Fleisher MCI 2014- Forum SLIDES

8/13/2019 Fleisher MCI 2014- Forum SLIDES

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TheRoleofAmyloidImagingintheDiagnosisofMildCognitive

ImpairmentAdamFleisher,MD,MAS

DirectorofImaging

BannerAlzheimer'sInstitute,Phoenix,Arizona

AssociateProfessor,DepartmentofNeurosciences

UniversityofCalifornia,SanDiego

SanDiego,California


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Disclosure

Duringthecourseofthislecture,Dr.Fleishermay

mentiontheuseofmedicationsforbothFDA

approvedandnonapprovedindications

Dr.FleisherservesasaconsultantforAVID,EliLilly,

Grifols,andQuintiles;isaninvitedspeakerforAVID,

Quintiles,andSiemens;hasDSMBmembershipwith

Merck,NIA,andPfizer;andreceivesgrantfunding

fromEliLillyandNIA. Dr.Fleisheralsohassponsored

studieswithAvanir,Baxter,BMS,Genentech,EliLilly,Merck,Neuroptix,Pfizer,Roche,Takeda,andWyeth


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APPA peptide

p-tau Synapticdysfunction

OxidationCell injury

Inflammation

Cell-to-cell

propagation

Cell death/

Atrophy

Transmitter deficits

NFT

Neuriticplaque

+ -secretase inhibitors

Aggregationinhibitors

Immunotherapies

Antioxidants

Antiinflammatories

Neurotransmitter

replacement

Neuroprotective

agents

Tau

phosphorylation

inhibitors

3Image courtesy of Cummings JL, 2012.


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BiomarkersofAD

Anyidentifiablemarkerthataccuratelyrepresentsunderlyingpathologyassociatedwithdisease

BloodorCSF

Imaging


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Alzheimers Disease Progression

CSF abeta42

Amyloid imaging

FDG-PET

CSF tau

MRI Hippocampal volume

Cognitive performance

Function (ADL)

CSF A42

Amyloidimaging

FDG-PET

MRI hipp

CSF tau

Cog

Fxn

Abnormal

Pre-Symptomatic eMCI LMCI Dementia

Normal

eMCI = early MCI; LMCI = late MCI.Aisen PS et al. Neurology. 2011;76:280-286.

5


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AmyloidImagingdevelopment


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18F-labeled Amyloid Imaging Compounds

Imaging

protocols

vary

between

compounds.

Injection,5090minutesuptaketime,1020minscans.

18FFlutametamol

GE

Florbetaben

Bayer/Piramel

Florbetapir

Lilly/Amyvid

FluorescentStilbene

NAV4694

Piridinyl Benzofuran

Navidea


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F18Amyloid ImagingTracers

1.Vandenberghe Retal.AnnNeurol.2010;68:319329.2.WongDFetal.JNuc Med.2010;51:913920.3.Barthel Hetal.LancetNeurol.2011;10:424435.4.ChenKetal.AAIC2012.

AD

NL

Flutemetamol1 Florbetapir2

Florbetaben3

AD

NL

Navidea NAV46944


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AmyloidImagingCorrelatesWithAmyloidPathology

59AUTOPSIES:ComparedtoPathologicdiagnosis

SUVR,cutpointof 1.1,

sensitivityof97%

specificityof100%

FleisherAS.AANAnnualMeeting2010.Abstract1165AAN10D1.ClarkCM.JAMA.2011;305:275283;ClarkCMetal.LancetNeurol.2012;11:669678.


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AmyloidImaginginAlzheimersprogression

10


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N=19 N=47

85.3% 46.7% 28.1%Percentpositive

N=68 N=82N=60

RoweCC.Neurology.2007;68:17181725.FleisherAS.ArchNeurol.2011;68:14041411.

Amyloid PET Measurements of Fibrillar A Burden:

AD spectrum

CCRowe,NBA2007


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APOE4, Age and Amyloid PET

Fleisher AS et al. Neurobiol Aging. 2013;34:822-831.

%florbetapirpositive

AGEEM Reiman, PNAS 2009.


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NL69,MCI51,dAD 31

CorticalAmyloidPredicts18MonthCognitiveDecline,MCI,and

DementiaDuetoADinNormalOlderControls

DoraiswamyPM,inpress,JAMANeurology,2013.

ADAScog

CDRSOB

MMSE


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MeanFDGPETCMRgl overMMPLSROIMeanPiB

PETDVR

overMMPLS

RO

I

IncreasedcorticalAmyloidisAssociatedwithreducedparieto

temporalGlucosemetabolismincognitivelynormalAPOE4carriers

MMPLS DualmodalitybrainmapsofPiBPETDVR(HOT)

andFDGPETCMRgl (COLD)patternsassociatedwith

APOE 4genedose

FleisherAS.HAI2010.


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Chetelat G et al. Neurology. 2012;78:477-485.

Cortical amyloid is associated with increased

annual rate of global atrophy in cognitivelynormal individuals


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PredictingProgressiontoMCIand

Dementia


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Biomarkerchangesinrelationtotheestimatedageatclinicalonset:

ADAD

studies

BatemanRetal.NEngl JMed.2012;367:795804.

20 10 0 +10EstimateYrFromMCIdiagnosis

FleisherAS,etal,LancetNeurol,2012

FleisherAS,AAIC,2013


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Biomarkerchangesinrelationtoageofdementiadiagnosis:

Australian

Imaging

Biomarker

and

Lifestyle

study

Villemagne VLetal.LancetNeurol.2013;12:357367.

