Michael J. Koronkowski, Pharm.D.
Spring 1998

Introduction to Aging: Alzheimer's Disease & the Dementias:
Presentation, Differentiation and Management

  1. Definitions
  2. Dementia - Scope and Prevalence
  3. Cortical vs. Subcortical Dementia
  4. Diagnosis
  5. Representative Syndromes
  6. Management of the Agitated Patient
  7. Case Study

Assigned Readings:

  1. Handout materials.
  2. Eggert A, Crismon ML, Ereshefsky L. "Alzheimer’s Disease" in Pharmacotherapy: A pathophysiologic approach, 3rd edition. eds. Depiro JT, Talbert RL, Yee GC, et al. New York, Elsevier, 1997, pp.1325-44.

Learning Objectives:

  1. Differentiate between dementia, depression, and delirium.
  2. Differentiate between the pathophysiology and clinical presentation of Alzheimer's disease and multi-infarct dementia.
  3. Describe the neurotransmitter changes associated with Alzheimer's disease and relate how pharmacologic therapies may affect them.
  4. Describe a treatment plan (nonpharmacologic and pharmacologic) for a demented patient based upon the symptoms of concern, the persons other medical problems, and concurrent drug therapy.
  5. Be able to initiate, titrate and manage cholinergic therapies in the treatment 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 occupational performance, secondary to brain dysfunction. ... memory defect with decreased cognition, poor judgment, deterioration of personality, abnormal affect, and 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 onset featuring global cognitive impairment, disturbances of attention, reduced level of consciousness, increased or reduced psychomotor activity, an disorganized sleep-wake cycle. Its duration may last hours, days, but rarely exceeds one month. The severity of symptoms fluctuate unpredictably.

II. Dementia - Scope and Prevalence

A. Median prevalence rate for mild to moderate dementia in persons ³ 65 is 9%; severe 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 increased with age. Death rates for presenile and senile dementias also increased during this period. The increase in rates may be explained by an increase in the incidence and prevalence of Alzheimer's disease and/or the more frequent diagnosis of Alzheimer's disease in patients with cognitive impairment.

III. Cortical vs. Subcortical Dementia

A. Cortical (Alzheimer's, Pick's disease)

1. Characteristics

  1. amnesia
  2. cognitive deficits (calculations, judgment, abstraction)
  3. unconcerned affect
  4. language deficits with normal articulation of speech
  5. normal motor function

B. Subcortical (Parkinson's, Huntington's, hydrocephalus toxic or metabolic encephalopathies)

1. Characteristics

  1. forgetful
  2. slow cognition
  3. apathetic or depressed affect
  4. dysarthric/hypophonic speech
  5. 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

  1. Memory impairment (impaired ability to learn new information or to recall previously learned new information)
  2. 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 function)

(4) disturbance of executive functioning (i.e., planning, organizing, sequencing, abstracting)

2. The cognitive deficits in (la) and (lb) cause significant impairment in occupational or social functioning and represent a significant decline from a previous 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:

  1. other central nervous system conditions that cause progressive deficits in memory and cognition (e.g., cerebrovascular disease, Parkinson's disease, Huntington's disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor)
  2. systemic conditions that are known to cause dementia (e.g., hypothyroidism, vitamin B12 or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection)
  3. 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 interlocking pentagrams)

6. Language screen for aphasia

7. Academic skills - 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 lesions

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

  1. 4 million in U.S.; may affect 10-47% of person ³ 85
  2. accounts for 50% of nursing home admissions

2. Pathology - effects the neocortex, limbic system, and basal forebrain which are involved in recent memory, emotional stability and control of attention. [See assigned reading for detailed discussion].

