pet and dementia gary w. small, m.d. parlow-solomon professor on aging professor of psychiatry and...

PET AND DEMENTIA

Gary W. Small, M.D.Gary W. Small, M.D.Parlow-Solomon Professor on AgingParlow-Solomon Professor on Aging

Professor of Psychiatry and Biobehavioral SciencesProfessor of Psychiatry and Biobehavioral Sciences

Director, Center on AgingDirector, Center on Aging

Director, Imaging Core, Alzheimer’s Disease CenterDirector, Imaging Core, Alzheimer’s Disease Center

University of California, Los AngelesUniversity of California, Los Angeles

Positron Emission Tomography (PET)Positron Emission Tomography (PET)• Imaging technique that provides information on brain structure and biochemical Imaging technique that provides information on brain structure and biochemical

basis of brain functionbasis of brain function• Studies of glucose metabolism using 18-F-fluorodeoxylucose (FDG) demonstrate Studies of glucose metabolism using 18-F-fluorodeoxylucose (FDG) demonstrate

metabolic patterns reflecting neuronal function specific to different dementiasmetabolic patterns reflecting neuronal function specific to different dementias• Extensive experience with FDG-PET in dementia evaluationExtensive experience with FDG-PET in dementia evaluation

– Kuhl et al. Kuhl et al. J Cereb Blood Flow MetabJ Cereb Blood Flow Metab 1987;7:S-406. 1987;7:S-406. – Small et al. Small et al. Arch Gen PsychiatryArch Gen Psychiatry 1989;46:527. 1989;46:527.– Salmon et al. Salmon et al. J Nucl Med J Nucl Med 1994;35:391.1994;35:391.– Mielke et al. Mielke et al. Acta NeuropatholActa Neuropathol 1996;91:174. 1996;91:174.– Minoshima et al. Minoshima et al. Ann NeurolAnn Neurol 1997;42:85. 1997;42:85.– Imamura et al. Imamura et al. Neurosci LettNeurosci Lett 1997;235:49. 1997;235:49.– Ishii et al. Ishii et al. J Nucl MedJ Nucl Med 1998;39:1875. 1998;39:1875.– Herholz et al. Herholz et al. Alzheim Disease Assoc DisordersAlzheim Disease Assoc Disorders 1995;9:6. 1995;9:6.– Hoffman et al. Hoffman et al. J Nucl MedJ Nucl Med 2000; 2000;

Positron Emission Tomography (PET)Positron Emission Tomography (PET) Cerebral Cerebral Metabolism in Alzheimer’s Disease Progression and in Metabolism in Alzheimer’s Disease Progression and in

Normal BrainsNormal Brains

Normal Normal Early Alzheimer’s Early Alzheimer’s Late Alzheimer’s Child Late Alzheimer’s Child

G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine

Glucose Metabolic Patterns in DementiaGlucose Metabolic Patterns in Dementia

NormalNormal Multiple InfarctMultiple InfarctDementiaDementia

Huntington'sHuntington's

NormalNormal Alzheimer'sAlzheimer's Pick'sPick's


Positron Emission Tomography in evaluation Positron Emission Tomography in evaluation of dementia: Regional brain metabolism and of dementia: Regional brain metabolism and

long-term clinical outcomelong-term clinical outcome • Silverman DHS, Small GW, Chang CY, Lu CV, Kung de Aburto Silverman DHS, Small GW, Chang CY, Lu CV, Kung de Aburto

MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps MEKowell AP, Gambhir SS, Hoh CK, Phelps ME

• Univ. of California, Los Angeles; National Inst. on Aging; Univ. of Univ. of California, Los Angeles; National Inst. on Aging; Univ. of Pisa, Italy; Univ. of California, Davis; Duke Univ.; Univ. of Pisa, Italy; Univ. of California, Davis; Duke Univ.; Univ. of Pennsylvania; Univ. de Liege, Belguim; New York Univ.; Max Pennsylvania; Univ. de Liege, Belguim; New York Univ.; Max Planck Inst., Germany; Univ. of California, San Diego; Univ. of Planck Inst., Germany; Univ. of California, San Diego; Univ. of Arizona; Arizona State Univ.Arizona; Arizona State Univ.

