Early Identification of Cognitive Disorders: Impact on Diagnosis and Treatment

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

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

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

4. 2000 2010 2020 2030 2040 2050 Projected Prevalence of AD 4.5 Million AD Cases Today—Over 14 Million Projected Within a Generation 16 14.3 14 11.3 12 10 8.7 Millions 8 6.8 5.8 6 4 4 2 0 Year Evans DA et al. Milbank Quarterly. 1990;68:267-289.

5. Definitions

6. Normal Mild Cognitive Impairment Dementia

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

8. Mild Cognitive Impairment (MCI) Definition • Memory complaint usually corroborated by an informant • Objective memory impairment for age - that represents a change in function for the person • Essentially preserved general cognitive function • Largely intact functional activities • Not demented • Alzheimer’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 instruments • 10% - 12% per year to AD is typical • 57% conversion to dementia after 3 years in one study • 25% 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) 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 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 AD • Change 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 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 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 Normal Brain AD Brain Provided courtesy of M. Mega, MD, PhD, Department of Neurology, UCLA School of Medicine.

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 tracer • Attaches to the amyloid beta peptide • MCI patients have more amyloid than normals and less that AD patients Klunk et al. Ann Neurol 2004;55(1)

21. Cognitive Screening

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

23. Barriers to Early Diagnosis of MCI and Dementia • Patients with MCI and early dementia have impaired insight • First present to the doctor an average of 3.5 years after cognitive symptoms start • Physicians may not notice subtle cognitive deficits in routine office visits • Little reimbursement for cognitive screens • Often too much time or personnel resources required to administer testing Barker WW et al. Alzheimer Dis Assoc Disord2005;19:1-7

24. Examples of Brief Cognitive Assessment/Screening Tests • MMSE • Clock Drawing Test • Mini-Cog • AD8 • 7-minute Screen • Montreal Cognitive Assessment (MoCA) • Self-Administered Gerocognitive Examination (SAGE)

25. MMSE • Score: 0 (worst) - 30 (best) • Tests orientation, attention, mental control, calculations, delayed memory (no clueing), language, and constructional praxis • Easy to use, well known • Not great for frontal or executive functions • Sensitivity 78% and specificity 84% for dementia with a cutoff of 26/30 • Takes 7 to 10 minutes; needs examiner • PAR 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. MMSE Folstein et al. J Psychiat Res 1975;12: 189-98

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

29. Clock Drawing Test • Various scoring methods • Tests constructional praxis, visuospatial skills, and executive functioning • Easy to use, well known • Limited in evaluating other cognitive domains • Sensitivity 83% and specificity 72% for AD • Takes 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 drawing • Easy to use • Limited in evaluating other cognitive domains • Sensitivity 76% and specificity of 89% for dementia • Score not influenced by language or education • Takes 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) • Informant rates changes in the patient’s judgment, interests, memory, functioning, and orientation • Easy to use • Does not measure patient cognition • Sensitivity 84% and specificity 80% for dementia with a cutoff of 2 or greater • Takes 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 required • Tests orientation, memory, clock drawing, verbal fluency • Not easy to use in primary care office • Low scores very specific for AD • Sensitivity 92% and specificity 96% for AD vs normal controls • Takes 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) • Tests orientation, memory, clock drawing, constructions, verbal fluency, naming, repetition, attention, abstraction, calculations, executive (trails B) • Not easy to give in primary care office • Sensitivity 100% and specificity 87% for AD vs normal controls with a cutoff of 26/30 • Takes 10-13 minutes; needs examiner Nasreddine et al. J Am Geriatr Soc 2005;53:695-699

38. MOCA Nasreddine et al. J Am Geriatr Soc 2005;53:695-699

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

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

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

42. SAGEPage 3 Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

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

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) • Cognitive 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 17/22 Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

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

47. Self-Administered Gerocognitive Exam (SAGE) • Validity against neuropsychological tests: r = 0.85 • Inter-rater reliability: correlation coefficient = 0.96 • Test-retest reliability: correlation coefficient = 0.86 • Age, 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 schooling 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