Alzheimer s Dementia May 5, 2008

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1 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page I. Dementia vs. delirium Alzheimer s Dementia May 5, 2008 Dementia Gradual onset (insidious) Chronic illness progressing over years Irreversible Not variable but progressive Consciousness not clouded Psychomotor changes late in the disease Delirium Abrupt onset Acute illness (days to weeks) Usually reversible Variable from hour to hour Changing level of consciousness Marked psychomotor changes II. Types of dementia A. Alzheimer s dementia Accounts for majority of dementias (50-65%) Characteristics: - gradual onset and continuing decline of cognitive function from a previously higher level, resulting in impairment of social and occupational function - impairment of recent memory and at least one of the following: language disturbance, word finding difficulties, apraxia, visual spatial deficits, visual agnosia, constructional disturbance, disturbance of executive function (abstract reasoning, judgement and concentration) - cognitive deficits are not due to other psychiatric disease, neurological disease, or systemic disease - cognitive deficits do not exclusively occur in the setting of delirium B. Vascular or multi-infarct dementia Accounts for 20-30% of all dementias Characteristics: - history: onset of cognitive deficit associated with stroke, symptomatic improvement following acute event, abrupt onset, step-wise deterioration - physical findings: focal neurological signs like hemiparesis, hemianopsia - imaging: infarcts above the tentorium - neuropsychologic: cognitive impairment corresponds to infarct loci seen on imaging C. Dementia with Lewy bodies (DLB) Accounts for 15-20% of all dementias Characteristics: - progressive cognitive decline: deficits in attention, fronto-cortical skills and visospatial ability may be especially prominent - two of the following for probable and one for possible DLB: 1) fluctuating cognition with pronounced variation in attention and alertness, 2) recurrent hallucinations that are typically well-formed and detailed, 3) spontaneous motor features of parkinsonism - Other supportive features: repeated falls, syncope or transient loss of consciousness, neuroleptic sensitivity, systemized delusions, hallucinations in other modalities

2 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page D. Fronto-temporal dementia Accounts for 1-10% of all dementias Characteristics: - cognitive impairment is insidious onset and slow progression of deficits less prominent in earlier stage - personality and behavioral changes are most prominent features - dominant deficit is loss of judgement with: disinhibition or impulsivity, social misconduct, loss of social awareness, social withdrawal - other supporting feature include one or more of the following: incessant oral or manual exploration, hyperphagia, echolalia, wanderlust, impetuous activities, excessive joviality, sexually inappropriate words or actions - deficit in judgement or social component is out of proportion to deficit in memory E. Others: Huntington s, infectious, etc (1-5%) III. Alzheimer s dementia (AD) A. History 1. First diagnosed by Alois Alzheimer in Primarily disease of the elderly. No direct cause is known and treatment is for palliative instead of a cure. 3. Has the most impact on the family or the caregiver. B. Epidemiology 1. AD affects 4.5 million people in the United States. Likely to affect 7.7 millions in 2030 and 13.2 millions in It is the fourth leading cause of death among the elderly. 3. Incidence and severity of disease increases with age: Age 65-74: 7% Age 75-84: 50% Age >85 : 40% 4. Over $100 billion is spent annually treating AD C. Diagnosis 1. Clinical presentation Progressive deterioration in memory, cognitive ability, and intellectual capabilities Four A s: Aphasia loss of language skills or verbal expression and comprehension Amnesia loss of recent or short tem memory initially and ultimately long term memory Apraxia inability to carry out a motor function Agnosia- loss of perceptive ability

3 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page Behavioral symptoms: agitation, aggression, psychosis, depression, anxiety, apathy, withdrawal, sleep and appetite disturbances Neurologic abnormalities usually not seen until late stages of AD 2. Diagnostic tests No specific diagnostic test is available. PET (positron emission tomography) or SPECT (single photon emission computerized tomography) imaging may be useful but not a standard for diagnosis. CT and MRI would be helpful in ruling out other diseases. Biomarkers: from CSF (T-tau, P-tau, ABeta42), ApoE, Presenillin 1,2 Gold Standard is the identification of clinical presentation and exclusion of other possible causes of dementia Criteria for diagnosis include: - dementia established by clinical exam documented by MMSE (mini-mental state exam) or similar test confirmed by neuropsychological testing - deficit in 2 or more areas of cognition - progressive worsening of memory and other cognitive functions - no disturbance of consciousness - age of onset between absence of systemic disorders that could account for progressive deficit 3. Stages of disease Stages Symptoms Autonomy Duration Mild short term memory impairment Independent living 2-3 years accompanied by anxiety and depression symptoms are subtle and undetected Moderate language abilities and ability to think abstractly and exercise judgement is impaired decline of visual and spatial skills neuropsychiatric manifestations (hallucinations, false beliefs, reversal of sleep pattern) Supervision required. Caregiver burden highest during this stage. 2 years Severe loss of long-term memory, problems sleeping, become more weak, unable to walk with motor rigidity, unable to talk, become incontinent Total dependence on caregiver for all ADLs (activities of daily living) 2-3 years