• Journal of the American Medical AssociationJournal of the American Medical Association 2001;286:2120-2127 2001;286:2120-2127

DIAGNOSIS: Accuracy of FDG-PET for Assessing Presence or Absence of Neurodegenerative Dementia

Neurodegenerative dementia present on autopsy?N

euro

dege

n. d

isea

se o

n P

ET

?

Sensitivity = 94%Specificity = 78%Overall Accuracy = 92%

Yes NoYes 113 4No 7 14

JAMAJAMA 2001; 286:2120-2127 2001; 286:2120-2127

DIAGNOSIS: Accuracy of FDG-PET for Assessing Presence or Absence of Alzheimer’s Disease

Alzheimer’s disease found on autopsy?A

lzhe

imer

’s d

isea

se o

n P

ET

?



JAMAJAMA 2001; 286:2120-2127 2001; 286:2120-2127

OVERALL: Accuracy of FDG-PET for Assessing Presence or Absence of Progressive Dementia

Progressive dementia actually present?P

rogr

essi

ve d

isea

se o

n P

ET

?



JAMAJAMA 2001; 286:2120-2127 2001; 286:2120-2127

Conclusion

• AD and other progressive dementias significantly AD and other progressive dementias significantly alter brain metabolism early, relative to the alter brain metabolism early, relative to the manifestations of cognitive symptoms.manifestations of cognitive symptoms.

• Clinical FDG-PET detects this altered metabolism, Clinical FDG-PET detects this altered metabolism, providing an accurate clinical tool for noninvasive providing an accurate clinical tool for noninvasive prognostic and diagnostic assessment.prognostic and diagnostic assessment.

JAMAJAMA 2001; 286:2120-2127 2001; 286:2120-2127

Accuracy of Early Diagnostic Assessment:Accuracy of Early Diagnostic Assessment:Standard Clinical vs. FDG-PETStandard Clinical vs. FDG-PET

• Clinical assessments over several years in 134 patients

• Diagnostic accuracy:– Sensitivity: 83% - 85%

– Specificity: 50% - 55%(Lim et al J Am Geriatr Soc 1999;47:564-569)1999;47:564-569)

• Single baseline PET scan in 284 patients (138 autopsy diagnosis)

• Diagnostic accuracy:– Sensitivity: 93% - 95%

– Specificity: 73% - 78%(Silverman et al JAMA 2001;286:2120-2127)2001;286:2120-2127)

Combining APOE and PET Measures: Combining APOE and PET Measures: Studies of Non-Demented PersonsStudies of Non-Demented Persons

Middle-aged people with genetic risk for Alzheimer’s Middle-aged people with genetic risk for Alzheimer’s disease (APOE-disease (APOE-4): PET shows metabolic deficits and 4): PET shows metabolic deficits and decline.decline.

• Small et al (Small et al (JAMAJAMA 1995;273:942-947) 1995;273:942-947)

(12 (12 4, 19 non-4, 19 non-4)4)

• Reiman et al (Reiman et al (N Engl J MedN Engl J Med 1996;334:752-8) 1996;334:752-8)

(11 (11 4 [homozygotes], 22 non-4 [homozygotes], 22 non-4)4)

• Small et al (Small et al (PNASPNAS 2000; 2000;97:6037-604297:6037-6042))

(27 (27 4, 27 non-4, 27 non-4 @ baseline; 10 4 @ baseline; 10 4, 10 non-4, 10 non-4 @ follow-up)4 @ follow-up)

• Reiman et al (Reiman et al (PNASPNAS 2001; 2001;98:3334-333998:3334-3339))

