Early and late onset Alzheimer disease Are they the same entity? ARTICLE IN PRESS+Model Neurología 2016;xxx xxx—xxx NEUROLOGÍA www elsevier es/neurologia REVIEW ARTICLE Early and late onset Alzheimer[.]
Trang 1www.elsevier.es/neurologia
P Tellecheaa, N Pujola, P Esteve-Bellocha, B Echevestea, M.R García-Eulateb,
J Arbizuc, M Riverola , ∗
aDepartamento de Neurología, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
bDepartamento de Radiología, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
cDepartamento de Medicina Nuclear, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
Received30April2015;accepted14August2015
KEYWORDS
Alzheimerdisease;
Early-onset;
Late-onset;
Neuropsychology;
Neuropathology;
Neuroimaging
Abstract Early-onsetAlzheimerdisease(EOAD),whichpresentsinpatientsyoungerthan65 years, hasfrequently been described ashaving differentfeatures from thoseoflate-onset Alzheimerdisease(LOAD).Thisreviewanalysesthemostrecentstudiescomparingtheclinical presentationandneuropsychological,neuropathological,genetic,andneuroimagingfindingsof bothtypes inordertodeterminewhether EOADandLOADaredifferententities ordistinct formsofthesameentity.WeobservedconsistentdifferencesbetweenclinicalfindingsinEOAD andinLOAD
Fundamentally,theonsetofEOADismorelikelytobemarkedbyatypical symptoms,and cognitiveassessmentspoint topoorerexecutiveandvisuospatialfunctioningandpraxiswith lessmarkedmemoryimpairment.Alzheimer-typefeatureswillbemoredenseandwidespread
inneuropathologystudies,withstructuralandfunctionalneuroimagingshowing greaterand morediffuseatrophyextendingtoneocorticalareas(especiallytheprecuneus).Inconclusion, availableevidencesuggeststhatEOADandLOADare2differentformsofasingleentity.LOAD
islikelytobeinfluencedbyageing-relatedprocesses
©2015SociedadEspa˜noladeNeurolog´ıa.PublishedbyElsevierEspa˜na,S.L.U.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/ 4.0/)
PALABRAS CLAVE
Enfermedadde
Alzheimer;
Inicioprecoz;
Iniciotardío;
Enfermedad de Alzheimer de inicio precoz y de inicio tardío: ¿son la misma entidad? Resumen LaenfermedaddeAlzheimerdeinicioprecoz(EAIP),definidacomolaquese mani-fiestaantesdelos65a˜nosdeedad,muestraciertascaracterísticasdiferentesdelaenfermedad
deAlzheimerdeiniciotardío(EAIT).Nuestroobjetivofueanalizarlostrabajosmásactualesque
夽 Pleasecitethisarticleas:TellecheaP,PujolN,Esteve-BellochP,EchevesteB,García-EulateMR,ArbizuJ,etal.Enfermedadde
Alzheimer de inicio precoz y de inicio tardío: ¿son la misma entidad? Neurología 2016 http://dx.doi.org/10.1016/j.nrl.2015.08.002
∗Correspondingauthor.
E-mail address:mriverol@unav.es (M Riverol).
2173-5808/© 2015 Sociedad Espa˜ nola de Neurolog´ıa Published by Elsevier Espa˜ na, S.L.U This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).
