2. Critical Challenges in Alzheimers Disease: A Global Approach for Optimizing Patient Care Patient Identification and Initial Strategies

3. Alzheimers Disease (AD): More Than Just Memory Loss AD is a progressive, degenerative disease involving: AD is a progressive, degenerative disease involving: l Loss of memory and other cognitive functions l Decline in ability to perform activities of daily living l Changes in personality and behavior l Increases in resource utilization l Eventual nursing home placement

4. Alzheimers Disease Overview Progressive, degenerative brain disease characterized by an increasing loss of memory & other cognitive functions Progressive, degenerative brain disease characterized by an increasing loss of memory & other cognitive functions Characterized by changes in activities of daily living (ADL), behavior & personality, cognition including judgment – ABCs Characterized by changes in activities of daily living (ADL), behavior & personality, cognition including judgment – ABCs Most common cause of dementia among people aged 65 or over Most common cause of dementia among people aged 65 or over

5. 1. Murphy SL. Natl Vital Stat Rep. 2000;48:1-106. 2. Evans DA et al. Milbank Quarterly. 1990;68:267-289. Current Prevalence of AD AD is the fourth leading cause of death due to disease for people > 65 years of age in the United States 1 AD is the fourth leading cause of death due to disease for people > 65 years of age in the United States 1 Approximately 4 million people in the United States have AD 2 Approximately 4 million people in the United States have AD 2

6. AD Is the Most Prevalent Type of Irreversible Dementia Guttman R et al. Arch Fam Med. 1999;8:347-353. McKeith IG et al. Neurology. 1996;47:1113-1124. Cherrier MM et al. J Am Geriatr Soc. 1997;45:579-583. VaD, vascular dementia; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia. reflects difficulties diagnosing/reporting dementias; only estimations of prevalence can be made. 0 20 40 60 80 100 ADVaDDLBFTDOther Irreversible dementias (%)

7. Mortality Due to AD: Impact of Age Reprinted with permission from Hoyert DL et al. Natl Vital Stat Rep. 1999;47:1-104. 1,000 100 10 1 0.1 0.01 Under 45 45–54 55–64 65–74 75–84 85+ Age (years) Rate per 100,000 population

8. Cost of AD in the US Annual treatment costs ~ $100 billion Annual treatment costs ~ $100 billion l $18,408/patient per year for mild AD l $30,096/patient per year for moderate AD l $36,132/patient per year for severe AD Leon J et al. Health Aff (Millwood). 1998;17:206-216.

9. Does Treatment Affect the Cost of AD? Savings are small for mild and very severe AD Savings are small for mild and very severe AD Prevention of even a small decline in cognition for patients with moderate AD would save ~ $3,700 per patient annually Prevention of even a small decline in cognition for patients with moderate AD would save ~ $3,700 per patient annually Relatively small improvements in patients with moderate AD would save ~ $7,100 per patient annually Relatively small improvements in patients with moderate AD would save ~ $7,100 per patient annually Ernst RL et al. Arch Neurol. 1997;54:687-693.

10. Who Are the Caregivers? The overwhelming majority of patients live at home and are cared for by family and friends The overwhelming majority of patients live at home and are cared for by family and friends l 77% are women l 73% are over 50 years of age l 33% are the sole providers l 45% are children of the patient l 49% are spouses l Remainder are close family members or friends Consumer Health Sciences, LLC. Princeton, NJ; December 1999.

11. Caregiver Burden Caregiver Burden Caregivers spend from 40–100 hours per week with the patient Caregivers spend from 40–100 hours per week with the patient 90% are affected emotionally (frustrated, drained) 90% are affected emotionally (frustrated, drained) 75% report feeling depressed; 66% have significant depression 75% report feeling depressed; 66% have significant depression Half say they do not have time for themselves and that the stress affects family relations Half say they do not have time for themselves and that the stress affects family relations Many experience a significant loss of income Many experience a significant loss of income Coping. Available at: http://www.alzheimers.com. Accessed September 2000.

12. Factors That Create Breaking Pointfor Caregiver Amount of time spent caring for the patient Amount of time spent caring for the patient Loss of identity Loss of identity Patient misidentifications and clinical fluctuations Patient misidentifications and clinical fluctuations Nocturnal deterioration of patient Nocturnal deterioration of patient Annerstedt L et al. Scand J Public Health. 2000;28:23-31.

