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Michael J. Koron ows i, Pharm.D.

Spring 1998 Introduction to Aging: Alzheimer's Disease & the Dementias: Presentation, Differentiation and Management I. Definitions II. Dementia - Scope and Prevalence III. Cortical vs. Subcortical Dementia IV. Diagnosis V. Representative Syndromes VI. Management of the Agitated Patient VII. Case Study Assigned Readings: 1. Handout materials. 2. Eggert A, Crismon ML, Ereshefs y L. "Alzheimer s Disease" in Pharmacothera py: A pathophysiologic approach, 3rd edition. eds. Depiro JT, Talbert RL, Yee GC , et al. New Yor , Elsevier, 1997, pp.1325-44. Learning Objectives: 1. Differentiate between dementia, depression, and delirium. 2. Differentiate between the pathophysiology and clinical presentation of A lzheimer's disease and multi-infarct dementia. 3. Describe the neurotransmitter changes associated with Alzheimer's diseas e and relate how pharmacologic therapies may affect them. 4. Describe a treatment plan (nonpharmacologic and pharmacologic) for a dem ented patient based upon the symptoms of concern, the persons other medical prob lems, and concurrent drug therapy. 5. Be able to initiate, titrate and manage cholinergic therapies in the tre atment of Alzheimer s World-Wide Web Resources: 1. Alzheimer s Association Home Page 2. Geriatric Teaching Site (University of Florida) 3. Alzheimer s Page (Washington University) 4. Alzheimer s Web I. DEFINITIONS Dementia - "intellectual deterioration, severe enough to impeded social or occup ational performance, secondary to brain dysfunction. ... memory defect with decr eased cognition, poor judgment, deterioration of personality, abnormal affect, a nd disturbances of higher cortical function (aphasia or apraxia)". Van Horn Am J Med 1987;83:101-10. Delirium (Acute confusional state) - an organic mental syndrome with an acute on set featuring global cognitive impairment, disturbances of attention, reduced le vel of consciousness, increased or reduced psychomotor activity, an disorganized sleep-wa e cycle. Its duration may last hours, days, but rarely exceeds one mon th. The severity of symptoms fluctuate unpredictably. II. Dementia - Scope and Prevalence A. Median prevalence rate for mild to moderate dementia in persons ? 65 is 9%; s evere dementia -5%. B. Type of dementia Percent of Cases Alzheimer's disease 45% Multi-infarct & Alzheimer's 15% Multi-infarct 15% Depression/Pseudodementia 15% Other causes 10% C. Mortality - from 1979-1987 the age-adjusted annual death rate in the U.S. for Alzheimer s disease increased from 0.4/100,000 to 4.2/100,000 persons. Rates incr eased with age. Death rates for presenile and senile dementias also increased du ring this period. The increase in rates may be explained by an increase in the i ncidence and prevalence of Alzheimer's disease and/or the more frequent diagnosi

s of Alzheimer's disease in patients with cognitive impairment. III. Cortical vs. Subcortical Dementia A. Cortical (Alzheimer's, Pic 's disease) 1. Characteristics a. amnesia b. cognitive deficits (calculations, judgment, abstraction) c. unconcerned affect d. language deficits with normal articulation of speech e. normal motor function B. Subcortical (Par inson's, Huntington's, hydrocephalus toxic or metabolic ence phalopathies) 1. Characteristics a. forgetful b. slow cognition c. apathetic or depressed affect d. dysarthric/hypophonic speech e. abnormal motor signs IV. Diagnosis A. DSM-IV Criteria - Dementia of the Alzheimer's Type 1. The development of multiple cognitive deficits manifested by both a. Memory impairment (impaired ability to learn new information or to recal l previously learned new information) b. At least one of the following cognitive disturbances: (1) aphasia (language disturbance) (2) apraxia (impaired ability to carry out motor activities despite intact motor function) (3) agnosia (failure to recognize or identify objects despite intact sensor func tion) (4) disturbance of executive functioning (i.e., planning, organizing, sequencing , abstracting) 2. The cognitive deficits in (la) and (lb) cause significant impairment in occup ational or social functioning and represent a significant decline from a previou s level of functioning. 3. The course is characterized by gradual onset and continuing cognitive decline . 