NRLENG-799; No of Pages 10
Trang 2Neuropatología;
Neuroimagen
comparanlaclínica,laneuropsicología,lapatología,lagenéticaylaneuroimagendelaEAIPy
laEAIT,paradeterminarsinosenfrentamosadosenfermedadesdistintasoavariantesdeuna mismaentidad.Comoresultado,hallamosconsistenciaenalgunascaracterísticasdiferenciales entrelos2cuadrosclínicos.Fundamentalmente,laEAIPcomienzaconmayorfrecuenciacon unaclínicaatípica;lavaloracióncognitivamuestramayorafectacióndelasfuncionesejecutiva
yvisuoespacialydelaspraxias,ymenorafectacióndelamemoria;laneuropatologíaevidencia mayordensidadyunadistribuciónmásdifusadelapatologíatipoAlzheimer;losestudiosde neuroimagenestructural y funcionalmuestran unaafectación cortical mayor y más difusa, afectandoalneocórtex(especialmenteelprecuneus) Enconclusión,lasevidencias actuales hacenpensarquelaEAIPylaEAITsonvariantesclínicasdeunamismaentidad,queenelcaso
delaEAITseveinfluidaprobablementeporfactoresasociadosalenvejecimiento
© 2015Sociedad Espa˜nola de Neurolog´ıa.Publicado porElsevier Espa˜na, S.L.U Estees un art´ıculoOpenAccessbajolalicenciaCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/)
Introduction
Alzheimerdisease(AD)isthemostfrequent
neurodegener-ativedisease.Itpresentsclinicallyasprogressivedementia
that predominantly affects episodic memory.1 Age is the
mainriskfactorfordevelopingAD,andinfact,prevalence
ofthediseaseishigherinoldersegmentsofthepopulation
AD is the most frequent cause of dementia and accounts
forapproximately60% ofthetotalcases,whetherbefore2
oraftertheageof65,3theagemarkingthearbitrarylimit
betweenearly-onsetandlate-onsetdementia
In 1907, Alois Alzheimer described the disease now
bearing hisname today in a 51-year-old woman whohad
developed dementia with predominant language
impair-ment andbehavioural changes.4 Foryears, thissyndrome
of early-onset dementia without amnesia was thought to
define AD and distinguish it from senile dementia, which
wascharacterisedbyalateronsetandsymptomsof
amne-sia andattributedto theageing process.However,in the
1960sand1970s,studies showed thatthe neuropathology
underlyingearly-onsetandseniledementiawasthesame;
assuch, both clinical variants are produced by the same
disease,AD.5,6Fromthat timeon,oncetheclinical
crite-riaforanADdiagnosishadbeenestablished,doctorswere
morelikelytorecognisethesenileonsetform7sinceitwas
far more common, while the other ‘atypical’ early-onset
variantwasalmostforgotten.However,anumberofrecent
studieshaveunderlinedtheclinicalheterogeneityofADand
investigateditsunderlyingcauses
This reviewaimstopresent the similaritiesand
differ-ences between early-onset AD (EOAD) and late-onset AD
(LOAD)withregard totheclinical features,
neuropsychol-ogy,neuropathology, genetics, and neuroimaging features
described to date This will serve to clarify if there are
indeed2differententitiesor2clinicalvariantsofthesame
disease
Clinical presentation
The most common initial clinical presentation of AD
is episodic memory loss, which is accompanied by
progressiveimpairmentofothercognitivedomains Never-theless,somepatientspresentalterationsinothercognitive areas and memory remains relatively well preserved AD mayevenpresentasa‘focal’syndromeinwhich the pre-dominantsymptomisapraxiaoranimpairmentoflanguage, visual function, or visuospatialreasoning.This wide array
ofcasesillustratestheheterogeneousclinicalpresentations
of AD, and this results in major challenges and frequent diagnosticerrors.8Somesuch‘atypical’syndromescan eas-ily bemistaken for other entities,suchasfrontotemporal dementia(FTD), whenexecutive or languagedysfunctions aredominant;orcorticobasaldegeneration,whenthereare signsofcorticobasalsyndrome.Assigningthecorrect diag-nosis to ‘focal’ syndromes of AD (especially when ruling out FTD in the differential diagnosis) will involve detec-tinganytemporallobeandposteriorhemispheresymptoms (amnesia,visuospatialdysfunction)ontheonehand,andon theother,verifyingwhetherthefocaldeficitsinthese syn-dromesseemtobelessselective(andprofound)thanthose
