1. Dementia Diagnostic and Therapeutic Considerations Summer 2010 Leon S. Kraybill, MD, CMD Geriatric Specialists, Lancaster General Hospital

2. A population explosion US population over 65 yo, in millions Source: Administration on Aging

3. Coming to your office…. In 2004, Americans > 65 were  36.3 million  12.4% of population  1 in 8 In 2050, Americans > 65 are predicted:  71.5 million  1 in 5 Americans

4. And older every year….  The old old (>85 yo) 2000 - 4.2 million (1.5%) 2010 – 5.5 million (2.0%) 2030 – 9.6 million (2.6%) 2050 – 19 million (5.0%)  In 2050 – 5% of the US population will be over 85 years old Source: Federal Interagency Forum on Aging Related Statistics

5. Dementia – disease of the 21 st century?  Dementia is most closely associated with advancing years  More older patients = more dementia  During a 1 hour lecture – 50 new cases of dementia in US (vs. 24 new breast cancers, 52 MI deaths, 4 MVA deaths)

6. Alzheimer’s dementia in US Ubiquitous & rising 2000: 4.5 million 2010: 5.3 million 2020: 5.7 million - 27% increase 2030 - 7.7 million - 70% increase 2050 – 13.2 million - 300% increase Source: National Institute on Aging

7. Prevalence of dementia in 2002  Dementia present in 37.4% of individuals aged 90 and older  Alzheimers dementia is more prevalent with advancing age. In age 90+ group, AD accounted for 79.5% of all dementia cases compared to 46.7% among those aged 71–79 years. Plassman, et al. Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study. Neuroepidemiology 2007;29:125–132.

8. Why should we care? In 2009 - Almost 11 million Americans provided unpaid care for a persons with dementia. They provided 12.5 billion hours of unpaid care Personal cost: In 2009, the economic value of the care provided by family and other unpaid caregivers of people with Alzheimer’s and other dementias was $144 billion 2010 Alzheimer’s Disease: Facts and Figures www.alz.org/documents_custom/report_alzfactsfigures2010.pdfwww.alz.org/documents_custom/report_alzfactsfigures2010.pdf

9. Why should we care? Dementia is under diagnosed and under treated Between 30-75% of cases of dementia or probable dementia are not diagnosed by primary care physicians 1 Only 35% of individuals with mild to moderate Alzheimer’s have ever been given a standard memory support drug 2 1) Does This Patient Have Dementia? JAMA. 2007;297:2391-2404. 2) Undertreatment of patients with Alzheimer’s disease in an elderly United States population. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 1, Issue 2, Pages 93-168 (October 2005).

10. Nursing Home costs 2009 Home care -the average hourly rate for non-medical home care, including personal care & homemaker services, was $19 or $152 for an 8-hour day. Adult day center services – average cost of adult day services was $67/day Assisted living facility -the average cost for basic services in an assisted living facility was $105/day, or $37,572/year Nursing home - the average cost for a private room in a nursing home was $219/day, or $79,935/year. The average cost of a semi-private room $198/day, or $72,270/year 2010 Alzheimer’s Disease: Facts and Figures www.alz.org/documents_custom/report_alzfactsfigures2010.pdfwww.alz.org/documents_custom/report_alzfactsfigures2010.pdf

11. Isn’t dementia incurable?  Yes, by current medical standards and treatments  But treatments can alter the disease trajectory, manage the symptoms, relieve the fears, and allow response  Most of your older patients will not expect you to cure their diseases, prevent their death, or return them to the health of their youth. But they do yearn for explanation of disease, understanding of what is to come, and the dignity of being known as a person.

12. Who will provide care?  Family physicians/internists will be called upon to provide care for older patients whether we choose to or not  The family practice training uniquely prepares us to see and treat these patients as people and not as a conglomeration of organ systems.

