Frontotemporal Michael Rosenbloom, MD, · PDF fileMichael Rosenbloom, MD, FAAN ... •...

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3/2/17 1 Meeting of the Minds 3/18/17 Frontotemporal Dementia Michael Rosenbloom, MD, FAAN Clinical Director, HealthPartners Center for Memory and Aging FTD Presenta1on Outline I. General Principles II. Epidemiology III. Clinical subtypes I. bvFTD II. nvf-PPA III. sv-PPA IV. Gene1cs/Neuropathology V. Management VI. Research

Transcript of Frontotemporal Michael Rosenbloom, MD, · PDF fileMichael Rosenbloom, MD, FAAN ... •...

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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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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

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FTDBiomarkersoftheFuture?

CSFTDP-43/tau18F-AV-1451FDG-PET/MRICogni1ve/Behavimpairment

Ques1ons?


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