Post on 30-Mar-2018
transcript
3/2/17
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Meeting of the Minds 3/18/17
Frontotemporal Dementia
Michael Rosenbloom, MD, FAAN
Clinical Director, HealthPartners Center for Memory and Aging
FTDPresenta1onOutline
I. GeneralPrinciplesII. Epidemiology
III. ClinicalsubtypesI. bvFTDII. nvf-PPA
III. sv-PPAIV. Gene1cs/NeuropathologyV. Management
VI. Research
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FTDPresenta1on:Goals
• Understandtheepidemiological,clinical,andneuropathologicaldifferencesbetweenFTDandAlzheimer’sdisease
• Recognizethemul1pleclinicalphenotypesassociatedwithFTD
• Developafamiliaritywithcurrentmanagementop1onsandpoten1alfuturetreatmentapproaches
Alzheimer’sDisease
FrontotemporalDemen3a
ClinicalPhenotype
ClinicalPhenotype
Anatomy/Neuropathology
Anatomy/Neuropathology
Pathophysiology/Biomarkers
Pathophysiology/Biomarkers
?
Frontotemporal dementia (FTD)
Semantic variant (svPPA)
Nonfluent/agrammatic variant (nfvPPA)
R
L L
Primary progressive aphasia (PPA) variants
Behavioral variant (bvFTD)
Dementia-movement syndromes FTD-MND
Corticobasal syndrome (CBS)
Progressive supranuclear palsy syndrome (PSP-S)
SlidecourtesyofSuzeeLee
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LR
A
P
FTD:ClinicalSubtypes
• Behavioralvariant-frontotemporaldemen3a(bvFTD)• Social/execu1ve/behavioraldysfunc1on• Motorneurondisease(~12.5-15%)
• PrimaryProgressiveAphasia(PPA)• Nonfluent/agramma1cvariantPPA(nfv-PPA)
• Agramma1cal,effor]ul,telegraphicspeech• Parkinsonspectrumdisorder(PSP/CBS)
• Seman1cvariant-PPA(sv-PPA)• Impairedsinglewordcomprehensionandconfronta1onalnaming
FTD:Epidemiology• Demen1aPrevalence
• Affects15-22per100,000• 2ndmostcommoncauseofdemen1ain<65yearoldpopula1on
• SurvivalTimefromFirstSymptom– Rangesfrom6-11yearsfromsymptomonset
• Fromclinicaldiagnosis– FTD-ALS
• 2years– Behavioralvariant-FTD
• 3-4years– Nonfluentvariant-PPA
• 5years– Seman1cvariant-PPA
• 5+years• BangLancet2015
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FTD:ADiagnos1cDilemma
• “FalseNega1ve”Dilemma• Bv-FTDreceivesanini1alpsychiatricdiagnosismorefrequentlythanpa1entswithAD(50.7%vs23.1%,[<0.001])
• WoolleyetalJClinPsychiatry2011
• “FalsePosi1ve”Dilemma• Amongpa1entspresen1ngtocommunityclinics,60%withini1alFTDdiagnosisweregivenalterna1vedemen1adiagnosisatUCSF(ter1aryreferralcenter)
• ShinagawaDementGeriatrCognDisord2016
International Research Criteria for Probable/Possible Behavioral Variant FTD A. Symptoms and Testing (3 of
following) 1. Early (2-3 yrs) behavioral
disinhibition 2. Early (2-3 yrs) apathy or inertia 3. Early (2-3 yrs) loss of emotional
reactivity/sympathy and empathy
4. Perseverative, stereotyped or compulsive/ritualistic behavior
5. Hyperorality and dietary changes
6. FTD neuropsychological profile B. Imaging results consistent
with FTD C. Exhibits significant functional
decline
Rascovsky et al. Brain 2011
EarlyBehavioralDisinhibi1on
VideocourtesyofUCSFMemoryandAgingCenter
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EarlyBehavioralDisinhibi1on
VideocourtesyofUCSFMemoryandAgingCenter
HyperoralityandDietaryChanges
VideocourtesyofUCSFMemoryandAgingCenter
PrimaryProgressiveAphasia
• PPAisagradualandisolatedimpairmentofwordusageandcomprehension.