13. AP = amyloid plaques NFT = neurofibrillary tangles Neuropathological Changes Characteristic of AD Normal AP AD NFT Courtesy of George T.Grossberg M.D.; St. Louis University

14. Key Risk Factors for AD Primary risk factors Primary risk factors l Age l Family history l Genetic marker such as APOE-4, trisomy 21, mutations in presenilin 1,2 l Cardiovascular risk factors e.g. hyperlipidemia/ hypertension (the role of statins and omega 3 fatty acids) Possible risk factors Possible risk factors l Head trauma l Low level of education l Depression l Increased zinc? l Increased homocysteine (the role of B-vitamins, e.g. Folic acid)

15. AD Is Often Misdiagnosed Patient initially diagnosed with AD Patients first diagnosis other than AD Yes 28% No 72% 21% 7% 9% 14% 35% Normal aging Depression No diagnosis Dementia (not AD)Stroke Other Source: Consumer Health Sciences, LLC. Alzheimers Caregiver Project. 1999.

16. Treatment Alternatives Symptoms Symptoms l Non-pharmacological l Neuroleptics l Anti-depressants l Anti-convulsants l ChEIs l NMDA receptor antagonists

17. AD Treatment Algorithm Stage of AD Mild Moderate Severe Treatment Options ChEI ChEI/ Memantine Memantine (alone or in (alone or in (alone or in (alone or in combination) combination) combination) combination)

18. Alzheimers Disease The Challenge of Early Diagnosis Overview and Introduction

19. Benefits of Early Diagnosis and Treatment of Alzheimers Disease Alzheimers disease can be diagnosed approximately 90% of the time with a general medical and psychiatric evaluation 1,2 Alzheimers disease can be diagnosed approximately 90% of the time with a general medical and psychiatric evaluation 1,2 Early diagnosis has many advantages 3,4 Early diagnosis has many advantages 3,4 l Allows time for planning l Empowers the patients to make treatment decisions early on l Facilitates caregiver participation May slow the progression of symptoms 2 May slow the progression of symptoms 2 Offers the patient potential for greater functioning and independence 2,3 Offers the patient potential for greater functioning and independence 2,3 Can help ease the stress for caregivers 2,3 Can help ease the stress for caregivers 2,3 Sources:1. Small GW, et al. JAMA. 1997;278:1363-1372. 2. National Institute on Aging. National Institutes of Health; 2000. NIH publication 00-4859:l-62. 3. Doraiswamy PM, et al. J Clin Psychiatry. 1998;59(suppl 13):6-18. 4. Knopman DS. In: Early Diagnosis of Alzheimers Disease. Totowa, NJ: Humana Press, Inc; 2000:298.

20. Discussion Points Dementia is underrecognized (even with behavioral symptoms) and undertreated 67.7% of residents* have dementia 67.7% of residents* have dementia l Of those with dementia 73% were adequately evaluated 52% were adequately treated 70% had clinically significant behavioral symptoms Used 262 min/d of staff time vs no dementia 126 min/d (P<.005) *The results are based on a randomized cohort of assisted living (AL) residents of 22 randomly selected AL facilities in Baltimore and 7 Maryland counties. Source: Rosenblatt A, et al. J Am Geriatr Soc. 2004;52:1618-1625.

21. Barriers to Early Diagnosis Stigma First-degree relatives of AD patients reluctant to approve cognitive status examination First-degree relatives of AD patients reluctant to approve cognitive status examination Those of patients with more behavioral problems show greater reluctance Those of patients with more behavioral problems show greater reluctance Misconceptions Perception of uselessness of examination Perception of uselessness of examination Perception of limited treatment options Perception of limited treatment options Early Stages Early Stages Patients maintain social skills in mild stages Patients maintain social skills in mild stages Source: Werner P, Heinik J. Int J Geriatr Psychiatry. 2004;19:479-486.

22. Barriers to Early Diagnosis (cont) Failure to Recognize the Importance of Cognitive/Functional Changes Racial Barriers Racial bias in screening tools Racial bias in screening tools Duality of respect for the patient normalization Duality of respect for the patient normalization Cultural ignorance or insensitivity Cultural ignorance or insensitivity Source: Cloutterbuck J, et al. Dementia. 2003;2:221-243.

23. Discussion Points Dementia Screening Tools: Effect of Ethnicity Brief screening tests often incorrectly classify African Americans with dementia (42%) compared to Caucasians (6%) Brief screening tests often incorrectly classify African Americans with dementia (42%) compared to Caucasians (6%) The specificity of standardized cognitive assessments for dementia is particularly bad for African Americans The specificity of standardized cognitive assessments for dementia is particularly bad for African Americans Comparison of the utility of the Clock Drawing Test (CDT), Cognitive Abilities Screening Instrument, and MMSE Comparison of the utility of the Clock Drawing Test (CDT), Cognitive Abilities Screening Instrument, and MMSE l All tests were affected by education level l CDT was most sensitive to poorly educated non-English speakers Sources:Stephenson J. JAMA. 2001;286:779-780. Lampley-Dallas VT. J Natl Med Assoc. 2001;93:323-328. Fillenbaum G, et al. J Clin Epidemiol. 1990;43:651-660. Borson S, et al. J Gerontol A Biol Sci Med Sci. 1999;54:M534-M540.

