神经系统疾病

NSCS730:FundamentalsofNeuroscience

ModuleC

NeurologicalDiseases:HumansApril20,2022JaneE.Joseph,PhDLearningobjectives:Thehealthyagingbrain(Ch.59)Dementia:Alzheimer’sDisease(Ch.59)LanguageDisorders:AphasiaandAlexia1.ThehealthyagingbrainIndividualvariabilityincognitivedeclineinhealthyaging:PeoplevaryintheageatwhichcognitivescoresdeclineVariousformsofmemorydeclinebutvocabularyremainsfairlyintactGlobalbrainchangesinhealthyaging:EnlargedventriclesBrainvolumeshrinksLossinbrainweight(lossofabout.2%peryearfromcollegeonward,but.5%peryearinthe70’s)Whitematterhyperintensities(correlatedwithcognitivedecline)Microstructuralbrainchanges

inhealthyaging:Someneuronalloss,butalso…LossofgliaFragmentationandlossofmyelinDendriticarbordensitydecreasesSynapticstructureisaberrantNumberofsynapsesdeclines“Preordained”aging:MitoticcellsplacedintissueculturedishwilldivideforonlyalimitedtimethendieThecauseispresumablyaccumulatedgeneticdamageortoxicwasteproductsCertainmutationscanextendthelifespan(inanimals)geneticregulatorymechanismsaffectagingOneexampleisinsulinregulatorypathway.DisruptionofthesegenesleadstoincreasedresistancetolethaloxidativedamageWheniscognitivedeclinepathological?:MildCognitiveImpairment(MCI)isanoticeabledeclineincognitiveperformancebuteverydayactivitiescanstillbeperformedDementiacognitiveimpairment+disruptionincapacitytoperformsomedailyactivities(+behavioralissueslikeagitation,aggressionandapathy)15%ofMCIcaseswillconverttodementiawithinafewyears;50%morewilleventuallyconvert2.Dementia:Alzheimer’sDiseaseAlzheimer’sDiseaseisthemostcommonseniledementiaMostcommonisthesporadicformofAD(occursin~mid-60’s+)Lesscommonisearlyonset,orfamilial,AD(canoccurasearlyas30’sand40’s)EpisodicmemoryisoftenthecognitivedomaininitiallyaffectedEventuallyothercognitivedomainsarealsodisrupted(language,problem-solving,visuospatialprocessing)Otherbehavioralsymptomsincludeaggression,agitation,apathy,hallucinationsanddelusionsDramaticallyenlargedventriclesDramaticchangesinbrainvolumeSignificantlossofgraymatterandwidespreaddeathofneuronsADismarkedbysignificantbrainatrophyGlobalbrainchangesinAD:Plaques–aggregatesofamyloidproteindepositsextracellularly;oftensurroundedbyswollenaxonsanddendritesTangles–cytoskeletalabnormalitiesincellbodies;tauproteinnormallybindstomicrotubulestoassistwithstabilization;buthyperphosphorylatedtaucannotbindandclumpstoformtangles

ADpathologyismarkedbyplaquesandtangles(post-mortemanalysisistheonlytruewaytodetermineifsomeonehasAD!)Plaquesandneurofibrillary

tanglesinAD:ProteolyticcleavageyieldsseveralfragmentsOnefragmentisanamyloidBpeptide(BAPP;40or42residuesinlength)whichultimatelyformstheplaqueTheamyloidprecursorprotein:Healthyneurons:tauproteinassociateswithnormalmicrotubulesbutnotpairedhelicalfilamentsInAD,taubecomeshyperphosphorylatedandisnolongerassociatedwithmicrotubulesThemicrotublesdisassembleandpairwithpairedhelicalfilamentswhichformatangleWhereasamyloidplaquesarethoughttobetheinitialpathologyinAD,neurofibrillarytanglesarethoughttobeaconsequenceorcorrelateMutanttauprotein:GeneticRiskforlate-onsetAD:ApoEE4alleleofApoEincreaseschanceofdevelopingADbyabout4-foldButabout1/3ofindividualswithADarehomozygousforE3RiskforADisgreaterforE4womenthanforE4menE2seemstobeprotectiveEarlyonsetAD(familialrisk)isassociatedwithpresenilin-1andpresenilin-2NIA/Alz.AssocGuidelinesforpost-mortemneuropathologicchangesinAD3mainelementstothescoringsystem:SpreadofcerebralAbusingThalstagesSpreadofneurofibrillarytanglesbasedonBraakstagesDensityofneuriticplaquesinkeycorticalregions–CERAD