4. The cognitive deficits in (la) and (lb) are not due to any of the following: a. other central nervous system conditions that cause progressive deficits in memory and cognition (e.g., cerebrovascular disease, Par inson's disease, Hun tington's disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor ) b. systemic conditions that are nown to cause dementia (e.g., hypothyroidi sm, vitamin B12 or folic acid deficiency, niacin deficiency, hypercalcemia, neur osyphilis, HIV infection) c. substance-induced conditions 5. The deficits do not occur exclusively during the course of delirium. 6. The disturbance is not better accounted for by another Axis I disorder (e.g., Major Depressive Disorder, Schizophrenia). B. Neuropsychological Testing - diagnosis and differentiation 1. Mental status - orientation 2. General intellectual status 3. Memory - short, intermediate, and long-term 4. Abstract reasoning - problem solving, fables 5. Visual-spatial and visual-constructional abilities (i.e. draw interloc ing pe ntagrams) 6. Language screen for aphasia 7. Academic s ills - math and reading 8. Sensory and perceptual functioning 9. Motor functioning - strength, speed, dexterity 10. Social-emotional or behavioral status C. Laboratory Evaluation

1. Neuroimaging (CAT, MRI, PET, SPECT) - atrophy, hydrocephalus, structural lesi ons 2. Thyroid studies (including TSH), fasting plasma glucose, serum and urine drug screens, serologic test for syphilis 3. B12 , Folate 4. EEG 5. Lumbar puncture (+/-) 6. Erythrocyte sedimentation rate 7. HIV (AIDS Screen) (+/-) V. Representative Syndromes A. Alzheimer's Disease 1. Prevalence a. 4 million in U.S.; may affect 10-47% of person ? 85 b. accounts for 50% of nursing home admissions 2. Pathology - effects the neocortex, limbic system, and basal forebrain which a re involved in recent memory, emotional stability and control of attention. [See assigned reading for detailed discussion]. a. cerebral atrophy b. neuronal loss c. senile (neuritic) plaques - clusters of degenerating nerve terminals sur rounded by a amyloid core. d. neurofibrillary tangles - cytoplasmic accumulation of axonal transport p roteins (paired helical filaments) e. Beta amyloid 3. Neurotransmitter changes [see text Table 58.1, pg 975] a. Cholinergic system - 40 to 90% decrease in choline acetyltransferase in the cerebral cortex and hippocampus. Decrease in Ml and M2 receptor densities. 1. strong association with memory impairment 2. similar memory impairment can be induced with anticholinergic drugs. b. Norepinephrine - variable, some reports of increased levels in CSF c. Serotonin - variable, but reduced upta e and loss of receptors reported d. Somatostatin - decreased e. Others 4. Diagnosis - see DSM-IV criteria 5. Etiology and Ris Factors a. Age b. Head trauma c. Thyroid disease d. Down's Syndrome e. Familial (genetic) Chromosome 21 - location of amyloid precursor protein gene. Associated with earl y-onset AD between the ages of 48-58 years. Also lin ed with dementia in Down's syndrome. Chromosome 14 very early-onset AD (30's an 40's) Chromosome 19 Apolipoprotein E gene. The number of copies of ApoE4 an individual has can be a mar er for their ris of late onset Alzheimer's disease. See table below. # of copies of ApoE4 Percent with Alz. disease * Mean age of onset (yrs .) 0 20 84 1 45 75 2 90 68 * in late onset families 6. Staging Many staging criteria have been proposed, but perhaps the most reliable and easy to remember is the following: Stage I - Cognitive changes and impairment is subtle, language and visual-spatia l deficits with preservation of personality. Activities in daily living (ADL S) be gin to regress. Anxiety can be a problem. Stage II - Deficits become severe, apathy, depression, restlessness, aphasia, ag

