TheRoleofAmyloidImaginginthe DiagnosisofMildCognitive Impairment

AdamFleisher,MD,MAS
DirectorofImaging BannerAlzheimer'sInstitute,Phoenix,Arizona AssociateProfessor,DepartmentofNeurosciences UniversityofCalifornia,SanDiego SanDiego,California

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

 + -secretase inhibitors

A peptide

Neuritic plaque Immunotherapies

Aggregation inhibitors

APP

p-tau
Tau phosphorylation inhibitors

NFT

Neuroprotective agents

Synaptic dysfunction

Cell injury
Antioxidants

Oxidation

Antiinflammatories

Inflammation Cell-to-cell propagation

Image courtesy of Cummings JL, 2012.

Neurotransmitter replacement

Transmitter deficits Cell death/ Atrophy

3

BiomarkersofAD
Anyidentifiablemarkerthat accuratelyrepresentsunderlying pathologyassociatedwith disease BloodorCSF Imaging

Alzheimers Disease Progression

Abnormal FDG-PET

CSF A42 MRI hipp Cog Amyloid imaging CSF tau

Normal Pre-Symptomatic
CSF abeta42 Amyloid imaging CSF tau eMCI = early MCI; LMCI = late MCI. Aisen PS et al. Neurology. 2011;76:280-286.

Fxn eMCI LMCI

FDG-PET

Dementia
Function (ADL)

MRI Hippocampal volume Cognitive performance 5

AmyloidImaging development

18F-labeled Amyloid Imaging Compounds

FluorescentStilbene

18FFlutametamol

GE Florbetaben Bayer/Piramel

Florbetapir Lilly/Amyvid

NAV4694 Piridinyl Benzofuran

Navidea

Imagingprotocolsvarybetweencompounds. Injection,5090minutesuptaketime,1020minscans.

F18Amyloid ImagingTracers
Flutemetamol1 Florbetapir2

AD

NL
Florbetaben3 Navidea NAV46944

AD

NL
1.Vandenberghe Retal.AnnNeurol.2010;68:319329.2.WongDFetal.JNuc Med.2010;51:913920. 3.Barthel Hetal.LancetNeurol.2011;10:424435.4.ChenKetal.AAIC2012.

AmyloidImagingCorrelatesWithAmyloidPathology

59AUTOPSIES:ComparedtoPathologicdiagnosis
SUVR,cutpointof1.1, sensitivityof97% specificityof100%
FleisherAS.AANAnnualMeeting2010.Abstract1165AAN10D1. ClarkCM.JAMA.2011;305:275283;ClarkCMetal.LancetNeurol.2012;11:669678.

AmyloidImaginginAlzheimersprogression

10

Amyloid PET Measurements of Fibrillar A Burden: AD spectrum

Percentpositive 85.3% 46.7% 28.1%

CCRowe,NBA2007

N=19

N=47

N=68

N=60

N=82

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

APOE4, Age and Amyloid PET

%florbetapirpositive

AGE
EM Reiman, PNAS 2009. Fleisher AS et al. Neurobiol Aging. 2013;34:822-831.

CorticalAmyloidPredicts18MonthCognitiveDecline,MCI,and DementiaDuetoADinNormalOlderControls

ADAScog

CDRSOB

MMSE

NL69,MCI51,dAD 31
DoraiswamyPM,inpress,JAMANeurology,2013.

IncreasedcorticalAmyloidisAssociatedwithreducedparieto temporalGlucosemetabolismincognitivelynormalAPOE4carriers
MMPLS DualmodalitybrainmapsofPiBPETDVR(HOT) andFDGPETCMRgl (COLD)patternsassociatedwith APOE4genedose

MeanPiBPETDVRoverMMPLSROI

MeanFDGPETCMRgl overMMPLSROI

FleisherAS.HAI2010.

Cortical amyloid is associated with increased annual rate of global atrophy in cognitively normal individuals

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

PredictingProgressiontoMCIand Dementia

Biomarkerchangesinrelationtotheestimatedageatclinicalonset: ADADstudies

20

10 0 EstimateYrFromMCIdiagnosis

+10

FleisherAS,etal,LancetNeurol,2012 FleisherAS,AAIC,2013 BatemanRetal.NEngl JMed.2012;367:795804.

Biomarkerchangesinrelationtoageofdementiadiagnosis: AustralianImagingBiomarkerandLifestylestudy NL, MCI, AD = 200 3-5 year f/u

Villemagne VLetal.LancetNeurol.2013;12:357367.

