The Forgetful Patient – Evaluation and Management

The Forgetful Patient – Evaluation and Management Michael Sha, MD, FACP Governor, Indiana ACP Chapter Indiana University School of Medicine 2011 Scientific Meeting Central America ACP Chapter Panama City, Panama

Dementia • Cognitive Spectrum • Normal • Mild Cognitive Impairment (MCI) • Definition - most commonly defined as a subtle but measurable memory disorder • American Academy of Neurology (2001) – • An individual’s report of memory problems, preferably confirmed by another person • Measurable, greater than normal memory impairment detected with standard memory assessment tests • Normal general thinking and reasoning skills • Ability to perform normal daily activities

Dementia • Spectrum • Dementia (DSM-IV) • Impairment of memory • Impairment of at least one other cognitive domain • Abstract thinking, • Judgment, • Language, or • Visuo-spatial abilities • Deterioration should be significant enough to interfere with work or social relationships

Outline • Screening Tools • Treatment Update • Prevention • Management Update

Dementia – Evaluation • Early diagnosis, early treatment • Preserve quality of life • Postpone institutionalization • Evaluate for reversible causes • Confounders to diagnosis • Psychiatric disorders (e.g. depression) • Medications • Cognitive decline with normal aging • Low educational attainment

Mini-Mental Status Exam Clock Drawing Short Portable Mental Status Questionnaire Blessed Dementia Scale 3MS (Modified-MMSE) Fuld Object-Memory Evaluation Cognitive Abilities Screening Instrument Structured Telephone Interview for Dementia Assessment MDS Cognitive Performance Scale Cognitive Impairment Diagnosing Instrument Baylor Profound Mental Status Exam Severe Impairment Battery (SIB) Guys Advanced Dementia Schedule East Boston Memory Test 7-minute Neurocognitive Screening Battery Katzman’s Short Orientation-Memory-Concentration Test Time and Change Test Mattis Dementia Rating Scale Hasegawa Dementia Scale-Revised Delayed-Word-Recall Test Cognitive Capacity Screening Examination Cortical Function Assessment Mental Status Questionnaire Screening Tests

Screening Tests • Mini-Mental Status Exam • Clock Drawing Test • Severe Impairment Battery

Mini-Mental Status Exam • Published in 1975 in the Journal of Psychiatric Research • An 11-item instrument designed for easy and quick administration

Mini-Mental Status Exam • 30 point scoring scale • 5 points for orientation to time • 5 points for orientation to place • 6 points total for retention and recall • 5 points for attention (serial 7’s or “WORLD”) • MMSE score of 23/24 generally accepted as cutoff for cognitive impairment • 83-87% sensitivity, 82-96% specificity • Sensitivity and specificity affected by age, educational level

Mini-Mental Status Exam • Influence of age • MMSE scores decline with age • MMSE declines 0.6 points per year in normal patients, 2.8 points in demented patients (Aevarsson O, Dementia and Geriatric Cognitive Disorders, 2000) (Crum, JAMA, 1993)

Mini-Mental Status Exam • Influence of education • Education accounts for more variance in MMSE scores than any other factor • MMSE is based on an 8th-grade level of education • High education • “Ceiling effect” (Crum, JAMA, 1993)

Mini-Mental Status Exam • Additional drawbacks • MMSE becomes less sensitive as the dementia progresses • “Floor Effect” – due to weighting of the MMSE point system • Does not adequately assess executive functioning

Mini-Mental Status Exam • How valid is the Spanish-language version of the MMSE? • Validity study (Taussig IM, Clinical Gerontologist, 1992 and Taussig IM, Journal of the International Neuropsychology Society, 1996) • Conducted through the Spanish-Speaking Alzheimer’s Disease Research Program at the University of Southern California • 168 patients were enrolled (81 dementia, 77 non-demented patients) • 42% from Mexico, rest were from other Latin American countries

Mini-Mental Status Exam • Validity of Spanish-language MMSE (S-MMSE) • Performance by non-demented older Hispanics did not differ from non-demented native English speakers • Implies there is a lack of cultural bias in total scores from the MMSE and the S-MMSE • Education provided similar confounding influence

