pet and dementia gary w. small, m.d. parlow-solomon professor on aging professor of psychiatry and...
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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
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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
?
Sensitivity = 94%Specificity = 73%Overall Accuracy = 88%
Yes NoYes 91 11No 6 30
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
?
Sensitivity = 93%Specificity = 76%Overall Accuracy = 88%
Yes NoYes 191 19No 15 59
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).
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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)
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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..
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
N
NC CN
R1
R
DDNP & FDDNPDDNP & FDDNP
DDNPDDNP R = RR = R11 = CH = CH33
FDDNPFDDNP R = CHR = CH33; R1 = CH; R1 = CH22CHCH221818FF
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine
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
G. Small, UCLA School of MedicineG. Small, UCLA School of Medicine