  1. cerebral atrophy
  2. neuronal loss
  3. senile (neuritic) plaques - clusters of degenerating nerve terminals surrounded by a amyloid core.
  4. neurofibrillary tangles - cytoplasmic accumulation of axonal transport proteins (paired helical filaments)
  5. Beta amyloid

3. Neurotransmitter changes [see text Table 58.1, pg 975]

  1. 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.
  1. Norepinephrine - variable, some reports of increased levels in CSF
  2. Serotonin - variable, but reduced uptake and loss of receptors reported
  3. Somatostatin - decreased
  4. Others

4. Diagnosis - see DSM-IV criteria

5. Etiology and Risk Factors

  1. Age
  2. Head trauma
  3. Thyroid disease
  4. Down's Syndrome
  5. Familial (genetic)

Chromosome 21 - location of amyloid precursor protein gene. Associated with early-onset AD between the ages of 48-58 years. Also linked 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 marker for their risk 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-spatial deficits with preservation of personality. Activities in daily living (ADL’S) begin to regress. Anxiety can be a problem.

Stage II - Deficits become severe, apathy, depression, restlessness, aphasia, agnosia and apraxia. Self-care (ADL’s), judgment and personality deteriorate. Psychopathology becomes more prevalent marked by hallucinations, delusions an agitation. 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 deteriorate. Infections become a problem. Death is frequently due to infection.

7. Treatment

  1. Historical Interest

(1) Ergoloid mesylates (Hydergine)

(a) A mixture of 4 hydrogenated alkaloids of ergotoxine (dihydroergocornine, dihydro- ergocristine, dihydro-alpha-ergocryiptine, and dihydroergo-betaergocryptine)

(b) Mechanism of action

  1. improved intracellular metabolism
  2. cognitive improvement may be from its antidepressant effect

(2) Cerebral Vasodilators - these drugs have no role in the management of dementias

(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 precursors 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 (salivation, 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 the assigned chapter.

Tacrine was approved by the FDA an became available on October 1, 1993. The following summarizes its pharmacology as well as its dosing and monitoring guidelines.

FDA indication: mild to moderate dementia of the Alzheimer's type.

Pharmacology:

Mechanism of action - a reversible cholinesterase inhibitor, presumable increasing the acetylcholine concentration in the cerebral cortex by slowing the degradation of acetylcholine. May also augment the actions of other neurotransmitters.

Pharmacoakinetics

Absorption - Time to peak 1-2 hours; absolute bioavailability -17%, food decreases the bioavailability by 30- 40%, hence doses should be given 1 hour before meals.

Distribution - 55% bound to plasma proteins; means volume of distribution =349L

Metabolism - metabolized by the cytochrome P450 system; significant first pass metabolism accounts for the

poor bioavailability; smokers mean steady-state concentrations (Css) are 1/3 of nonsmokers; 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 dose adjustment necessary in renal failure.

Common Adverse Events:

Elevated ALT/AST (³ 3x upper limit of normal [ULN]) 29%; headache 11%, nausea +/or vomiting 28%; diarrhea 16%; other g.i. complaints (dyspepsia, anorexia, abdominal pain) 8-9%; dizziness 12%; and rhinitis 8~%.

WARNINGS:

1) Tacrine is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

2) Use cautiously in patients with sick sinus syndrome because of tacrine's cholinomimetic action may result in bradycardia. Also monitor heart rate in patients taking other drugs which may slow heart rate.

3) Monitor patients at increased risk for ulcers (e.g., history of PUD, NSAID use) since tacrine may increase gastric acid secretion.

Drug Interactions:

Anticholinergic drugs: Potential for drugs with anticholinergic activity to negate the effects of tacrine or visa versa.

Cholinomimetics and cholinesterase inhibitors: The cholinergic effects of succinylcholine and bethanechol may be enhanced.

Theophylline: Tacrine will increase theophylline's serum concentration and elimination half-life by about 2-fold. Thus, monitoring of theophylline's plasma concentrations and appropriate dose reductions are recommended.

Cimetidine: Cimetidine increased tacrine's Cmax and AUC by 54% and 64%, respectively.

Dosing: Available as 10, 20, 30, and 40 mg capsules

Initiation - 10 mg po qid (40 mg/day) for at least 6 weeks

Titration - after a minimum of 6 weeks the dose can be increase to 20 mg po qid (80 mg/day), then if well tolerated and if no significant transaminase elevations, increase to 30 mg po qid (120 mg/day), then if well tolerated and no significant transaminase elevations increase to 40 mg po qid (160 mg/day).

