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Ростовский Государственный Медицинский Университет

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TheMontrealCognitiveAssessment(MOCA)testsmultiplecognitivedomains,includingvisuospatial function(i.e.,thepatientmustcopythecube),naming(nametheanimals),andmemory(rememberalist of5words).(CopyrightZ.Nasreddine,MD.Reproducedwithpermission.http://www.mocatest.org)

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WhenTestingIsAbnormal.WhenyourclinicalassessmentleadsyoutosuspectthediagnosisofMCIor dementia,youneedtoruleoutotherconfoundingdisordersaswellasanyreversiblefactorsthatmaybe contributingtothepatient’sdecline.Inparticular,youwanttoconsider:

Depression Sleepdisorders Alcoholandsubstanceabuse Thecontributionofprescriptionmedications Reversibledisorders,suchasvitaminB12deficiencyandhypothyroidism Normalpressurehydrocephalus(NPH)

Therecommendedlaboratorytestsforabasicdementiawork-upincludeacompletebloodcount,basic metabolicpanel,vitaminB12,andthyroid-stimulatinghormone(TSH).Arapidplasmareagin(RPR)and HIVtestcanalsobeconsideredinspecifichigh-riskpatientpopulations.Allpatientsshouldundergo depressionscreening.AbrainMRIisalsooftenappropriatetoruleoutanyunderlyingstructural pathologyandassesstheburdenofvasculardisease.Additionaltestingsuchascerebrospinalfluid(CSF) analysisandpositron-emissiontomography(PET)scanningmaybevaluabledependingontheclinical presentationbutarenotindicatedintheroutineworkupofdementia.

Dementia(akaMajorNeurocognitiveDisorder)

Aspreviouslystated,patientswithdementiawillshowadeclineinatleastoneofthefollowingdomains: memoryandlearning,executivefunctioning,language,socialcognition,complexattention,andperceptual motorfunction.Whenthisdeclineimpairsthepatient’sabilitytofunctionindependently,thatpatientis diagnosedwithdementia.

Importanttypesofdementiainclude:

Alzheimerdisease Vasculardementia DementiawithLewybodies Frontotemporaldementia Priondiseases(includingCreutzfeldt-Jakobdisease)

AlzheimerDisease(AD)

ThelifetimeprevalenceofADisover11%amongmenandover21%amongwomen.Mostofthese patientswillhavelate-onsetAD(65yearsofageandolder).Early-onsetADisfarlesscommon.ADis themostcommoncauseofdementiaworldwide.

Genetics.Late-onset(i.e.,sporadic)ADhasbeenmostcloselylinkedgeneticallytothegenesthatcode forapolipoproteinE,inparticulartheapolipoproteinEepsilon4allele(APOE4),whichispresentin 14%ofthegeneralpopulation.Heterozygoteshavea3-foldincreasedriskofAD,whereashomozygotes havean8-to12-foldincreasedrisk.However,30%to60%ofpatientswithADdonotcarrythisallele. UsingAPOE4asascreeningtoolisnotrecommended,bothbecauseitisnotspecificandbecausethere arenopreventiveortherapeuticinterventionsthatwecanofferbasedonthetestresults.Forpatientswho wanttoproceedwithtesting,referraltoageneticcounselorshouldbeconsidered.

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Box7.2Early-OnsetAlzheimerDisease

Presentinginpatientsyoungerthan65,early-onsetADcanoccursporadically,butmore oftenthereisanidentifiablegeneticcomponentwithastrongautosomalpatternof inheritanceassociatedwithmutationsinseveralgenes.Mostcommonisamutationin presenilin1onchromosome14,aproteinthatisinvolvedintheconversionofamyloid precursorprotein(APP)intobeta-amyloid,andlessoftenmutationsinpresenilin2(on chromosome1)andAPPitself(onchromosome21).Early-onsetADisfarlesscommon thanlate-onsetAD.Ittendstopursueamoreaggressivecourse,andmemoryimpairment canbeovershadowedbyothercognitivedeficits.

Justasasidenote,theimpactoftheAPOE4alleleisnotlimitedtoincreasingtheriskofAD;italso increasestheriskofdementiawithLewybodies.Inaddition,APOE4carriersarelessabletomaintain neuronalhealthfollowingastrokeorheadtrauma.DatasuggestthatAPOE2,ontheotherhand,canbe protectiveagainstAD,andisassociatedwithincreasedlifespaninbothpatientswithandwithoutAD.

