Alzheimer's
Disease
A diagnosis of
Alzheimer's usually falls into one of the following three categories:
A diagnosis of
probable Alzheimer's indicates that the physician has ruled out all other disorders
that may be causing dementia, and has come to the conclusion that symptoms are
most likely the result of Alzheimer's disease.
A diagnosis of
possible Alzheimer's indicates the presence of another disorder that may be
affecting the known progression of Alzheimer's, so that the disease process is
somewhat different than what is seen normally. In this case, however, it is
still Alzheimer's disease that is the primary cause of dementia symptoms.
A diagnosis of
definite Alzheimer's only can be made at time of autopsy and requires
examination of brain tissue. Autopsy allows for confirmation of the presence of
plaques and tangles, which are the characteristic lesions of Alzheimer's, and
is the only way to diagnose the disease with 100% accuracy. A brain autopsy
confirming Alzheimer's can provide a vital record of the familial medical
history.
For cognitive
symptoms Alzheimer's disease is most often characterized by loss of memory and
decline in cognitive abilities, such as thinking and reasoning. Two drugs that
have been approved by the Food and Drug Administration (FDA) to treat these
symptoms are tacrine (Cognex), available by prescription since 1993, and
donepezil (Aricept), available since 1996. Neither tacrine nor donepezil will
cure Alzheimer's, nor do they stop the progression of the disease. Both are
indicated for the treatment of individuals with mild to moderate Alzheimer's
and may not be as effective for those in the advanced stages of the disease.
Some general
facts about donepezil
It is available
in 5mg or 10mg tablets. It is administered once daily, at bedtime. It can be
taken with or without food. To date, individuals with Alzheimer's have
generally responded well to donepezil, showing improvement in cognition,
general function, and behaviour, with few harmful side effects. Most frequent
side effects include diarrhoea, nausea, vomiting, insomnia, fatigue, and
anorexia, all mild in most cases, usually lasting from one to three weeks and
declining with continued use of the drug.
Some general
facts about tacrine
It is
administered four times a day. The most common side effect is an increase in
the liver enzyme alanine aminotransferase (ALT), potentially leading to liver
damage. Individuals on tacrine must be monitored regularly for increased levels
of ALT. If abnormal levels of ALT are present, physicians must adjust the
dosage accordingly, or discontinue administration of this drug. Other frequent
side effects include nausea, vomiting, diarrhoea, abdominal pain, indigestion,
and skin rash. Tacrine has provided relief to some individuals, yet is
intolerable by others.
Currently, there
is no known way to predict whether or not an individual with Alzheimer's will
benefit from these drugs. Therefore, it is important to have a thorough
discussion with your physician about the possible results of treatment, and
potential benefits, risks, and costs associated with the use of these drugs.
Damage to the
brain from Alzheimer's disease can cause a person to act in different or
unpredictable ways. Some individuals with Alzheimer's become anxious or
aggressive, while others repeat certain questions or gestures. Often these
behaviours occur in combination, making it difficult to distinguish one from
another. Behavioural problems do not always become apparent immediately after
onset of disease, and often change as the disease progresses. Challenging
behaviours not only cause discomfort to individuals with the disease, but also
can be frustrating and stressful for caregivers who cannot understand them.
When a
problematic behaviour surfaces, the individual with Alzheimer's first needs to
be evaluated by a physician for potential underlying causes. Behavioural
symptoms often result from a variety of treatable problems that the individual
cannot communicate, such as physical discomfort, medication side effects,
chronic pain, infection, nutritional deficiencies, dehydration, or impaired
vision or hearing. When behavioural symptoms are brought on by causes other
than physical problems, they may be treatable through non-drug treatments or
drug treatments.
Non-drug
treatments
Non-drug
treatments of behavioural symptoms are recommended as a first option, since
symptoms are best modified without the use of medication. Some suggestions for
caregivers and families are:
á
Family education and counselling. Learn what to expect when afflicted
with or caring for someone with Alzheimer's. Family members who are familiar
with the disease and know how to effectively communicate with their loved one
may be able to better cope with challenging behaviours. Counselling and support
for individuals with the disease and their families is available through local
chapters of the Alzheimer's Association.
á
Modifying the environment. Environmental factors such as lighting, colour,
and noise can greatly affect behaviour. Dim lighting, for example, makes some
individuals uneasy, while loud or erratic noise often causes confusion and
frustration. Modify the environment to reduce confusion, disorientation, and
agitation. Keep familiar personal possessions visible to ensure comfort and
feelings of warmth in your loved ones surroundings.
á
Planning activities. Help individuals with Alzheimer's organize their
time and know what to expect each day. Planned activities help individuals feel
independent and needed by focusing their attention on pleasurable or useful
tasks. Daily routines such as bathing, dressing, cooking, cleaning, and laundry
can be turned into productive activities. Other more creative leisure
activities can include singing, playing a musical instrument, painting,
walking, playing with a pet, or reading. Planned activities may relieve
depression, agitation, and wandering and help affected loved ones enjoy the
best quality of life.