Monitoring: Weekly monitoring of serum transaminases (specifically ALT/GPT) for 18 weeks after initiation of tacrine, afterwards every 3 months is recommended. In addition, weekly monitoring is recommended for at least another 6 weeks following any dosage increase. Full monitoring (18 weeks) is required for patient whose tacrine dosing as been suspended for more than 4 weeks.

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 when transaminase levels return to within normal limits
>5 x ULN Stop treatment. Monitor transaminases until they are within normal 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 transaminase levels (>5 xULN) may be rechallenged when transaminase levels have returned to normal. A rechallenge appears to be safe, (i.e. no serious liver injury, in patients whose transaminase values where <10 xULN). However, experience with rechallenge is limited in patients whose transaminase values were >10 xULN. Rechallenge dose initiation (40 mg/day for 6 weeks) and titration is the same as outlined above, as is transaminase monitoring .

Patient and Caregiver Information:

1) Must be taken at regular intervals and between meals for best results. Take with food only if gi upset is intolerable.

2) Advise about adverse effects that occur temporally to initiation of therapy or a dosage increase (primarily g.i.) and those with a delayed onset (rash, jaundice, changes in stool color). Stress importance of liver enzyme monitoring.

3) Contact their physician should new adverse events appear or existing ones worsen.

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 (patient specific)

b. acetylcholine precursors

Choline and Lecithin - These compounds have been studied alone and in combination 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 'leakage" 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 cognitive impairment and function.

B. Multi-infarct Dementia

1. Syndrome of impaired intellect secondary to multiple strokes whose progression 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 previously learned information)

(2) one (or more) of the following cognitive disturbances

  1. aphasia
  2. apraxia
  3. agnosia
  4. 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 previous level

c. Focal neurological signs and symptoms or laboratory evidence indicative of cerebrovascular disease that are judged to be etiologically related to the disturbance.

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

  1. wandering and pacing - make sure doors are locked and places to sit available
  2. eating in smaller groups or alone may improve intake, finger foods for apraxic patients
  3. hallucinations and paranoia - remove stimuli such as television, radio, overhead paging system, and threatening art work
  4. visiting hours may need to be limited, avoid heavy traffic periods such as the change of shift
  5. toileting - regular times and intervals

B. Antipsychotics

Drug Sedation Orthostatic Hypotension Cholinergic Blockade EPS Dose
Thorazine strong strong 2 3  
Thioridazine moderate moderate 1 4 25mg
Fluphenazine weak weak 3 2  
Haloperidol weak weak 4 1 0.5

Scale 1=greatest, 4=weakest

1. Only 39% of patients studied showed significant improvement, 20% showed minimal improvement and 10 worsen when given an antipsychotic.

2. Behavioral outbursts tend to be episodic

3. Symptoms most responsive

  1. suspiciousness
  2. hallucinations
  3. sleeplessness
  4. agitated behavior

4. Little if any response - pacing, calling out, memory unsociable, poor self-care

There are very few comparison studies between antipsychotics in demented patients. The studies that have been done often have included any patient with a dementia (multi-infarct, Alzheimer's, etc.). Therefore, a drug of choice does not exist, but drug selection should be based upon anticipated adverse effects and accepted risks.

C. Benzodiazepines - few studies comparing them to the antipsychotics.

1. See more sedation with the benzodiazepines, greater memory impairment, and more ataxia.

2. Role may be in the early stages when anxiety an sleep /disturbances are common

3. Avoid long-acting agents such a diazepam, flurazepam, chlordiazepoxide and others with active metabolites.

4. Paradoxical reactions can be a problem and may signify pathology in the limbic system.

D. Propranolol and Pindolol - some case reports suggest the may be useful for aggressive/combative behavior an sexual aggressiveness not responsive to antipsychotics.

