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Highlights From the Annual Scientific Assembly: Managing the Stages of Alzheimer's Disease--new management options. (Special Feature).

Highlights From the Annual Scientific Assembly: Managing the Stages of Alzheimer's Disease--new management options (*)

Alzheimer's disease is the most common form of dementia, affecting 1 in 10 people aged 65 years and older. Loss of memory is the most common presenting symptom. Other common symptoms include: loss of interest in life, personality changes, and sometimes anti-social and uninhibited behavior. The progressive nature of Alzheimer's disease leads to feelings of denial, confusion, fear and guilt until cognitive loss is sufficient to leave the patient unaware of his/her condition. A number of medications are now available to improve or at least arrest or slow down the rate of deterioration. These medications are most effective if started early in the disease process.

This symposium was developed to help clinicians suspect, diagnose and manage Alzheimer's disease with confidence.


Ronald C. Hamdy, MD, FRCP, FACP, ACOS/EC&G, VAMC, and Professor of Medicine, Cecile Cox Quillen Chair of Geriatric Medicine & Gerontology, East Tennessee State University, Johnson City, Tenn

The diagnosis of Alzheimer's disease has changed from a process of exclusion to one of inclusion. Characteristic features of Alzheimer's disease include a global memory impairment (ie, affecting trivial as well as important topics) interfering with the patient's daily activities. There is also evidence of cognitive deficit as manifested by anomia (inability to name objects), agnosia (inability to recognize objects), and apraxia (inability to carry out voluntary activities even though there is no muscle weakness). In addition, judgment is impaired. The onset is insidious.

Alzheimer's disease may coexist with other dementias. The characteristic features of some common types are shown in the accompanying tables. A number of other medical conditions also may further impair the patient's mental functions.

Various classifications are available to stage Alzheimer's disease. A commonly accepted one is to classify patients in three stages: mild, moderate and severe. Patients with mild Alzheimer's disease may appear to be "quite normal" to a person who has not known them. In that stage it is important to protect patients from predators in society who may take advantage of the patient's impaired judgment. It is also during that stage that various legal actions should be taken to protect the patient's and family's assets and to ensure that the patient's wishes as far as advanced directives are clear.

In the second or moderate stage, the mental impairment is quite obvious even to the unsuspecting observer. In this stage it is important to protect patients from themselves as in that stage patients will take risks such as going out inappropriately dressed, may get lost, or may cause a road accident to happen. Patients in that stage are a hazard to themselves and to the community; they may, for instance, forget that they have switched the stove on and may trigger a fire.

In the third or severe stage, patients have evidence of physical impairment, become less mobile, may have repeated falls, and need nursing attention to meet their physical deficits in addition to their mental deficits. They often become incontinent. As the disease progresses they become less mobile, more chair-bound or bedridden, adopt the fetal position, and are more prone to developing pressure ulcers. Common causes of death include septicemia and pneumonia.

In order to develop a management strategy that best fits the needs of individual patients, it is necessary to identify other factors that may worsen the patient's cognitive functions, identify the predominant problem (such as acute confusional states, irritability, aggression, urinary incontinence, etc), and evaluate the patient's social network to provide the necessary support and to refer the patient and family to appropriate organizations.

The availability of specific medications such as the acetyl choline esterase inhibitors mandates that patients with Alzheimer's disease be diagnosed as early as possible during the disease because most of these medications work best when started early in the disease process. Symptoms suggestive of dementia include an impaired ability to learn and retain new information and to handle complex tasks. Reasoning is impaired. Behavioral changes, especially depression, mood lability and irritability, and language difficulties, should also alert the astute clinician that the patient may have an early dementia.


Daniel I. Kaufer, MD, Director of the Dementia Treatment Program, Associate Director, Clinical Core Alzheimer's Disease Research Center, Assistant Professor of Neurology and Psychiatry, University of Pittsburgh Medical Center, Pennsylvania

Over 4 million cases of Alzheimer's disease (AD) exist today, and it is estimated that. its prevalence will exceed 14 million by the year 2050. These facts make a comprehensive understanding of management strategies for patients with AD essential. Perhaps most importantly, it is estimated that only about half of all individuals with AD are actually diagnosed, and less than half of those who are diagnosed receive drug therapy. Although the drugs currently available cannot cure AD, they may stabilize or in some cases improve symptoms over the short term, and slow the progression of symptoms over one to several years.

