1. Agenda 3:00 PMIntroduction to Workshop Barry Reisberg, M.D. 3:05 PM Cognitive dynamics: how variability in brain Kenneth Rockwood M.D., FRCPC, FRCP function influences the risk of cognitive decline 3:35 PMCurrent Knowledge of Methodologies for Barry Reisberg, M.D. Clinical Trials in Pre-MCI Persons with Subjective Cognitive Impairment (SCI) 4:25 PMDiscussion of Current Knowledge and Joel Sadavoy M.D., FRCPC Methodologies 4:35 PMDiscussion of Clinical Instrumentation forBarry Reisberg, M.D. Subject Selection and Assessment 4:55 PMSubject InterviewWorkshop Faculty and Participants 5:25 PMFinal DiscussionJoel Sadavoy M.D., FRCPC

2. Current Knowledge of Methodologies for Clinical Trials in Pre-MCI Persons with Subjective Cognitive Impairment (SCI)

3. Barry Reisberg, M. D. Professor of Psychiatry Director, Fisher Alzheimer's Disease Program Clinical Director, Aging & Dementia Research Center Director, Clinical Core, NYU Alzheimer's Disease Center New York University School of Medicine

4. Barry Reisberg, M.D. Adjunct Professor Center for Studies in Aging, Faculty of Medicine McGill University, Montreal, Canada (1993 – present) Member ADI Medical & Scientific Advisory Panel (MSAP) (1997 – present) Founder and Chair ADI Prevention Work Group

5. Research Support (1978 to Present) USDHHS National Institute on Aging AG 03051, AG 08051, AG 11505, AG 09127, AG 01344 National Institute on Mental Health MH 43486, MH 38275, MH 29590, MH 42216, MH 35976, MH 40410, MH 32577, MH 29590 National Institute of Neurologic Diseases and Stroke NS 15638 Adminstration on Aging AR 2160, AM 2552 FOUNDATION Zachary and Elizabeth M. Fisher Medical Foundation William and Sylvia Silberstein Bequest Mr. Leonard Litwin The Louis J. Kay and June E. Kay Foundation

6. Disclosures I am the developer, and copyright holder with respect to some of the instruments and procedures which I will be discussing.

7. Copyrights These include the: Global Deterioration Scale (GDS) Functional Assessment Staging (FAST) Brief Cognitive Rating Scale (BCRS) Behavioral Pathology in Alzheimer’s Disease Assessment (BEHAVE-AD)

8. U.S. Government Patents * 1 Management, care and treatment of Alzheimer’s Disease and related dementias - US Patent No. 7,122,006 System for diagnosis and staging of dementia by neurologic examination - US Patent No. 5,150,716 Method for diagnosis of incontinence of corticocerebral origin by neurologic examination - US Patent No. 5,826,585 Method for assessment of severe dementia - US Patent No. 5,082,446 * Among Others 1 Developed with associates

9. I have coined the terms and, with my associates, developed the concepts behind: Mild Cognitive Impairment Subjective Cognitive Impairment

10. Disclosures My measures have been made freely available to: All researchers, academics and students Governmental bodies e.g., US: Medicare (Center for Medicare and Medicaid Services [CMS]) US Veterans Administration 5 Canadian Provinces Not for profit associations e.g., Alzheimer’s Association American Psychiatric Association

11. > 90 % of currently used Alzheimer’s disease medications in the U.S. have been approved by the FDA in pivotal trials employing methods (scales) developed by myself and my colleagues

12. Industry Research Support * (1978 to Present) Exelon (rivastigmine) Novartis Namenda (memantine) Merz Forest Aricept (donepezil) Pfizer * and others

