1. Early Identification of Cognitive Disorders: Impact on Diagnosis and Treatment Ohio State University Douglas W. Scharre, MD

2. Disclosures Research Support 1.National Institutes of Health - NIA 2.Alzheimer’s Disease Cooperative Study 3.Eisai, Elan, Wyeth, Eli Lily, GalxoSmithKline, Bristol Meyers Squibb, Sonexa, Wyeth Speakers Bureau Eisai, Novartis, Forest Consultant GalaskoSmithKline I own no stocks or equity in any pharmaceutical company Objective: Review early identification techniques for cognitive disorders. Review cognitive assessment instruments for MCI and early dementia. Discuss the impact on diagnosis and treatment.

3. Prevalence of Dementia Increases with Age Evans, et al. JAMA 1989;262:2551-2556

4. Projected Prevalence of AD 16 14 12 0 2 4 6 8 10 2000 20102020203020402050 4 5.8 6.8 8.7 11.3 14.3 Millions 4.5 Million AD Cases Today— Over 14 Million Projected Within a Generation Year Evans DA et al. Milbank Quarterly. 1990;68:267-289.

5. Definitions

6. Normal Mild Cognitive Impairment Mild Cognitive Impairment Dementia Dementia

7. Dementia Definition Syndrome of acquired persistent intellectual impairmentSyndrome of acquired persistent intellectual impairment Persistent deficits in at least three of the following: memoryPersistent deficits in at least three of the following: memory language language visuospatial visuospatial personality or emotional state personality or emotional state cognition cognition Resulting in impairment in Activities of Daily Living (ADL)Resulting in impairment in Activities of Daily Living (ADL)

8. Mild Cognitive Impairment (MCI) Definition Memory complaint usually corroborated by an informantMemory complaint usually corroborated by an informant Objective memory impairment for age - that represents a change in function for the personObjective memory impairment for age - that represents a change in function for the person Essentially preserved general cognitive functionEssentially preserved general cognitive function Largely intact functional activitiesLargely intact functional activities Not dementedNot demented Alzheimer’s disease may start like this but many non- AD conditions present like this alsoAlzheimer’s disease may start like this but many non- AD conditions present like this also Petersen J Int Med 2004;256;183-194

9. MCI: Rates of Dementia Conversion Vary from 1% - 25% per year to AD depending on the definition used and measurement instrumentsVary from 1% - 25% per year to AD depending on the definition used and measurement instruments 10% - 12% per year to AD is typical10% - 12% per year to AD is typical 57% conversion to dementia after 3 years in one study57% conversion to dementia after 3 years in one study 25% do not convert to dementia even with long term follow-up25% do not convert to dementia even with long term follow-up Chertkow et al. Neurology 2001;56:B46

10. Methods of Screening

11. Screening with Biomarkers

12. Biomarkers in AD Cerebrospinal fluid (CSF) biomarkersCerebrospinal fluid (CSF) biomarkers –Tau (  in CSF in AD) –A  42 (  in CSF in AD) –Neural thread protein (NTP) –Homocysteine (  level,  risk of AD) –Isoprostanes (oxidative/nitrative damage -  levels in blood and CSF in AD) –Sulfatide (  in CSF in AD) Blood and urine biomarkersBlood and urine biomarkers –Genetic blood tests and genotyping –Plasma A  42, Homocysteine, isoprostanes, sulfatide –Urine neural thread protein (NTP)

13. Motter et al. Ann Neurol 1995;38:643-48

14. Screening with Neuroimaging

15. Early Diagnosis: Structural Neuroimaging Volumetric measurement of hippocampus and entorhinal cortex atrophy with MRI is sensitive (95%) but not specific (40%) for ADVolumetric measurement of hippocampus and entorhinal cortex atrophy with MRI is sensitive (95%) but not specific (40%) for AD Change in MRI hippocampal volume may be predictive over time in both MCI and individuals at genetic risk for ADChange in MRI hippocampal volume may be predictive over time in both MCI and individuals at genetic risk for AD 7-Tesla and 8-Tesla MRI being used in AD research7-Tesla and 8-Tesla MRI being used in AD research Laakso et al. Neurology 1996;46:678-81 Golomb et al. Neurology 1996;47:810-3 Whitaker et al. Society for Neuroscience 2001