AD is characterized by loss of the brain neurotransmitter, acetylcholine; thus, currently available drugs for treating AD act by increasing brain levels of acetylcholine via blockade of the enzyme that normally breaks it down. This class of drugs, the cholinesterase inhibitors, first became available in 1993 with tacrine. Tacrine, which has a high incidence of gastrointestinal side effects and hepatotoxicity, is of little more than historical interest and has been replaced by newer agents, donepezil and rivastigmine. Donepezil appears to be effective and is better tolerated than tacrine, with the majority of adverse events being cholinergic in nature. Similar to donepezil, rivastigmine is also effective in slowing the progression of AD and primarily causes gastrointestinal side effects such as vomiting and weight loss, particularly at higher doses.

Galantamine is a new, second-generation cholinesterase inhibitor that has also been shown to provide benefits to patients with AD in clinical studies. These studies have demonstrated that galantamine is generally safe and well tolerated, with gastrointestinal upset being the most common adverse event reported. In addition to documented clinical benefits of galantamine treatment in AD patients, both subjective caregiver distress in relation to behavioral disturbances and time spent by caregivers either supervising or assisting patients with activities of daily living were reduced for patients receiving galantamine compared to placebo-treated patients.

Galantamine is unique among cholinesterase inhibitors in that it also may enhance the release of acetylcholine and other neurotransmitters through allosteric modulation of nicotinic cholinergic receptors. The potential clinical benefits provided by this additional mode of action, including both enhanced cholinergic function and disease-modifying effects, are currently being investigated. In addition, a number of new therapies and therapeutic approaches are being studied, including ginkgo biloba, memantine, antiinflammatory agents, and vaccines. Promising results emphasize the need for and benefits of pharmacotherapy in patients with AD.


William E. Reichman, MD, Dean and Associate Professor of Psychiatry, University of Medicine and Dentistry of New Jersey, Newark, New Jersey

Disturbed behavior is common during Alzheimer's disease (AD) progression, with symptoms that may include delusions, hallucinations, and agitation. Behavioral changes can greatly increase caregiver distress and often are primary reasons for institutionalization. Thus, treatment that delays or decreases these symptoms may ease caregiver burden and postpone institutionalization of the patient.

Before initiating treatment, the physician must rule out any potential contributing factors, such as medical disorders, physical discomfort, medication effects, and preexisting psychiatric illness. Target behaviors must then be identified in order to initiate appropriate treatment (pharmacologic and/or environmental) that is aimed at those behaviors. Pharmacologic treatment usually includes the use of either a conventional (typical) or atypical antipsychotic. Conventional antipsychotics (eg, haloperidol, thioridazine, chlorpromazine), introduced in the 1950s and 1960s, act by blocking dopamine receptors. This group is rarely used as first-line agents since the development of the atypical antipsychotics in the 1990s, which have a more positive side-effect profile. The atypical antipsychotics block dopamine and serotonin receptors and include drugs such as clozapine, risperidone, olanzapine, and quetiapine.

Clozapine is an efficacious atypical agent, but its adverse events prevent it from being used as a first-line agent. Conversely, risperidone is the most prescribed atypical agent in the elderly, demonstrating significant improvement in symptoms of psychosis and aggressive behavior versus placebo. It also has a more favorable side-effect profile compared with conventional antipsychotics. Olanzapine has also displayed clinical efficacy, more specifically by improving agitation, delusions, and hallucinations, in patients with dementia. Quetiapine and ziprasidone are more recent additions to the atypical antipsychotics; thus, there are currently no published, controlled studies evaluating their safety and efficacy in AD.

Treatment of behavioral and psychological symptoms associated with AD can be a challenging task, because multiple contributing factors are often involved. It is important to consider drug and nondrug interventions that will provide the most effective and tolerable relief of patient symptoms and decrease caregiver burden.

(*.) Presented as a Symposium at the 95th Annual Meeting of the Southern Medical Association, November 8-10, 2001, Nashville, Tenn.

