4alleleisassociatedwithincreasedriskofAD-rangesfrom2550%earlieronset,earliermortality,moreseverecourseAPOE4doesnotprecludeADanditspresencedoesnotinvariablyleadtoAD,ManagementofAD,PharmacologicManagementNewDirectionsforTreatmentPsychosocialManagement,PharmacologicManagement,AChE-IsNeuroprotectivestrageties,AChE-Is,FourFDA-approvedtreatmentsforAD-AChEIsMild-to-moderateADAChE-Isdifferintermsoftargetenzymes,allostericmodulationofthenicotinicreceptor,half-life,andsideeffectprofileTacrinehydrochloride(Cognex)Rivastigrivastigminetartrate(Excelon)Donepezilhydrochloride(Aricept)Galantaminehydrobromide(Reminyl),Tacrinehydrochloride,NolongerusedItwasassociatedwithincreasedhepaticenzymesand/orgastrointestinalintoleranceinmorethan50%ofpatients,Rivastigrivastigminetartrate,NauseaandvomitingActonthebutylcholinesteraseinthegastrointestinaltract,Donepezilhydrochloride,Increasearousalanddisturbsleepmorethantheothermedications,Galantaminehydrobromide,ThenewestFDA-approvedtreatmentinhibitsacetylcholinesteraseandallostericallymodulatesthenicotinicreceptorGalantaminehasbeenstudiedinmixedAlzheimersandvasculardementia,andwasshowntobeeffectiveinmaintainingcognitionandbehavior,CautionshouldbeusedinstoppinganAChE-Is,asthereisoftenamarkeddeclineincognitionandfunctionwhendiscontinuedTherearenoavailablestudiescomparingtheeffectivenessofoneagenttotheotherAllagentsshowsomeimprovementincognitionTheselectionofacholinesteraseinhibitorshouldbebasedoneaseofdoseadministrationandtolerability,Neuroprotectivestrageties,AimatslowingprogressioninADAntioxidants:VitEReducedamageofexcessiveROSEstrogenreplacementtharapyincreasedendriticspinesinhippocampalcellsandenhancelearningDecreaseriskofADAnti-inflammatoryagentsTargetthecentralnervoussysteminflammatoryresponseobservedinAD,NewDirectionsforTreatment,ProtectionofneuronsDegenerationofcholinergiccellsfromglutamatemaybemitigatedwithmemantine,anNMDAreceptorantagonist;thisstrategymayslowcognitivedeclineinADCholesterol-loweringstatins,forexample,mayloweramyloidinthebodyanti-amyloidaggregativeagentsInterventionsaimedatdecreasingplasmahomocysteine:folicacid,pyridoxinecobalaminInhibitorsofthesecretases:targetthepresenilingene,Insummary,thecurrentevidence-basedregimenforADpatientsincludesacholinesteraseinhibitorandvitaminEContinuetreatmentwiththeAChE-IsAnti-inflammatoryagentsandestrogenreplacementtherapymaydecreaserelativerisk,PsychosocialManagement,Adialoguebetweentheclinician,patient,family,lovedonesandcareUnde