1. 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

2. Positron Emission Tomography (PET) Imaging technique that provides information on brain structure and biochemical basis of brain functionImaging 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 dementiasStudies 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 evaluationExtensive 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;

3. Positron Emission Tomography (PET) Cerebral Metabolism in Alzheimer’s Disease Progression and in Normal Brains Normal Early Alzheimer’s Late Alzheimer’s Child Normal Early Alzheimer’s Late Alzheimer’s Child G. Small, UCLA School of Medicine

4. Glucose Metabolic Patterns in Dementia Normal Multiple Infarct DementiaHuntington's NormalAlzheimer'sPick's G. Small, UCLA School of Medicine

5. 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 MESilverman 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.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;286:2120-2127Journal of the American Medical Association 2001;286:2120-2127

6. DIAGNOSIS: Accuracy of FDG-PET for Assessing Presence or Absence of Neurodegenerative Dementia Neurodegenerative dementia present on autopsy? Neurodegen. disease on PET? Sensitivity = 94% Specificity = 78% Overall Accuracy = 92% YesNo Yes113 4 No 7 14 JAMA 2001; 286:2120-2127

7. DIAGNOSIS: Accuracy of FDG-PET for Assessing Presence or Absence of Alzheimer’s Disease Alzheimer’s disease found on autopsy? Alzheimer’s disease on PET? Sensitivity = 94% Specificity = 73% Overall Accuracy = 88% YesNo Yes 91 11 No 6 30 JAMA 2001; 286:2120-2127

8. OVERALL: Accuracy of FDG-PET for Assessing Presence or Absence of Progressive Dementia Progressive dementia actually present? Progressive disease on PET? Sensitivity = 93% Specificity = 76% Overall Accuracy = 88% YesNo Yes191 19 No 15 59 JAMA 2001; 286:2120-2127

9. Conclusion AD and other progressive dementias significantly alter brain metabolism early, relative to the manifestations of cognitive symptoms.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.Clinical FDG-PET detects this altered metabolism, providing an accurate clinical tool for noninvasive prognostic and diagnostic assessment. JAMA 2001; 286:2120-2127

10. Accuracy of Early Diagnostic Assessment: Standard Clinical vs. FDG-PET Clinical assessments over several years in 134 patients Diagnostic accuracy: –Sensitivity: 83% - 85% –Specificity: 50% - 55% 1999;47:564-569) (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% 2001;286:2120-2127) (Silverman et al JAMA 2001;286:2120-2127)

11. Combining APOE and PET Measures: Studies of Non-Demented Persons Middle-aged people with genetic risk for Alzheimer’s disease (APOE-  4): PET shows metabolic deficits and decline. Small et al (JAMA 1995;273:942-947) Small et al (JAMA 1995;273:942-947) (12  4, 19 non-  4) Reiman et al (N Engl J Med 1996;334:752-8) Reiman et al (N Engl J Med 1996;334:752-8) (11  4 [homozygotes], 22 non-  4) Small et al (PNAS 2000;97:6037-6042) Small et al (PNAS 2000;97:6037-6042) (27  4, 27 non-  4 @ baseline; 10  4, 10 non-  4 @ follow-up) Reiman et al (PNAS 2001;98:3334-3339) Reiman et al (PNAS 2001;98:3334-3339) (10  4, 15 non-  4 @ baseline & follow-up) G. Small, UCLA School of Medicine

12. 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

13. 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

14. 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) Estimated Drug Treatment Effect Number of Subjects *lateral temporal metabolism G. Small, UCLA School of Medicine

15. 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) Estimated Drug Treatment Effect Number of Subjects *posterior cingulate metabolism

16. AAMI Clinical Trials Program: PET as a Surrogate Marker of Outcome Time Metabolic Function AAMI = age-associated memory impairment Active Drug (APOE ¾) Placebo (APOE ¾) Baseline Follow-up G. Small, UCLA School of Medicine

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

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

19. 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.

20. 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)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 2 points on MMSE) and metabolism increased (temporal, parietal, frontal)(p<.01) Rivastigmine (Potkin et al. Int J Neuropsychopharmacol 2001;4:223)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)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

21. Mega et al. Neuropsychiatry, Neuropsych Behav Neurol 2001;14:63 Averaged PET Scans Before and After Treatment with Metrifonate

22. DDNP: 1,1-dicyano-2-[6-(dimethylamino)-2- naphthalenyl]propene Fluorescent small molecule probeFluorescent small molecule probe Neutral, lipophilic probe originally developed for use with fluorescence microscopyNeutral, lipophilic probe originally developed for use with fluorescence microscopy Fluorinated analogue (FDDNP) provides visualizations of NFTs, NPs, and diffuse amyloidFluorinated 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

23. DDNP & FDDNP DDNPR = R 1 = CH 3 FDDNPR = CH 3 ; R1 = CH 2 CH 2 18 F G. Small, UCLA School of Medicine Shoghi-Jadid, Small, Agdeppa, et al. Am J Geriatr Psychiatry 2002;10:24-35

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

25. MMSE Scores vs. Residence Time (RT) Values Hypothetical Stages V-VI Hypothetical Stages III-IV Hypothetical Stages I-II 98765432 10 20 30 Residence Time MMSE 15 5 25 35 Controls AD Shoghi-Jadid, Small, Agdeppa, et al. Am J Geriatr Psychiatry 2002;10:24-35 G. Small, UCLA School of Medicine

26. Immediate Memory Recall and Rey-O Test Scores vs. Residence Time (RT) Values Delayed Figure Recall Test Score 10 8 6 4 2 0 51520100 AD (n = 6) Controls (n = 7) p = 0.0074 Shoghi-Jadid, Small, Agdeppa, et al. Am J Geriatr Psychiatry 2002;10:24-35 2530 10 8 6 4 2 0 51520100 Immediate Paragraph Recall Test Score Relative Residence Time (min) AD (n = 6) Controls (n = 7) p = 0.0076

27. Residence Time vs Diagnosis 9 8 7 6 5 4 3 2 1 Residence Time Diagnosis ADControls Shoghi-Jadid, et al. Am J Geriatr Psychiatry 2002;10:24-35

28. Cognitive reserve fMRI Neuronal function FDG-PET Plaque/tangle load FDDNP-PET Regional atrophy Structural MRI Genetic risk profile Neuropsychological profile DiagnosisTreatment Using Information from Multiple Sources to Improve Early Diagnosis and Treatment G. Small, UCLA School of Medicine

29. 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 Medicine

30. 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 Medicine

31. 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 Medicine