Southern Medical Association acknowledges Janssen Pharmaceutica for an unrestricted educational grant in support of this session, and appreciates their commitment to medical excellence.
Treatment of Alzheimer's Disease

Patients (millions)

Prevalence 4,523,100
Diagnosed 2,261,600
Treated (*) 904,600
Treated With AChEls 543,800

(*)Any drug treatment, not limited to acetylcholinesterase inhibitors.

Source: Decision Resources, March 2000

Note: Table made from bar graph
Feature Comparison: Cholinergic Agents

Drug MoA Binding Escalation Dosing

Galantamine AChEI Competitive, reversible 4-week steps BID
 nAChR Allosteric modulation
Donepezil AChEI Noncompetitive, 4-6-week steps QD
Rivastigmine AChEI Noncompetitive, 2-week steps BID
Prevalence of Symptoms of Psychosis and Agitation in Dementia

Neuropsychiatric Dementia No Dementia
Inventory Item (n = 329) (n = 673)

Apathy 27.4 3.1
Depression 23.7 7.0
Agitation/aggression 23.7 2.8
Irritability 20.4 4.5
Delusions 18.5 2.4
Anxiety 17.0 5.6
Aberrant motor behavior 14.3 0.4
Hallucinations 13.7 0.6
Disinhibition 9.1 0.9
Elation 0.9 0.3

Adapted from Lyketsos CG, et al. Am J Psychiatry 2000; 157:708-714.
Summary of Controlled Trials in Dementia: Atypical Antipsychotics

Antipsychotic Study N Duration Results

Risperidone Katz et al 625 12 wks Improved symptoms
 De Deyn et al 344 13 wks Improved symptoms
Olanzapine Satterlee et al 238 8 wks No difference
 Street et al 206 6 wks Improved symptoms
Quetiapine None
Ziprasidone None

Katz IR, et al. J Clin Psychiatry 1999; 60:107-115.

De Deyn PP, et al. Neurology 1999; 53:946-955.

Satterlee WG, et al. Psychopharmacol Bull 1995; 31:534.

Street J, et al. Arch Gen Psychiatry 2000; 57:968-976.

RELATED ARTICLE: Laboratory Investigations


* Chem-29

* Thyroid stimulating hormone

* Serum [B.sub.12] and ? Folic Acid

* Serologic tests for syphilis

* Electrocardiogram?

* Brain imaging

* Others as indicated

Vascular Dementias

* Onset: Abrupt

* Progress: Stepwise

* History: TIA, strokes

* Clinical examination:

* Evidence of atherosclerosis

* Neurologic deficits

Parkinson's Disease and Dementia

* About 25% of patients with Parkinson's disease

* Impaired executive functions

* Psychomotor retardation, depression

* Hallucinations, delusions

* Speech disturbances

* Low educational or socioeconomic status

* Dopamine precursors may trigger confusional states or delirium

* Neuroleptics may worsen condition

Dementia With Lewy Bodies

* Fluctuating course, rapidly progressive

* Hallucinations are detailed and prominent

* Psychosis, delusional or paranoid ideation

* Mild extrapyramidal signs

* Cortical deficits: 4 As (amnesia, anomia, agnosia, apraxia)

* Subcortical deficits:.attention, verbal fluency

* Neuroleptics may aggravate symptoms

HIV Dementia

* Rapidly progressive course

* Depression and anxiety: common

* Motor dysfunction: tremors, ataxia, repeated falls

* Behavioral abnormalities: apathy, withdrawal

* Younger age

* Risk factors


* Rigid gait

* Urinary incontinence

* Dementia

Pick's Disease

* Disinhibition

* Personality changes

* Emotional lability

* Speech impairment

* ? Hyperorality

Donepezil Summary

* Donepezil (5 and 10 mg) improves cognition and global function in patients with mild to moderate AD

* Long-term efficacy is maintained for up to 52 weeks

* ADL may be partially maintained by donepezil

* Donepezil is generally safe and well tolerated

Rivastigmine Summary

* Rivastigmine (6-12 mg) improves cognition and global function in patients with mild to moderate AD

* Positive effects on ADL have been observed in some studies

* Rivastigmine is generally safe and well tolerated, although cholinergic side effects occur at high doses