16. Gray Matter Reductions in AD Using Voxel Based Morphometry Alexander GE et al., ADNI MRI Core Team, 2007

17. Functional Neuroimaging: PET PET shows hypometabolism in bilateral parietal, temporal, and posterior cingulate cortex in AD subjects and those who are asymptomatic but at increased risk for AD (those with Apo E  4)PET shows hypometabolism in bilateral parietal, temporal, and posterior cingulate cortex in AD subjects and those who are asymptomatic but at increased risk for AD (those with Apo E  4) PET predicted 94% of mild cognitive impairment (MCI) subjects whose disease progressed to dementia during a 3 year periodPET predicted 94% of mild cognitive impairment (MCI) subjects whose disease progressed to dementia during a 3 year period Minoshima et al. J Nucl Med 1995;36:1238-48 Minoshima et al. Ann Neurol 1997;42:85-94 Small et al. JAMA 1995;273:942-47

18. Typical AD PET Scan Provided courtesy of M. Mega, MD, PhD, Department of Neurology, UCLA School of Medicine. Normal BrainAD Brain

19. Preliminary FDG PET Comparisons: Regional Hypometabolism in Probable AD (purple) & MCI (blue) Chen, K, et al., ADNI PET Coordinating Center, 2007

20. PET with Pittsburgh Compound B (PIB) PIB is a hydroxylated benzothiozole PET tracerPIB is a hydroxylated benzothiozole PET tracer Attaches to the amyloid beta peptideAttaches to the amyloid beta peptide MCI patients have more amyloid than normals and less that AD patientsMCI patients have more amyloid than normals and less that AD patients Klunk et al. Ann Neurol 2004;55(1)

21. Cognitive Screening

22. Treatment of Alzheimer’s Disease Source: Decision Resources, March 2000. 0 1 2 3 4 5 PrevalenceDiagnosedTreated* Patients (millions) * Any drug treatment, not limited to acetylcholinesterase inhibitors.

23. Barriers to Early Diagnosis of MCI and Dementia Patients with MCI and early dementia have impaired insightPatients with MCI and early dementia have impaired insight First present to the doctor an average of 3.5 years after cognitive symptoms startFirst present to the doctor an average of 3.5 years after cognitive symptoms start Physicians may not notice subtle cognitive deficits in routine office visitsPhysicians may not notice subtle cognitive deficits in routine office visits Little reimbursement for cognitive screensLittle reimbursement for cognitive screens Often too much time or personnel resources required to administer testingOften too much time or personnel resources required to administer testing Barker WW Barker WW et al. Alzheimer Dis Assoc Disord 2005;19:1-7

24. Examples of Brief Cognitive Assessment/Screening Tests MMSEMMSE Clock Drawing TestClock Drawing Test Mini-CogMini-Cog AD8AD8 7-minute Screen7-minute Screen Montreal Cognitive Assessment (MoCA)Montreal Cognitive Assessment (MoCA) Self-Administered Gerocognitive Examination (SAGE)Self-Administered Gerocognitive Examination (SAGE)

25. MMSE Score: 0 (worst) - 30 (best)Score: 0 (worst) - 30 (best) Tests orientation, attention, mental control, calculations, delayed memory (no clueing), language, and constructional praxisTests orientation, attention, mental control, calculations, delayed memory (no clueing), language, and constructional praxis Easy to use, well knownEasy to use, well known Not great for frontal or executive functionsNot great for frontal or executive functions Sensitivity 78% and specificity 84% for dementia with a cutoff of 26/30Sensitivity 78% and specificity 84% for dementia with a cutoff of 26/30 Takes 7 to 10 minutes; needs examinerTakes 7 to 10 minutes; needs examiner PAR bought rights - costs about $1 per usePAR bought rights - costs about $1 per use Folstein et al. J Psychiat Res 1975;12:189-98 Feher et al. Arch Neurol 1992;49:87-92