RiskFactors.Aging,femalesex,andtheAPOE4allelearewell-establishednon-modifiableriskfactors. Potentiallypreventableorreversibleriskfactorsinclude:

The same factors that raise the risk of cardiovascular disease (e.g., hypertension, metabolic syndrome,andhyperglycemia) Ahistoryoftraumaticbraininjury Sleepdisorders Some drugs with anticholinergic activity (e.g., antidepressants, antipsychotics, and anti-Parkinson drugs) Alowlevelofbothphysicalandcognitiveactivitythroughoutone’slifetime

Histology.ThepathologichallmarksofADareneurofibrillarytangles(composedofintracellularflame- shapedaggregatesofhyperphosphorylatedtauprotein,amicrotubule-associatedprotein),andsenile neuriticplaques(extracellularaggregatesofamyloid-beta).Accumulationofthesesubstancesinbrain tissueisassociatedwithneuronaldegeneration,celldeath,andcerebralangiopathy.AretauandamyloidbetathecausesofAD?Westilldon’tknowforcertain,butthesmartmoneysaysyes—staytuned.

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(A)Neurofibrillarytangles,and(B)neuriticplaquesinhematoxylinandeosin(H&E)-stainedbrainsections. (ModifiedfromMillsSE.HistologyforPathologists.4thed.WoltersKluwer;2012.)

ClinicalPresentationandDiagnosis.ADtypicallypresentswiththeinsidiousprogressionofmemory deficits.Problemswithshort-termmemory—difficultyrecallingrecenteventsasopposedtoremote events—areusuallythefirsttoappear.Overtimeothercognitivedeficitswillappear,oftenfluctuating fromdaytoday,andmayincludeimpairedintellectual,executiveandvisuospatialfunctioningalongwith languagedeficitsandchangesinpersonalityandbehavior.Patientsmayexhibitimpairedjudgment, confusion,disorientation,depression,anxiety,and—ultimately—delusionsandhallucinations.Some patientsmaydevelopprofoundapathy,othersagitation,andstillothersalternatingperiodsofonewiththe other.ExceptwhenADisinitsearlieststages—whenintellectualfunctionisstilltosomeextent preserved—patientsareunawareofwhatishappeningtothem.Eventually,patientsbecomebed-bound, unabletowalkindependently,anddevelopbladderandbowelincontinence.

Withtheexceptionofthementalstatusexamination,neurologicexaminationistypicallynormaluntilthe verylatestagesofthedisease.Thepresenceoffocalneurologicsignsorparkinsonianfeaturesshould promptanevaluationforothercauses.

ThedifferentialdiagnosisofADisbroad,anditisimportanttoruleoutothercausesofdementia, particularlyreversiblecauses(seepage199).Laboratorytesting,asoutlinedabove,shouldbeordered. Detectionoftauproteinsinthebloodisanewtest,notyetcommerciallyavailable,thatmayeventually offeranexpeditedmeansofmakingthediagnosisofAD.

AnMRIisrecommendedtoruleoutstructuralcausesofdementia.ClassicfeaturesthatsuggestADon abrainMRIincludecorticalatrophywithventricularenlargementalongwithatrophyofthehippocampus andmedialtemporallobes.ThesechangesarenotspecifictoADbuthighlysuggestiveofthediagnosisin therightclinicalcontext.PETscanning,whilenotroutinelydone,candemonstratehypometabolisminthe posteriortemporoparietallobes.

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Ahealthybrain(A)comparedwiththebrainofapatientwithAlzheimerdisease(B).Notethesignificant corticalatrophy,characterizedbywidenedsulciandthinnedgyri.(CourtesyofDr.F.StephenVogel,Duke University.)

CSFbiomarkersarestillmostlyusedforresearchprotocols,butthefindingofelevatedtauproteinand lowlevelsofamyloid-betaarereasonablysensitiveandspecificforAD.

Treatment.ThereisunfortunatelynocureforAD.Theavailablemedicationsdonotreverseexisting symptomsandmayatbestonlyslightlyslowapatient’sdecline.

Disease-DirectedTherapies.Bothcholinergicandglutaminergicpathwaysappeartobeimportantin corticalfunction,andthesearetargetedbycurrenttherapies.Acetylcholinesteraseinhibitors(e.g., donepezil)mayshowsomemodestbenefitinslowingdiseaseprogressionforpatientswithmildtosevere AD,andmemantine,anNMDA(N-methyl-d-aspartate)receptorantagonist,maybenefitsomepatients withmoderatetoseveredisease.Acombinationofmemantineandanacetylcholinesteraseinhibitormay beslightlymoreefficaciousthaneitheralone.