1. Dose varies - 20 - 400mg per day of propranolol

2. Results may not be immediate, up to several weeks 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 - 10mcg/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 week, with maximum effect in 2 - 4 weeks.

F. Trazodone is another alternative. Doses of 50mg - 100mg are most common. Sedation 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. Wilkins 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 complications 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 Dosage 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 Alkaloid Preparation (Hydergine) 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. Geriatrics 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 Treatment of Behavioral Symptoms in Senile Dementia of the Alzheimer's Type: Preliminary findings. J Clin Psychiat 1986,47:310-312.
  10. Summers WK, Majovski LV, Marsh GM, et al. Oral Tetrahydroaminoacridine in Long-term Treatment of Senile Dementia, Alzheimer's type. New Eng J Med 1986;315:1241-5.
  11. Katzman R, Jackson JE. Alzheimer Disease: Basic and clinical advances. J Am Geriatric Soc 1991;39:516-25.
  12. Davis KL, Thal LJ, Elkan ER, et al. A Double-blind, Placebo controlled Multicenter Study of Tacrine for Alzheimer's Disease. N Eng1 J Med 1992;327:1253-9.
  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-Week Randomized Controlled Trial of High-Dose Tacrine in Patients with Alzheimer's Disease. JAMA 1994;271:985-991.

CASE STUDY

Mrs. U.P. Allknight accompanies her husband to the Geriatric Assessment Clinic. Mr. Allknight is 70 year old black male who was diagnosed as having probable Alzheimer's Disease 5 years ago. He is otherwise healthy and is not taking any medications. Mrs. Allknight states that for the past several months Mr. Allknight's behavior has changed in that he is more confused, often becoming agitated, talks to people who are not there and this often upset him, his ability to care for himself has decreased, and he is sleeping less. For example, he is eating less, has become resistant to dressing and undressing at appropriate times during the day and routinely wakes up around 1 a.m. and wanders around the house.

What stage of the illness is Mr. Allknight experiencing?

What symptoms or behavior support our conclusion?

Mrs. Allknight would like to know if there is a medication that would help control his behavior and make him sleep at night. For the past month she has been taking Valium to help her sleep and calm her nerves.

How do you respond to Mrs. Allknight?

What interventions can you suggest? (For drugs be specific as to agent, dose, frequency and time of dosing)

What adverse effects are you trying to take 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. Allknight is taking Valium suggest to you?

Several months later Mr. Allknight is admitted to the hospital for a sudden change in mental status. He is extremely confused an agitated, he is striking out at the nurses and does not recognize his wife. On physical exam he is stiff and cogwheeling 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 last visit to the clinic Mrs. Allknight had taken 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. Allknight 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. Allknight's dementia has advanced.

What else could explain Mr. Allknight's current state?

What evidence in the history and physical exam does not support the intern's diagnosis?

What do you suggest be done for Mr. Allknight?

KEY TO CASE

Mr. Allknight is most likely in Stage II since he has developed increased psychopathology (hallucinations), more combative, and unable to care for and feed himself.

I would inform Mrs. Allknight that her husbands illness is advancing. She should never give her husband a medication without asking his physician. She needs to try simple interventions such as finger foods, fewer distractions during meal time (take the phone off the hook, turn off the television). Dressing an undressing 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 instead of buttons).

When to start pharmacologic treatment in such a patient is always a difficult decision. Because he is talking to people who are not there and this upsets him, a low dose of an antipsychotic may be indicated. His sleep and agitation may improve if the hallucinations are eliminated or diminished. It should be taken either 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 paradoxical reaction.

The fact that the wife needs something for her nerves and sleep is also an indicator of the advancement of his illness. This serves to point out that you have two 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. Allknight is experiencing drug-induced delirium from the thioridazine, alprazolam and diphenhydramine. He also has drug-induced Parkinson's disease. Evidence includes orthostatic hypotension, sudden change in mental status (remember Alzheimer's disease is a progressive illness), cogwheeling and rigidity.

Supportive measures are in order. Hydration and nutrition, calm, quiet environment and withdrawal of all offending agent should be provided.

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