• Preserva1onofothermentalfacul1essuchasmemory,visuospa1alskills,reasoning,andcomportment
• Languageistheonlyareaofdysfunc1onforatleastthefirst2yearsofthedisease
• MesulamAnnNeurol2001
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PrimaryProgressiveAphasiaSubtypes
• Non-fluent/agramma1cvariant
• Seman1cvariant
• Logopenicvariant
• OthersWilsonetalBrainLang2012
Non-Fluent/Agramma1cVariantPrimaryProgressiveAphasia
• Agramma1cal,telegraphic,non-fluentspeech
• Apraxiaofspeech• Rela1vepreserva1onofcomprehensionofsinglewords/simplesentences
• Parkinsonism– Cor1cobasalsyndrome
– Progressivesupranuclearpalsy
Non-fluent/agramma1cvariantPPA:TelegraphicSpeech
VideocourtesyofUCSFMemoryandAgingCenter
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Non-fluent/Agramma1cVariantPrimaryProgressiveAphasia
• IncreasedVisualCrea3vitywithnvf-PPA• PriortoPPAdiagnosis,pa1entAAdemonstratedincreasedvisualcrea1vityinsenngofatrophyinvolvinginferiorfrontal-insular,temporalandstriatalregions
• Structural/func1onalstudiesshowedincreasedgreymaoervalueandperfusioninvolvingtherightposteriorneocortex(polysensoryintegra1onregion)
SeeleyetalBrain2008
AA painted 6 years before PPA symptoms began.
Seman1cVariantPPA
• Focaldegenera1onaffectstheanteriortemporalpole(TP)
• TPfunc1onsinclude• Seman1cknowledge
• Personality/emo1onalregula1on/socialbehavior
• Facialrecogni1on• Theoryofmind
OlsonetalBrain2007
Seman1cVariantPPA
RightHemisphere• Emo1onaldetachment• Inappropriateuseof
objects• Lossoffacialrecogni1on• Mentalrigidity• Pooremo1onal
recogni1on• Irritability• Foodfads• Aspectsofbv-FTD
(disinhibi1on,ea1ngdisorders,lossofempathy)
LeLHemisphere• Primaryprogressive
aphasia• Anomia/impaired
confronta1onalnaming
• Lossofwordmeaning
• Wordfindingdifficulty
• Surfacedyslexia• Verbalepisodic
memoryloss
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FTD:Diagnos1cCriteriaforClinicalSubtypes
BangetalLancet2015
FTD:NeuropathologicalExamina1on
Tau TDP-43 FUS* *
*PreviouslydescribedasFTLD-ubiqui1n
Bang2015/NeumannBrain2009(36-50%) (50%) (10%)
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FTLD-tau FTLD-TDP FTLD-FUS
Frontotemporal lobar degeneration (FTLD)
FTLD-3 CHMP2b
FTD-MND
Pick’s 3R tau
CBD 4R tau
PSP 4R tau
FTDP-17 MAPT Type C Type D
VCP
Type B (C9orf72) (TARDP?)