Aducanumab,arecombinantmonoclonalantibody,isthefirstdrugthatspecificallytargetstheamyloidbetaprotein.Ithasbeenshowntoreduceamyloidaccumulationinthebrain,butevidenceofclinical benefithasbeenatbestverymodest.ItsapprovalbytheFDAhasbeencontroversial,butasofthis writingitcanbeconsideredforpatientswithmildmemoryorcognitiveissues.

SupportiveTherapies.Socialsupportsystems(forboththepatientandthepatient’scaregivers)are paramount.Antipsychotics(oftenquetiapine)andantidepressants(selectiveserotoninreuptakeinhibitors [SSRIs]andserotoninandnorepinephrinereuptakeinhibitors[SNRIs])canbeusedtohelpmanage behavioralsymptoms.Nocomplementaryoralternativetherapieshavebeenfoundtoofferanysignificant benefit.Inparticular,ginkgobiloba,apopularover-the-counter“memoryenhancer,”hasnotbeenfoundto slowcognitivedeclineinolderadults.

NeverforgetthatthetollADtakesonthepatient’scaregiverscanbeoverwhelming,andtheymay

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benefitfromcounselingandsupport.

Table7.1DrugsforAlzheimerDisease

Medication MechanismofAction Indications

Memantine NMDAReceptor

Antagonist

Formoderatetoseveredementia;usuallywelltoleratedalthoughworseningconfusion,

hallucinations,anddizzinesshavebeenreported Donepezil, Rivastigmine, Galantamine

Acetylcholinesterase Inhibitors

Formildtoseveredementia;GIsideeffectsarecommon(includingnauseaand

diarrhea),especiallywhenstartingtherapy

Aducanumab Monoclonalantibody

targetingamyloid-beta

Formilddementia;appearstobewelltolerated

GI,gastrointestinal;NMDA,N-methyl-d-aspartate.

Prevention.NosingleinterventionappearstomakeameaningfuldifferenceinreducingtheriskofAD, butthereisevidencethatamultimodalapproachcanbehelpful:bloodpressureshouldbecontrolled, physicalandmentalactivityencouraged,andahealthydiet(suchastheMediterraneandiet)consumed. NosupplementsormedicationshavebeenshowntoreducetheriskofdevelopingAD.

VascularDementia

Thisistheotherdementiayouwillseemostfrequently.Sometimesreferredtoas“multi-infarct dementia,”vasculardementiaisresponsibleforapproximately8%to15%ofcasesofcognitive impairment.ManypatientshaveelementsofbothADandvasculardementia,hardlysurprisingbecause (1)theyarebothcommon,and(2)theysharemanyofthesameriskfactors.

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MRIofapatientwithvasculardementia.Notethesignificantburdenofmicrovascularischemicdisease, characterizedbyextensivewhitematterandperiventricularfluid-attenuatedinversionrecovery(FLAIR) hyperintenselesions.(ReprintedfromGuermaziA,MiauxY,Rovira-CañellasA,etal.Neuroradiological findingsinvasculardementia.Neuroradiology.2007;49(1):1-22.)

Vasculardementiaistheresultofcerebrovasculardisease,aresultofthecumulativeburdenofyearsof uncontrolledhypertension,hyperlipidemia,diabetes,andobesityonthebrain.Smokingalsosignificantly increasestherisk.

ClinicalFeaturesandDiagnosis.Vasculardementiashouldbesuspectedinanypatientwithcognitive dysfunctionwhoalsohasriskfactorsforcerebrovascularandcardiovasculardisease.UnlikeAD,which progressesslowlyandsteadily,vasculardementiacanevolveinastepwisefashion;newcognitive deficitsmayappearsuddenly,presumablytheresultofnewcerebralinfarctions.ComparedwithAD,the

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physicalexaminationismoreoftenabnormal,notableforfocaldeficitsresultingfromtheaccumulating strokeburden.MRIwillshowevidenceofmicrovasculardisease(seefigureabove)andoften,more discreteandlargerareasofinfarction.

Treatment.Cardiovascularriskfactorsshouldbecontrolled.Antihypertensives,cholesterol-lowering agents(usuallystatins),andmedicationstoensuretightglycemiccontrolarerecommendedasindicatedto preventprogression—which,takingastepbackandrememberingtheglobalburdenofdementia worldwide—iscritical.ThecholinesteraseinhibitorsthatareusedforADmaybeofsomesmallbenefit forsomeofthesepatientsaswell.