13. Collaborators Primary – NYU Institute for Basic Research- Steven H. Ferris, Ph.D. Staten Island, N.Y. Mony J. de Leon, Ed.D. Jerzy Weigel, DVM Other NYU Collaborators Henry Wisniewski, M.D., Ph.D. Emile H. Franssen, M.D. Maciek Bobinski, M.D. Liduin Souren, RN, MSN MAS Austria Sunnie Kenowsky, DVM Stefanie Auer, Ph.D. Alan Kluger, Ph.D. Tohoku University, Sendai, Japan Carol Torossian, Psy.D. Masumi Shimada, O.T. Isabel Monteiro, M.D. Kenichi Meguro, M.D., Ph.D. Industry Collaborators Ravi Anand, M.D. (Switzerland & US) Hans Jorg Mobius (Frankfurt, Germany) Albrecht Stoëffler (Frankfurt, Germany)

14. Prevention of Alzheimer’s Disease New Treatment Horizons

15. Is the umbrella organization of Alzheimer’s Disease Associations throughout the world. Seeks to establish and strengthen Alzheimer’s Associations worldwide & Raise global awareness of AD & dementia, more generally.

16. ADI Now has a history of success in bringing diverse areas of the world together to address important problems. E.g. 10/66 project Directed by Martin Prince Many ADI members from throughout the world have contributed Many important successes in the past decade in improving understanding and awareness of AD worldwide

17. ADI Prevention Workgroup Founded in December, 2008. A majority (n=55) of ADI’s Medical and Scientific Advisory Panel Members have joined ADI’s Prevention Workgroup. Workgroup members come from 6 continents.

18. Goals of the ADI Prevention Work Group Postpone the development of MCI and eventual AD 1. The identification of pre – Alzheimer’s disease stages prior to MCI 2. To conduct epidemiologic studies to identify remediable risk factors for eventual AD 3. To conduct multinational AD prevention studies

19. The first ADI Prevention Workgroup planning meeting was held in July, 2009 in conjunction with the International Conference on Alzheimer’s Disease (ICAD) in Vienna, Austria

20. The first ADI Prevention Workgroup symposium was held in September, 2009 in Montreal, Canada This symposium was the first public activity of the ADI Prevention Workgroup.

21. First ADI Prevention Work Group Symposium “ Predicting MCI and Dementia” Montreal, Canada September, 2009 Participants: Chairs: Barry Reisberg Serge Gauthier Presenters: Barry Reisberg Henry Brodaty Philip Scheltens John O’ Brien All members of ADI’ s Medical and Scientific Advisory Panel (MSAP)

22. Risk Factors for AD. Now Appear to Operate Early in Life For example: ApoE – є4 allele genotypic risk for AD

23. Reiman, et al., Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia., Proc Natl Acad Sci U S A., 2004 101(1):284-9.

24. http--www_kavlifoundation_org-uploads 1215817302_Moser_EntorhinalCortex_jpg.mht

25. Development of neurofibrillary changes (n=2369) Braak, H. & Braak, E., Aspects of cortical destruction in Alzheimer’s disease, in Hyman, B.T., Duykaerts, C., & Christen, Y. (Eds.), Connections Cognition and Alzheimer’s Disease, Springer-Verlag, Berlin Heidelberg, 1997.

26. CV, Cresyl Violet Stain Weigel, J., Dowjat, K., Kaczmarski, W., Kuchna, I., Nowicki, K., Frackowiak, J., Kolecka, B.M., Weigel, J., Silverman, W.P., Reisberg, B., de Leon, M.J., Wisniewski, T., Gong, C.-X., Liu, F., Adayev, T., Chen-Hwang, M.-C., Hwang, Y.-W. The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome, Acta Neuropathologica, 116: 391-407’, 2008.. n = 20 r = - 0.87 (p < 0.05) Neuronal Cellular Loss Second Layer of the Entorhinal Cortex: A Region Affected Early in AD