26. Folstein et al. J Psychiat Res 1975;12: 189-98 MMSE

28. Mini-Mental State Examination: Typical change over time Mild Cognitive Impairment (MCI)

29. Clock Drawing Test Various scoring methodsVarious scoring methods Tests constructional praxis, visuospatial skills, and executive functioningTests constructional praxis, visuospatial skills, and executive functioning Easy to use, well knownEasy to use, well known Limited in evaluating other cognitive domainsLimited in evaluating other cognitive domains Sensitivity 83% and specificity 72% for ADSensitivity 83% and specificity 72% for AD Takes 1 minute; needs no examinerTakes 1 minute; needs no examiner Shulman et al. Int Geriatr Psychiatry 1986;1:135-40 Cahn et al. Arch Clin Neuropsych 1996;11:529-39

30. Early Diagnis: Cognitive Screening

31. Mini-Cog 3-item recall and clock drawing3-item recall and clock drawing Easy to useEasy to use Limited in evaluating other cognitive domainsLimited in evaluating other cognitive domains Sensitivity 76% and specificity of 89% for dementiaSensitivity 76% and specificity of 89% for dementia Score not influenced by language or educationScore not influenced by language or education Takes 3 minutes; needs examinerTakes 3 minutes; needs examiner Borson S et al. Int J Geriatr Psychiatry 2000;15:1021-1027 Borson S et al. JAGS 2003;51:1451-1454

32. Mini-Cog

33. AD8 Score: 0 (best) - 8 (worst)Score: 0 (best) - 8 (worst) Informant rates changes in the patient’s judgment, interests, memory, functioning, and orientationInformant rates changes in the patient’s judgment, interests, memory, functioning, and orientation Easy to useEasy to use Does not measure patient cognitionDoes not measure patient cognition Sensitivity 84% and specificity 80% for dementia with a cutoff of 2 or greaterSensitivity 84% and specificity 80% for dementia with a cutoff of 2 or greater Takes 3 minutes; needs examiner and informantTakes 3 minutes; needs examiner and informant Folstein et al. J Psychiat Res 1975;12:189-98 Feher et al. Arch Neurol 1992;49:87-92

34. AD8 Galvin et al. Neurology 2006;67:1942-1948

35. 7 Minute Screen Special scoring calculator requiredSpecial scoring calculator required Tests orientation, memory, clock drawing, verbal fluencyTests orientation, memory, clock drawing, verbal fluency Not easy to use in primary care officeNot easy to use in primary care office Low scores very specific for ADLow scores very specific for AD Sensitivity 92% and specificity 96% for AD vs normal controlsSensitivity 92% and specificity 96% for AD vs normal controls Takes 7 - 12 minutes; needs examinerTakes 7 - 12 minutes; needs examiner Solomon et al. Arch Neurol 1998;55:349-55

36. 7 Minute Screen

37. Montreal Cognitive Assessment (MOCA) Score: 0 (worst) - 30 (best)Score: 0 (worst) - 30 (best) Tests orientation, memory, clock drawing, constructions, verbal fluency, naming, repetition, attention, abstraction, calculations, executive (trails B)Tests orientation, memory, clock drawing, constructions, verbal fluency, naming, repetition, attention, abstraction, calculations, executive (trails B) Not easy to give in primary care officeNot easy to give in primary care office Sensitivity 100% and specificity 87% for AD vs normal controls with a cutoff of 26/30Sensitivity 100% and specificity 87% for AD vs normal controls with a cutoff of 26/30 Takes 10-13 minutes; needs examinerTakes 10-13 minutes; needs examiner Nasreddine et al. J Am Geriatr Soc 2005;53:695-699

38. MOCA

39. Self-Administered Gerocognitive Exam (SAGE) Score: 0 (worst) - 22 (best)Score: 0 (worst) - 22 (best) Tests orientation, memory, language, fluency, naming, visuospatial, abstraction, calculations, executive functioning, and problem solvingTests orientation, memory, language, fluency, naming, visuospatial, abstraction, calculations, executive functioning, and problem solving Self-administered, easy to useSelf-administered, easy to use Limited memory evaluation; excellent executive measuresLimited memory evaluation; excellent executive measures Takes 10 to 15 minutes; needs no examinerTakes 10 to 15 minutes; needs no examiner at sagetest.osu.edu Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

40. SAGE Page 1 at sagetest.osu.edu Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

41. SAGE Page 2 at sagetest.osu.edu Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

42. SAGE Page 3

43. at sagetest.osu.edu Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu SAGE Page 4