Box7.3TheRoleofStrokeinVascularDementia

Recallthatthedefinitionofstroke—theacuteonsetoffocalneurologicdeficits—isaclinical one.Patientswithvasculardementiaoftenhaveahistoryofstroke,butitisnotnecessary forthediagnosisofvasculardementia.AlthoughtheMRIwillshowsignificantmicrovascular ischemicdiseasesufficienttocauseprogressivecognitivedecline,wewouldnotdiagnose themashavingahistoryofstrokeintheabsenceofahistoryofsuddenfocalneurologic deficits.

DementiaWithLewyBodies(DLB)

Whenyouseeapatientwithcognitiveimpairmentandatleastoneparkinsonian2feature,suchas bradykinesia(i.e.slownessofmovement),rigidityorposturalinstability,considerthediagnosisofDLB.

WhatisthedifferencebetweenthisentityandParkinsondiseasewithoverlappingdementia?The distinctionisnotaneasyonetomake,andthetwodisordersmayrepresenttwoendsofasinglespectrum; thereisconsiderableclinicalandpathologicoverlapbetweenthetwo.ThediagnosisofDLBshouldonly bemadeifdementiaandparkinsonismappearwithin1yearofeachother.Tremoralsotendstobeless prominentinDLB.

Lewybodies,thepathologichallmarkofDLB,areinclusionsofalpha-synucleinwithinneuronsand canonlyberecognizedatautopsy.

https://t.me/med1917

Lewybodiesareconcentricintraneuronalhyalineinclusions.(ReprintedfromJankovicJ,TolosaE. Parkinson’sDiseaseandMovementDisorders.6thed.WoltersKluwer;2015.)

ThereareseveralhallmarkfeaturesofDLBthatcanmakeiteasytorecognizeandthatdistinguishit fromotherformsofdementia:

Featuresofparkinsonism,asjustdiscussed. Fluctuatinglevel of cognition.Patientsoften displayvaryinglevels ofattentionandalertness over the courseoftheday.Butunfortunately, aswith the otherdementias, the naturalhistory ofDLB is ultimatelyoneofrelentlessprogression. Earlyandprominent visualhallucinations.Lilliputian hallucinations—inwhichpatients see nonthreateningtinypeopleandanimals—areclassicforDLB,butmoreabstracthallucinationscanoccur aswell.VisualhallucinationsinADarerare.

Anxietyisalsocommon,andnewonsetofanxiety(oftenfluctuatingaswell)laterinlifeshouldprompt considerationofDLB.

Treatment.Treatmentissymptomatic;aswiththeotherdementias,notreatmenthasbeenshowntomodify thecourseofthedisease.PatientswithDLBaredeficientinbothcholinergicanddopaminergicactivity. Therefore,anticholinesteraseinhibitorsareoftenusedwithsomemodestsuccess,andlevodopacanbe helpfulfortheparkinsonianfeatures(althoughitisoftenlesseffectivethanwithidiopathicParkinson disease).Antipsychoticmedicationscanbeconsideredinpatientswithseverepsychosis,butkeepin mindthatthesemedicationsactasdopamineantagonistsandcanthereforeworsenparkinsonian symptoms.Interestingly,levodopa—whentitratedcarefully—isusuallywelltoleratedanddoesnotseem tosignificantlyexacerbatepsychoticfeatures.

LifeexpectancyislessthanhalfthatofpatientswithAD.

FrontotemporalDementia(FTD)

Thisisactuallyagroupofdementias,themostseriousandcommonformbeingbehavioralvariant frontotemporaldementia(bvFTD).BvFTDisoneofthemostcommoncausesofearly-onsetdementia,

withaprevalencesimilartothatofADinpatientsyoungerthan65.Itismostoftensporadic,although therearefamilialforms.

ClinicalPresentation.BvFTDaffectsayoungerpopulationthanAD,withameanageofonsetinthe50s. Becausetheclinicalpictureisdominatedbybehavioralandpersonalitychanges,itcanbeconfusedwith aprimarypsychiatricillness.Thefirstsigns,suchaspoorperformanceatwork,maritalproblems,social disinhibition,apathy,andalackofempathy,maybedismissedandfalselyattributedtothenormal stressorsoflife.Repetitiveandcompulsivebehaviorsarecommon,asarechangesineatingbehavior (overeatingandastrongpredilectionforsweetsarecommon,butthesedietarybehaviorshardly distinguishthesepatientsfromthegeneralpopulation!).LesscommonvariantsofFTDinclude progressivenonfluentaphasiaandprogressivefluentaphasia,characterizedbyprominentword-finding difficultyandimpairedlanguagecomprehension,respectively.Memoryimpairmenteventuallyoccurs withallvariantsbutisoftennotthemostsalientfeature.

https://t.me/med1917

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