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PET AND DEMENTIA. Gary W. Small, M.D. Parlow-Solomon Professor on Aging Professor of Psychiatry and Biobehavioral Sciences Director, Center on Aging Director, Imaging Core, Alzheimer’s Disease Center University of California, Los Angeles. Positron Emission Tomography (PET).

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Pet and dementia

PET AND DEMENTIA

Gary W. Small, M.D.

Parlow-Solomon Professor on Aging

Professor of Psychiatry and Biobehavioral Sciences

Director, Center on Aging

Director, Imaging Core, Alzheimer’s Disease Center

University of California, Los Angeles


Positron emission tomography pet
Positron Emission Tomography (PET)

  • Imaging technique that provides information on brain structure and biochemical basis of brain function

  • Studies of glucose metabolism using 18-F-fluorodeoxylucose (FDG) demonstrate metabolic patterns reflecting neuronal function specific to different dementias

  • Extensive experience with FDG-PET in dementia evaluation

    • Kuhl et al. J Cereb Blood Flow Metab 1987;7:S-406.

    • Small et al. Arch Gen Psychiatry 1989;46:527.

    • Salmon et al. J Nucl Med 1994;35:391.

    • Mielke et al. Acta Neuropathol 1996;91:174.

    • Minoshima et al. Ann Neurol 1997;42:85.

    • Imamura et al. Neurosci Lett 1997;235:49.

    • Ishii et al. J Nucl Med 1998;39:1875.

    • Herholz et al. Alzheim Disease Assoc Disorders 1995;9:6.

    • Hoffman et al. J Nucl Med 2000;


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

Normal Early Alzheimer’s Late Alzheimer’s Child

G. Small, UCLA School of Medicine


Glucose Metabolic Patterns in Dementia

Normal

Alzheimer's

Pick's

Normal

Multiple Infarct

Dementia

Huntington's

G. Small, UCLA School of Medicine


Positron Emission Tomography in evaluation of dementia: Regional brain metabolism and long-term clinical outcome

  • Silverman DHS, Small GW, Chang CY, Lu CV, Kung de Aburto MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps ME

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

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


Diagnosis accuracy of fdg pet for assessing presence or absence of neurodegenerative dementia
DIAGNOSIS: Accuracy of FDG-PET for Assessing Regional brain metabolism and long-term clinical outcomePresence or Absence of Neurodegenerative Dementia

Neurodegenerative dementia present on autopsy?

Yes

No

Neurodegen. disease on PET?

Yes

113

4

7

No

14

Sensitivity = 94%

Specificity = 78%

JAMA 2001; 286:2120-2127

Overall Accuracy = 92%


Diagnosis accuracy of fdg pet for assessing presence or absence of alzheimer s disease
DIAGNOSIS: Accuracy of FDG-PET for Assessing Regional brain metabolism and long-term clinical outcomePresence or Absence of Alzheimer’s Disease

Alzheimer’s disease found on autopsy?

Yes

No

Alzheimer’s disease on PET?

Yes

91

11

6

No

30

Sensitivity = 94%

Specificity = 73%

JAMA 2001; 286:2120-2127

Overall Accuracy = 88%


Overall accuracy of fdg pet for assessing presence or absence of progressive dementia
OVERALL: Accuracy of FDG-PET for Assessing Regional brain metabolism and long-term clinical outcomePresence or Absence of Progressive Dementia

Progressive dementia actually present?

Yes

No

Yes

191

19

Progressive disease on PET?

15

No

59

Sensitivity = 93%

Specificity = 76%

JAMA 2001; 286:2120-2127

Overall Accuracy = 88%


Conclusion
Conclusion Regional brain metabolism and long-term clinical outcome

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

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

JAMA 2001; 286:2120-2127


Accuracy of early diagnostic assessment standard clinical vs fdg pet

Clinical assessments over several years in 134 patients Regional brain metabolism and long-term clinical outcome

Diagnostic accuracy:

Sensitivity: 83% - 85%

Specificity: 50% - 55%

(Lim et al J Am Geriatr Soc 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)

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


Combining apoe and pet measures studies of non demented persons
Combining APOE and PET Measures: Regional brain metabolism and long-term clinical outcomeStudies of Non-Demented Persons

  • Middle-aged people with genetic risk for Alzheimer’s disease (APOE-e4): PET shows metabolic deficits and decline.