24. Ethnic Differences in Knowledge and Perception of AD Elderly have misperceptions about the prevalence, etiology, diagnosis, and financial coverage for AD treatments Elderly have misperceptions about the prevalence, etiology, diagnosis, and financial coverage for AD treatments Older Hispanic and Asian adults frequently consider AD a contagious but curable disease Older Hispanic and Asian adults frequently consider AD a contagious but curable disease Hispanic, Asian, and African Americans more often consider AD a form of insanity Hispanic, Asian, and African Americans more often consider AD a form of insanity Education levels partially explain differences in AD knowledge between Caucasians and Hispanics Education levels partially explain differences in AD knowledge between Caucasians and Hispanics For Asians, the number of years speaking English is correlated with better knowledge of AD For Asians, the number of years speaking English is correlated with better knowledge of AD Source: Ayalon L, et al. Int J Geriatr Psychiatry. 2004;19:51-57. Discussion Points

25. Barriers to Early Diagnosis (cont) Barriers associated with PCPs Barriers associated with PCPs Differential diagnosis Differential diagnosis l Vascular dementia, frontotemporal dementia, Lewy body dementia Comorbid conditions Comorbid conditions l Differentiating dementia, delirium, and depression Time Time l 1 hour required for diagnosis, but only 15 minutes reimbursed l Knowledge of appropriate reimbursement codes Overabundance of tests Overabundance of tests

26. Discussion Points Vascular Dementia (VaD) - Key Elements Cognitive impairment caused by cerebrovascular disease or cerebrovascular accident Cognitive impairment caused by cerebrovascular disease or cerebrovascular accident Mixed dementia = VaD + AD Mixed dementia = VaD + AD Stairstep progression of illness Stairstep progression of illness May have motor impairment early in the course of illness May have motor impairment early in the course of illness Care Notes Care Notes l Treat hypertension, diabetes, lipids l May be associated with severe or refractory depression l Accommodate hemiplegia in interactions with staff/environment Source: Black SE. Postgrad Med. 2005;117(1):15-16,19-25.

27. Discussion Points Dementia With Lewy Bodies - Key Elements Wide fluctuations in cognition, responsiveness, and function Wide fluctuations in cognition, responsiveness, and function Vivid visual hallucinations and paranoid delusions Vivid visual hallucinations and paranoid delusions Parkinsonism occurs early Parkinsonism occurs early Care notes Care notes l Some antipsychotics will cause severe parkinsonism at low doses l Quetiapine, aripiprazole, or clozapine may be tolerated best l Cholinesterase inhibitors are helpful l Levodopa and Parkinsons disease medications have limited effectiveness for movement disorders Sources: McKeith IG, et al. Neurology. 1996;47:1113-1124. McKeith IG, et al. Neurology. 1999;53:902-905.

28. Discussion Points Frontotemporal Dementia - Key Elements Frontal lobe dementia, Picks disease Frontal lobe dementia, Picks disease Earlier age of onset than AD Earlier age of onset than AD Gradual decline Gradual decline Early problems with memory and language expression Early problems with memory and language expression Prominent personality changessocially inappropriate, disinhibited, and compulsive (sexualized, eating) behaviors often observed Prominent personality changessocially inappropriate, disinhibited, and compulsive (sexualized, eating) behaviors often observed Care notes Care notes l Cholinesterase inhibitors not very effective l Safe environment for harmful compulsive behaviors Source: McKhann GM, et al. Arch Neurol. 2001;58:1803-1809.