13. Geriatric physicians 2007  7,128 - physicians certified in geriatric medicine  1,596 - physicians certified in geriatric psychiatry  36,000 – estimated need for geriatricians in 2030  Decrease to (+)700 - estimated actual change of geriatricians by 2030 2010 Alzheimer’s Disease: Facts and Figures www.alz.org/documents_custom/report_alzfactsfigures2010.pdf

14. You are the specialist! The well trained and compassionate family physician/internist is the best equipped and most appropriate person to diagnose, manage and treat dementia. Plus, it’s rewarding and fun.

15. Lecture Objectives  Describe why identification of dementia is important and who should manage it  Outline an evaluation and assessment approach to dementia – from presentation to death  Identify the most common forms of dementia  Compare medications for dementia

16. To screen or not to screen?  2003 US Preventive Services Task Force (USPSTF) said no  Have our treatment options changed?  Does intervention prevent or delay the consequences?  Does early diagnosis allow for better social and emotional support?

17. Dementia criterion: DSM-IV Requires multiple cognitive deficits Memory impairment Plus 1 of following  Agnosia – impaired ability to recognize and identify objects  Aphasia – impaired language  Apraxia – impaired motor activities despite intact ability  Executive function – impaired ability to organize, abstract, plan Impairs function, and is a decline American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision ed. Washington, DC: American Psychiatric Association; 2000.

18. 2010 The diagnosis of dementia is a clinical diagnosis, based on the clinical course of the disease, after other conditions are ruled out.

19. When to suspect dementia  Missed or late office visits  Poor recollection of past important medical treatments  Medication “noncompliance”  Family complaints of memory loss exceed the patient’s recognition of a problem  Loss of engagement in the office visit  Tentativeness in a previously confident patient  Inattentive to appearance, hygiene or continence  Unexplained weight loss or failure to thrive  Unusually jovial or evasive responses  De novo depression

20. Know the 10 signs  Alzheimer’s Association checklist - see handout www.alz.org/national/documents/checklist_10signs.pdf

21. Cognitive screening tests  Every medical provider needs to be comfortable with at least 2 cognitive screening tests  …. And use them!  Each has strengths and weaknesses Good review - Does This Patient Have Dementia? JAMA. 2007;297:2391-2404.

22. Cognitive screening test principles  They do not diagnose, only provide supportive evidence  They provide a numerical score (not necessarily a functional assessment)  Not all patients with normal scores are normal, nor abnormal = impaired  Better to follow over time, than define dementia at any one point

23. Mini-Mental® State Examination (MMSE™) by Folstein et. al.  Widely used and available  Tests multiple cognitive domains  Influenced by educational level  May not detect mild cognitive impairment  Administration time 5-10 minutes  Protected by copyright, unauthorized reproduction is forbidden www.minimental.com www.aafp.org/afp/20010215/703.html

24. Montreal Cognitive Assessment (MOCA)  Tests a broad range of cognitive domains  More sensitive to mild cognitive impairment  Administration time – 10 minutes  Free access to test, instructions, and multiple languages at www.mocatest.org

25. Clock drawing test  Ask patient to place the numbers on the face of a clock, and then place hands for a specific time (i.e. 11:10)  Many different instructions and scoring approaches  Tests construction, visuospatial function, conceptualization, executive function  Sensitivity (59-85%), specificity (85%) Clock-drawing: is it the ideal cognitive screening test? Int J Geriatr Psychiatry 2000: 15, 548-561

26. Clock drawing test  Benefits Simple, quick (1-2 minutes) Easy to administer Less affected by level of education, language, cultural differences Better for patient with poor concentration  Limitations Poor screening for mild dementia Does not absolutely define different types of dementia

27. Animal naming test (verbal fluency)  Timed test : Name as many animals as possible in 1 minute  Scoring: > 18 Normal 13-17 Borderline < 12 Abnormal

28. Blessed Orientation Memory Concentration Test (Modified Blessed)  Tests orientation, recall, attention  Requires 4-6 minutes  Does not require paper, pencil, use of hands  Scoring is weighted towards short term memory loss