Mini-Mental Status Exam • SUMMARY • Rapid to administer and score • MMSE is valid with high sensitivity and specificity and understanding its limitations with education and age • Longitudinally useful until patients progress beyond moderate dementia • S-MMSE appears equally valid as the MMSE in diagnosing dementia

Clock Drawing Test • Assesses multiple cognitive domains • Relatively quick to administer • Drawbacks • Many types of errors are possible • Multiple scoring systems

Clock Drawing - Scoring • Most of the scoring systems are complex – limits utility

Clock Drawing Test • Despite the significant variations in scoring systems, all of the published scoring systems have good reliability and inter-rater reliability • Most scoring systems have a sensitivity of 85% and specificity of 85% • Level of education does influence clock drawing scores • Correlation between clock drawing scoring systems • Correlation with MMSE • Can use with MMSE to increase MMSE sensitivity and specificity

Severe Impairment Battery • 40 item, 100 point scale instrument • Focused on evaluating cognitive ability in severely demented patients • Simple one-step commands with gestural cues • Allows for nonverbal and partially correct responses • Composed of 6 major subscales

Severe Impairment Battery • Ability of instrument to differentiate cognitive performance in dementia patients categorized as “severe impairment” by MMSE

Screening Tests • Need to understand the performance characteristics of the tests used • Need to balance utility (i.e. ease of use) with need to document longitudinal progression • Prognosis • Response to treatment

Treatment • Acetylcholinesterase inhibitors • Neuropeptide modifying agent - Memantine • Not helpful • Tacrine • Vitamin E • Ginkgo biloba

Acetylcholinesterase Inhibitors • High-dose Donepezil study (Farlow MR, Clinical Therapeutics, 2010) • Randomized double-blind study • International, multicenter study (219 centers in Asia, Europe, Australia, North and South America, and South Africa) • Study arms • High-dose Donepezil (23mg qd) for 24 weeks • Standard-dose Donepezil (10mg qd) for 24 weeks

Acetylcholinesterase Inhibitors • High-dose Donepezil study • Inclusion criteria: • Enrolled patients with probable Alzheimers with a MMSE score of 0 to 20 • Taking Donepezil 10mg qd for > 12 weeks • Exclusion criteria: • Other neurologic disorders • Outcome measures: Severe Impairment Battery (SIB) and Clinician’s Interview-Based Impression of Change Plus Caregiver Input Scale (CIBIC+)

Acetylcholinesterase Inhibitors • High-dose Donepezil study • Results – 1467 patients randomized (981 in the high-dose treatment arm, 486 in the standard dose treatment arm) • Global participation • 10 sites from South America • 10% of study participants from South America

Acetylcholinesterase Inhibitors • High-dose Donepezil study • SIB • +2.5 in high dose arm vs +0.4 in standard dose (p < 0.001) • CIBIC + • 4.23 in high dose arm vs 4.29 in standard dose (p = NS) • No benefit in ADL or MMSE scores

Acetylcholinesterase Inhibitors • High-dose Donepezil study • Side effects • 11.8% with nausea in high dose arm vs 3.4% in standard dose arm • 9.2% with vomiting in high dose arm vs 2.% in standard dose arm • 8.3% with diarrhea in high dose arm vs 5.3% in standard dose arm

Acetylcholinesterase Inhibitors, Memantine • Where to we stand with drug treatment? • Most drugs with statistically significant benefit but little clinical improvement (Qaseem A, Annals of Internal Medicine 2008) • High dose Donepezil falls in the same category • May be marginally better standard dose Donepezil • Cost will be a factor • Need to caution patient and family about higher incidence of side effects • Need to focus on helping families and caregivers adapt and cope

Dementia • Prevention • Exercise • Mentally stimulating activities (“Cognitive Training”) • Acetylcholinesterase inhibitors and Memantine

Prevention - Exercise • Fitness for the Aging Brain Study (Lautenschlager NT, JAMA 2008) • Randomized, single site, 18-month study • Study arms • 24-weeks of home-based program of physical activity • Education and usual care • Outcome measure – Alzheimer Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) • Scale consists of 11 brief cognitive tests, scored 0 to 70 (higher number is worse!)