in FTD.Here,an exhaustiveneurologicalexamination will revealdeficitsinothercognitivedomainsandthose affect-ingmultiplefunctionalsystemswithinasingledomain(for example,phonology,spelling,andsyntaxwithinlanguage).9
Inlightofthisheterogeneousarray,someauthorshave attempted to facilitate diagnosis by elaborating classifi-cation systems for specific AD subtypes: the typical form (memorylosswithotherdeficits)andthetemporalvariant (with isolated memory loss) are late-onset syndromes In contrast, theleft/language variant (anonfluent aphasia), progressivelogopenicaphasia (with preservedfluency and predominantrepetitiondeficit),right/visuoperceptive vari-ant (including posterior cortical atrophy, which is almost always due to AD) and the frontal/executive variant are early-onsetsyndromes.10 Usingasimilarapproach,another studygroupedADpatientsin3categories:thosewithfrontal lobe dysfunction, very early onset, and a family history; another with primarily posterior deficit (temporoparietal and/or occipitallobes) andearlyonset,andathird group with predominantly temporal lobe dysfunction in elderly patients.11Lastly,currentdiagnosticcriteriaforADdescribe
a typical amnestic presentation and other non-amnestic presentations,includingthosewithpredominantdeficitsin language,visuospatialfunction,andexecutivefunctions.12
Trang 3or atypicalclinical presentationsaremore frequently
dis-playedbypatientswithEOAD.8,10,13,14Infact,athirdofthe
patientswithEOADdisplayanatypicalpresentation,
com-paredto6%ofthosewithLOAD.8,11Ontheotherhand,most
studies15—18 haveconcludedthatEOADrunsamore
aggres-sivecourse
Neuropsychology
Numerous articles have compared the neuropsychological
profilesofpatientswithADtodeterminewhethersome
cog-nitivedomainsaremoreaffectedthanothersgivendifferent
agesofonset.Mostsuchstudies19—27indicatesignificant
dif-ferences.Here,weofferasummaryoftheresultsforeach
cognitivedomain
Memory
Ingeneral,studiesshowthatthepatientswiththegreatest
impairmentofthisdomainhave LOAD.16,17,20Furthermore,
memory seems to be relatively well-preserved in the
early stages of EOAD with respect to LOAD.19
Specifi-cally,researchers have observed that LOAD hasa greater
impact on memory, whether of recent events17,20 or of
well-consolidatedinformation,16 althoughsomecasesonly
exhibitimpairedrecognition.21Otherstudies22,23indicatea
qualitativedifferenceinimpairmentwithmemoryloss
pre-dominatinginEOADvsmemoryencodingfailureinLOAD.23
Researchershavealsoobservedpoorertemporalorientation
inthegroupwithLOAD,17,22whichcanbeattributedtothe
accentuatedmemorylossinthisgroupofpatients.22
Language
PatientswithLOADperformmorepoorlyonvisual
confronta-tionnamingtests,suchastheBostonNamingTest.20,21Some
studiesreachedthesameconclusion,butalsofoundthatthe
naming function deteriorated more quicklyin EOAD.24 On
theotherhand,subjectswithEOADscoreloweronwriting
tasks.20Nevertheless,otherstudieshavenotfoundany
dif-ferencesinlanguage,19,25meaningthatthelanguagedomain
is one of the most controversial when comparing these 2
variants
Executive function
DifferentstudiesindicatethatpatientswithEOADwill
per-formmorepoorlyoncomplexattentionandworkingmemory
tasks16,19—21,23andshowmoreerrorsonresponseinhibition
tasks.21
Visuospatial function
Ingeneral,patientswithEOADwillhavepoorerresultsthan
thelate-onsetgrouponvisual-cognitivetasks,19,20,26
refer-ringtoboththeobjectperceptiondomain19andthespatial
perception19,26andconstructiondomains.20,26
Learned motor behaviours
NumerousstudieshaveshownthatpatientswithEOADshow moreseverelyaffectedmotorbehaviours.17,22
Behaviour disturbances
One study compared the prevalence of psychiatric and behavioural symptoms between subjects with EOAD and LOAD andcomparable severity of dementia; it concluded thatthelate-onsetgroupwasmoreaffected Inanycase, thefactthatdysphoriaandapathyarerelativelyfrequent
intheEOADgroupmayberelevant.28
In summary, patients with EOAD perform more poorly