27. Bobinski et al., Dementia, 1995, 6: 205-210.

28. n = 20 r = - 0.76 (p < 0.05) Tau-1 antibody immunostaining of NFTs detects pretangles, stage 1 and stage 2 tangles, but not ghost tangles. Weigel, J., Dowjat, K., Kaczmarski, W., Kuchna, I., Nowicki, K., Frackowiak, J., Kolecka, B.M., Weigel, J., Silverman, W.P., Reisberg, B., de Leon, M.J., Wisniewski, T., Gong, C.-X., Liu, F., Adayev, T., Chen-Hwang, M.-C., Hwang, Y.-W. The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome, Acta Neuropathologica, 116: 391-407, 2008. Density of Neurofibrillary Tangles in the 2 nd Layer of the Entorhinal Cortex

29. Bobinski et al., Dementia, 1995, 6: 205-210.

31. Bobinski et al., Dementia, 1995; 6: 205-210.

35. GDS Stage 3 Mild Cognitive Impairment 1,2 Earliest subtle deficits Objective evidence of memory deficit obtained only with an intensive interview Decreased performance in demanding employment and social settings 1 Reisberg, et al., Drug Development Research, 1988; 15:101-114. 2 Flicker, C., Ferris, S.H., Reisberg, B. Mild Cognitive Impairment in the elderly: prediction of dementia. Neurology, 1991, 41:1006-1009.

36. Psychometric/Mental Status/Behavior SCI vs MCI Significant differences on the: MMSE Blessed Dementia Scale Blessed et al., information test, memory test, and concentration test, WAIS vocabulary scores Paragraphs, initial and delayed recall tests Paired associates, initial and delayed recall Designs test Shopping list selective reminding test Digits backward recall Digit symbol substitution test Finger tapping speed (mean R & L) Comprehensive psychometric test Reisberg, et al., Drug Dev Res, 1988; 15:101-114.

37. Kluger et al., Journal of Geriatric Psychiatry and Neurology, 1999; 12: 168-179

38. No Cognitive Subjective Cognitive Mild Cognitive Impairment Impairment Impairment (NCI) (SCI) (MCI) Kluger et al., Journal of Geriatric Psychiatry and Neurology, 1999; 12: 168-179

39. This study verified our earlier estimate that the MCI stage of eventual AD lasts approximately 7 years in otherwise healthy persons. This estimate of duration is almost precisely in the midpoint of the timecourse observed for MCI in subsequent worldwide studies.

40. Selected Studies of Clinically Defined MCI (GDS stage 3) with Ddx from Normal Aging and/or Dementia, 1983-2001 Abbrev. Citation * Modality Finding Reisberg, et al., 1983Clinically assessed Ddx MCI vs Psychopharm. Bull. modalities e.g., SCI & concentration, Mild AD Reisberg & Ferris, 1988, calculation, etc. Psychopharm. Bull. Reisberg, et al., 1992, Int. Psychoger. Reisberg, et al., 1988, Mental status, Ddx MCI Drugs. Dev. Res. Psychometric testsvs SCI & Mild AD

41. Abbrev. Citation * Modality Finding Reisberg, et al., 1985, Subjective complaints,Ddx MCI in B. Stanley (ed.), American subject & spouse rated, vs SCI & Psychiatric Pressinsight & denial Mild AD Reisberg, et al., 1989Nature of behavioralDdx MCI Bull. Clin. Neurosci.disturbancesvs. SCI and and Mild AD de Leon, et al., 1989, MRI hippocampal MCI atrophy Lancet. atrophy predicts AD de Leon, et al., 1993, Am. J. Neuroradiology Franssen et al., 1991,Neurological reflexes ↑ DTRs, glabellar Arch. Neurology blink & palmomental reflexes in MCI vs NL aged

42. Abbrev. Citation * Modality Finding Prichep, et al., 1994, Neurobiol.QEEG ↑ theta activ. In Aging MCI vs. SCI Kluger, et al., 1997,Motor measuresDdx MCI vs. Journ. Gerontology SCI & Mild AD Franssen et al., 1999,Equilibrium and coordinationDdx MCI Joun. Am. Geriatr. Soc.measures vs NL aged Reisberg, et al., 2001,ADLs, Ddx MCI Int. Psychogeriatrics13 areas vs SCI and Mild AD * Complete citations in Reisberg, Ferris, Kluger, Franssen, Wegiel, and de Leon, Mild cognitive impairment (MCI): a historical perspective, International Psychogeriatrics, 20:1, 18-31, 2008.