(ConsortiumtoEstablishaRegistryforAlzheimer’sDisease)scoreRepresentationofThalphasesofAβplaqueaccumulationandtheircorrespondencetoclinicalstatus(22).IvanKoychevetal.JNuclMed2020;61:1413-1418Copyright©SocietyofNuclearMedicineandMolecularImagingThalstagingRepresentationofBraakstages1–6.IvanKoychevetal.JNuclMed2020;61:1413-1418Copyright©SocietyofNuclearMedicineandMolecularImagingHealthyaging(entorhinalctx)EarlyMCI(amygdala,hippocampus,thalamus)AD(prefrontal,parietal,temporalctx)BRAAKstagingCERADscoringNatureCommunications

doi:

10.1038/s41467-019-10212-1TanglesandplaqueshavedifferentdistributionsConcentrationoftanglesinmedialtemporallobe(entorhinalcortex,hippocampus,amygdala,temporalpole)andbasalnucleusPlaquesarefoundmoreinparietalandtemporalcortexRegionalbrainchangesinAD:TemporalpoleHippocampusEntorhinalAmygdalaBasalnucleusDifferentmemorysystemsofthebrain:TemporalpoleHippocampusEntorhinalHippocampusandentorhinalcortex–memoryencoding(formationofnewmemories;LTP;e.g.,patientH.M.)Amygdala–conditionedresponses(e.g.“learnedfear”)Basalnucleus(ofMeynert)–acetylcholine(alertnessandfocus)Temporalpole–autobiographicalmemoryAmygdalaBasalnucleusDifferentmemorysystemsofthebrain:TemporalpoleHippocampusEntorhinalLateralparietalcortex–playsamajorroleinworkingmemory(morethanjustdelayedmatchtosamplebutalsoinvolvesa“manipulation”component);workswiththedorsolateralprefrontalcortexforworkingmemoryLateraltemporalcortex–semanticmemory(e.g.,facts,generalknowledge,wordmeanings)Medialparietalcortex–posteriorcingulatecortex(PCC)/retrosplenialcortex(RSC)playaroleinmemoryretrievalLateralparietalcortexRetrosplenialcortexLateraltemporalcortexStrongconnectivitywiththemedialtemporallobePCC=posteriorcingulatecortex(highdensityofamyloidplaques)DifferentmemorysystemsinMCIrevealedbyfunctionalconnectivity:Retrosplenialcortex(memoryretrieval)DifferentmemorysystemsinMCIrevealedbyfunctionalconnectivity:LeftdorsalPCCRightdorsalPCCLeftventralPCCRightventralPCCWide-spreadconnectivitywithfrontalandparietalcortexWithin-PCCconnectivityConnectivitywithparietal/temporalcortexStrongconnectivitywiththemedialtemporallobeProgressionofAlzheimer’sDiseaseADBiomarkersNeuronalinjury↓FDG-PET↓↑fMRI↑CSF-tau&p-tau↑18FT807tauPETCorticalatrophy