29. Comparison of screening tests Sens%Spec% Minutes  MMSE80-90<805-10  MOCA1008710  Mini cog76892-4  Clock drawing59-85901-2  Modified Blessed69904-6  Animal naming (ANT) 50-7290-982  ANT + Memory phrase 79-8790-983

30. Initial dementia evaluation Evidence supports (to rule out other conditions):  CBC  Glucose, electrolytes, BUN/creatinine, Liver function tests  Serum Vitamin B12  Thyroid function tests  Noncontrast CT or MRI (MRI improves specificity)  Depression screening Detection, Diagnosis and Management of Dementia, American Academy of Neurology Guideline summary, www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf

31. Evidence does not support routine use of:  Syphilis screening  EEG  Lumbar puncture (with some exceptions: mets, CNS infection, hydrocephalus, <55 yo, unusual dementia)  Linear or volumetric MR or CT (for hippocampal atrophy)  SPECT  APOE-e4 genotyping for AD Detection, Diagnosis and Management of Dementia, American Academy of Neurology Guideline summary, www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf

32. Insufficient evidence to support/refute:  PET  Other genetic markers for AD  CSF or other biomarkers for AD Detection, Diagnosis and Management of Dementia, American Academy of Neurology Guideline summary, www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf

33. Genetic testing - ApoE-e4  ApoE gene on chromosome 19 determines a protein that carries cholesterol  ApoE-e4 is one of 3 common forms of the ApoE gene, and is more common in AD  One ApoE-e4 gene increases the risk of developing AD  Two ApoE-e4 genes further increase the AD, but does not guarantee the development of Alzheimer’s Conclusion - ApoE-e4 does not add substantially to diagnostic confidence. Not recommended for routine screening

34. Genetic testing Familial autosomal dominant early-onset AD Less than 1 percent, caused by rare genetic variations found in a small number of families worldwide Disease tends to develop before age 65, sometimes in individuals as young as 30. Presenilin 1 (PSEN1) on chromosome 14, commercially available, consider for families with AD onset < 50 yo Presenilin 2 (PSEN2) on chromosome 1 – not commercially available Amyloid precursor protein (APP) on chromosome 21 – not commercially available

35. Neuroimaging (CT or MRI)  Usually recommended as part of the initial evaluation  Especially important if: Onset less than 1 year Symptoms before 65yo Vascular risk factors suggesting cerebrovascular involvement Focal neurological finding, metastatic disease  Value in late-stage disease is not established APA Practice GuidelinesAPA Practice Guidelines: Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias, Second Edition. Published in October 2007. http://www.psychiatryonline.com/content.aspx?aid=152139.http://www.psychiatryonline.com/content.aspx?aid=152139

36. Neuroimaging details  CT – used to rule out reversible causes of cognitive impairment  MRI – maybe better at showing early signs of AD, and differentiating from other forms of dementia (ie silent cerebrovascular disease) In AD, MRI can show left sided atrophic changes in entorhinal cortex, amygdala, and anterior hippocampus several years before onset of clinical symptoms Henry-Feugeas MC, MRI of the “Alzheimer syndrome”, J Neuroradiol. 2007 Oct;34(4);220-7.

37. Neuroimaging: White matter disease  Terms: Leukoaraiosis, leukoencephalopathy, small vessel ischemia, white matter disease  Scattered loss of white matter in the brain due to subcortical vascular disease  Inconsistently associated with cognitive function…does not equate with dementia  Ischemic burden  Poor prognosis for death, stroke, and MI

38. Other neuroimaging tests  PET – assesses function via cerebral metabolism. Since function may be disrupted before structural changes occur, may show changes of AD 3 years before clinical diagnosis. Recently approved by Medicare to differentiate between AD and FTD  SPECT – evaluates function via cerebral blood flow. Conflicting results – not appropriate for routine AD assessment

