1. Understanding Mild Cognitive Impairment

2. Objectives Understand the concept of MCI Identify risk factors for progression to dementia Review clinical trial data regarding CHEI in patients with MCI Develop a clinical approach to recognition and management of MCI

3. Case of Mr. T. 80 yo male c/o 2 years of difficulty recalling names and phone numbers Concerned that his memory was “getting worse” Managing money, medications, shopping and all IADLs without difficulty Initial MMSE 29/30, 1 off for recall 3/3 with cueing

4. Questions Should you be concerned? What would you do at this point? Is the patient demented? Is there evidence for cognitive impairment?

5. Cognitive Changes With Aging Preserved (crystallized) –Language –Vocabulary –Semantic memory –Factual knowledge Decline (fluid) –Working memory –Psychomotor speed –Complex problem solving –Memory retrieval

6. Crystallized Vs. Fluid Intelligence in Aging

7. Dementia (DSM IV) Memory impairment Associated impairment in abstract thinking, judgment, other disorders of cortical function or personality change Significant severity to cause impairment in social or occupational functioning Decline from a previously higher level of functioning NOT occurring exclusively during delirium

8. Spectrum of Cognitive Impairment

9. Petersen Arch Neur 1999 Mild Cognitive Impairment Complaint of memory problem ideally corroborated by informant Objective evidence of memory impairment Preserved global cognitive function Preserved social & occupational function

10. Controversies in MCI A label or a diagnosable condition? How much memory impairment and which tests? What about other cognitive domains? Definition of preserved social and occupational function?

11. J Int Med 2004

12. Mild cognitive impairmentAmnestic impairment Multiple domains slightly impaired Mild cognitive impairment Single non- memory domain Alzheimer’s disease ? normal aging Frontotemporal dementia Lewy body dementia Parkinson’s disease Alzheimer’s disease Vascular dementia

13. Case of Mr. T. Returned 8 months later complaining of further “worsening memory” Still managing all his IADLs, medications, taxes, money, shopping, etc. MMSE 30/30 up from 29/30 What would you do now?

14. Case of Mr. T. Labs all normal MRI “mild cortical atrophy appropriate for age” Learned 5/6 words after 3 trials, 1/6 on delayed recall after 15 minutes No benefit from cueing, several intrusion errors

15. Case of Mr. T. Continued Slightly diminished category fluency –13 supermarket items one minute, down from 19 –Clock drawing showed misplacement of hands Impaired visual memory with impaired recognition

16. Visuospatial Skills

17. Visual Memory

18. Visual Memory-recognition

19. Questions Is the patient demented? What is your diagnosis at this point? What is the risk for developing dementia? Can we predict the likelihood of developing dementia? Is treatment indicated and what is the role of cholinesterase inhibitors?

20. Can We Predict Who Will Develop Alzheimer’s Disease?

21. Mild Cognitive Impairment (MCI) MCI  AD 12%/yr Control  AD 1-2%/yr Petersen RC et al: Arch Neurol 56:303-308, 1999 50 60 70 80 90 100 50 60 70 80 90 100 Initial12243648 exam MCI AD Controls AD Months Initial12243648 exam Months

22. Petersen Arch Neur 1999 Stable(%) Years MildCognitiveImpairment Risk of Progression to AD

23. Progression to AD Highly varied progression rates across studies related to study population Ranges from 11-33% over 2 years Up to 44 % return to normal cognition at one year Risk factors predicting transition to AD are only partially understood

24. Predictors of Progression Neuropsychological measures Genetic factors Neuroimaging findings Risks factors for progression mimic risk factors for development of AD

25. Neuropsychological Predictors Poor performance on tests of free recall Impaired executive functioning Depression/dysexecutive syndrome Apathy and social withdrawal may be early behavioral markers for cognitive dysfunction

26. Genetic Predictors of Progression APOE allele status APOE 4 allele positivity increases risk of AD APOE E 4 positivity increases risk for conversion from MCI to AD

27. Petersen Oxford Press 2003 MCI: Conversion to Dementia % Years APOE 4 non carrier APOE 4 carrier

28. Neuroimaging Predictors Medial temporal lobe atrophy Hippocampal atrophy Global atrophy Parietal hypometabolism on FDG- PET

29. Petersen Oxford Press 2003 Stable(%) Years W  0 -2.5 < W <  0 W  -2.5 Hippocampal Atrophy & Risk of AD

30. What Is the Role of Cholinesterase Inhibitors in MCI?

31. Cholinesterase Inhibitors in MCI 5 completed randomized clinical trials –2 for donepezil –2 for galantamine –1 for rivastigmine Duration from 24 weeks to 3 years Widely varying conversion rates to AD High dropout rates and adverse effects

32. Petersen et. al NEJM 2005 Donepezil and Vitamin E Fewer donepezil treated patients converted to AD at 6 and 12 months but effect was lost over three years ~16% annual conversion rate APOE 4 allele was a strong predictor of conversion Donepezil associated with lower risk of conversion among APOE 4 positive throughout first 24 months

33. Vitamin E & Donepezil for the Treatment of MCI

34. Risk for Progression to AD

35. Jelic J. Neur Neurosurg Psych 2006 Galantamine for MCI Gal-INT-11 Gal-INT-18 –24 month RCT placebo controlled studies –2000 patients included in both studies No effect on rate of conversion to AD in either study Rates 13% vs. 18% and 17% vs. 21%

36. Galantamine for MCI Greater mortality in the galantamine treated groups 5 deaths placebo vs. 15 with galantamine RR death 3.04 (95% CI 1.26-7.32) Recent “Dear Doctor” letter and change to labeling

37. Returning to Mr. T. Seen again in 2004 after several episodes of getting lost from his way back home Increasing troubles managing medications and some troubles with finances Family expressing concerns about his safety Diagnosed with probable Alzheimer’s disease and begun on cholinesterase therapy

38. MRI Showing Bilateral Hippocampal Atrophy

39. Evaluation of MCI in Clinical Practice Take memory complaints seriously Don’t attribute to simply “getting older” Review medications and stop those with significant anticholinergic effects Screen for depression Evaluate and treat cardiovascular risk factors

40. Ancelin, M. L et al. BMJ 2006;332:455-459 Mean z scores for consistent users of anticholinergic drugs vs. non-users

41. Evaluation of MCI in Clinical Practice Consider usual lab w/u for dementia –TSH, vitamin b12/folate, cmp, cbc Consider neuroimaging, particularly MRI Neuropsychological testing if available Further bedside testing can also be very useful

42. Montreal Cognitive Assessment (MOCA) http://www.mocatest.org/

43. Nasreddine ZS. J Am Geriatr Soc 2005 MOCA Vs. MMSE in MCI Sensitivity 87% Vs. 18%

44. Summary MCI is a concept still in evolution Most will ultimately develop dementia but many will not Treatment remains speculative and focuses on close attention to general health and cardiovascular risk factors Thoroughly assess and follow older patients with memory complaints no matter how slight