Drug
Treatments
Non-drug
treatments are not always effective, therefore, severe behavioural symptoms may
be best treated with medication. In some cases, drugs that are available for
the treatment of cognitive symptoms [such as donepezil (Aricept), or tacrine
(Cognex)] also may improve behavioural problems. Several drugs are available
for treating problematic behaviours and many more are being studied for
specific use in helping those who suffer from Alzheimer's. Drugs commonly used
to treat behavioural symptoms such as agitation, aggression, paranoia,
delusions, or depression associated with Alzheimer's include:
Antipsychotics
(neuroleptics)
á
Haloperidol (Haldol)
á
Olanzapine (Zyprexa)
á
Quetiapine (Seroquel)
á
Risperidone (Risperdal)
Anti-anxiety
drugs
á
Alprazolam (Xanax)
á
Buspirone (Buspar)
á
Diazepam (Valium)
á
Lorazepam (Ativan)
Antidepressants
á
Amitriptyline (Elavil or Endep)
á
Bupropion (Wellbutrin)
á
Desipramine (Norpramin or Pertofrane)
á
Fluoxetine (Prozac)
á
Fluvoxamine (Luvox)
á
Nefazodone (Serzone)
á
Nortriptyline (Pamelor or Aventyl)
á
Paroxetine (Paxil)
á
Sertraline (Zoloft)
á
Trazodone (Desyrel)
Like any other
drugs, these treatments can cause undesirable side effects. Because individuals
with Alzheimer's may have difficulty identifying medication side effects, ask
your physician or pharmacist about what to expect and warning signs to watch
for with any drug that is prescribed.
Although two
drugs are currently available, by prescription, for the treatment of
Alzheimer's, several other studies are currently underway. Clinical drug studies
currently enrolling individuals with mild to moderate Alzheimer's disease
include donepezil (Aricept) and estrogen galantamine lazabemide melatonin
propentofylline (HWA 285)
Clinical drug
studies currently enrolling individuals with mild cognitive impairment (MCI)
include:
Memory Impairment
Study Index Study
Drug development
process. The Food and Drug Administration (FDA) requires that all potential
drug treatments pass through several phases of experimentation and review
before they are deemed safe and effective in treating a disease, such as
Alzheimer's. This approval process usually takes more than 10 years, from start
to finish, and involves the following steps:
á
Preclinical Testing - Phase I
á
Clinical Trials - Phase II
á
Clinical Trials - Phase III
á
Clinical Trials - New Drug Application (NDA)
á
FDA Review
á
Continued Studies
Preclinical
Testing
One purpose of
preclinical testing is to establish a "mechanism of action" for the drug
compound, which involves a close examination of how the drug works. Test tube
studies are performed to seek out potential benefits of the drug compound and
to learn how the drug interacts with other substances within a test tube (in
vitro). Drug compounds for Alzheimer's are tested against various processes
thought to be involved in the disease, such as accumulation of amyloid, the
presence of apolipoprotein E4, or deficiencies in certain neurotransmitters.
During these studies, researchers are looking for both effective and
potentially harmful interactions between the drug and other molecules.
Next, the drug is
tested in animal studies in order to determine its ability to achieve desirable
results (preclinical efficacy). Used as partial models for Alzheimer's disease,
both aged animals and those suffering from neurological defects are tested to
see how the drug acts within a living system (in vivo), and how a
living system, in turn, reacts to the drug. Varying doses of the experimental
drug are administered to test the drugs ability to improve performance and
behaviour in animals, and to reveal harmful side-effects that may occur.
Further testing also is done to determine the toxicity of the drug, whether it
may be cancer-causing, or whether it is likely to cause genetic mutation within
living systems. Based on results from these studies, the drug compound may be
altered slightly to make it more effective. Animal studies are an integral part
of most drug studies because they help researchers predict reactions in living
organisms before the drug is given to humans.
Preclinical
testing of a new drug compound can last from one to six years, because
extensive data needs to be gathered and analyzed before the drug moves into
human studies. If data proves that the experimental drug may be effective in
treating a specific disease, the pharmaceutical company will file an
Investigational New Drug Application (IND) with the FDA. The IND gives specific
details of all experiments completed during the preclinical testing phase,
including the chemical structure of the drug compound and how it is
manufactured. The IND must also explain how the new drug works in living
systems, how it may be beneficial in treating symptoms of the disease, and
known side effects.
In this
application, the pharmaceutical company also must describe its plans for the
next phase of human clinical study, specifically including
á
how many participants the study will involve
á
what criteria will be used for enrolling participants
á
where the studies will take place
á
how drug safety and efficacy will be measured
If the FDA
accepts the IND, drug testing in human subjects can begin within 30 days.
Phase I
Clinical Trials
Human clinical trials
generally occur in three phases. In Phase I clinical trials, the experimental
drug is tested in approximately 20-100 healthy volunteers. Researchers are
testing to see how the body absorbs, breaks down, and eliminates the drug, and
how the drug affects the different organ systems within the body. Different
dosage levels of the drug are administered and all side effects are documented.