43. MCI Peterson, et al., 2001 1 Memory complaint Objective memory impairment Normal general cognitive function Intact activities of daily living Not demented 1 Peterson, Stevens, Ganguli, et al., Neurology, 56:1133-1142.

44. MCI International Working Group (IWG) Criteria 2004 * Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med., 2004; 256: 240-6.

45. MCI International Working Group (IWG) Criteria (2004) * Do not require self report of decline Instead suggest that MCI subjects have: “self and/or informant report and impairment on objective cognitive tests and/or, evidence of decline over time on objective cognitive tasks”

46. Global Deterioration Scale Stage Diagnosis and Nl Nl MCI Mild Mod Mod- Severity without with AD AD Severe SCI SCI AD Questions referring to the subject’s status. Category 1: memory functioning: Query 1: What kinds of problems do you (does your spouse) have with memory?

47. Recommend a clinical, rather than a psychometric definition of MCI Functioning “A wide range of cognitive functions appear to decline … including memory, attention, language, visuospatial skill, perceptual speed and executive functioning.” Entirely compatible with the original GDS Stage 3 MCI definition. * Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med., 2004; 256: 240-6.

49. Adapted from Reisberg, Dementia, Geriatrics, 1986; 41(4): 30-46. Subjective Cognitive Impairment Clinical Diagnosis Normal Adult Subjective Cognitive Impairment Mild Cognitive Impairment Mild Mod Mod to Seve Severe NL SCI MCI AD AD AD AD

50. Subjective Cognitive Impairment Very common Jonker, et al., 2000 Reviewed 3 community based studies of persons ≥ 65 years of age Prevalence = 25% to 56%

51. Subjective Cognitive Impairment Quite troubling For the past 30 years, ~ 1/3 of the persons presenting at the NYU School of Medicine, Aging and Dementia Research Center have SCI These people frequently want help.

52. Subjective Cognitive Impairment Persons with these symptoms need to be differentiated from – Healthy non-SCI persons Persons with MCI

53. The Global Deterioration Scale (GDS) 1 which we have been using for the past 30 years makes these distinctions. Other elements of the GDS Staging System also make these distinctions. Brief Cognitive Rating Scale (BCRS) Functional Assessment Staging (FAST) 1 Reisberg, B., Ferris, S.H., de Leon, M.J., and Crook, T., The global deterioration scale for assessment of primary degeneration dementia. American Journal of Psychiatry, 1982; 139:1136-1139.

55. GDS Stage 1 Healthy older persons Free of subjective complaints of cognitive impairment Free of objective evidence of cognitive impairment

56. GDS and FAST Stages of AD GDSStageFASTStageFAST Functional Assessment No functional difficulties, either subjectively or objectively 1 1.Normal

57. GDS Stage 2 Subjective complaints of memory deficit. e.g., forgetting names one formerly knew well Forgetting where one has placed familiar objects. No objective evidence of memory deficit on clinical interview No objective deficit in employment or social situations

58. GDS and FAST Stages of AD GDSStageFASTStageFAST Functional Assessment Subjective complaints only, e.g., forgetting names, forgetting location of objects 22.SCI

59. Duration of the SCI stage Hypothesized duration = 15 years (Reisberg, 1986) Longitudinal Study of 44 GDS Stage 2 Subjects Followed for 8.9 ± 1.8 Years (Prichep, et al., 2006) The hypothesized mean duration of the subjective cognitive impairment (SCI) stage, synonymous with Global Deterioration Scale (GDS) stage 2, was published in Reisberg, B. (1986). Dementia: a systematic approach to identifying reversible causes. Geriatrics, 41(4), 30-46. The observed results for the duration of the SCI stage, synonymous with GDS stage 2, are calculated from Prichep, L.S., et al. (1994). Quantitative EEG correlates of cognitive deterioration in the elderly. Neurobiology of Aging, 15, 85-90. Result: For a stage with a 15 year duration, the observed result differed from the hypothesized result by 2 %. Reisberg, B. and Gauthier, S., International Psychogeriatrics, 20:1, 1-16, 2008..