4 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page D. Etiology 1. No known cause of AD in most patients 2. Chromosomes involved in mutation are: 21, 14, 1 3. Apolipoprotein E-4 genotype has an association of AD 4. Other risk factors: advanced age, history of head trauma, low educational level, female gender, small head size E. Pathophysiology 1. Areas of brain affected are hippocampus, neocortex (temporal and frontal lobe), brain stem, and basal forebrain. 2. Neurotransmitters involved are Ach (acetylcholine), NE (norepinephrine), 5HT (serotonin) 3. Cholinergic activity is reduced by 80-90% in cortical region 4. Classic pathological changes include senile plaques (SP) or beta-amyloid plaques, neurofibrillary tangles (NFT) and loss of neurons in the cerebral cortex 5. Free radical toxicity and glutamate toxicity may further neuronal death 6. Amyloid beta protein forms the core of neuritic plaques 7. Neurons with high concentration of tau protein are likely to form NFT F. Goals of management 1. Accurate diagnosis 2. Education of the patient and caregiver 3. Treatment of concomitant disorders such as depression 4. Keep patient independent as possible. Individualize treatment plan based on patient s functional and cognitive ability. 5. Provide comprehensive support and counseling

5 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page G. Assessing efficacy and effective of medication therapy 1. Difficulty in assessing effective of medication therapy due to progressive disease 2. Clinical trials measure efficacy using tools/scales that are not use in clinical practice. Be familiar with common tests: MMSE, FAST, NPI and what they meansure. 3. Many methodological flaws in clinical trials exist due to high drop out rate and not using intention to treat assessment. Statistical significance does not translate to clinical significance 4. Current controversies in clinical practice: using combination therapy, when to stop medication therapy, how to assess effectiveness of medication 5. Three important domains to assess medication effectiveness are: cognitive ability, functional ability (able to perform ADL), and behavioral complication. H. Pharmacologic options 1. Preventative Estrogen - potential neuroprotective mechanisms include: affecting cholinergic neurons through estrogen receptor, promote neuron growth, may alter Apo E and beta amyloid levels, may increase cerebral blood flow - Three large-scale randomized controlled trials did not show any benefit in treatment of AD with either short or long term estrogen therapy - Women s Health Initiative Memory Study (WHIMS) with estrogen and progesterone did not prevent mild cognitive impairment and may increase the risk of probable dementia Anti-inflammatory agents (NSAIDs) - longitudinal study showed NSAIDs users have lower risk of developing AD compared to ASA or acetaminophen users - a trial comparing celecoxib, rofecoxib, naproxen, and placebo did not slow the clinical or cognitive decline in mild to moderate stage of Alzheimer s patients - no strong evidence and the risk outweighs the benefit Antioxidants (vitamin E, ginkgo) - may prevent or delay AD - both vitamin E and ginkgo have been studied for treatment of AD (see below) Others - Statins - Amyloid vaccine - Gamma-secretase inhibitors - Neotrophin - TNF alpha - DHEA

6 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page Treatment Vitamin E - antioxidant - mechanism of action: decreases senile plaque formation and reduces cell death associated with amyloid protein - dose used in clinical trials: 1000 IU twice daily - used in mild to moderate AD - most effective in maintaining functional status (ability to perform activities of daily living), and minimal effect on cognitive function - adverse effect: bruising and anticoagulation due to affect on platelets and clotting factors - cost: <$10/month Ginkgo - antioxidant - mechanism of action: decreases neuron death - dose used in clinical trials: 120mg -240mg/day - used in mild to moderate AD and vascular dementia - mix results from clinical trials and meta-analyses - most effective in maintaining cognitive function but less affect on activities of daily living - adverse effect: nausea, headache, effects coagulation (do not use with warfarin) - cost: <$10/month - product quality and selection important Acetylcholinesterase (AchE) inhibitors Clinical trials showed benefit in cognitive, functional and behavioral symptoms in mild to moderate stages of AD Limited evidence on moderate to severe AD No good quality head to head trials 1. Tacrine (Cognex) - first AchE inhibitor approved for use in US (1993) - nonselective inhibitor for AchE and CNS site - short half-life requiring QID dosing (10-40mg QID) - hepatotoxicity is a major drawback. Required liver enzymes monitoring every 2 weeks. - not using in current practice 2. Donepezil (Aricept) - approved in selective for inhibiting AchE enzyme (reversible inhibitor) and for CNS site - highly protein bound (96%), and metabolized by P450 - dose: 5-10mg daily - used in mild to severe AD - most effective in maintaining cognitive function, minimal effect on ADL and behavioral manifestations - adverse effects: nausea, vomiting, diarrhea, dizziness, insomnia, worsening of depressive symptoms, bradycardia, muscle cramps - cost: $130/month (same cost for 5-10mg dose)