44. SAGE: Validity Against Neuropsychologic Tests Scharre et al. Alzheimer Dis Assoc Disord 2009

45. SAGE Validity Study Correlation between SAGE & neuropsychology battery was 0.84 (0.76 for MMSE)Correlation between SAGE & neuropsychology battery was 0.84 (0.76 for MMSE) Cognitive impaired group = MCI + dementiaCognitive impaired group = MCI + dementia ROC analysis for SAGE, normal vs cognitive impaired: sensitivity is 95% (90% for MMSE) and specificity is 79% (71% for MMSE) with a cut off score of 17/22ROC analysis for SAGE, normal vs cognitive impaired: sensitivity is 95% (90% for MMSE) and specificity is 79% (71% for MMSE) with a cut off score of 17/22 at sagetest.osu.edu Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

46. ROC for SAGE: Differentiating normal vs MCI + Dementia at sagetest.osu.edu Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

47. Self-Administered Gerocognitive Exam (SAGE) Validity against neuropsychological tests: r = 0.85Validity against neuropsychological tests: r = 0.85 Inter-rater reliability: correlation coefficient = 0.96Inter-rater reliability: correlation coefficient = 0.96 Test-retest reliability: correlation coefficient = 0.86Test-retest reliability: correlation coefficient = 0.86 Age, gender, and version of SAGE (4 different forms available) had no effect on SAGE scoreAge, gender, and version of SAGE (4 different forms available) had no effect on SAGE score Education had a moderate effect on SAGE score (p = 0.025) only in those less than 12 years of schoolingEducation had a moderate effect on SAGE score (p = 0.025) only in those less than 12 years of schooling at sagetest.osu.edu Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

49. SAGE Scores 17-22:Very likely to be normal - no further evaluation 15-16: Likely to have MCI - staged screening evaluation recommended 0-14:Likely to have a dementia condition - staged screening evaluation recommended

50. Staged Screening: Impact of Diagnosis

51. Screening for Cognitive Impairment No cognitive screening test is diagnosticNo cognitive screening test is diagnostic If normal, serious conditions are less likelyIf normal, serious conditions are less likely The “worried well” can be relieved that they were “tested” and they did fineThe “worried well” can be relieved that they were “tested” and they did fine Serial screening could be suggested over timeSerial screening could be suggested over time If abnormal, further evaluation may be consideredIf abnormal, further evaluation may be considered

52. Staged Screening Approach for Cognitive Impairment One single test or score should not be the only criteria to embark on an expensive dementia evaluationOne single test or score should not be the only criteria to embark on an expensive dementia evaluation Doing a screening process in stages may provide better evidence for diagnosis of MCI or dementiaDoing a screening process in stages may provide better evidence for diagnosis of MCI or dementia A staged screening process is recommendedA staged screening process is recommended

53. Staged Screening Approach SAGE Test Age over 65? Screen if concerns Schedule appointment with patient and informant Consider dementia evaluationRe-screen in one year or consider neuropsychological testing <17 17-22 No Yes Re-screen yearly AD8 > 1 MOCA < 26 AD8 25 Re-screen in 2 years Age over 80? No Yes

54. Impact on Treatment

55. Importance of Early Diagnosis of MCI and Dementia Amyloid plaques probably start 20 years before clinical symptoms of ADAmyloid plaques probably start 20 years before clinical symptoms of AD 16 million projected to have AD by 205016 million projected to have AD by 2050 Current AD meds work better if started earlierCurrent AD meds work better if started earlier Disease modifying agents are comingDisease modifying agents are coming Preventing or delaying AD could save billions of dollars and lead to improved quality of life for patients and familiesPreventing or delaying AD could save billions of dollars and lead to improved quality of life for patients and families

56. Raskind et al. Neurology. 2000. Galantamine: Mean Change From Baseline in ADAS-cog Open-ExtensionDouble-blind galantamine 24 mg/galantamine 24 mg (n = 212/116) Historical placebo group * P <.05 vs placebo/galantamine and not statistically different from baseline.ImprovementDeterioration 036912 Mean (± SE) Change From Baseline in ADAS-cog Score –4 –3 –2 –1 0 1 2 3 4 5 6 7 Months Placebo/galantamine 24 mg (n = 213/135) *