39. Do I have dementia or Alzheimer’s? Dementia Alzheimer’s dementia (AD) Vascular dementia (VaD) Lewy body dementia (LBD) Frontotemporal dementia (FTD) Mild Cognitive Impairment (MCI)

40. Dementia types  Alzheimer’s 50-80% of dementing illness  Vascular 10-20%  Lewy body 5-10%  Frontotemporal 4-20%  Mixed 10-30% Does This Patient Have Dementia? JAMA. 2007;297:2391-2404. See addendum –spread sheet on different types

41. Mild cognitive impairment (MCI)  Problems with memory, language, or other cognitive domains severe enough to be noticeable to other people and to show up on tests, but not serious enough to interfere with daily life  Prevalence: About 12% (10-20%) of those > 70  About 15% per year progress to dementia - but some never progress to overt dementia  Nearly half of all people who have visited a physician about MCI symptoms will develop dementia in three or four years

42. MCI types  Amnestic MCI Memory loss is predominant Progress to Alzheimer’s disease at a rate of approximately 10% to 15% per year  Non-amnestic MCI Impairments in other domains At risk for progression to other dementias

43. MCI treatment  There is no specific treatment for MCI  Meta-analysis of randomized controlled trials shows that treatment of MCI with cholinesterase inhibitors does not delay onset of dementia or AD 1  Small study (15 patients) – calcium channel blocker, nilvadipine, may delay cognitive decline 2 1. Raschetti R, Cholinesterase inhibitors in mild cog imp, PLoS Med 2007; 4(11):e338. 2. Hanyu H, Nilvadipine prevents cognitive decline of patients with mild cognitive impairment, Intl J Geriatr Psychiatry 2007;22(12):1264-1233

44. Alzheimer’s disease – DSM-IV  Impaired memory  At least one of the following cognitive disturbances: aphasia, apraxia, agnosia, and disturbed executive function.  The cognitive abnormalities must represent a change from a previous higher level of function, be progressive, & impair functioning  Gradual onset and continued decline  Not present exclusively during a period of delirium. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision ed. Washington, DC: American Psychiatric Association; 2000.

45. Structural hallmarks of AD 1. Amyloid plaques – abnormal extracellular protein deposits 2. Neurofibrillary tangles – intracellular tau proteins 3. Irreversible impairment and loss of neurons  These changes are especially evident in the hippocampus and cerebral cortex where memory, language, reasoning, perception, and judgment occur

46. AD characteristics:  A progressive disorder affecting cognition, personality, behavior, and activities of daily living (ADLs)  Memory impairment, especially short term, rapid forgetting of new material  Gradual and steady inexorable decline  Anosognosia – lack of recognition of disease

47. Early changes of AD  Early impaired psychological reasoning – impaired understanding of the intention of others  Become oblivious to the emotions of others, before memory loss is evident  Likely why family members become so frustrated & feel the patient is manipulative *****Family education is imperative*****

48. Diagnosis of AD  Listen to your patients and families, listen to your intuition, suspect, screen  Look for red flags (ADLs, depression, change in appearance, change in dress, change in personality, change in engagement)  An experienced clinician can make a diagnosis of AD with 90% reliability based on medical, neurological and psychiatric evaluations

49. Staging of dementia  See Addendum – seven stages in FAST scale  See Addendum – Mild/Moderate/Severe

50. Evolving science  First updates in the Alzheimer’s diagnosis in 25 years  Proposed three stages of the disease process Preclinical (new) Mild cognitive impairment (MCI) Alzheimer’s dementia http://www.alz.org/research/diagnostic_criteria/

51. Preclinical disease  Like carcinoma in situ, or cholesterol and CAD  Three diagnostic criteria Asymptomatic amyloidosis – abnormal levels of amyloid but no cognitive or functional symptoms Amyloidosis + one other marker of disease – atrophy on imaging, abnormal PET, abnormal levels of phosphorylated tau protein Amyloidosis + a biomarker + slight cognitive symptoms