7 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page Rivastigmine (Exelon) - approved in selective for inhibiting AchE and butyrlacetylchoinesterase (reversible inhibitor) - not metabolized by P450 system (less drug interaction) - dose: 3-6mg twice daily (3mg bid is minimally effective). Require slow titration of dose to minimize GI symptoms (i.e.: 1.5mg BID, increase by 1.5mg/dose q 4weeks) - used in mild AD - most effective in maintaining cognitive function, global impression of change, and ADL - adverse effects: nausea and vomiting more frequent than donepezil and with higher dose - Cost: $137/month (same cost for all dosage strengths) - Also available as patch 4. Galantamine (Razadyne) - approved in late selective for inhibiting AchE (reversible and competitive inhibitor) - also modulates nicotinic receptors (enhances cholinergic function) - metabolized by CYP 2D6 and 3A4 - dose: 4-16mg twice daily (no significant difference in outcome with 16mg and 24mg daily doses). ER tablet with once daily dosing is also available - for mild to moderate AD - most effective in maintaining cognitive function, global impression of change, ADL and possibly behavior manifestations - adverse effects: nausea, vomiting, diarrhea, anorexia, dizziness - due to increase mortality rates in some of the clinical trial, FDA has issued a safety warning with this drug. - Cost: $140/month (same cost for all dosage strengths) Memantine (Namenda) - approved in late NMDA (N-methyl-D-aspartate) receptor antagonist - indicated for moderate to severe stage of Alzheimer s dementia - also studied in vascular dementia - no CYP involvement - therapeutic dose is 10mg po bid, titrate dose over 4 weeks: 5mg/day week1, 10mg/day week2, 15mg/day week3, 20mg/day, week4 - dosage adjustment recommended for moderate to severe renal impairment - current data suggests cognitive and functional outcomes (ADL) were better than patients not taking memantine - mix results on behavior effect - drug interaction with other NMDA antagonists: amantadine, ketamine, dextromethorphan - adverse effects: headache, dizziness, confusion, hallucination - cost: $130/month

8 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page Combination therapy - combination of memantine 20mg/day + donepezil 10mg/day vs. donepezil 10mg/day in moderate to severe AD - combination of memantine 5-20mg/day + rivastigmine 3-12mg/day vs. rivastigmine 3-12mg/day in moderate to severe AD - combination therapy showed improvement in cognitive, functional, behavioral and global measurements than AchE inhibitors alone - combination therapy had significantly higher rate of confusion and headache but less GI side effects 3. Behavioral symptom management Behavioral symptoms that are unlikely to respond to medications are: wandering, pacing, exit seeking, screaming, inappropriate verbalization, resistant to personal care, inappropriate voiding, defecation, spitting, sexual behaviors Psychosis, hallucination, delusion, physical aggressiveness consider antipsychotic medications (be aware of FDA black box warning of increase vascular events) Anxiety relating to medical procedure- consider benzodiazepines Non-psychotic physical aggressiveness or manic type symptoms - consider anticonvulsants (valproate, carbamazepine) Depression antidepressants (SSRIs over TCA) Sleep disturbances- consider low dose trazodone or hypnotics (i.e.: low dose temazepam, zolpidem) I. Non-pharmacologic management for behavioral symptoms 1. General rules Modifying the person s environment to reduce confusion caused by overstimulation (i.e.: reducing noise and glare from window) Explaining a task before you do it (i.e.: I m going to help you put on your shirt) Providing a predictable routine at home with structured times for meals, bathing, exercise, and bedtime Providing reassurance without challenging their accusations or misperceptions and by redirecting their attention 2. Specific problem management Agitation eliminate or minimize environmental stresses, distract and redirect not confront Sleep disorder increase activity level or exercise in daytime, practice good sleep hygiene Delusion provide validation, not reality orientation Depression counseling and socialization by attending day care center for activities

9 Sharon Leigh, PharmD. BCPS Alzheimer s Dementia Page J. Conclusion No curative therapy exist currently for the treatment of Alzheimer s dementia Early diagnosis is the key in initiating acetylcholinesterase inhibitors There is no evidence to suggest different acetylcholinesterase inhibitors have varied therapeutic effect. Side effect profile and pharmacokinetic parameters are important for product selection Memantine is the first agent approved for moderate to severe dementia. More data is needed to evaluate the role of this medication in clinical practice Combination of memantine with acetylcholinesterase inhibitors seem to be safe but additive or synergistic effect is still inconclusive Current controversies in practice include using combination therapy, assessing effectiveness of medication therapy, difficulty in translating evidence to practice, and when to discontinue therapy In managing symptoms related to Alzheimer s dementia, non-pharmacological interventions are the first choice before psychotropic medications are used K. Appendix MMSE (Mini Mental Status Exam) NPI (Neuro-Psyhiatric Inventory Scale) FAST (Functional Assessment Staging Scale)