29. Adapted from: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:142-143. Alzheimers Disease Multiple cognitive deficits, with both memory impairment and 1 or more of the following deficits: Multiple cognitive deficits, with both memory impairment and 1 or more of the following deficits: Aphasia (language) Aphasia (language) Apraxia (learned motor skills) Apraxia (learned motor skills) Agnosia (visuospatial/sensory) Agnosia (visuospatial/sensory) Executive functioning (planning, insight anticipation) Executive functioning (planning, insight anticipation) Impairment in social or occupational functioning, representing a significant decline from a previous level of functioning Impairment in social or occupational functioning, representing a significant decline from a previous level of functioning Gradual onset and progressive cognitive decline Gradual onset and progressive cognitive decline

30. Overcoming Barriers to AD Diagnosis Time Time l Schedule high-risk patients at end of day l AD does not have to be diagnosed in a single visit Reimbursement Reimbursement l Know appropriate codes for AD diagnosis and for extra time Coexisting illnesses Coexisting illnesses l AD treatments may permit sustained self-management of other illnesses Depression Depression l Evaluate patients using Geriatric Depression Scale (15 questions) Screening tools Screening tools l Start slowly in gathering information, eg, MMSE (10-15 minutes) and CDT (1-5 minutes) l FAQ 10 questions completed by family

31. Targeted Screening Patients at least 65 years of age, when clinical presentation suggests the possibility of dementia (eg, forgetfulness, poor hygiene, poor compliance) Patients at least 65 years of age, when clinical presentation suggests the possibility of dementia (eg, forgetfulness, poor hygiene, poor compliance) All patients at least 80 years of age, with regular frequency All patients at least 80 years of age, with regular frequency Sources: Kaiser Permanente Care Management Institute. Guidelines for the diagnosis and management of dementia in primary care. Available at: http://members.kaiserpermanente.org/kpweb/pdf/feature/247clinicalpracguide/CMI_ DementiaGuideline_public_web_020604.pdf. Accessed August 17, 2005. Knopman DS, et al. Neurology. 2001;56:1143-1153. Screening assesses quantitative and objective measures rather than qualitative responses.

32. Discussion Points Is there a relationship between mild cognitive impairment (MCI) and AD? (16% of MCI patients convert to AD per year) Is there a relationship between mild cognitive impairment (MCI) and AD? (16% of MCI patients convert to AD per year) How do we differentiate MCI from AD? How do we differentiate MCI from AD? Government recommendation not to screen (Agency for Healthcare Research and Quality) Government recommendation not to screen (Agency for Healthcare Research and Quality)

33. The Case for Universal Cognitive Screening Memory complaints are common and can be associated with subsequent dementia Memory complaints are common and can be associated with subsequent dementia Early dementia symptoms can be difficult to recognize Early dementia symptoms can be difficult to recognize Cognitive impairment affects how medical care is provided Cognitive impairment affects how medical care is provided l Management (and costs) of other diseases l Follow through with medical recommendations l Prevention of complications

34. Discussion Points Which screening tools do you recommend? Which screening tools do you recommend? l A dialogue on the utility of screening tools Educational preceptorshipwarning signs and public awareness Educational preceptorshipwarning signs and public awareness l Community l Doctors l Consumers l Alzheimers Association

35. Dementia Diagnostic Process General screen General screen l Signs of acute/chronic disease: how well controlled? l Common conditions l Weight loss, dehydration, subnutrition Include obstructive sleep apnea, insomnia, depression Neurologic screen Neurologic screen l Vascular or Parkinsons dementia, frontal signs l Gait, balance, and falls l Neuropathy Laboratory screen Laboratory screen l Vitamin B 12 deficiency, hypothyroidism l Associated problems, secondary complications, and additional causes Brain structural screen Brain structural screen l Noncontrast CT or MRI l Surgical and vascular lesions

36. Evaluation of the AD Patient In approximately 90% of patients who have AD, the diagnosis can be made on the basis of: In approximately 90% of patients who have AD, the diagnosis can be made on the basis of: l Detailed medical history obtained from the patient and a reliable informant l Medical examination l Mental status examination A 15-minute office visit is insufficient for fully evaluating the AD patient. For patients seen regularly, a 3-stage assessment may be more appropriate A 15-minute office visit is insufficient for fully evaluating the AD patient. For patients seen regularly, a 3-stage assessment may be more appropriate Source: Cefalu C, Grossberg GT. Diagnosis and Management of Dementia. American Family Physician Monograph, No. 2. Leawood, Kan: American Academy of Family Physicians; 2001.

37. The Office History Memory impairment: repetitive; trouble remembering recent conversations, events, appointments; frequently misplaces objects Memory impairment: repetitive; trouble remembering recent conversations, events, appointments; frequently misplaces objects Executive impairment: deterioration of complex task performance; decreased ability to solve problems; impaired driving Executive impairment: deterioration of complex task performance; decreased ability to solve problems; impaired driving Drugs: alcohol, prescriptions, over-the- counter (OTC) medications Drugs: alcohol, prescriptions, over-the- counter (OTC) medications Focal motor or sensory neurologic symptoms Focal motor or sensory neurologic symptoms