52. Mild cognitive impairment  Three proposed criteria Patient aware, measurable deficits, preserved cognitive and functional skills Change in brain topography – hippocampal atrophy or hypo-metabolic brain regions Confirmed amyloid abnormality – reduced in CSF (and thus increased in brain), or positive amyloid brain imaging

53. Vascular dementia  Second most common in US, especially in old old patients  Memory loss, plus loss in one other cognitive domain, in setting of cerebrovascular disease  Stepwise progression with periods of stability  Frequently combined with other dementias, pure vascular dementia is likely uncommon  Concurrent depression is common

54. Vascular dementia treatment  Insufficient data to support cholinesterase inhibitors and memantine in vascular dementia 1  Insufficient evidence to support use of aspirin, gingko biloba, calcium blockers or pentoxifylline 2 1. Kavirajan H, Schneider LS: Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: A meta-analysis of randomized controlled trials. Lancet Neurol 2007; 6(9):782-792. 2. Waldemar G, Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol - 01-JAN-2007; 14(1): e1-26

55. Lewy body dementia (see handout)  Required: progressive cognitive decline, occurring before or with the parkinsonism  Core: Delirium-like fluctuation, visual hallucinations, parkinsonism  Suggestive: REM sleep behavior disorder, neuroleptic sensitivity  Dementia onset within 12 months of motor features of parkinsonism McKeith IG, Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology - 27-DEC-2005; 65(12): 1863-72.

56. Treatment of Lewy body dementia  14 small studies of ChEI showed benefit in cognition and neuropsychiatric symptoms  Possible greater ChEI benefit than in AD  Insufficient data to evaluate memantine  Avoid neuroleptics, if required – quetiapine  Low dose parkinson’s meds, only if necessary Waldemar G, Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol - 01-JAN-2007; 14(1): e1-26

57. Frontotemporal dementia (FTD)  Deficits in frontal system tasks: verbal fluency, executive function (attention, abstraction, planning, problem solving)  Behavior: early personal and social disinhibition, emotional blunting, loss of insight, hyperorality, perseverative behavior  Mean age of onset is 53-56  No evidence that current antidementia meds are effective in FTD

58. Cholinergic theory of AD  Acetylcholine  Acetylcholinesterase breaks down the acetylcholine for repeat use  Alzheimers dementia is associated with decreased cholinergic activity  Cholinesterase inhibitors slow the breakdown process, thus increasing the amount of acetylcholine present in the synapse

59. Cholinesterase inhibitors (ChEIs) Evidence suggests that early treatment of mild-to- moderate AD with ChEIs can: Prolong Functioning Preserve Cognitive abilities Improve behavioral & psychological symptoms Postpone transfer to skilled nursing Ease Caregiver burden Reduce costs for residents and caregivers Institutionalized severe dementia residents – less decline, some cognitive change Tracey Holsinger, MD; Janie Deveau, MD; Malaz Boustani, MD, MPH; John W. Williams, Jr, MD, MHS. Does This Patient Have Dementia? JAMA. 2007;297:2391-2404. Symposium Reporter 2007: Opportunities to Improve the Prognosis of Severe Alzheimers Disease, released Nov 2007, from American Medical Director Association annual symposium.

60. Metanalysis of studies 1986 - 2006  96 publications, 59 unique studies  Both cholinesterase inhibitors and memantine had consistent effects in the domains of cognition and global assessment, but summary estimates showed small effect sizes.  CONCLUSIONS: Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. AURaina P; Santaguida P; Ismaila A; Patterson C; Cowan D; Levine M; Booker L; Oremus M SOAnn Intern Med. 2008 Mar 4;148(5):379-97.