57. Cognitive Rx in AD Efficacy of Cholinesterase Inhibitors Donepezil, Rivastigmine, GalantamineDonepezil, Rivastigmine, Galantamine All of them workAll of them work Up to 80% of patients show no decline after 6 months of Rx and 50% no decline after 1 yearUp to 80% of patients show no decline after 6 months of Rx and 50% no decline after 1 year Need to give for at least 6 to 12 months to determine utilityNeed to give for at least 6 to 12 months to determine utility Side effects: weight loss, diarrhea, nauseaSide effects: weight loss, diarrhea, nausea Always titrate to highest doseAlways titrate to highest dose

58. Cognitive Rx in AD NMDA Antagonists: Memantine N-methyl-D-aspartate (NMDA) antagonists potentially prevent neuronal injury by reducing excitatory amino acid toxicity by glutamateN-methyl-D-aspartate (NMDA) antagonists potentially prevent neuronal injury by reducing excitatory amino acid toxicity by glutamate Side effects include headache, dizziness, fatigue, confusionSide effects include headache, dizziness, fatigue, confusion Titrate to 10 mg bidTitrate to 10 mg bid

59. Phase III Studies: Rx Strategies SB-742457: 5-HT6 receptor antagonist - increases release of Ach and glutamateSB-742457: 5-HT6 receptor antagonist - increases release of Ach and glutamate LY450139, BMS708163: gamma secretase inhibitorsLY450139, BMS708163: gamma secretase inhibitors Bapineuzumab : Passive immunotherapyBapineuzumab : Passive immunotherapy

60. Proteolytic Cleavages of Amyloid Precursor Protein (APP) That Produce A  Peptide Selkoe DJ et al. JAMA. 2000;283:1615-1617.  -amyloid precursor protein  -secretase A  peptide  -secretase Extracellular space TMCytoplasm COOH NH 2

61. Immunization: Bapineuzumab (Phase III) Passive immunotherapyPassive immunotherapy Monoclonal antibody against beta-amyloid peptide administered intravenously (IV)Monoclonal antibody against beta-amyloid peptide administered intravenously (IV) Binds and removes beta-amyloid peptide that accumulates in plaquesBinds and removes beta-amyloid peptide that accumulates in plaques

62. Future Rx Strategies Anti-amyloid strategiesAnti-amyloid strategies Combined drug treatmentsCombined drug treatments Tau interventions (methylene blue:Tau interventions (methylene blue: Phase II trials - disrupts tau aggregation) Phase II trials - disrupts tau aggregation) Gene therapyGene therapy Brain transplantsBrain transplants

63. Importance of Early Diagnosis of MCI and Dementia Leads to earlier treatmentLeads to earlier treatment Reduces patient poor judgment with finances, driving, medication use, symptom reportingReduces patient poor judgment with finances, driving, medication use, symptom reporting Lead to increased supervision of individuals to adequately perform their activities of daily livingLead to increased supervision of individuals to adequately perform their activities of daily living Improves treatment compliance rates of other chronic medical conditionsImproves treatment compliance rates of other chronic medical conditions Reduces medication errorsReduces medication errors

64. Importance of Early Diagnosis of MCI and Dementia Decreases hospital admissions or emergency room visitsDecreases hospital admissions or emergency room visits Improves quality of life of patient and caregiverImproves quality of life of patient and caregiver Reduces burden and chronic stress effects on caregiversReduces burden and chronic stress effects on caregivers Preventing or delaying AD could save billions of dollarsPreventing or delaying AD could save billions of dollars

65. Summary Cognitive disorders are increasingCognitive disorders are increasing MCI and early AD are under recognizedMCI and early AD are under recognized Biomarkers (serum and CSF) and neuroimaging are too expensive for screeningBiomarkers (serum and CSF) and neuroimaging are too expensive for screening Cognitive screening with a staged approach should be doneCognitive screening with a staged approach should be done More study is needed to identify which MCI subjects will progress to dementia or ADMore study is needed to identify which MCI subjects will progress to dementia or AD Treatment and increased supervision should be started as soon as possible after MCI or dementia identificationTreatment and increased supervision should be started as soon as possible after MCI or dementia identification

66. Questions and Answers