ontasks related towritten language, executive function, attention,visuospatialabilities,andmotor skills,whereas patients with LOAD show poorer performance on tasks involvingepisodicmemoryandvisualconfrontationnaming
Neuropathology
CharacteristicneuropathologicalfindingsinADare extracel-lulardepositsof senileplaquesconsisting ofamyloid beta andintracellularneurofibrillarytanglescomposedof hyper-phosphorylatedtauprotein.Depositionofamyloidplaques begins in the basal regions of the frontal, temporal, and occipitallobesandprogressestoaffecttheprimarysensory areas.Neurofibrillarytangles, ontheotherhand, willfirst affectthe transentorhinalregion andprogresstoward the limbicsystembeforefinallyreachingtheneocortex.29
Thebrain’sdistributionofAD-specificpathologyis corre-latedwiththetypeofclinicalpresentation.Infact,Murray
etal.30 describe3patternsofneurofibrillarytangle distri-butioninAD:thetypicalpatterndescribedabove,another patterninwhichthehippocampusisspared(withmore tan-gles in the cortexthan in the hippocampusand withless hippocampalatrophy),andapredominantlylimbicpattern
In ourstudy, curiously enough, senile plaque density was similarinall3ofthelistedpatterns.Thepatternpreserving thehippocampuswasassociated withearly onset,amore aggressivecourse,andahigherprevalenceofatypical pre-sentations(upto30%).Basedontheseobservations,some researchershavepostulatedthataslightlydifferent patho-logicalcascademaybeatworkinpatientswithanatypical presentation Here, although onset would also be deter-minedbyamyloiddeposits,theformationofneurofibrillary tanglesoccursearlieranditstopographicalpatternisvery different.27
Variousteams have attemptedtoquantifypathological features in AD to compare patients withearly- and late-onsetformsofthedisease.Generallyspeaking,authorshave determinedthattypicalEOADpatientsdisplayagreater den-sityofsenileplaques15andneurofibrillarytangles10,31,32and greaterneuronallosscomparedtotheircounterpartswith LOAD14ortothosewithatypicalEOAD.31Thelatteralsoshow moremarkedimpairmentoftheneocortexthandotypical cases.31ThisseemstoindicatethatEOADhasamore aggres-sive course, but some interpret these findings within the contextof thebrain’s functional reserve; they state that
Trang 4Table 1 SummaryofthearticlesconsultedonthesubjectofneuropsychologyinEOADandLOAD.
Study Areaofstudy Results
Gradyetal.65 All NosignificantdifferencesbetweenEOADandLOADfor
anyarea
LOAD:poorerremoterecall
LOAD:poorerrecallofrecentevents,poorerorientation andnaming
Imamuraetal.24 Language EOAD:impairedverbalcomprehensionandnaming Fujimorietal.26 Visuocognitive EOAD:moreimpairmentinattentionand
spatial/constructionalperception Suribhatlaetal.20 All EOAD:poorerwrittenlanguage,attention,and
visuoconstructiveskills;nosubstantialdifferences Kalpouzosetal.23 Working,semantic,and
episodicmemory
EOAD:poorerworkingmemorythaninLOAD;no differencesinepisodicmemory
Snowdenetal.11 All Youngerageofonsetforfrontalneuropsychological
profiles,‘typicalAD’withlossofmemoryand language/arithmetic/spatialskills,andvisual neuropsychologicalprofiles,comparedtoamnesticand semanticprofiles
function;differencesnotsignificantaftercorrectingfor ageandeducationallevel
Toyotaetal.28 Psychiatricandbehavioural
symptoms
EOAD:lowerprevalenceofpsychiatric/behavioural symptoms(delirium,hallucinations,agitation, disinhibition,abnormalmotorbehaviour)comparedto LOADatequivalentdementiaseverity
dysfunction/apraxia,languageimpairment, aphasia-agnosia-apraxiasyndrome,dysexecutive syndrome,andposteriorcorticalatrophy,withless memoryloss
Kaiseretal.21 Language,visuospatial
abilities,executivefunction, andattention,memory
EOAD:poorerfluencywithphoneticcue,more pull-to-stimuluserrorsonvisuoconstructivetasks, poorercomplexattentionandworkingmemory,poorer executivefunction
LOAD:poorernaming,poorerdeferredrecall
apraxias LOAD:poorerorientationandvisualmemory Smitsetal.19 Memory,language,visuospatial
ability,executivefunction,and attention