aFTLD-U BIBD Type A (PGRN)
(C9orf72)
Type U (C9orf72)
NIFID/ NIBD
FUS NOS FUS
Other: CTE, AGD, MST, GGT
svPPA nfvPPA CBS PSPS bvFTD svPPA FTD-MND CBS PSP-S nfvPPA bvFTD
SlidecourtesyofSuzeeLee
FTD:Gene1cs
• General• Familyhistoryreportedin40%ofFTD
• Muta1onsinC9ORF72,microtubuleassociatedproteintau(MAPT),andprogranulin(GRN)genesaccountfor60%ofinheritedFTD
• Gene1ccounselingandtes1ngrecommendedinpa1entswithFTDandstrongfamilyhistoryofneurodegenera1vedisease
FTD:Gene1cs• C9ORF72
• Hexanucleo1derepeatin5’non-codingregionofchromosome9• Possibleroleincellulartrafficking
• Mostcommongene1ccauseofFTD(13-50%)
• AssociatedwithALS• TDP-43pathology
• Progranulin(GRN)• Synap1candneurotrophicfunc1on/TNFalphaantagonism
• 5-20%ofFTDcases• TDP-43pathology
• Microtubleassocia1onproteintau(MAPT)gene
• 5-20%ofFTDcases• Alteredmicrotubulestabiliza1on
• Taupathology
BangetalLancet2015/TsaiandBoxerJournalofNeurochemistry2016
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FTD:PharmacologicalManagement• BasicPrinciples
• TherearenoFDA-approveddisease-modifyingtreatmentsavailableforFTD• CholinesteraseinhibitorsmayworsenbehaviorinFTD(MendezAJofGeriatPsych2007)• Noevidencethatmeman1neiseffec1veforcogni1veorbehavioralsymptoms(Boxer
ADAD2009)• Noroleforbiologicals1mulants
• MoodStablizers• MinimalevidenceforvalproicacidorLamotriginebeyondcasereports
• SerotoninergicAgents• Fluoxe1ne,sertraline,orparoxe1nereducedisinhibi1on,depressivesymptoms,
carbohydratecraving,andcompulsions(Swartzetal.JofClinPsych1997).• Trazodone(NardellAmerJAlzDiseaseandotherdemen1as2014)andcitaloprammay
beeffec1veforagita1on(HerrmannAJGeriatricPsych2012)
• An3psycho3csandDopaminergicAgents• Casereportswithrisperidone(Cur1sandReschJClinPsychopharm2000)and
aripiprazole(FellgiebeletalWorldJournalBiolPsych2007),aswellasanopen-labeluncontrolledstudyofolanzapine(MorenetalAmJAlzheimersDisOtherDemen2003b)providelimitedsupportfortheiruse.
FTD:Non-PharmacologicalManagement
• Speechtherapy• Communica1onaugmenta1onandstrategies
• Mee3ngwithsocialworker• Diseaseeduca1on• Psychologicalsupportforfamilies
• Strategiesforbehavioralmanagement• Limi1ngou1ngs/providingexplanatoryleoer• Caregiverapproachtobehavioralexpressions
• Safety• Teamapproachtofinances/medica1ons• OTassessment/drivingre1rement
• AdvanceCarePlanning
Alzheimer’sDisease
FrontotemporalDemen3a
ClinicalPhenotype
ClinicalPhenotype
Anatomy/Neuropathology
Anatomy/Neuropathology
Pathophysiology/Biomarkers
Pathophysiology/Biomarkers
?
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FTD:Research
• LongitudinalEvalua3onofFamilialFrontotemporalDemen3aSubjects(LEFFTDS)– NIHsponsored,jointlyMayo/UCSF-ledmul1centertrialenrolling300f-FTDfamilieswithknownMAPT,GRN,or9ORF72muta1ons(100symptoma1ccarriers/100asymptoma1ccarriers/100normalcontrols)
– Annualmeasurementofbiomarkers:brainMRI,CSF,blood,behavioral,neuropsychological,andfunc1onalassessments
– Developmentofbiomarkeroutcomemeasuretoaddressclinicalefficacy
FTD:Research
• AdvancingResearchandTreatmentforFrontotemporalLobarDegenera1on(ARTFL)Consor1um/Project– NIHfunded,UCSF-basedconsor1umof14academicmedicalcentersenrollingN=1560subjectswithsporadicandfamilialFTD
– Medicalexams,clinicalassessments,ques1onnaires/surveys,bloodspecimens(plasma/DNA)gathered
– Goalsinclude• DiscoveringnewbiomarkersforFTD• Standardizediagnos1ccriteria• Subjectrecruitmentforclinicaltrials
Alzheimer’sBiomarkers