nosia and apraxia. Self-care (ADL s), judgment and personality deteriorate. Psycho pathology becomes more prevalent mar ed by hallucinations, delusions an agitatio n. This stage ends when the person no longer is ambulatory . Stage III - is characterized by inability to fee ones self, chair or bed bound, seizures and myoclonus can occur, and infantile behavior. Language will deterior ate. Infections become a problem. Death is frequently due to infection. 7. Treatment a. Historical Interest (1) Ergoloid mesylates (Hydergine) (a) A mixture of 4 hydrogenated al aloids of ergotoxine (dihydroergocornine, dih ydro- ergocristine, dihydro-alpha-ergocryiptine, and dihydroergo-betaergocryptin e) (b) Mechanism of action i. improved intracellular metabolism ii. cognitive improvement may be from its antidepressant effect (2) Cerebral Vasodilators - these drugs have no role in the management of dement ias (a) Papaverine (c) Nylidrin (b) Cyclandelate (d) Isoxsuprin (3) Agents enhancing cerebral acetylcholine levels These agents have been tried as a response to the cholinergic hypothesis, (i.e. supplement of acetylcholine p recursors or inhibition of acetylcholine metabolism) a. anticholinesterase 1) Physostigmine has been reported to be effective but had to be given i.v. Its duration of action was very short and many side effects were reported (salivatio n, lacrimation, urination and defecation). An oral sustained release preparation is being studied. 2). Tetrahydroaminoacridine(Tacrine, Cognex) NOTE: A detailed discussion of tacrine's history and its clinical trials is in t he assigned chapter. Tacrine was approved by the FDA an became available on October 1, 1993. The foll owing summarizes its pharmacology as well as its dosing and monitoring guideline s. FDA indication: mild to moderate dementia of the Alzheimer's type. Pharmacology: Mechanism of action - a reversible cholinesterase inhibitor, presumable increasi ng the acetylcholine concentration in the cerebral cortex by slowing the degrada tion of acetylcholine. May also augment the actions of other neurotransmitters. Pharmacoa inetics Absorption - Time to pea 1-2 hours; absolute bioavailability -17%, food decreas es the bioavailability by 30- 40%, hence doses should be given 1 hour before mea ls. Distribution - 55% bound to plasma proteins; means volume of distribution =349L Metabolism - metabolized by the cytochrome P450 system; significant first pass m etabolism accounts for the poor bioavailability; smo ers mean steady-state concentrations (Css) are 1/3 of nonsmo ers; the Css in women is -2x that of men. Elimination - t 1/2= 2-3 hours (not dose-related); time to Css 24-36 hours. No d ose adjustment necessary in renal failure. Common Adverse Events: Elevated ALT/AST (? 3x upper limit of normal [ULN]) 29%; headache 11%, nausea +/ or vomiting 28%; diarrhea 16%; other g.i. complaints (dyspepsia, anorexia, abdom inal pain) 8-9%; dizziness 12%; and rhinitis 8~%. WARNINGS: 1) Tacrine is li ely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 2) Use cautiously in patients with sic sinus syndrome because of tacrine's chol inomimetic action may result in bradycardia. Also monitor heart rate in patients ta ing other drugs which may slow heart rate. 3) Monitor patients at increased ris for ulcers (e.g., history of PUD, NSAID us

e) since tacrine may increase gastric acid secretion. Drug Interactions: Anticholinergic drugs: Potential for drugs with anticholinergic activity to nega te the effects of tacrine or visa versa. Cholinomimetics and cholinesterase inhibitors: The cholinergic effects of succin ylcholine and bethanechol may be enhanced. Theophylline: Tacrine will increase theophylline's serum concentration and elimi nation half-life by about 2-fold. Thus, monitoring of theophylline's plasma conc entrations and appropriate dose reductions are recommended. Cimetidine: Cimetidine increased tacrine's Cmax and AUC by 54% and 64%, respecti vely. Dosing: Available as 10, 20, 30, and 40 mg capsules Initiation - 10 mg po qid (40 mg/day) for at least 6 wee s Titration - after a minimum of 6 wee s the dose can be increase to 20 mg po qid (80 mg/day), then if well tolerated and if no significant transaminase elevation s, increase to 30 mg po qid (120 mg/day), then if well tolerated and no signific ant transaminase elevations increase to 40 mg po qid (160 mg/day). Monitoring: Wee ly monitoring of serum transaminases (specifically ALT/GPT) for 18 wee s after initiation of tacrine, afterwards every 3 months is recommended. In addition, wee ly monitoring is recommended for at least another 6 wee s follo wing any dosage increase. Full monitoring (18 wee s) is required for patient who se tacrine dosing as been suspended for more than 4 wee s. Dose Regimen Modification in Response to Transaminase Elevation Transaminase Level Treatment Regimen <3 x ULN continue according to recommended titration >3 to <5 x ULN reduce