10 NEUROPSYCHIATRIC INVENTORY QUESTIONNAIRE Name of patient: Informant: Caregiver Family Member: Circle yes only if the symptom has been present in the past month. Otherwise, circle no. For each item marked yes Rate the severity of the symptom (how it affects the patient) Rate the distress you experience because of the symptom (how it affects you) Severity: 1 = Mild (noticeable, but not a significant change) Distress: 0 = Not distressing at all 2 = Moderate (significant, but not a dramatic change) 1 = Minimal (slightly distressing, not a problem to cope with 3 = Severe (very marked or prominent, a dramatic change) 2 = Mild (not very distress, generally easy to cope with) 3 = Moderate (fairly distressing, not always easy to cope with) 4 = Severe (very distressing, difficult to cope with) 5 = Extreme or very severe (extremely distressing, unable to cope with) Please answer each question honestly and carefully. Ask for assistance if you are not sure how to answer any question Delusions Does the patient believe that others are stealing from him or her, or planning to harm him or her in some way? Hallucinations Does the patient act as if he or she hears voices? Does he or she talk to people who are not there? Agitation or Aggression Is the patient stubborn and resistive to help from others? Depression or dysphasia Does the patient act as if he or she is sad or in low spirits? Does he or she cry? Anxiety Does the patient become upset when separated from you? Does he or she have any other signs of nervousness, such as shortness of breath, sighing, being unable to relax, or feeling excessively tense? Elation or euphoria Does the patient appear to feel too good or act excessively happy? Apathy or indifference Does the patient seem less interested in his or her usual activities and in the activities & plans of others? Disinhibition Does the patient seem to act impulsively? For example, does the patient talk to strangers as if he or she knows them, or does the patient say things that my hurt people s feelings? Irritability or liability Is the patient impatient and cranky? Does he or she have difficulty coping with delays or waiting for planned activities? Motor disturbance Date: Does the patient engage in repetitive activities, such as pacing around the house, handling buttons, wrapping string, or doing other things repeatedly? Nighttime behaviors Does the patient awaken you during the night, rise too early in the morning, or take excessive naps during the day? Appetite and eating Has the patient lost or gained weight, or had a change in the food he or she likes?

11 FAST (Functional Assessment STaging) Scale Resident Name: Fast Stage Functional Assessment 1 No difficulties, either subjectively or objectively. 2 Complains of forgetting location of objects; subjective word finding difficulties only. 3 Decreased job functioning evident to coworkers; difficulty in traveling to new locations. Decreased ability to perform complex tasks (e.g., planning dinner for guests; handling 4 finances; marketing). 5 Requires assistance in choosing proper clothing for the season or occasion. 6a Difficulty putting clothing on properly without assistance. 6b Unable to bathe properly; may develop fear of bathing. Will usually require assistance adjusting bath water temperature. 6c Inability to handle mechanics of toileting (i.e., forgets to flush; doesn't wipe properly). 6d Urinary incontinence, occasional or more frequent. 6e Fecal incontinence, occasional or more frequent. 7a Ability to speak limited to about half a dozen words in an average day. 7b Intelligible vocabulary limited to a single word in an average day. 7c Nonambulatory (unable to walk without assistance). 7d Unable to sit up independently. 7e Unable to smile. 7f Unable to hold head up by Barry Reisberg, M.D NOTE: Functional staging score = Highest FAST Stage checked

12 Folstein Examination Mini Mental Status exam Client Date Orientation Other Diagnostic 1 Date Abstract Reasoning 2 Year 3 Month 4 Day 5 Season Judgement 6 Clinic (hospital) 7 Floor 8 City (Town) 9 County Animals 10 State Registration "A" words 11 Ball 12 Flag Clock Test? 13 Tree Attention & Calculation Comments 14 D L R O W 65 Recall 19 Ball 20 Flag 21 Tree Language 22 Watch 23 Pencil 24 No if's, and's, or buts 25 Takes paper in right hand Interpretation of Score 26 Folds paper in half Normal 27 Puts paper on floor Mild Impairment or 28 Closes eyes pseudodementia 29 Writes sentence Moderate Impairment 30 Draws pentagons 0-11 Severe Impairment Score Interviewer MMSE.xls 7-00

13 Close Your Eyes MMSE.xls 7-00