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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.

DIAGNOSING ALZHEIMER'S DISEASE

Ronald C. Hamdy, MD, FRCP FRCP Fellow of the Royal College of Physicians.

FRCP
abbr.
Fellow of the Royal College of Physicians
, FACP FACP Fellow of the American College of Physicians.

FACP
abbr.
1. Fellow of the American College of Physicians

2. Fellow of the American College of Prosthodontists
, ACOS/EC&G, VAMC, and Professor of Medicine, Cecile Cox Quillen Chair of Geriatric Medicine & Gerontology, East Tennessee State University East Tennessee State University (ETSU) is an accredited American university, founded October 21911 and located in Johnson City, Tennessee. It is part of the Tennessee Board of Regents system of colleges and universities. , 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 anomia /ano·mia/ (ah-no´me-ah) anomic aphasia.

a·no·mi·a
n.
See nominal aphasia.
 (inability to name objects), agnosia Agnosia

An impairment in the recognition of stimuli in a particular sensory modality. True agnosias are associative defects, where the perceived stimulus fails to arouse a meaningful state.
 (inability to recognize objects), and apraxia apraxia

Disturbance in carrying out skilled acts, caused by a lesion in the cerebral cortex; motor power and mental capacity remain intact. Motor apraxia is the inability to perform fine motor acts. Ideational apraxia is loss of the ability to plan even a simple action.
 (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 septicemia (sĕptĭsē`mēə), invasion of the bloodstream by virulent bacteria that multiply and discharge their toxic products. The disorder, which is serious and sometimes fatal, is commonly known as blood poisoning.  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 choline: see vitamin.
choline

Organic compound related to vitamins in its activity. It is important in metabolism as a component of the lipids that make up cell membranes and of acetylcholine.
 esterase esterase /es·ter·ase/ (es´ter-as) any enzyme which catalyzes the hydrolysis of an ester into its alcohol and acid.

es·ter·ase
n.
Any of various enzymes that catalyze the hydrolysis of an ester.
 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 lability /la·bil·i·ty/ (lah-bil´i-te)
1. the quality of being labile.

2. in psychiatry, emotional instability.


lability

the quality of being labile.
 and irritability, and language difficulties, should also alert the astute clinician that the patient may have an early dementia.

SPECIFIC PHARMACOLOGIC MANAGEMENT OF ALZHEIMER'S DISEASE

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 The University of Pittsburgh Medical Center (UPMC) is a leading American healthcare provider and institution for medical research. It consistently ranks in US News and World Report's "Honor Roll" of the approximately 15 best hospitals in America. , 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 /tac·rine/ (tak´ren) a cholinesterase inhibitor used to improve cognitive performance in dementia of the Alzheimer type; used as the hydrochloride salt. . Tacrine, which has a high incidence of gastrointestinal side effects and hepatotoxicity hepatotoxicity (hepˑ··tō·t , 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 allosteric /al·lo·ster·ic/ (al?o-ster´ik) pertaining to allostery.

allosteric

pertaining to an effect on the biological function of a protein, produced by a compound not directly involved in that function (an allosteric
 modulation of nicotinic nicotinic /nic·o·tin·ic/ (nik?o-tin´ik) denoting the effect of nicotine and other drugs in initially stimulating and subsequently, in high doses, inhibiting neural impulses at autonomic ganglia and the neuromuscular junction.  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.

PHARMACOLOGIC TREATMENT FOR DISTURBED BEHAVIOR IN ALZHEIMER'S DISEASE

William E. Reichman, MD, Dean and Associate Professor of Psychiatry, University of Medicine and Dentistry of New Jersey The University of Medicine and Dentistry of New Jersey is the state-run health sciences institution of New Jersey and comprises eight distinct academic units: the New Jersey Medical School, the New Jersey Dental School, the Graduate School of Biomedical Sciences, the School of , 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 pre·ex·ist or pre-ex·ist  
v. pre·ex·ist·ed, pre·ex·ist·ing, pre·ex·ists

v.tr.
To exist before (something); precede: Dinosaurs preexisted humans.

v.intr.
 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 haloperidol /hal·o·peri·dol/ (hal?o-per´i-dol) an antipsychotic agent of the butyrophenone group with antiemetic, hypotensive, and hypothermic actions; used especially in the management of psychoses and to control vocal utterances and , thioridazine thioridazine /thi·o·rid·a·zine/ (-rid´ah-zen) a tranquilizer with antipsychotic and sedative effects, used as the base or hydrochloride salt.

thi·o·rid·a·zine
n.
, chlorpromazine chlorpromazine (klōrpräm`əzēn'), one of a group of tranquilizing drugs called phenothiazines that are useful in halting psychotic episodes. ), 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 clozapine /clo·za·pine/ (klo´zah-pen) a sedative and antipsychotic agent; used in the treatment of schizophrenia.

clo·za·pine
n.
, 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

                                                   Dose
Drug           MoA   Binding                    Escalation    Dosing

Galantamine   AChEI  Competitive, reversible   4-week steps    BID
              nAChR  Allosteric modulation
Donepezil     AChEI  Noncompetitive,          4-6-week steps    QD
                     reversible
Rivastigmine  AChEI  Noncompetitive,           2-week steps    BID
                     reversible
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

* CBC (1) (Cell Broadcast Center) See cell broadcast.