daily dose by 40 mg/day. Dose titration can be resumed wh en transaminase levels return to within normal limits >5 x ULN Stop treatment. Monitor transaminases until they are within norm al limits. See rechanllenge recommendations Note: Patients with clinical jaundice confirmed by a total bilirubin of >3mg/dL should permanently discontinue tacrine and not be rechallenged. Rechallenge: Patients required to discontinue tacrine because of elevated transa minase levels (>5 xULN) may be rechallenged when transaminase levels have return ed to normal. A rechallenge appears to be safe, (i.e. no serious liver injury, i n patients whose transaminase values where <10 xULN). However, experience with r echallenge is limited in patients whose transaminase values were >10 xULN. Recha llenge dose initiation (40 mg/day for 6 wee s) and titration is the same as outl ined above, as is transaminase monitoring . Patient and Caregiver Information: 1) Must be ta en at regular intervals and between meals for best results. Ta e w ith food only if gi upset is intolerable. 2) Advise about adverse effects that occur temporally to initiation of therapy o r a dosage increase (primarily g.i.) and those with a delayed onset (rash, jaund ice, changes in stool color). Stress importance of liver enzyme monitoring. 3) Contact their physician should new adverse events appear or existing ones wor sen. 4) Do not increase or decrease dose unless under the instructions of the patient 's physician. Donepazil (Aircept) 5mg and 10mg tablets FDA early 1997 Advantages over tacrine include once daily dosing, no liver function monitoring required Limitations: as with tacrine the cholinergic system may not respond favorably (p atient specific) b. acetylcholine precursors Choline and Lecithin - These compounds have been studied alone and in combinatio n with other drugs such as Hydergine and THA. Limited success has been observed. Limitations of cholinergic interventions 1. must have normal neuronal function for acetylcholine (ACh) synthesis and release

2. higher synaptic ACh concentrations secondary to 'lea age" may lower the signal-to-noise ratio. 3. cholinesterase inhibitors may be limited by inadequate ACh levels 4. muscarinic agonists show a narrow therapeutic window because of receptor interactions, (i.e. adverse effects can be a problem) 5. other neurotransmitters or neuropeptides may be contributing to cognitiv e impairment and function. B. Multi-infarct Dementia 1. Syndrome of impaired intellect secondary to multiple stro es whose progressio n has been described as step-wise with some remission following each insult. 2. DSM-IV Diagnostic Criteria a. The development of multiple cognitive deficits by both (1) memory impairment (impaired ability to learn new information or to recall pr eviously learned information) (2) one (or more) of the following cognitive disturbances a. aphasia b. apraxia c. agnosia d. disturbance in executive functioning b. The cognitive deficits in a(l) and a(2) each cause significant impairment in social or occupational functioning and represent a significant decline from a pr evious level c. Focal neurological signs and symptoms or laboratory evidence indicative of ce rebrovascular disease that are judged to be etiologically related to the disturb ance. d. The deficits do not occur exclusively during the course of a delirium. VI. Management of the Agitated Patient A. Control the Environment, Don't Let It Control the Patient 1. Methods depend on the stage of illness 2. Lower stimuli, decrease stress 3. Scheduled rest periods 4. Simple interventions can solve or minimize problems a. wandering and pacing - ma e sure doors are loc ed and places to sit avai lable b. eating in smaller groups or alone may improve inta e, finger foods for a praxic patients c. hallucinations and paranoia - remove stimuli such as television, radio, overhead paging system, and threatening art wor d. visiting hours may need to be limited, avoid heavy traffic periods such as the change of shift e. toileting - regular times and intervals B. Antipsychotics Drug Sedation Orthostatic Hypotension Cholinergic Bloc ade EPS Dose Thorazine strong strong 2 3 Thioridazine moderate moderate 1 4 25mg Fluphenazine wea wea 3 2 Haloperidol wea wea 4 1 0.5 Scale 1=greatest, 4=wea est 1. Only 39% of patients studied showed significant improvement, 20% showed minim al improvement and 10 worsen when given an antipsychotic. 2. Behavioral outbursts tend to be episodic 3. Symptoms most responsive a. suspiciousness b. hallucinations c. sleeplessness d. agitated behavior 4. Little if any response - pacing, calling out, memory unsociable, poor self-ca re There are very few comparison studies between antipsychotics in demented patient