EOAD:poorerperformanceinvisuospatialability, executivefunction,andattention
LOAD:poorermemory
patientswithLOADwillnotrequiresuchahigh
pathologi-calloadaspatients withEOAD inordertoexhibitclinical
symptoms.32
Theroleofsolubleoligomericformsofamyloidbetain
EOADandLOADhasalsobeenstudied;theseformsmayhave
a more direct effect on the loss of neural function than
doesfibrillaryamyloidbeta.Infact,studiespointtoagood
correlationbetweenthelevelofoligomersand
neurotrans-mitter activity (measured by cholineacetyltransferase).33
They also reveal a distinct pattern of oligomer subtypes
for each group: there is a higher level of pentamers
in the insoluble fraction in EOAD than in LOAD,33 which
indicatespotentialdifferencesinthepathogenesisofeach type
Lastly,whenlinkingneuropathologyfindingswithclinical expression for these 2 patient groups, we cannot over-looktheeffectofconcomitantillness.Inyoungerpatients, the correlation between the amyloid load and the level
of dementia is strong, but this is not the case in older patientsinwhomvasculardiseasemayplayastrongerrole
indementia.34
Insummary,studiesindicatethattheearly-onsetformof
AD is moreextensive, andthat differencesaremore pro-nouncedoutsideofthetemporallobe.35
Trang 5Cerebrospinal fluid (CSF) markers
The biomarkers recentlydeveloped for CSFarehelpful in
diagnosingAD,andresearchershaveexaminedthe
possibil-ity that theymay be especiallyuseful for EOAD given its
atypicalpresentation Studiesshow thatlevelsofamyloid
beta,totaltauprotein,andphosphorylatedtauproteinare
abnormalinbothEOADandLOAD,butvaluesaresimilarfor
bothgroups.36,37Ontheotherhand,thereseemstobea
cor-relationbetweenthe(pathologically low)levelofamyloid
betainCSFandthedegreeofbrainatrophyinareasthatare
specifictoeachvariant (especiallytheprecuneusinEOAD
andthehippocampusinLOAD).37AmongEOADcases,there
does seem to bea difference between typical and
atypi-calprofiles;thelatterdisplayahigherleveloftotaltauin
CSF,regardlessofdiseasedurationandthedegreeofclinical
severity.Thisfindingindicatesmoreintensedegenerationin
patientswithanatypicalprofile.38
Genetics
ItcannotbeoverlookedthatADmaybecausedbyan
autoso-maldominantmutationonthePSEN1,PSEN2,orAPPgene.35
Thesecasesaccountforlessthan1%ofallpatientswithAD
andtheyareusuallycharacterisedbyearlyonset35;
never-theless,theymakeuponlyasmallpercentageofallpatients
withEOADandremainoutsideofthescopeofthisarticle
Allele4ofapolipoproteinE(APOE*4)isthemost
impor-tant risk factor for sporadic AD Presence of this allele,
whetherheterozygousorhomozygous,hasbeenassociated
with a younger age of onset of the disease.35,39,40
How-ever, various neuroimaging studies coincide in that they
show more pronounced atrophy of the medial temporal
lobe and especially the hippocampus in patients carrying
the 4 allele in APOE compared to non-carriers,
regard-less of age of onset of the disease.41,42 There was more
extreme hypometabolism in the medial temporal lobe in
4/4patientsthaninthosewiththe3/3genotypewithin
theEOADgroup,butnogenotype-relateddifferencesinthe
LOAD group.43 This is consistent with the greater
preva-lenceofbearersofthisalleleamongpatientswithamnestic
presentation9,35andthelowerpercentageofbearersamong
patients exhibiting preservation of the hippocampus.29 To
summarise, we may therefore state that although the 4
alleleislinkedtoyoungerageatADonset,thisonlyoccurs
in patients withtypical ADwho necessarily belongto the
LOADgroup,affectingtheyoungerpatientsinthatgroup.35
On the other hand, some studies have indicated that
APOE*4 determines EOAD progression.17,35 As such,in the
absence of 4, progression is quicker for EOAD than for
LOAD;where 4is present, progressionis similarinthe 2
groups.35 Likewise, patients with EOAD and the 4 allele
havebeenfoundtobeatgreaterriskofdeveloping
myoclo-nias with less tremor; this indicates a different clinical
course,determinedbytheAPOEgenotype,withinthegroup
ofpatientswithEOAD.35
It shouldbeunderstood that,inrecent years,