60. Psychometric/Mental Status/Behavior SCI vs MCI Significant differences on the: MMSE Blessed Dementia Scale Blessed et al., information test, memory test, and concentration test, WAIS vocabulary scores Paragraphs, initial and delayed recall tests Paired associates, initial and delayed recall Designs test Shopping list selective reminding test Digits backward recall Digit symbol substitution test Finger tapping speed (mean R & L) Comprehensive psychometric test Reisberg, et al., Drug Dev Res, 1988; 15:101-114.

61. Cross Sectional Studies are Beginning to Show Differences between SCI Subject Groups and Healthy, Non-SCI as well as MCI Subjects Groups

62. Prichep, et al., Neurobiology of Aging, 1994, 15: 85-90.

63. Physiologic Differences between GDS Stage 2 SCI Subjects and GDS Stage 1 Subjects with No Cognitive Impairment (NCI)

64. SCI vs NCI and SCI vs MCI Subject Group Differences

65. Physiologic Changes Hormonal NCI vs SCI ↑ 12 hour urinary cortisol levels in SCI subjects Wolf, et al., Neurobiol Aging, 2005; 26:1357-1363.

66. Brain Changes: Function Neurometabolism NCI vs SCI ↓ metabolism: parahippocampal gyrus (bilaterally 18% reduction) middle temporal gyrus inferior parietal lobe inferior frontal gyrus fusiform gyrus thalamus right putamen Mosconi, et al., Biological Psychiatry, 63: 609-18, 2008.

67. P<0.05 FWE correctedMosconi e al, Biol Psych 2008: 63:609-18. Subjective Cognitive Impairment Hypometabolism in SCI, Mosconi, et al. Biological Psychiatry, 2008 middle-age NL with SCI (n=13) vs NCI (n=15) n=15 n=13

68. Prevalence of CSF Markers of AD Pathology:* Percentage of Subjects with an AD Type CSF profile a a The CSF AD profile was defined as a score < 1 calculated with the formula: Aβ 42 /(240+[1.18 x T-tau]) *Visser, Verhey, Knol, et al., Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study, Lancet Neurology, 8, 619-627, 2009.

69. SCI vs NCI Prognostic Group Differences Prediction of Dementia: Positive Studies Geerlings, et al., Am J. Psychiatry, 1999. 3.2 year F/U; MMSE ≥ 26; MCI not excluded → 3 x risk of AD for SCI vs non-SCI van Oijen, et al., Alzheimer’s and Dementia, 2007. 9.0 year F/U; MMSE = 29 or 30 → 3 x risk of AD in high educat. group

70. SCI vs NCI Prognostic Group Differences Prediction of Dementia: Other Studies St. John and Montgomery International Journal of Geriatric Psychiatry, 2002. After adjusting for age, gender, and depressive symptoms → SCI predicted dementia 15% developed dementia in 5 yrs. After adjusting for mental status assessment scores, → SCI did not predict dementia

71. SCI vs NCI Prognostic Group Differences Prediction of Dementia: Negative Studies Wang, et al., Journal of the American Geriatrics Society, 2000 3 yr study All persons ≥ 65 in a Chinese rural population → Subjective complaints subjects had ↓ cognitive performance at baseline → Subjective memory complaints did not predict faster cognitive decline or dementia

72. Our studies, Glodzik-Sobanska, et al. 1 and the present study ( Reisberg, et al., Alzheimer’s & Dementia, 2010; 6: 11-24) are the first to use MCI as well as dementia, as an outcome in long term studies of non-SCI (GDS stage 1) and SCI (GDS stage2) cohorts. Glodzik-Sobanska, Reisberg, De Santi, et al., Subjective memory complaints: Presence, severity and future outcome in normal older subjects, Dementia Geriatr Cogn Disord, 2007; 24:177-184.