61. APA guidelines 2007 ChEIs should be offered to patients with mild to moderate AD, after a thorough discussion of their potential risks and benefits ChEIs may be helpful for severe AD ChEIs should be considered for mild to moderate dementia with Parkinson’s (only rivastigmine approved, but others likely similar) ChEIs can be considered for Lewy Body dementia Memantine may provide modest benefits and few adverse reactions in moderate to severe AD (very limited evidence in vascular dementia) APA Practice GuidelinesAPA Practice Guidelines: Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias, Second Edition. Published in October 2007. http://www.psychiatryonline.com/content.aspx?aid=152139.http://www.psychiatryonline.com/content.aspx?aid=152139

62. Up to Date R conclusions  Suggest treatment trial of ChEI in mild to moderate dementia (Grade 2A).Grade 2A  Do not routinely use tacrine (Grade 1A).Grade 1A  Suggest trial of ChEI in vascular dementia (VaD), mixed dementia, dementia with Lewy bodies (DLB), and dementia in Parkinson's disease (PD). (Grade 2B).Grade 2B  In severe dementia, ChEIs can be discontinued, but they should be restarted if the patient worsens without the medication (Grade 2C).Grade 2C  Do not routinely recommend ChEI in mild cognitive impairment (MCI), but if memory problems are particularly troubling, then a trial for symptomatic benefit may be warranted (Grade 2C).Grade 2C ©2008 UpToDate® accessed 8/8/08 Recommendation grades 1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients 2. Weak recommendation: Benefits and risks closely balanced and/or uncertain Evidence grades A. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other form B. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some other form C. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials with serious flaws

63. AAFP & Am College of Physicians  Review of 24 high quality studies of ChEIs Statistical improvement, not clinical difference Subgroups may show clinical difference, but not defined who that is  Recommendation: Base the decision to initiate therapy on the individualized assessment of benefit and risk (weak rec, moderate quality evidence)  Rec: Insufficent evidence to suggest that one agent is superior (weak rec, low quality data) Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008 Mar 4;148(5):370-8.

64. Alzheimer’s Association 2010 summary: “No treatment is available to slow or stop the deterioration of brain cells in Alzheimer’s disease. The U.S. FDA has approved 5 drugs that temporarily slow worsening of symptoms for 6-12 months, on average, for about half of the individuals who take them.” 2010 Alzheimer’s Disease: Facts and Figures www.alz.org/documents_custom/report_alzfactsfigures2010.pdfwww.alz.org/documents_custom/report_alzfactsfigures2010.pdf

65. Dr. Kraybill’s recommendations  Don’t be afraid to try a ChEI  Be realistic with patient and family about the disease and current treatments  Discuss adverse reactions  Establish the goals of therapy, and be willing to stop treatment if unsuccessful  Followup regularly - the care of the caregiver (education, understanding, praise) may give more benefit than medication

66. What is success?  Average untreated patient with dementia will lose 2-4 points per year on MMSE, and have functional decline  Is stability sufficient reason to justify use?  Symptoms progress more slowly than anticipated  Clinical benefit is rarely sustained longer than 12-18 months, when clinical decline again resumes

67. BUT….. Clinical benefit is small, not permanent, and not without potential adverse reactions  Study: 2 point cognitive benefit on ADAS-cog score (70 point scale) 1  Study: 3 point gain on SIB score (100 point scale) at 24 weeks 2  Study in severe AD: 6 point gain on SIB score (100 point scale) at 6 months 1) Burns, Alistair, Efficacy and safety of donepezil over 3 years: an open-label, multicentre study in patients with Alzheimer’s disease, Int J Geriatr Psychiatry 2007: 22(8):806-812 2) Tariot PN, Memantine treatment in patients with moderate to severe Alzheimer Disease. JAMA. 2004;291:317-324.