(10 (10 4, 15 non-4, 15 non-4 @ baseline & follow-up)4 @ baseline & follow-up)G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine

Baseline Differences in Cerebral Metabolism According to Baseline Differences in Cerebral Metabolism According to Genetic Risk in AAMI SubjectsGenetic Risk in AAMI Subjects

(Small et al. (Small et al. PNASPNAS 2000;97:6037-42) 2000;97:6037-42)

Significantly lower metabolism (yellow/red areas) for the APOE-4 Significantly lower metabolism (yellow/red areas) for the APOE-4 vs. non-APOE-4 groups, in left lateral temporal, inferior parietal and vs. non-APOE-4 groups, in left lateral temporal, inferior parietal and posterior cingulate regions (SPM).posterior cingulate regions (SPM).


PET Scans Show Areas of Brain Function Decline (Red) PET Scans Show Areas of Brain Function Decline (Red) After Two Years in APOE-4 CarriersAfter Two Years in APOE-4 Carriers

(Small et al (Small et al PNASPNAS 2000;97:6037-42) 2000;97:6037-42)


No. of Subjects Per Treatment Group Needed to Detect No. of Subjects Per Treatment Group Needed to Detect a Drug Effect in Two Years Using PET* a Drug Effect in Two Years Using PET* (based on data from Small et al, PNAS 2000; 97:6037-6042)(based on data from Small et al, PNAS 2000; 97:6037-6042)

05

10

1520

2530

3540

4550

0.8 0.65 0.56 0.5

APOE-4 carriers

Estimated Drug Treatment EffectEstimated Drug Treatment Effect

Num

ber

of S

ubje

cts

Num

ber

of S

ubje

cts

*lateral temporal *lateral temporal metabolismmetabolism


No. of Subjects Per Treatment Group Needed to Detect No. of Subjects Per Treatment Group Needed to Detect a Drug Effect in Two Years Using PET* a Drug Effect in Two Years Using PET*

(based on data from Reiman et al, PNAS 2001; 98:3334-9)(based on data from Reiman et al, PNAS 2001; 98:3334-9)

0

50

100

150

200

250

300

0.5 0.33 0.25

APOE-4 carriersAPOE-4 non-carriers

Estimated Drug Treatment EffectEstimated Drug Treatment Effect

Num

ber

of S

ubje

cts

Num

ber

of S

ubje

cts

*posterior cingulate *posterior cingulate metabolismmetabolism

AAMI Clinical Trials Program:AAMI Clinical Trials Program:PET as a Surrogate Marker of OutcomePET as a Surrogate Marker of Outcome

TimeTime

Met

abol

ic F

un

ctio

nM

etab

olic

Fu

nct

ion

AAMI = age-associated memory impairmentAAMI = age-associated memory impairment

Active Drug Active Drug (APOE ¾)(APOE ¾)

Placebo Placebo (APOE ¾)(APOE ¾)

BaselineBaseline

Follow-upFollow-up


Brain Areas with Lowered Glucose Metabolism in Alzheimer’s Disease

(Alexander et al. Am J Psychiatry 2002;159:738-45)

2828

Brain Areas with Significant 1-Year Decline in Glucose Metabolism in Alzheimer’s Disease(Alexander et al. Am J Psychiatry 2002;159:738-45)

FDG-PET Surrogate Markers in Brain Aging Clinical Trials with 33% Treatment Effect

• Pre-symptomatic cases– Study of APOE-4 subjects– 60 subjects per treatment group– 2 year study

• Patients with Alzheimer’s disease– 36 subjects per treatment group regardless of genetic

risk status– 1 year study

Small et al, Small et al, PNASPNAS 2000; 97:6037-6042; Reiman et al. 2000; 97:6037-6042; Reiman et al. PNASPNAS 2001;98:3334-3339; 2001;98:3334-3339;Alexander et al. Alexander et al. Am J PsychiatryAm J Psychiatry 2002;159:738-45. 2002;159:738-45.