Prevention - Exercise • Fitness for the Aging Brain Study • Inclusion criteria • Community-based older adults recruited • Exclusion criteria • Patients with significant cognitive impairment, likely depression (based on the Geriatric Depression Scale), significant alcohol use, history of chronic mental illness, lack of fluency in English • Intervention – encouragement of 150 minutes of moderately intense physical activity per week (three 50-minute sessions) with periodic reminders

Prevention - Exercise • Fitness for the Aging Brain Study • Results – 170 patients in study (85 in each arm) • Patients in the exercise arm has a statistically significant improvement in cognition as measured by the ADAS-Cog and in recall of word lists • 0.69 point improvement comparing the arms at 18 months

Prevention - Exercise • Fitness for the Aging Brain Study • Results – 170 patients in study (85 in each arm)

Prevention - Exercise • Adult Change in Thought (ACT) Study (Larson EB, Annals of Internal Medicine 2006) • Prospective cohort study to evaluate regular exercise (at least 3 times per week) on risk for dementia • 1740 participants, 65 years of age and cognitively intact at baseline • Reassessed every 2 years (1994-2003)

Prevention - Exercise • Adult Change in Thought (ACT) Study • Persons who exercised 3 or more times a week had a relative hazard of 0.68 (CI, 0.48 to 0.96) for developing dementia compared with those who exercised fewer than 3 times per week • 32% risk reduction in developing dementia

Prevention - Cognitive Training • Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study (Willis SL, JAMA 2006) • Randomized, single blinded, , multi-center, 4 group design • 5 year longitudinal study • Treatment arms • Control (no contact) • Memory training • Reasoning training • Speed of processing training

Prevention - Cognitive Training • ACTIVE Study • Inclusion: older than 65 years old • Exclusion: substantial functional impairment, major medical conditions likely to lead to death or functional decline, dementia, severe sensory impairment • Outcome measures: • a variety of instruments were used to assess the cognitive effects of each intervention • functional outcomes were assess by independent activities of daily living (IADLs)

Prevention - Cognitive Training • ACTIVE Study • Results - 2832 patients were randomized

Prevention - Cognitive Training • ACTIVE Study • Participants in the 3 training arms were statistically better able to perform IADLs than controls

Prevention - Cognitive Training • ACTIVE Study • Cognitive training improves cognitive function in older adults • The improvement from cognitive training lasts at least 5 years from the beginning of the intervention • Improvements in cognitive function can have a positive effect on daily function.

Prevention – Drugs • Can acetylcholinesterase inhibitors and Memantine provide neuroenhancements in health individuals? • Not enough data for using these drugs to improve memory or to prevent dementia (Rapantis D, Pharmacological Research, 2010)

Prevention • Exercise is likely very beneficial • Mentally stimulating activities can have long term benefits • There is no data to support using acetylcholinesterase inhibitors or memantine in healthy adults

Atypical Antipsychotics and Dementia • Behavorial disturbances can be quite problematic for patients and particularly caregivers • Incidence of hallucinations and delusions • Alzheimer’s Disease – 20-40% • Lewy Body Dementia – 70-90% • Some evidence of efficacy in treating dementia-related conditions like delirium (Cochrane Database of Systematic Reviews, www.cochrane.org)

Atypical Antipsychotics and Dementia • Antipsychotics are associated with increased mortality (Rossom RC, Journal of the American Geriatrics Society, 2010) • Higher rates of comorbidities in treatment cohorts

Atypical Antipsychotics and Dementia • What to do about behavorial disturbances? • Acetylcholinesterase inhibitors, SSRI or SNRI, antiepileptics • Non-drug therapy – music therapy, hand massage, gentle touch, physical activity, reality orientation, reminiscing • Minimize use of atypical antipsychotics • Psychotic symptoms that potentially endanger the patient, caregiver, or family • Discuss risk with family

Take Home Points • Need a low threshold for screening for dementia, but be aware of diagnoses that mimic dementia • Many screening instruments – pick one (or two) and understand the performance characteristics • High dose Donepezil may provide marginal benefit but side effect risk does increase • Exercise and cognitive training are likely helpful in preventing dementia and delaying progression • Minimize atypical antipsychotics in managing behavior disturbance in demented patients • Care for the patient and the family

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The Forgetful Patient – Evaluation and Management