StructuralMRIMedialtemporallobesParalimbicTemporoparietalcortexBrainAßamyloidosis↑florbetapir-PET(fluorine-18)↑PiB(PittsburghcompoundB;thioflavinT)↓CSFAß-42↓plasmaAß-42,Aß-40ADBiomarkers-amyloidosisADBiomarkers-amyloidosisADBiomarkers–amyloid+morelikelytopredictlatercognitivedeclineAmyloid+increasestheriskofcognitivedecline,butAmyloid+doesnotshowgreatspecificityADBiomarkers–amyloiddepositionnotasstronglylinkedtocognitivedeclineastauaccumulationCDR=ClinicalDementiaRatingScale.0=cognitivelynormal.>0=cognitiveimpairmentSUVR=standarduptakevalueratioTauappearstoshowgreaterspecificitytocognitiveimpairmentthanAmyloidADBiomarkers–tauaccumulationrelatedtocognitiveimpairmentFromJohnsonetal.(2016).Ann.NeurolADBiomarkers–tauaccumulationrelatedtocognitiveimpairmentFromJohnsonetal.(2016).Ann.NeurolADBiomarkers–tauaccumulationrelatedtoCSFtauFromGordonetal.(2016).BrainADBiomarkers–neuronalinjuryasreflectedinFDG-PET(glucosemetabolism)NotethereductioninMCIandAD(especiallyintemporo-parietalcortex)ADBiomarkers–structuralMRIatrophyDuaraetal.(1986).Neurology3.LanguageDisorders:AphasiaandAlexiaFunctionalBrainArchitectureofLanguageLefthemisphereAngularandsupramarginalgyriSometimescombinedwithWernicke’sareainferiorfrontalgyrus(triangularandopercularportions)andsometimestheinsulaPosteriorsuperiortemporalgyrusBroca’sareaisjuxtaposedtofacemotorareasspeechproductionMotorstripWernicke’sareaisjuxtaposedtoprimaryauditorycortexspeechcomprehensionTonotopicorganizationArcuateFasciculus:whitemattertractthatconnectsBroca’s&Wernicke’sAcquiredDisordersofLanguageAphasia–disordersoflanguageproductionandcomprehensionAlexia–disordersofreadingCanresultfromstroke,tumor,traumaorothercerebralinsultOthercognitivefunctionsmayremainsomewhatintactAphasia-NeuroanatomyMCA=middlecerebralarteryACA=anteriorcerebralarteryPCA=posteriorcerebralarteryBroca’sv.Wernicke’sAphasiaBroca’sarea:SpeechproductionDifficultyarticulatingthoughtsintospeechusuallytelegraphicormonosyllabicoutput;perseverationcanunderstandlanguageWernicke’sarea:SpeechcomprehensionFluentspeechthatmakeslittlesensegrammaticallyandsemanticallydifficultyunderstandinglanguageXXBroca’sv.Wernicke’sAphasia/watch?v=aVhYN7NTIKUXX/watch?v=f2IiMEbMnPMExampleofaBroca’sAphasiapatient:ExampleofaWernicke’sAphasiapatient:Broca’sv.Wernicke’sAphasiaBroca’s:MotorspeechproductionWernicke’s:SpeechcomprehensionMCAinfarct–sup.divisionFluency--Comprehension+Repetition--Paraphasia+--Reading--Writing--Visualdeficit--Awarenessofdeficit+R.Hemiparesis+MCAinfarct–inf.divisionFluency+Comprehension--Repetition--Paraphasia+Reading--Writing--Visualdeficit+R.upperv.f.lossAwarenessofdeficit--R.Hemiparesis+--Naming--Naming--+=intact;--=deficitTypesofAphasiaBroca’s:difficultywithspeechproductionWernicke’s:difficultywithspeechcomprehensionAnomic/nominalaphasia:difficultyretrievingnamesforthings(confrontationnamingpoor)butspontaneousspeechandcomprehensionok(temporalorparietallobelesion)/watch?v=LWAUmsgk8egGlobal:Broca’s+Wernicke’scombined(extensivelesion)Conductionaphasia:difficultyrepeatingwords(arcuatefasciculuscompromised)Transcorticalmotoraphasia:problemswithspeechproductionbutrepetitionintact(frontallesion)Transcorticalsensoryaphasia:problemswithspeechcomprehensionbutrepetitionintact;echolalia(temporallobelesion)Mixedtranscorticalaphasia:productionandcomprehensionproblemsbutrepetitionintact(Broca’s,Wernicke’sandarcuatefasciculusintact,butwatershedareascompromised)TypesofAphasiaBroca’s:difficultywithspeechproduction(fluency)Wernicke’s:difficultywithspeechcomprehensionAnomic/nominalaphasia:difficultyretrievingnamesforthings(confrontationnamingpoor)butspontaneousspeechandcomprehensionok(temporalorparietallobelesion)/watch?v=LWAUmsgk8egGlobal:Broca’s+Wernicke’scombined(extensivelesion)Conductionaphasia:difficultyrepeatingwords(arcuatefasciculuscompromised)Transcorticalmotoraphasia:problemswithspeechproductionbutrepetitionintact(frontallesion)Transcorticalsensoryaphasia:problemswithspeechcomprehensionbutrepetitionintact;echolalia(temporallobelesion)Mixedtranscorticalaphasia:productionandcomprehensionproblemsbutrepetitionintact(Broca’s,Wernicke’sandarcuatefasciculusintact,butwatershedareascompromised)NeuroanatomyofAphasiaAphasia-NeuroanatomyFridrikssonetal.,(2010),J.NeuroAlmosttheentirelefthemisphereisimplicatedacrosssubjectsHowcanweaverageacrosssubjectsoraccountforthevariationinlesionsite?Voxel-basedlesionsymptommapping(VLSM):ExploitthevariationinlesionsiteOnavoxel-by-voxelbasis,assessbehavioralscoresinsubjectsthathadalesionornot(inthatvoxel)Dronkersetal.,2004VLSMDronkersetal.,2004AphasicptswhohadalesionherescoredworseonsentencecomprehensionthanptswhodidnothavealesionhereVLSMBroca’sorWernicke’sarealesionsdidnotaffectperformance;Instead,5regionsaffectedperformanceMiddleTemporalgyrus(MTG)importantforsinglewordcomprehensionMiddletemporalgyrusAnteriorsuperiortemporalsuperiortemporalsulcus/inferiorparietalMiddlefrontalgyrusInferiorfrontalgyrusDronkersetal.,2004AlexiaTypesofalexia:Purealexia(alexiawithoutagraphia,orinabilitytowrite):/watch?v=b_sHZRoXs6AOrthographicorsurfacealexiaPhonologicalalexiaSomewhatdifferentlesionsites(butmessy)Assess“paralexias”orerrorsinreadingAlexiaLesionintheleftvisualcortex+spleniumofthecorpuscallosumLesionsandbehavioralpatternsarenotthisclearcut!!!Canwriteandspeakbutcan’treadwhat