68. Individual response is variable  Maximal benefit should be seen by 3 months  30 – 50% of patients will show no benefit Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 2003 Mar-Apr;11(2):131-45. Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies. Ann Intern Med 2003 Mar 4;138(5):400-10.  A smaller proportion (up to 20%) will show a greater than average response Mixed dementia: emerging concepts and therapeutic implications. JAMA 2004 Dec 15;292(23):2901-8. Management of Alzheimer's disease. J Gerontol A Biol Sci Med Sci 2003 Apr;58(4):331-53

69. ChEI’s NNT (number needed to treat to benefit 1)  Improved cognition 6-12  Global decline 12  Nursing home placement 6  Versus: Statin to prevent MI = 28 BP meds for MI/CVA/death = 29-86 Recommendations for best practices in the treatment of Alzheimer’s disease in managed care. Am J Geriatr Pharmacother. 2006;4 Suppl A:S9-S24.

70. ChEIs adverse reactions  Secondary to cholinergic increase  Most frequent: nausea, vomiting, diarrhea  Also flushing, rhinorrhea, insomnia, nightmares, agitation  Treating 12 patients results in one additional patient having a treatment-related adverse event (mostly gastrointestinal side effects) Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. SOCMAJ 2003 Sep 16;169(6):557-64.

71. Cholinesterase Inhibitor class  All three (donepezil, rivastigmine, galantamine) are approved for mild to moderate AD, and are equally efficacious  Donepezil is approved for severe AD  Each drug has a unique pharmacologic profile, thus reasonable to try a different drug if not responding to the first (no efficacy evidence for choosing one over another)

72. ChEI dosages Donepezil (Aricept) Tabs, ODT5-10 mg Rivastigmine (Exelon) Capsules, Liquid, Patch 6-12 mg Galantamine (Razadyne) Tabs, Liquid16-32 mg

73. Monthly cost at maximum dose  Cholinesterase Inhibitors Donepezil (Aricept) 10 mg$260 Rivastigmine (Exelon) 6 mg tab $257 Rivastigmine (Exelon) 9.5 Patch$231 Galantamine ER (Razadyne) 24 mg$212  Memantine (Namenda) 10 mg$191  Combined: ChEI + Memantine$403+ Source: Epocrates 8/10

74. Rivastigmine Patch  Similar efficacy to capsule  Transdermal route provides continuous delivery of the drug over 24 hours  Superior tolerability profile CapsulePatch Nausea: 23%7% Vomiting: 17%6% Decreased appetite: 4%1% Dizziness: 8% 2% A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer’s disease – rivastigmine patch versus capsule, Int J Geriatric Psychiatry 2007; 22: 456-467

75. Rivastigmine Patch  Initial dose: 4.6 mg/24 hour patch x 4 weeks  Maintenance dose: 9.5 mg/24 patch  If on oral preparation and receiving < 6 mg, start with 4.6 mg/24 hour patch  If on oral preparation and receiving 6-12 mg/day, start with 9.5 mg/24 hour patch  First patch is applied on the day following the last oral dose  No dosage adjustments for renal or hepatic impairment  Rotate sites, not repeating site within 14 days

76. Starting ChEIs  Warn about adverse reactions: nausea, vomiting, nightmares, agitation  Most cholinergic side effects wane in 2-4 days  Caution if: urinary obstruction, COPD, conduction delay, or seizure history  Start at low dose, titrate up q4 weeks  Seek to get to maximal dose

77. ChEIs and acute illness  Interruption of treatment (2-6 weeks?) may result in irretrievable loss of cognition and function  Continue antidementia therapy during acute illness and hospitalization, unless contraindicated  If stopped, resume as quickly as possible Recommendations for best practices in the treatment of Alzheimer’s disease in managed care. Am J Geriatr Pharmacother. 2006;4 Suppl A:S9-S24.

78. When to stop ChEIs?  No clear guidelines  Consider discontinuing if: MMSE <9 and dependent in all basic ADLs No longer possible to have meaningful social interactions or quality of life (in opinion of family and physician) Weight loss (even without cognitive decline)  Consider reintroduction if there is any deterioration Reconsidering medication appropriateness for patients late in life. Arch Intern Med 2006;166:605–609.