Galantamine Summary

* Efficacy

Maintains cognitive function at or above baseline for 12 months

Maintains ADL, delays emergence of behavioral symptoms, saves caregiver time

* Dosing regimen:

4 mg BID for at least 4 weeks

8 mg BID maintenance dose

* Generally safe and well tolerated

Current Treatment Summary

* Cholinergic agents initially improve and transiently maintain cognitive and functional abilities in patients with mild to moderate AD

* Abilities worsen over time, indicating treatment does not stop (but may delay) progression of AD

* Treatments such as donepezil and galantamine maintain cognitive ability for at least 12 months and slow the progression of AD

Selegiline and Vitamin E: Results

* Each agent delayed progression to moderate to severe dementia, loss of basic ADL, nursing home placement, or death

* Less benefit with combined therapy

* Vitamin E (1000 IU BID) delayed nursing home placement by ~230 days compared with placebo

* Contraindications: vitamin K deficiency, significant bleeding tendency, warfarin use

Adapted from Sano M, et al. Nengl J Med 1997; 336:1216-1222.

Ginkgo Biloba (Egb 761)

* 52-week, double-blind, placebo-controlled trial, N = 309 (202 evaluable at endpoint)

* Mild to moderate AD or multi-infarct dementia

* Primary outcomes: ADAS-cog, CGIC, GERRI

* Small benefit vs placebo on ADAS-cog and GERRI; none on CGIC

* Well tolerated

* High dropout rate (50% Egb, 62% placebo)

Adapted from LeBars et al. JAMA 1997; 178:1327-1332.

Anti-inflammatory Agents

* Inflammatory markers are elevated in AD

* Anti-inflammatory agents may delay onset or slow progression of AD (MeGeer et al, 1996)

* Small study with indomethacin showed benefit (Roberts et al, 1993)

* Additional studies ongoing (COX II inhibitors, nonselective COX inhibitors, colchicine, chloroquine)

* Not presently recommended in AD

Differential Diagnosis of Behavioral Problems

* Dementing disorders

* Delirium

Medical illness


* Psychosocial triggers

* Physical discomfort

* Primary psychiatric illness

Adapted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4th Ed. Washington, DC, American Psychiatric Association, 1994.

Psychosis and Agitation in the Elderly: Key Concepts

* Psychosis and agitation are common symptoms in elderly patients, especially in patients with dementia

* Physical conditions, physical discomfort, and medication side effects need to be ruled out as causative factors

* Treatment involves caregiver education and support, patient-centered behavioral interventions, milieu adaptations, and pharmacotherapy

* Atypical antipsychotics are the mainstay of pharmacologic treatment

Psychosis and Agitation: Management

* Reassure, distract patient; provide structure

* Identify and adjust environmental triggers

* Assemble an interdisciplinary treatment team

* Educate patient, family, and staff about treatment plan, including goals of pharmacotherapy

* Monitor and evaluate pharmacologic interventions

* Ensure support for the caregiver to prevent burnout

Atypical Antipsychotics

* Risperidone

* Olanzapine

* Quetiapine

* Ziprasidone

* Clozapine


* May have efficacy for explosive, paroxysmal nonpsychotic agitation

* Sodium valproate (1-3)

* Carbamazepine (4-6)

1. Mellow AM, et al. J Geriatr Psychiatry 1993; 6:205-209.

2. Lott AD, et al.J Neuropsychiatry Clin Neurosci 1995; 7:314-319.

3. Porsteinsson AP, et al. Am J Geriatr Psychiatry 1997; 5:344-351.

4. Gleason RP, Schneider LS. J Clin Psychiatry 1990; 51:115-118.

5. Tariot PN, et al. J Am Geriatr Soc 1994; 42:1150-1166.

6. Tariot PN, et al. Am J Psychiatry 1998; 155:54-61.

Psychosis and Agitation in the Elderly: Summary

* Environmental triggers, medical disorders, and medication side effects need to be ruled out as contributing factors

* Interdisciplinary treatment approach must include appropriate nondrug interventions, as well as thoughtfully chosen medications

* Primary caregiver requires attention, support, and respite
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Publication:Southern Medical Journal
Geographic Code:1USA
Date:Jan 1, 2002
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