genome-wide association studies (GWAS) have detected
polymor-phismsincertaingenesassociatedwithLOAD,suchasCLU,
CR1,PICALM,SORL1,BIN1,CTNNA3,GAB2,DNMBP,ABCA7,
TREM2,andTOMM40;thelatterisassociatedwithanearlier onsetofLOADdeterminedbytheAPOEgenotype.44
Structural neuroimaging
Structuralneuroimagingstudies,includingcomputed tomo-graphy (CT) and magnetic resonance (MR) studies, are extremely important for the assessment of patients with cognitiveimpairment,andtheyaremainlyusedtoruleout secondarycauses.Furthermore,MRhasshownhigh sensitiv-ityasameansofevaluatingthecerebralatrophyassociated withneurodegenerativeprocesses;inAD,atrophytypically affectsthemedialtemporalregionandextendsposteriorly
totheparietotemporalandfrontalregions.45
Assessment of overall cerebral volume
Multiple MR studies have calculated the rate of cerebral atrophyin patients withAD andfound it tobegreater in EOAD,withadecreaseof2%to3%oftotalbrainvolumein
ayear46vs0.8%inLOADpatients47(notethatthefirststudy includedbothfamilialandsporadiccases).Therateof atro-phyfor allpatients ingeneralis 1.4%and0.6% inhealthy controls.48 Furthermore,studies indicatethat theatrophy rateincreasesby0.32%peryear2inpatientswithEOAD46;
ontheotherhand,studiesofADmakingnodistinctionsby ageof onsethave notpointed tosignificant accelerations
inatrophyandindicateameanvalueof0.09%peryear2.48
AlloftheabovedescribesEOADashavingamoreaggressive course
Assessment of grey matter
Numerousstudieshave comparedatrophy patternsingrey matter between patients with EOAD and LOAD Frisoni
etal.49foundmorepronouncedoverallatrophyinEOADthan
in the late-onset form (19.5% vs 11.9%) Atrophy primar-ilyaffectedneocorticalareas,especiallytheoccipitallobe
inEOADandthehippocampusinLOAD,andthese topogra-phiescorrespondwiththe2differentclinicalpatterns.Later studieshavereplicatedthesefindingsandattachedspecial relevancetotheprecunealatrophyoccurringinEOAD.50—52
Furthermore,the cortical maps that Frisoni etal.49 com-pared showed that atrophy was very diffuse in EOAD, whereasinLOADitwasdirectedatthetemporallobeand thetemporoparietaljunction.53
We know of only one longitudinal study carried out to date that has compared progression of cortical thinning betweenthese groups; it revealed, for EOAD, more rapid and diffuse atrophy of the association cortices (the left middleand frontalgyri, left inferiorparietal lobe, poste-riorareaoftheleftsuperiortemporalgyrus,leftfusiform gyrus,bilateralposteriorcingulargyri,andprecuneus)and comparativelymore atrophy of the left parahippocampal gyrus in LOAD.54 This pattern of atrophy corresponded to themorepronouncedclinicalimpairmentdisplayedbythe EOADgroupintheareasofexecutivefunctions,attention, andlanguage.54
Trang 6One recent study investigatedimpairment in the deep
cerebralnucleiinEOAD andLOAD.55 The differentpatient
groupsdisplaydistincttopographicalatrophypatternsinthe
striate.PatientswithEOADexhibitedmoreextensive
atro-phyofthedorsalstriatum,comparedtotheventralstriatum
in thosewithLOAD The authors’ interpretation wasthat
the changes might have been secondary to loss of
affer-encesofthemedialtemporallobeinthecaseoftheventral
striatum,andof theparietallobefor thedorsal striatum
Another longitudinal study compared the atrophy rate of
subcorticalstructuresbetweenthese2patientgroups.56 It
foundgreaterlossesofvolumeinthecaudate,putamen,and
thalamusin patientswithEOAD thanin thosewithLOAD,
whereaslossesinthehippocampusandamygdalafollowed
similarpatterns.Thesefindingsmayberelatedtothefact
that frontal functions decline more rapidly than memory
doesinEOAD
Assessment of white matter
Studieshavepointedtoapredominantly parahippocampal
patternofatrophyinLOAD,comparedtoamorediffuse
pat-ternofposterioratrophyinEOADthatprimarilyaffectsthe
spleniumofthecorpuscallosumandthedorsal
temporopari-etalregions.Thesewhite-matterfindingscoincidewiththe
topographyof affectedgrey matter, indicating thatwhite
matteratrophyissecondarytoatrophyofthegreymatter.41