(2) (Cipher Block Chaining) In cryptography, a mode of operation that combines the ciphertext of one block with the plaintext of the next block.
 

* Chem-29

* Thyroid stimulating hormone Thyroid stimulating hormone (thyrotropin)
A hormone that stimulates the thyroid gland to produce hormones that regulate metabolism.

Mentioned in: Pituitary Dwarfism
 

* 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 (1) (Telecommunications Industry Association, Arlington, VA, www.tiaonline.org) A membership organization founded in 1988 that sets telecommunications standards worldwide. It was originally an EIA working group that was spun off and merged with the U.S. , 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 Neuroleptics
Any of a class of drugs used to treat psychotic conditions.

Mentioned in: Stuttering, Tardive Dyskinesia
 may worsen condition

Dementia With Lewy Bodies Dementia with Lewy bodies is the second most frequent cause of hospitalization for dementia, after Alzheimer's disease. Current estimates are that about 60-to-75% of diagnosed dementias are of the Alzheimer's and mixed (Alzheimer's and vascular dementia) type, 10-to-15% are Lewy  

* Fluctuating course, rapidly progressive

* Hallucinations are detailed and prominent

* Psychosis, delusional or paranoid ideation ideation /ide·a·tion/ (i?de-a´shun) the formation of ideas or images.idea´tional

i·de·a·tion
n.
The formation of ideas or mental images.
 

* Mild extrapyramidal extrapyramidal /ex·tra·py·ram·i·dal/ (-pi-ram´i-d'l) outside the pyramidal tracts; see under system.

ex·tra·py·ram·i·dal
adj.
 signs

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

* Subcortical subcortical /sub·cor·ti·cal/ (-kor´ti-k'l) beneath a cortex, such as the cerebral cortex.  deficits:.attention, verbal fluency

* Neuroleptics may aggravate symptoms

HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States.  Dementia

* Rapidly progressive course

* Depression and anxiety: common

* Motor dysfunction: tremors, ataxia, repeated falls

* Behavioral abnormalities: apathy, withdrawal

* Younger age

* Risk factors

Hydrocephalus hydrocephalus (hī'drəsĕf`ələs), also known as water on the brain, developmental (congenital) or acquired condition in which there is an abnormal accumulation of body fluids within the skull.  

* Rigid gait

* Urinary incontinence

* Dementia

Pick's Disease

* Disinhibition dis·in·hi·bi·tion
n.
1. A loss of inhibition, as through the influence of drugs or alcohol.

2. A temporary loss of an inhibition caused by an unrelated stimulus, such as a loud noise.
 

* 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 Vitamin K Deficiency Definition

Vitamin K deficiency exists when chronic failure to eat sufficient amounts of vitamin K results in a tendency for spontaneous bleeding or in prolonged and excessive bleeding with trauma or injury.
, 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 JAMA
abbr.
Journal of the American Medical Association
 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 colchicine (kŏl`chəsēn'), alkaloid extracted from plants of the genus Colchicum and especially from the corms of the autumn crocus, Colchicum autumnale (see meadow saffron). , chloroquine chloroquine /chlo·ro·quine/ (klor´o-kwin) an antiamebic and anti-inflammatory used in the treatment of malaria, giardiasis, extraintestinal amebiasis, lupus erythematosus, and rheumatoid arthritis; used also as the hydrochloride and )

* Not presently recommended in AD

Differential Diagnosis of Behavioral Problems

* Dementing disorders

* Delirium

Medical illness

Iatrogenic iatrogenic /iat·ro·gen·ic/ (i-a´tro-jen´ik) resulting from the activity of physicians; said of any adverse condition in a patient resulting from treatment by a physician or surgeon.  

* Psychosocial triggers

* Physical discomfort

* Primary psychiatric illness

Adapted from American Psychiatric Association The American Psychiatric Association (APA) is the main professional organization of psychiatrists and trainee psychiatrists in the United States, and the most influential world-wide. Its some 148,000 members are mainly American but some are international. : Diagnostic and Statistical Manual of Mental Disorders Diagnostic and Statistical Manual of Mental Disorders /Di·ag·nos·tic and Sta·tis·ti·cal Man·u·al of Men·tal Dis·or·ders/ (DSM) a categorical system of classification of mental disorders, published by the American Psychiatric Association, that delineates objective  (DSM-IV DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). This reference book, published by the American Psychiatric Association, is the diagnostic standard for most mental health professionals in the United States.
). 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

Anticonvulsants Anticonvulsants
Drugs used to control seizures, such as in epilepsy.

Mentioned in: Antipsychotic Drugs, Osteoporosis
 

* May have efficacy for explosive, paroxysmal paroxysmal (per´ksiz´ml),
adj recurring in paroxysms.
 nonpsychotic agitation

* Sodium valproate (1-3)

* Carbamazepine carbamazepine /car·ba·maz·e·pine/ (kahr?bah-maz´e-pen) an anticonvulsant and analgesic used in the treatment of pain associated with trigeminal neuralgia and in epilepsy manifested by certain types of seizures.  (4-6)

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

2. Lott AD, et al.J Neuropsychiatry neuropsychiatry /neu·ro·psy·chi·a·try/ (noor?o-si-ki´ah-tre) the combined specialties of neurology and psychiatry.

neu·ro·psy·chi·a·try
n.
 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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