79. Glutamate Hypothesis  Main excitatory neurotransmitter in the CNS, released normally in a phasic manner  Released in large amounts in injured or dying glutamate-producing neurons  Increased tonic extracellular glutamate increases NMDA-receptor activation, triggering a series of events leading to toxicity and death in downstream neurons

80. Memantine  N-methyl-D-aspartate antagonist (NMDA inhibitor)  Approved by FDA October 2003 for use in moderate to severe dementia  Prevents glutamate excitotoxicity  Side effects; dizziness, confusion, headache, constipation…but similar to placebo

81. Does Memantine work?  Meta-analysis of all published studies – small improvement in patients with agitation and other behavioral sx  Improvement of about 2 points in NPI (score range is 0-120)  Studies too small and effect too small for conclusive recommendations  Large scale controlled clinical trial is being conducted world wide on effects of memantine on agitation. Efficacy of Memantine on Behavioral and Psychological Symptoms Related to Dementia: A Systematic Meta- Analysis, Ann Pharmacother 2008; 32-38.

82. Combination tx: Memantine + ChEI  Theoretically: two classes have different mechanisms of action, thus expect additive benefit  Study - Donepezil gave improvement of 3 points on SIB score (0-100). Donepezil plus Memantine gave 4 points Tariot PN, Memantine treatment in patients with moderate to severe Alzheimer Disease. JAMA. 2004;291:317-324.  Tolerated well – increased headache and mild confusion

83. AD: Conflicting data for:  Vitamin E – no longer recommended due to limited efficacy and safety concerns. Do not use greater than 400 IU. APA Practice GuidelinesAPA Practice Guidelines: Practice Guideline for the Treatment of Patients With Alzheimer's Disease, Second Edition. Published in October 2007.  Gingko biloba – benefit is disproved, not recommended in AD

84. AD:No supportive data, or limited data  Vitamin C  Hormone replacement therapy (i.e. estrogen) - Women’s Health Initiative study showed 2 fold increase in dementia  Non-steroidal anti-inflammatory drugs  Lecithin  Acetyl-I-carnitine  Melatonin  Vitamin B12  Vitamin B6

85. When does Dad need to go to a nursing home?  ADL tool is used extensively as a flag signaling functional capabilities of older adults in clinical and home environments (see addendum for ADLs)  Common reasons for transfer Exhaustion of family Wandering/safety/falls Incontinence/hygiene/skin care Agitation/anxiety/fearfulness  Should we transfer sooner? Many residents thrive, eat better, have better hygiene and better medication management in a structured environment.

86. How long will Mom live?  Study in AD - duration from incident dementia to death = 4.6 years (female), 4.1 years (male) Larson, Survival after initial diagnosis of Alzheimer disease, Annals of Internal Medicince 2004;140:501-509.  Study in dementia Median survival time in years from dementia onset to death = 4.6 (female), 4.1 (male), overall 4.5 years Age based:  65-69 yo 10.7 years  70-79 yo 5.4 years  80-89 yo4.3 years  >89 yo3.8 years Xie J, Survival times in people with dementia: analysis from population based cohort study with 14 year follow-up, BMJ. 2008 Feb 2;336(7638):225-6.

87. How will Grandma die?  Anticipatory guidance is key  Dysphagia and aspiration are common in final stages. Altered food consistency can limit symptoms (quality of life issue?) PEG tubes do NOT prevent aspiration, and may prolong the dying process.  Most common cause of death – infection originating in the respiratory tract, skin, or urinary tract.

88. Protective against dementia  Viewing the brain as a highly vascular organ, and taking vascular protection measures are probably the best prevention  Exercise (walk >2 miles/day)  High fish/DHA, low sat. fat  Green tea  Red wine, modest alcohol  Mediterranean diet

89. Dementia care….  The opportunities are many  The ability to help is great  The rewards are unlimited  The personal and professional satisfaction is high