NL, MCI, AD = 200

3-5 year f/u


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AustralianADNI(AIBL)

3

year

risk

of

progression:PositiveversusNegativeAmyloidPETscan

0

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

77%

(47/60)to AD dmentia

29%

(8/27)AD dementia

25%to MCI/AD

Negative(n = 130)

Positive(n = 53)

Negative(n = 27)

Positive(n = 60)

Odds Ratio 14Odds Ratio 4.8

MCI

(n=87)

HC

(n=183)

Rowe CC. AAIC 2013.


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Whatwenowknow

Amyloid on PET is:

Associated with fibrillar amyloid on pathology

It distinguishes clinical stages of AD

Influenced by age and APOE gene

Associated with degree of lifetime cognitive activity

Associated with increased rate of memory decline incognitively intact elderly.

Associated with increased rate of brain atrophy and

brain metabolism

It is associated with progression to MCI and Dementia More is worse


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229patientswithprogressivecognitivedeclineandan

uncertaindiagnosis

AfterAmyloidPETphysicianschangedtheirdiagnosisin54.6%(125/229)

ofcases

Diagnosticconfidenceincreasedbyanaverageof21.6%

86.9%ofcaseshadatleastonechangeintheirmanagementplan

Cholinesteraseinhibitorormemantineuseincreasedby17.7%among

Amyloidpositivecasesanddecreasedby23.3%amongthosewith

negativescans Plannedbrainstructuralimagingdecreasedby24.4%

Plannedneuropsychologicaltestingdecreasedby32.8%

AmyloidPETUseImpactsClinicianDecisionMaking

SiderowfAetal.HumanAmyloidImagingConference,2013.GrundmanMetal.AlzheimerDisAssocDisord.2013;27:415.


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TheRoleofAmyloidimagingintheClinic FDA

IndicationforAmyloidImagingAmyloidPET

Indication Toestimatebetaamyloidneuriticplaquedensity

InadultpatientswithcognitiveimpairmentwhoarebeingevaluatedforADandothercausesofcognitivedecline

AnegativeAmyloidscanindicatessparsetononeuriticplaquesandisinconsistentwithaneuropathologicaldiagnosisofADatthetimeofimageacquisition

Anegativescanresultreducesthelikelihoodthatapatient'scognitiveimpairmentisduetoAD

ApositiveAmyloidscanindicatesmoderatetofrequentamyloidneuriticplaques

Neuropathologicalexaminationhasshownthisamountofamyloid

neuriticplaqueispresentinpatientswithAD,butmayalsobepresentinpatientswithothertypesofneurologicconditionsaswellasolderpeoplewithnormalcognition.

Amyloidisanadjuncttootherdiagnosticevaluations

Amyloid [prescribing information]. Indianapolis, MN; Eli Lilly and Company; 2013.


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Amyloidimagingisappropriateinthefollowingsituations:

1. Acognitivecomplaintwithobjectivelyconfirmedimpairment

2. Performedonlyafterfullstandardw/uiscompleted: Structuredclinicalevaluationwithobjectiveneurocognitivetesting

Structuralbrainimaging

Relevantlaboratorytests

3. ADasapossiblediagnosis,butuncertain

4. KnowledgeofApathologywouldincreasediagnosticcertaintyandalter

management

5. Shouldonlybeorderedbydementiaexperts:

Specialtytraining,25%dementiacarepractice

Geriatric/behavioralPsychiatryandNeurology

JohnsonKAetal.AlzheimersDement.2013Jan;9(1):e116;JohnsonKAetal. JNuclMed.2013;54:13.

SuggestedUseofAmyloidImaging

AmyloidImagingTaskforce:AppropriateUSECriteria


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Who Pays for Amyloid Imaging

Amyloid Imaging is now available in the clinic

Jan 30th, 2013:

Medicare Evidence Development Coverage AdvisoryCommittee (MEDCAC)

not sufficient evidence to support current Medicare

reimbursement at this time

July 3, 2013

Centers for Medicare & Medicaid Services (CMS)

Draft decision- Coverage with Evidence Development

Therefore: Amyloid imaging is only available to thosewho can afford it ($3-4k)


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Earlierdiagnosis

Careplanning

Reducedhospitalization Reducedcostoflifetimecare

Improveaccuracyofdiagnosis

Near50%ofpatientswithclinicallydiagnosedMCI,and20%of

DementiaaremissdiagnosedwithAlzheimersDisease Leadstoexcessdiagnostictesting

Inappropriatetreatmentsgiven

Inappropriatelongtermplanninganduseofresources

Missingtruediagnosis

Untreatedunderlyingdisease leadingtofuturecomplicationsandcostofcare

INCREASEDCOST

ValueofAmyloidImagingintheclinic


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ConclusionThereisaneedfordiagnosticbiomarkersinAD,forboth

clinicalandresearchapplication. AmyloidPETasanimportanttoolforbetterunderstandingADstage

Importanttoolinsymptomatic&presymptomatictherapydevelopmentAmyloidimagingcanbeavaluabletooltosupplement

clinicaldiagnosisandprognosisdecisions.Itcanidentifycorticalamyloid,andruleoutAlzheimersdisease.

CannotentirelyruleinADinisolation,butisastrongindicatorgiventheappropriateclinicalsetting.

Amyloid Imaging is now available in the clinic Indications and guidelines for use have been defined Who will have access and how broadly this tool will be

used is yet to be seen.

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