38. Take comprehensive history Take comprehensive history l Medical history, medications (including OTC drug use) Interview immediate family member/caregiver Interview immediate family member/caregiver If time permits and patient is cooperative, perform MMSE If time permits and patient is cooperative, perform MMSE Assess family needs and caregiver stress Assess family needs and caregiver stress First Visit Source: Cefalu C, Grossberg GT. Diagnosis and Management of Dementia. American Family Physician Monograph, No. 2. Leawood, Kan: American Academy of Family Physicians; 2001. Evaluation of the AD Patient (cont)

39. Second Visit CBC, electrolytes, LFTs, TSH, B 12, folate, UA, EKG, HIV, VDRL, ESR, homocysteine Neuroimaging Perform MMSE if not performed on first visit Reassess family needs and caregiver stress Consider neuropsychological testing CBC = complete blood count; LFTs = liver function tests; TSH = thyroid-stimulating hormone; UA = unstable angina; EKG = electrocardiogram; HIV = human immunodeficiency virus; VDRL = Venereal Disease Research Laboratory test; ESR = erythrocyte sedimentation rate. Source: Cefalu C, Grossberg GT. Diagnosis and Management of Dementia. American Family Physician Monograph, No. 2. Leawood, Kan: American Academy of Family Physicians; 2001. Evaluation of the AD Patient (cont)

40. Review laboratory findings and results of testing Review laboratory findings and results of testing Discuss treatment options, follow-up plans for patient Discuss treatment options, follow-up plans for patient Readdress family and caregiver needs Readdress family and caregiver needs Third Visit Source: Cefalu C, Grossberg GT. Diagnosis and Management of Dementia. American Family Physician Monograph, No. 2. Leawood, Kan: American Academy of Family Physicians; 2001. Evaluation of the AD Patient (cont)

41. Discussion Points What Is the Place for Imaging? Noncontrast CT or MRI scan in the initial evaluation is appropriate (American Academy of Neurology Guideline) Noncontrast CT or MRI scan in the initial evaluation is appropriate (American Academy of Neurology Guideline) The use of positron emission tomography The use of positron emission tomography Value of imaging is to rule out other forms of intracranial pathology that may be contributing to cognitive change or for unusual presentations: Value of imaging is to rule out other forms of intracranial pathology that may be contributing to cognitive change or for unusual presentations: l Rapid onset (duration <3 months), subdural hematoma, cerebral neoplasms, head trauma, history of cerebrovascular accident(s), seizures, new-onset urinary or fecal incontinence, abnormal gait, postural instability, focal signs, visual field deficit, headaches, suspect malignant tumor Sources: American Academy of Neurology. Neurology. 2001;56:1133-1142. American Academy of Neurology. Neurology. 2001;56:1143-1153.

42. Practical Consequences of Improved Diagnostic Accuracy Accurate diagnostic information and education reduce family/caregiver burden Accurate diagnostic information and education reduce family/caregiver burden Decreased likelihood of repeated diagnostic assessments and testing Decreased likelihood of repeated diagnostic assessments and testing AD label improves caregiver attitudes AD label improves caregiver attitudes Information about the disease improves quality of life for family/patient and delays nursing home placement Information about the disease improves quality of life for family/patient and delays nursing home placement Sources: Mittelman M, et al. JAMA. 1996;276:1725-1731. Wadley V, et al. J Gerontol B Psychol Sci Soc Sci. 2001;56:P244-P252.

43. Stages of Alzheimers Disease Mild Moderate Severe Cognition Difficulty recognizing family and friends Chronic loss of recent memory Loss of speech Misidentifies or is unable to recognize familiar people Confusion and memory loss, eg: Needs help with basic ADL (eg, feeding, dressing, bathing) Progresses to total dependence on caregiver (eg, feeding, toileting) Problems with routine tasks Activities of daily living (ADL) Behavior Anxiety, suspicion, pacing, insomnia, agitation, wandering Crying, screaming, groaning Changes in personality – Misplacing objects – Forgetting names – Disorientation Sources: National Institute on Aging. National Institutes of Health; 2003. NIH publication 02-3782. Available at: http:www.alzheimers.org/unraveling/index.htm. Accessed January 10, 2005. Alzheimers Association. Available at: http://www.alz.org/AboutAD/Stages.asp. Accessed January 13, 2005.

44. Summary Marked changes in memory are not a normal part of aging and may signal a developing dementia Marked changes in memory are not a normal part of aging and may signal a developing dementia Universal screening for AD is important Universal screening for AD is important Effective diagnosis and management take time Effective diagnosis and management take time l Three separate visits may be required It is important to recognize and overcome the barriers to early diagnosis of AD It is important to recognize and overcome the barriers to early diagnosis of AD