FDG-PET as a Surrogate Marker in Clinical Trials of FDG-PET as a Surrogate Marker in Clinical Trials of Cholinesterase Inhibitors: Mild to Moderate ADCholinesterase Inhibitors: Mild to Moderate AD

• Metrifonate Metrifonate (Mega et al. (Mega et al. Neuropsychiatry, Neuropsych Behav NeurolNeuropsychiatry, Neuropsych Behav Neurol 2001;14:63) 2001;14:63)

– 6-12 weeks of treatment (n=6)6-12 weeks of treatment (n=6)– Cognition improved (> 2 points on MMSE) and metabolism increased Cognition improved (> 2 points on MMSE) and metabolism increased

(temporal, parietal, frontal)(p<.01)(temporal, parietal, frontal)(p<.01)• Rivastigmine Rivastigmine (Potkin et al. (Potkin et al. Int J NeuropsychopharmacolInt J Neuropsychopharmacol 2001;4:223) 2001;4:223)

– 26 weeks of double-blind, placebo-controlled treatment (n=27)26 weeks of double-blind, placebo-controlled treatment (n=27)– 33% increase in hippocampal metabolism (p<.05) in responders; decreased 6% 33% increase in hippocampal metabolism (p<.05) in responders; decreased 6%

in non-responders and 4% in placebo-treated patientsin non-responders and 4% in placebo-treated patients

• Donepezil Donepezil (Tune et al. (Tune et al. Am J Geriatr PsychiatryAm J Geriatr Psychiatry, in press), in press) – 24 week of treatment (n=28)24 week of treatment (n=28)– Mean brain glucose metabolism remained stable in active drug group and Mean brain glucose metabolism remained stable in active drug group and

declined 10% in placebo group (p=.014); significant parietal, temporal and declined 10% in placebo group (p=.014); significant parietal, temporal and frontal treatment differencesfrontal treatment differences

Mega et al. Mega et al. Neuropsychiatry, Neuropsychiatry, Neuropsych Behav NeurolNeuropsych Behav Neurol 2001;14:63 2001;14:63

Averaged PET Scans Before and After Treatment Averaged PET Scans Before and After Treatment with Metrifonatewith Metrifonate

DDNP:DDNP: 1,1-dicyano-2-[6-(dimethylamino)-2- 1,1-dicyano-2-[6-(dimethylamino)-2-naphthalenyl]propenenaphthalenyl]propene

• Fluorescent small molecule probeFluorescent small molecule probe

• Neutral, lipophilic probe originally developed for Neutral, lipophilic probe originally developed for use with fluorescence microscopyuse with fluorescence microscopy

• Fluorinated analogue (FDDNP) provides Fluorinated analogue (FDDNP) provides visualizations of NFTs, NPs, and diffuse amyloidvisualizations of NFTs, NPs, and diffuse amyloid

Barrio JR, Huang S-C, Cole GM, Satyamurthy N, Barrio JR, Huang S-C, Cole GM, Satyamurthy N,

Petric A, Small GW. Petric A, Small GW. J Nucl Med J Nucl Med 1999;40[Suppl]:70P-71P1999;40[Suppl]:70P-71P..


N

NC CN

R1

R

DDNP & FDDNPDDNP & FDDNP

DDNPDDNP R = RR = R11 = CH = CH33

FDDNPFDDNP R = CHR = CH33; R1 = CH; R1 = CH22CHCH221818FF


Shoghi-Jadid, Small, Agdeppa, et al. Shoghi-Jadid, Small, Agdeppa, et al. Am J Am J Geriatr Psychiatry Geriatr Psychiatry 2002;10:24-352002;10:24-35

UCLA School of MedicineUCLA School of MedicineShoghi-Jadid, et al. Shoghi-Jadid, et al. Am J Am J Geriatr Psychiatry Geriatr Psychiatry 2002;10:24-352002;10:24-35

MMSE Scores vs. Residence Time (RT) ValuesMMSE Scores vs. Residence Time (RT) Values