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

      • (12 e4, 19 non-e4)

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

      • (11 e4 [homozygotes], 22 non-e4)

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

      • (27 e4, 27 non-e4 @ baseline; 10 e4, 10 non-e4 @ follow-up)

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

G. Small, UCLA School of Medicine


Baseline Differences in Cerebral Metabolism According to Genetic Risk in AAMI Subjects(Small et al. PNAS 2000;97:6037-42)

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

G. Small, UCLA School of Medicine


PET Scans Show Areas of Brain Function Decline (Red) After Two Years in APOE-4 Carriers(Small et al PNAS 2000;97:6037-42)

G. Small, UCLA School of Medicine


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

Number of Subjects

*lateral temporal metabolism

Estimated Drug Treatment Effect

G. Small, UCLA School of Medicine


No. of Subjects Per Treatment Group Needed to Detect a Drug Effect in Two Years Using PET* (based on data from Reiman et al, PNAS 2001; 98:3334-9)

Number of Subjects

*posterior cingulate metabolism

Estimated Drug Treatment Effect


Aami clinical trials program pet as a surrogate marker of outcome
AAMI Clinical Trials Program: Effect in Two Years Using PET* PET as a Surrogate Marker of Outcome

Active Drug (APOE ¾)

Baseline

Placebo (APOE ¾)

Metabolic Function

Follow-up

Time

AAMI = age-associated memory impairment

G. 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)


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
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, PNAS 2000; 97:6037-6042; Reiman et al. PNAS 2001;98:3334-3339;

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


Fdg pet as a surrogate marker in clinical trials of cholinesterase inhibitors mild to moderate ad
FDG-PET as a Surrogate Marker in Clinical Trials of Cholinesterase Inhibitors: Mild to Moderate AD

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

    • 6-12 weeks of treatment (n=6)

    • Cognition improved (> 2 points on MMSE) and metabolism increased (temporal, parietal, frontal)(p<.01)

  • Rivastigmine (Potkin et al. Int J Neuropsychopharmacol 2001;4:223)

    • 26 weeks of double-blind, placebo-controlled treatment (n=27)

    • 33% increase in hippocampal metabolism (p<.05) in responders; decreased 6% in non-responders and 4% in placebo-treated patients

  • Donepezil (Tune et al. Am J Geriatr Psychiatry, in press)

    • 24 week of treatment (n=28)

    • Mean brain glucose metabolism remained stable in active drug group and declined 10% in placebo group (p=.014); significant parietal, temporal and frontal treatment differences


Averaged PET Scans Before and After Treatment with Metrifonate

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


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

  • Fluorescent small molecule probe

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

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

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

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

G. Small, UCLA School of Medicine


DDNP & FDDNP Metrifonate

DDNP R = R1 = CH3

FDDNP R = CH3; R1 = CH2CH218F

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

G. Small, UCLA School of Medicine


Shoghi-Jadid, et al. MetrifonateAm J

Geriatr Psychiatry 2002;10:24-35

UCLA School of Medicine


Shoghi jadid small agdeppa et al am j geriatr psychiatry 2002 10 24 35
Shoghi-Jadid, Small, Agdeppa, et al. MetrifonateAm J Geriatr Psychiatry 2002;10:24-35

MMSE Scores vs. Residence Time (RT) Values

35

30

Hypothetical

Stages I-II

25

MMSE

Hypothetical

Stages III-IV

20

15

Hypothetical

Stages V-VI

10

Controls

AD

5

2

3

4

5

6

7

8

9

Residence Time

G. Small, UCLA School of Medicine


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

10

10

AD (n = 6)Controls (n = 7)p = 0.0074

AD (n = 6)Controls (n = 7)p = 0.0076

8

8

6

6

Relative Residence Time (min)

4

4

2

2

0

0

0

5

10

15

20

0

5

10

15

20

25

30

Immediate Paragraph Recall Test Score

Delayed Figure Recall Test Score

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


Residence Time vs Diagnosis Time (RT) Values

9

8

7

6

5

Residence Time

4

3

2

1

AD

Controls

Shoghi-Jadid, et al. Am J

Geriatr Psychiatry 2002;10:24-35

Diagnosis


Using information from multiple sources to improve early diagnosis and treatment
Using Information from Multiple Sources to Improve Early Diagnosis and Treatment

Neuronal function

FDG-PET

Cognitive reserve

fMRI

Diagnosis

Treatment

Plaque/tangle load

FDDNP-PET

Regional atrophy

Structural MRI

Genetic risk

profile

Neuropsychological

profile

G. Small, UCLA School of Medicine


Conclusions
Conclusions Diagnosis and Treatment

  • 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 Medicine


Collaborators
Collaborators Diagnosis and Treatment

  • 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 Medicine


Outside funding sources
Outside Funding Sources Diagnosis and Treatment

  • 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 Medicine


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