s. The studies that have been done often have included any patient with a dement ia (multi-infarct, Alzheimer's, etc.). Therefore, a drug of choice does not exis t, but drug selection should be based upon anticipated adverse effects and accep ted ris s. C. Benzodiazepines - few studies comparing them to the antipsychotics. 1. See more sedation with the benzodiazepines, greater memory impairment, and mo re ataxia. 2. Role may be in the early stages when anxiety an sleep /disturbances are commo n 3. Avoid long-acting agents such a diazepam, flurazepam, chlordiazepoxide and ot hers with active metabolites. 4. Paradoxical reactions can be a problem and may signify pathology in the limbi c system. D. Propranolol and Pindolol - some case reports suggest the may be useful for ag gressive/combative behavior an sexual aggressiveness not responsive to antipsych otics. 1. Dose varies - 20 - 400mg per day of propranolol 2. Results may not be immediate, up to several wee s until maximum effect E. Carbamazepine - case reports and one clinical trial have shown carbamazepine to be effective in controlling aggressive and agitated behavior in patients who have failed or not tolerated antipsychotics and/or benzodiazepines. 1. Dose varies - 400 - 1200 mg/day. Usually a serum concentration between 6 - 10 mcg/ml is attempted. However, there are no controlled trials to demonstrate this as the therapeutic range. 2. A decrease in the number or intensity of behaviors is usually seen in 1 wee , with maximum effect in 2 - 4 wee s. F. Trazodone is another alternative. Doses of 50mg - 100mg are most common. Seda tion is a frequent adverse effect. G. Gonadal hormones - For refractory cases. 1. Conjugated estrogens - 0.625mg - 1.25mg/day or transdermal 2. Diethystilbesterol - 1-2 mg/day 3. Medroxyprogesterone 4. Safety and tolerance REFERENCES 1. Wil ins RH, Brody IA. Alzheimer's Disease. Arch Neuro 969,21:109-110. 2. Katzman R. Alzheimer's Disease. New Eng J Med 1986;314:964-73. 3. Helms PM. Efficacy of antipsychotics in the treatment of the behavior co mplications of dementia: A review of the literature. J Am Geriatric Soc 1985;33: 206-209. 4. Yesavage JA, Hollister LE, Burian E. Dihydroergotoxine: 6m versus 3mg Do sage in the treatment of Senile Dementia. Preliminary Report. J Am Geriatric Soc 1979;27:80-82. 5. Hughes JR, Williams JG, Currier RD. An Ergot Al aloid Preparation (Hyder gine) in the Treatment of Dementia: Critical Review of the Clinical Literature. J Am Geriatric Soc 1976,24:490-497. 6. Reisberg B. Dementia: A systematic approach to identifying uses. Geriatr ics 1986;41:30-46. 7. Risse SC, Barnes R. Pharmacologic Treatment of Agitation With Dementia. J Am Geriatric Soc 1986;34:368~-76. 8. Butler FR, Burgio LD, Engel BT. Neuroleptics and Behavior A comparative study. J Gerontological Nursing 13:15-9. 9. Steele C, Lucas MJ, Tune L. Haloperidol vs. Thioridazine in the Treatmen t of Behavioral Symptoms in Senile Dementia of the Alzheimer's Type: Preliminary findings. J Clin Psychiat 1986,47:310-312. 10. Summers WK, Majovs i LV, Marsh GM, et al. Oral Tetrahydroaminoacridine i n Long-term Treatment of Senile Dementia, Alzheimer's type. New Eng J Med 1986;3 15:1241-5. 11. Katzman R, Jac son JE. Alzheimer Disease: Basic and clinical advances. J Am Geriatric Soc 1991;39:516-25. 12. Davis KL, Thal LJ, El an ER, et al. A Double-blind, Placebo controlled M