73. Subjects Consecutive series Healthy subjects, GDS stage 1 or 2 ≥ 40 years of age Presenting to the NYU ADRC between 1-1-1984 and 12-31-1997 (14 year window) Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

74. N = 260 NCI (GDS stage 1) n = 60 SCI (GDS stage 2) n = 200 Subjects were scheduled for F/U at ~ 2 yr intervals Analysis cut off date: 12-31-2001 (18 years after the baseline) Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

75. Outcome: Stable: if subject remained normal and had not declined to MCI or dementia over the F/U observation period Decline: if the subject declined to MCI or dementia; the first observation period of decline was used for time to decline Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

76. Results Follow-up was completed in 213 subjects (81.9%) Lost to follow-up: NCI n = 13 SCIn = 34 N.S. stage, age or MMSE; Education, p =.02; Gender, more men lost to F/U, p = 0.05 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

77. Characteristics of Subjects Followed NCI SCI (GDS Stage 1) (GDS Stage 2) n = 47 n = 166 Age 64 68* MMSE 29.6 29.0*** Hamilton 3.1 4.4* * p < 0.05, *** p < 0.001 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

78. Characteristics of Subjects Followed No significant difference at baseline in: Gender: Majority > 60% female Education: Mean: 16 years Any psychometric test or PDS Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

79. NCI SCI (GDS Stage 1) (GDS Stage 2) Time in study: 6.7 yrs 6.8 yrs Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

80. Outcome NCI SCI (GDS Stage 1) (GDS Stage 2) n=47 n=166 Progressed Stable % Progressed Stable % 7 40 15% 90 76 54%**** Differences between the groups in outcome were significant P < 0.0001 Fisher’s exact test Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

81. Mean Time to Decline NCI SCI (GDS Stage 1) (GDS Stage 2) 8.8 years 5.3 years Savage two sample test for event time, p = 0.0003 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

82. Survival Analysis Weibull Proportional Hazards Model Controlling for: Age Gender Education Level Follow-up time The hazard ratio of SCI subjects 4.5 times the risk of decline as NCI subjects (95% Confidence limits, 1.9 to 10.3) Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

83. Survival Analysis: Kaplan-Meier Method Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

84. Fig. 1. Plot of survival distribution functions for the NCI and SCI baseline groups. The y-axis is the probability of not declining to MCI or dementia. The x-axis is the time (in years) to decline. This survival curve plot extends until observation year 14. There were no SCI subject observations beyond year 14. One NCI subject was followed up beyond year 14. This subject was observed to decline at year 16. There was a significant difference between the NCI and the SCI baseline groups in the survivor function of absence of decline to MCI or dementia in favor of the NCI baseline group (P <.0001, Wilcoxon test and Log-Rank test). Survival Analysis: Kaplan-Meier Method Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

85. Conclusion SCI is a condition in which: (1) Persons score in the normal range on tests, but complain of impairment (2) SCI persons have a ~ 4.5 x greater risk of decline to MCI or dementia than same gender, similarly aged and educated, non-SCI persons Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

86. Conclusions Continued SCI is a condition in which: (1) Persons declined more rapidly at 60% of the rate of NCI persons (2) SCI persons declined sooner Mean decline time was 3.5 years longer for NCI Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

87. Survival Analysis Accelerated Failure Time Model Controlling for: Age Gender Education level Follow-up time SCI subjects took on average 60% of the time to decline of NCI subjects (Estimated ratio of the expected decline time, 0.60, 95% confidence limits, 0.45 to 0.80) Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

88. Accelerated Failure Time Model Analysis Controlling for: Baseline group Age Gender Education level Follow-up time Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