HypotheticalStages V-VI

HypotheticalStages III-IV

HypotheticalStages I-II

9988776655443322

1010

2020

3030

Residence TimeResidence Time

MM

SE

MM

SE

1515

55

2525

3535

Controls

AD

Shoghi-Jadid, Small, Agdeppa, et al. Shoghi-Jadid, Small, Agdeppa, et al. Am J Am J Geriatr Psychiatry Geriatr Psychiatry 2002;10:24-352002;10:24-35 G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine

Immediate Memory Recall and Rey-O Test Scores vs. Residence Time (RT) Values

Immediate Memory Recall and Rey-O Test Scores vs. Residence Time (RT) Values

Delayed Figure Recall Delayed Figure Recall Test ScoreTest Score

1010

88

66

44

22

0055 1515 2020101000

AD (n = 6)AD (n = 6)

Controls (n = 7)Controls (n = 7)

p = 0.0074p = 0.0074

Shoghi-Jadid, Small, Agdeppa, et al. Shoghi-Jadid, Small, Agdeppa, et al. Am J Geriatr Psychiatry Am J Geriatr Psychiatry 2002;10:24-352002;10:24-35

2525 3030

1010

88

66

44

22

0055 1515 2020101000

Immediate Paragraph Recall Immediate Paragraph Recall Test ScoreTest Score

Rel

ativ

e R

esid

ence

Tim

e (m

in)

Rel

ativ

e R

esid

ence

Tim

e (m

in)

AD (n = 6)AD (n = 6)

Controls (n = 7)Controls (n = 7)

p = 0.0076p = 0.0076

Residence Time vs DiagnosisResidence Time vs Diagnosis99

88

77

66

55

44

33

22

11

Re

sid

en

ce T

ime

Re

sid

en

ce T

ime

DiagnosisDiagnosis

ADAD ControlsControls

Shoghi-Jadid, et al. Shoghi-Jadid, et al. Am J Am J Geriatr Psychiatry Geriatr Psychiatry 2002;10:24-352002;10:24-35

Cognitive reservefMRI

Neuronal functionFDG-PET

Plaque/tangle load FDDNP-PET

Regional atrophyStructural MRI

Genetic riskprofile

Neuropsychological profile

DiagnosisDiagnosis

TreatmentTreatment

Using Information from Multiple Sources to Using Information from Multiple Sources to Improve Early Diagnosis and TreatmentImprove Early Diagnosis and Treatment


Conclusions

• Complements structural imaging • Can serve as an in vivo biomarker to improve clinical

care and research in AD and related memory disorders• Can confirm the presence of neurological disease in

mild dementia and assist in differential diagnosis• Should be considered an option for the clinical

diagnosis of Alzheimer’s disease• PET should be included in clinical trials where AD is

sought as the pathological substrate for the therapy


Collaborators

• Amyloid-PET: Barrio JR, Huang S-C, Cole GM, Satyamurthy N, Petric A, Vinters H, ED Agdeppa, Z Kiziloglu, A Petric, Vinters H

• FDG-PET: Silverman DHS, Ercoli LM, Komo S, Siddarth P, Huang S-C, Phelps ME

• Genetics: Saunders AM, Pericak-Vance MA, Roses AD, Haines JL, Scott WK

• Geriatric Psychiatry/Neuropsychology/Neurology: Lavretsky H, Miller K, Cummings JL, Masterman D


Outside Funding Sources

• National Institute on Aging

• National Institutes of Mental Health

• Department of Energy

• Institute for the Study of Aging, Inc.

• American Federation of Aging Research

• Alzheimer’s Association

• Charles A. Dana Foundation

• Montgomery Street Foundation

• Fran and Ray Stark Foundation Fund for Alzheimer’s Research

• Hillblom Foundation

• Price Foundation


pet and dementia gary w. small, m.d. parlow-solomon professor on aging professor of psychiatry and...

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