AustralianADNI(AIBL)
3yearriskofprogression: PositiveversusNegativeAmyloidPETscan
HC (n=183)
100 90 80 70 60 50 40 30 20 10 0 10 0 50 40 100 90 80 70 60

MCI (n=87)
77% (47/60)
to AD dmentia

25%
to MCI/AD

30 20

29% (8/27)
AD dementia

Negative Positive
(n = 130) (n = 53)

Negative Positive
(n = 27) (n = 60)

Odds Ratio 4.8

Rowe CC. AAIC 2013.

Odds Ratio 14

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 in cognitively intact elderly. Associated with increased rate of brain atrophy and brain metabolism It is associated with progression to MCI and Dementia More is worse

AmyloidPETUseImpactsClinicianDecisionMaking
229patientswithprogressivecognitivedeclineandan uncertaindiagnosis
AfterAmyloidPETphysicianschangedtheirdiagnosisin54.6%(125/229) ofcases Diagnosticconfidenceincreasedbyanaverageof21.6% 86.9% ofcaseshadatleastonechangeintheirmanagementplan Cholinesteraseinhibitorormemantineuseincreasedby17.7%among Amyloidpositivecasesanddecreasedby23.3%amongthosewith negativescans Plannedbrainstructuralimagingdecreasedby24.4% Plannedneuropsychologicaltestingdecreasedby32.8%

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

TheRoleofAmyloidimagingintheClinic FDA IndicationforAmyloidImaging

AmyloidPET Indication
Toestimatebetaamyloidneuriticplaquedensity Inadultpatientswithcognitiveimpairmentwhoarebeingevaluated forADandothercausesofcognitivedecline AnegativeAmyloidscanindicatessparsetononeuriticplaquesand isinconsistentwithaneuropathologicaldiagnosisofADatthetimeof imageacquisition Anegativescanresultreducesthelikelihoodthatapatient'scognitive impairmentisduetoAD ApositiveAmyloidscanindicatesmoderatetofrequentamyloidneuritic plaques Neuropathologicalexaminationhasshownthisamountofamyloid neuriticplaqueispresentinpatientswithAD,butmayalsobepresent inpatientswithothertypesofneurologicconditionsaswellasolder peoplewithnormalcognition. Amyloidisanadjuncttootherdiagnosticevaluations
Amyloid [prescribing information]. Indianapolis, MN; Eli Lilly and Company; 2013.

SuggestedUseofAmyloidImaging
AmyloidImagingTaskforce:AppropriateUSECriteria
Amyloidimagingisappropriateinthefollowingsituations:
1. 2. Acognitivecomplaintwithobjectivelyconfirmedimpairment Performedonlyafterfullstandardw/uiscompleted: 3. 4. 5. Structuredclinicalevaluationwithobjectiveneurocognitivetesting Structuralbrainimaging Relevantlaboratorytests

ADasapossiblediagnosis,butuncertain KnowledgeofA pathologywouldincreasediagnosticcertaintyandalter management Shouldonlybeorderedbydementiaexperts: Specialtytraining,25%dementiacarepractice Geriatric/behavioralPsychiatryandNeurology

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

Who Pays for Amyloid Imaging

Amyloid Imaging is now available in the clinic
Jan 30th, 2013: Medicare Evidence Development Coverage Advisory Committee (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 those who can afford it ($3-4k)

ValueofAmyloidImagingintheclinic
Earlierdiagnosis Careplanning Reducedhospitalization Reducedcostoflifetimecare Improveaccuracyofdiagnosis Near50%ofpatientswithclinicallydiagnosedMCI,and20%of DementiaaremissdiagnosedwithAlzheimersDisease Leadstoexcessdiagnostictesting Inappropriatetreatmentsgiven Inappropriatelongtermplanninganduseofresources Missingtruediagnosis Untreatedunderlyingdisease leadingtofuture complicationsandcostofcare INCREASEDCOST

Conclusion
ThereisaneedfordiagnosticbiomarkersinAD,forboth clinicalandresearchapplication.
AmyloidPETasanimportanttoolforbetterunderstandingADstage Importanttoolinsymptomatic&presymptomatictherapydevelopment

Amyloidimagingcanbeavaluabletooltosupplement clinicaldiagnosisandprognosisdecisions.
Itcanidentifycorticalamyloid,andruleoutAlzheimers disease. CannotentirelyruleinADinisolation,butisastrongindicator giventheappropriateclinicalsetting.

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.