Arecentstudyuseddiffusiontensorimaging(DTI)to
com-parewhitematter microstructuraldamagebetween the2
patientgroups.57 Theseauthorsobservedmoresevereand
diffuse atrophy in patients with EOAD, and theydescribe
damagetotheinterhemisphericconnections,limbicsystem
and main associative pathways, and the posterior
cingu-latecortex;LOADwasobservedtoaffectmainlythecorpus
callosum
Insummary,EOADdisplaysamorediffuseatrophypattern
in both grey and white matter, and it affects
neocorti-cal areas (especially the precuneus); atrophy in LOAD is
restricted to the hippocampus Furthermore, progression
seemstobequickerinEOAD,anditextendstosubcortical
areas,mostlytotheputamen
Functional neuroimaging
Functionalneuroimagingtechniquesallowdoctorstoassess
numerousfunctions ofthe brain.Oneofthe most
widely-used techniques is positron emission tomography (PET)
with18F-fluorodeoxyglucose(FDG),whichestimatesneural
activity based on the regional rate of glucose uptake.45
Singlephotonemissioncomputedtomography(SPECT)with
99mTc-HMPAO (99mTc-hexamethylpropyleneamineoxime)
estimatesneuralactivitybyprovidinganimageofregional
blood flow in the brain.45 On the other hand, functional
MRIletsusanalysethebrain’sresponsetospecificstimuli,
which is reflected by the haemodynamic changes in the
brainregionsactivatedbyeachstimulus
PET of glucose metabolism
ThetypicalpatternofADanomaliesinPETstudiesconsists
of hypometabolism in the posterior cingulate, the poste-riortemporoparietalcortex,andtheanteriorregionofthe medialtemporallobes.45 Hypometabolismintheseregions
ismoremarkedinEOADthaninLOADaccordingtostudies employing regionof interest analysistechniques (examin-ingstructuresthatarechosenapriori),andalsoaccording
tovoxel-basedtechniques (analysingthe brainasawhole withnoneedforaprioriselectionofspecificregions).45,58,59
Given the same degree of functional impairment accord-ing to the Clinical Dementia Rating (CDR), the patients withEOADshowedgreaterhypometabolism,butthiscould
be attributed tothe younger subjects’ greater functional reserve Furthermore,the hypometabolismcurve is more pronouncedthanthatoftheCDR,whichindicatesthatthe metabolicdysfunctionprogressesmorerapidly.59
Fig.1showsaPET-FDGstudyfromapatientwithLOAD andanotherfromapatientwithEOAD(lowerrow)
SPECT
ThepatternnormallyseenusingSPECTintypicalADis simi-lartothatdescribedusingPET.45Furthermore,patientswith EOAD exhibitmarked hypoperfusionof theposterior asso-ciative corticalareas, whereas late-onset caseswill show hypoperfusioninthemedialtemporalareas.60
In summary, evidence points once again to more pro-nouncedimpairmentoftheneocortex(parieto-occipitaland even frontal) in patients with EOAD, whereas atrophy in LOADismorelimitedtothemedialtemporallobe
Brain functional magnetic resonance imaging
Functional MRI was used in one study that attempted to characterisefunctional connectivitypatternsin EOAD and LOAD.61TheEOADgroupdisplayeddecreasedconnectivityof thedorsolateralprefrontalnetwork(DLPFN,relatedto exec-utive function) andincreased connectivity in theanterior temporal network (ATN, related to declarative memory); patients with LOAD exhibited the opposite pattern The authorslinkedtheirfindingstothedistincttopographiesof neural damage (decreased connectivity) in each of the 2 groups, andthefactthatdamagewouldgiveriseto com-pensatorymechanisms(increasedconnectivity)
PET
Therecentdevelopmentofradiotracersabletobindto amy-loidprotein hasmade it possible toevaluate AD features
in vivo.45 Most of the studies performed using Pittsburgh compound B (PiB) in patients with EOAD and LOAD did notrevealsignificantintergroupdifferences.55,62 According
to theauthors, the discrepancy between PET-FDGimages (which differ significantlybetween groups, asmentioned) and PET-PiB images (which are similar in both groups) indicates that other pathological processes, such as the formationofneurofibrillarytangles,neuroinflammation,or