89. Baseline variables contributing significantly to the time to decline: MMSE p=0.05 BCRS (I-V) Total Scorep<0.01 BCRS Axis 1 (Concentration & Calculation)p<0.01 BCRS Axis 5 (Functioning)p<0.05 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

90. Baseline variables contributing significantly to the time to decline: Hamilton - Item 8 p<0.05 (Slowness of thought and speech and/or impaired concentration & decreased motor activity) Hamilton - Item 11 Somatic Anxietyp<0.01 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

91. Baseline variables contributing significantly to the time to decline: Psychometric Deterioration Score (Composite of 9 tests) p<0.0001 Seven of 9 individual test variables p<0.05 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

92. NCI Subject Group Baseline Variables Showing Significant Differences Between Stable and Decline Groups at Follow-up Stable (n=40)Decline (n=7)P Age62.573.0< 0.01 Hamilton – Item 12 (Decreased appetite) < 0.05 DSST57.046.7< 0.05 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

93. SCI Subject Group Baseline Variables Showing Significant Differences Between Stable and Decline Groups at Follow-up Stable (n=76)Decline (n=90)P Age65.369.4< 0.01 Education16.215.1< 0.01 MMSE29.328.7< 0.01 BCRS, Total score8.59.3< 0.01 BCRS Axis 1: Concentration and Calculation 2.02.4< 0.001 BCRS Axis 5: Functioning 1.651.88< 0.01 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

94. SCI Subject Group Baseline Variables Showing Significant Difference Between Stable and Decline Groups at Follow-up Behavior Stable (n=76)Decline (n=90) P Hamilton – Item 10 (Tension, worry) < 0.05 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

95. SCI Subject Group Baseline Variables Showing Significant Difference Between Stable and Decline Groups at Follow-up Behavior Stable (n=76)Decline (n=90) P Hamilton – Item 10 (Tension, worry) < 0.05 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

96. SCI Subject Group Baseline Variables Showing Significant Differences Between Stable and Decline Groups at Follow-up Psychometric Stable (n=76)Decline (n=90)P Psychometric Deterioration Score (PDS) 1.752.56< 0.001 Paired Associates, Initial recall 5.224.17< 0.01 Paired Associates, Delayed recall 5.664.47< 0.01 Digit Span Forwards7.266.58< 0.001 Digit Span Reverse5.865.12 0.001 DSST54.648.8< 0.01 WAIS Vocabulary70.562.9< 0.001 Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

97. Conclusion SCI is a condition in which: (1) Persons score in the normal range on tests, but complain of impairment (2) SCI persons have a ~ 4.5 x greater risk of decline to MCI or dementia than same gender, similarly aged and educated, non-SCI persons (3) Is accompanied by cognitive losses which are evident in aggregate but not in individual cases Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

98. Implications for AD Prevention and ADI Prevention Workgroup We are now in a position to address the prevention of AD in persons with complaints beginning >20 years before dementia develops

99. Using some of the same measures and kinds of measures For example MMSE, BCRS, FAST Psychometric measurements as have been used in current medication approvals for mild to severe AD by worldwide regulatory agencies

101. 78 y/o, MMSE = 26, 2009

103. JUNE 27, 2005

106. Agenda 3:00 PMIntroduction to Workshop Barry Reisberg, M.D. 3:05 PM Cognitive dynamics: how variability in brain Kenneth Rockwood M.D., FRCPC, FRCP function influences the risk of cognitive decline 3:35 PMCurrent Knowledge of Methodologies for Barry Reisberg, M.D. Clinical Trials in Pre-MCI Persons with Subjective Cognitive Impairment (SCI) 4:25 PMDiscussion of Current Knowledge and Joel Sadavoy M.D., FRCPC Methodologies 4:35 PMDiscussion of Clinical Instrumentation forBarry Reisberg, M.D. Subject Selection and Assessment 4:55 PMSubject InterviewWorkshop Faculty and Participants 5:25 PMFinal DiscussionJoel Sadavoy M.D., FRCPC