ulticenter Study of Tacrine for Alzheimer's Disease. N Eng1 J Med 1992;327:12539. 13. Farlow M, Gracon SI, Hershey LA, et al. A Controlled Trial of Tacrine in Alzheimer's Disease. JAMA 1992;268:2523-29. 14. Knapp J, Knopman DS, Solomon PR, et al. A 30-Wee Randomized Controlled Trial of High-Dose Tacrine in Patients with Alzheimer's Disease. JAMA 1994;271:9 85-991. CASE STUDY Mrs. U.P. All night accompanies her husband to the Geriatric Assessment Clinic. Mr. All night is 70 year old blac male who was diagnosed as having probable Alz heimer's Disease 5 years ago. He is otherwise healthy and is not ta ing any medi cations. Mrs. All night states that for the past several months Mr. All night's behavior has changed in that he is more confused, often becoming agitated, tal s to people who are not there and this often upset him, his ability to care for h imself has decreased, and he is sleeping less. For example, he is eating less, h as become resistant to dressing and undressing at appropriate times during the d ay and routinely wa es up around 1 a.m. and wanders around the house. What stage of the illness is Mr. All night experiencing? What symptoms or behavior support our conclusion? Mrs. All night would li e to now if there is a medication that would help contr ol his behavior and ma e him sleep at night. For the past month she has been ta ing Valium to help her sleep and calm her nerves. How do you respond to Mrs. All night? What interventions can you suggest? (For drugs be specific as to agent, dose, fr equency and time of dosing) What adverse effects are you trying to ta e advantage of in your selection? Which adverse effects are you trying to avoid? Which symptoms should respond to drug therapy? What does the fact that Mrs. All night is ta ing Valium suggest to you? Several months later Mr. All night is admitted to the hospital for a sudden chan ge in mental status. He is extremely confused an agitated, he is stri ing out at the nurses and does not recognize his wife. On physical exam he is stiff and co gwheeling is present. Vitals - BP: laying down 144/86, pulse 80; standing 110/66 , pulse 88; respiration s and temperature are normal. You learn that after his las t visit to the clinic Mrs. All night had ta en him to se a psychiatrist who had prescribed the following: Thioridazine 50mg every morning and 100mg at bedtime Alprazolam 0.25mg as needed for anxiety In addition, Mrs. All night had been giving him diphenhydramine 50mg every night to help him sleep. The intern orders haloperidol 2mg po every 12 hours and 5mg IM prn for agitation and reasons that Mr. All night's dementia has advanced. What else could explain Mr. All night's current state? What evidence in the history and physical exam does not support the intern's dia gnosis? What do you suggest be done for Mr. All night? KEY TO CASE Mr. All night is most li ely in Stage II since he has developed increased psycho pathology (hallucinations), more combative, and unable to care for and feed hims elf. I would inform Mrs. All night that her husbands illness is advancing. She should never give her husband a medication without as ing his physician. She needs to try simple interventions such as finger foods, fewer distractions during meal ti me (ta e the phone off the hoo , turn off the television). Dressing an undressin g have become a difficult time and the type of clothes Mr. tired wears may need to be adapted so they are easier for him (an her) to put on and off (velcro inst ead of buttons). When to start pharmacologic treatment in such a patient is always a difficult de cision. Because he is tal ing to people who are not there and this upsets him, a low dose of an antipsychotic may be indicated. His sleep and agitation may impr

ove if the hallucinations are eliminated or diminished. It should be ta en eithe r after dinner or at bedtime. The choice of agent is up to you. I would not use a benzodiazepine since it would not treat his hallucinations and may cause a par adoxical reaction. The fact that the wife needs something for her nerves and sleep is also an indic ator of the advancement of his illness. This serves to point out that you have t wo patients. Therefore, treating his sleep and behavior may allow his caregiver to get the proper physical and mental rest she requires. You should not agree with the intern diagnosis. Rather, it would appear that Mr. All night is experiencing drug-induced delirium from the thioridazine, alprazol am and diphenhydramine. He also has drug-induced Par inson's disease. Evidence i ncludes orthostatic hypotension, sudden change in mental status (remember Alzhei mer's disease is a progressive illness), cogwheeling and rigidity. Supportive measures are in order. Hydration and nutrition, calm, quiet environme nt and withdrawal of all offending agent should be provided. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Jan 6, 1998