Trang 7Figure 1 Positron emission tomography (PET) studies with florbetapir (upper row; images fused with CT) and 18 F-fluorodeoxyglucose(FDG; lowerrow)inpatients diagnosedwithAlzheimerdisease (A)Womanaged 79diagnosedwithtypical Alzheimerdisease.ThePETstudywithflorbetapirgivesapositiveresultforcorticalamyloidplaques.ThePET-FDGstudyindicates hypometabolismintheposteriorassociationcortex,predominantlyontheleftside.(B)Managed57diagnosedwithleft/language variantAlzheimerdisease.ThePETstudywithflorbetapirgivesapositiveresultforcorticalamyloidplaques.ThePET-FDGstudy indicateshypometabolismintheposteriorassociationcortex,predominantlyontheleftside
amyloid oligomers (mentioned previously and not visible
withPET-PiB),maybemoreinvolvedthanfibrillaramyloid
deposition in eliciting metabolic changes.62 Nevertheless,
Ossenkoppeleetal.63 observed agreaterconcentrationof
theradiotracerintheparietalcortexofpatientswithEOAD
andarecentstudyshowedthatpatientswithEOADdisplayed
more amyloid deposition in the basal ganglia, thalamus,
leftsuperiortemporalcortex,andleftcuneus.64 Thisisto
beexpectedbasedonthePET-FDGmetabolicneuroimaging
studiesthatwehavealreadydescribed,anditwouldfitthe
ideaofapathologicalcascadeinwhichdepositionof
amy-loidbetawouldprecedemetabolicdysfunction.Itremains
tobe seen what would causeamyloid depositsin certain areasandnotinothers.63
Fig.1alsoshowsaPETstudyofamyloiddepositsinone patientwithLOADandanotherwithEOAD(upperrow)
Conclusion
EOAD and LOAD have many traits in common, but they alsoexhibitnumerous differences(Table2).The factthat they display the same pathological process, which is the only defining diagnostic criterion for AD, obliges us to
Table 2 GeneralcharacteristicsofEOADandLOAD
Age at onset 65yearsandolder Youngerthan65years
Form of onset Amnestic Non-amnestic(visuospatialdysfunction,apraxias)
Progression Slower Faster
Neuropsychology Poorermemory Poorerexecutivefunction,visuospatialskill,and
motorskill
Pathology findings Senileplaquesand
neurofibrillarytangles
Senileplaquesandneurofibrillarytangles,with betterpreservationofthehippocampus
Biomarkers in CSF LowerlevelofA42and
increaseintauandP-tau
LowerlevelofA42andincreaseintauandP-tau
APOE genotype Favouredby1or24alleles Favouredbyabsenceof4alleles
Neuroimaging
StructuralMRI Hippocampalatrophy Frontal/temporoparietalatrophy
PET-FDG Decreasedmetabolismin
medialtemporallobe
Decreasedmetabolismintemporoparietalcortex PET11C-PiB Increaseduptake Increaseduptake(moreinparietalzone?)
Modified from van del Flier et al 35
Trang 8conclude that they are technically variants of the same
disease.Nevertheless,thesubstantialdifferencesbetween
these variants, which we have listed in this study, raise
the question of whether anatomical pathology findings
alone should constitute what defines a nosologicalentity
when it comes to classifying these neurodegenerative
diseases
In addition, neuropathology and neuroimaging findings
pose interesting questions regarding whether or not the
underlying pathophysiologicalprocess is thesame in both
forms.Perhapsthedifferencesbetweentheseclinical
vari-antscanonlybeexplainedbythefactorsinvolvedinageing
Onthe other hand, theseeminglymore aggressivecourse
ofEOAD calls for furtherinvestigation ofwhy thedisease
wouldexhibitdifferentbehaviourinsomecasesandnotin
others
Insummary, EOADmorefrequentlyexhibits anatypical
early clinical course; furthermore, patients will be more
affected in the areas of executive function, visuospatial
function, and motor skills, and display less memory loss
EOADcasesshowagreaterdensityofamyloidplaquesand
amorediffusedistributionpatternthanthatseeninLOAD
Lastly,EOADcaseswillshowagreaterextensionofatrophy
witha more diffuse pattern and more rapid progression;
these tendencies arealso observed using PET and SPECT
functionalimaging.Ontheotherhand,theleastconsistent
resultsareprovided byPETstudies evaluatingthe brain’s
amyloidload
Conflicts of interest
Theauthorshavenoconflictsofinteresttodeclare
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