This helps researchers establish appropriate dosage levels and determine what
precautions may need to be established (such as warnings about mixing the drug
with alcohol or other substances that may cause adverse reactions). As more is
known about the safety of the drug, the number of participants in Phase I
trials will likely increase. If a new drug provides few therapeutic benefits
and causes many harmful side effects, it may fail this round of testing. Phase
I clinical trials can take approximately one year to complete before enough
data is gathered to begin Phase II clinical trials.
Phase II
Clinical Trials
In Phase II
clinical trials, the experimental drug is tested in approximately 100-300
individuals who suffer from the disease or condition the drug was intended to
treat. At this stage, researchers primary objectives are:
(1) to determine the
effectiveness of the drug in treating the intended disease or condition
(2) to uncover less
common side effects, that may not have appeared during the animal studies or
the smaller Phase I clinical trials
(3) to determine
effective dosage levels and decide how often the drug should be administered.
In Phase II, researchers are mostly interested in gathering data about the
safety and efficacy of the experimental drug.
During Phase II
clinical trials, researchers employ a method known as a double-blind,
placebo-controlled study to ensure observations made during these trials remain
unbiased. In a double-blind placebo-controlled study, participants are randomly
placed into two groups. One group is given the experimental drug, while the
other group receives a placebo (sugar pill). The studies are considered
double-blind because neither the participants nor the researchers know who is
receiving the drug and who is receiving the placebo until after the study is
complete. A third party keeps record of this information and can access it if a
participant experiences extreme side effects or other complications resulting
from the medication. During the study, participants are carefully monitored and
all pertinent information is recorded and analyzed by the researchers. The double-blind
placebo-controlled study design prevents researchers from allowing their
expectations to influence their observations, and also prevents participants
from being influenced by what they expect to gain from using the drug.
Phase II clinical
trials can last up to two years. At the end of this round of testing, if the
side effects of the drug outweigh the therapeutic effects, it may be dropped
from further testing. If the results of Phase II clinical trials are positive,
the drug will then move into Phase III trials.
Phase III
Clinical Trials
The number of
participants involved in a Phase III study of Alzheimer drugs increases
considerably -- usually including 1,000 or more people who have received a
diagnosis of "probable Alzheimer's." As in Phase II, double-blind
placebo-controlled studies are employed to ensure accuracy of the data
collected. The results of Phase III clinical trials should determine whether
the use of the drug is beneficial and if its "user-friendly" (easy to
access and administer).
Phase III
clinical trials can last from two to four years. The FDA requires results from
two completed Phase III studies to ensure accuracy of the findings, and to
eliminate the possibility that the findings occurred by chance. If the results
of Phase III clinical trials do not show clear, positive results, the drug may
be dropped from further study.
Also, during
Phase III clinical trials researchers may offer an open-label study to the
participants to enhance enrolment. In an open-label study, all participants
(both in the experimental drug group and placebo group) who have successfully
completed the study are given the option of continuing to take the experimental
drug for six months to one year prior to FDA approval. This allows participants
to continue receiving the drug treatment until their own physicians can begin
prescribing it. At this point, the experimental drug trials are complete, and
the pharmaceutical company can move forward to the next step of development by
filing a New Drug Application with the FDA.
The New Drug
Application, FDA Review, Continued Studies
The New Drug
Application (NDA) is an extensive report the pharmaceutical company must submit
to the FDA for review. This report gives general information about the drug and
its chemical structure, and also includes everything that has been learned
about the drug -- from preclinical testing through Phase III clinical trials.
The FDA reviews all information collected in order to determine the overall
safety of the drug, weighs potential benefits against risks, and ultimately
determines whether the drug should be approved for public use. If the amount of
information provided in the NDA is not sufficient, the FDA may require future
clarification from the pharmaceutical company or request additional testing.
Once the NDA is
approved by the FDA, the drug can be made available to the public (usually
through a doctors prescription). However, testing of the drug does not end at
this point; the pharmaceutical company is still required by the FDA to continue
submitting reports describing the drugs efficacy and long-term effects, as its
use becomes more widespread.
Diagnostic
Procedures
Diagnostic
procedures Alzheimer's disease is characterized primarily by a gradual onset of
progressive symptoms, including memory loss, changes in personality, noticeable
decline in cognitive abilities (eg. speech, motor, understanding), loss of
executive function (decision-making), and losses impairing activities of daily
living (dressing, eating, toileting, etc.).
Today, new
diagnostic tools and criteria make it possible for all physicians (primary
care, as well as specialists) to make a positive clinical diagnosis of probable
Alzheimer's with an accuracy of 85-90%. Being able to recognize symptoms early
and accurately diagnose a patient with Alzheimer's is important. Although the
onset of Alzheimer's disease cannot yet be stopped or reversed, an early
diagnosis gives patients a greater chance of benefiting from existing
treatments, and allows them and their families more time to plan for the
future.
Cognitive
function should be assessed not only in those concerned about memory loss, but
also in patients who may not yet exhibit obvious symptoms but have risk factors
for the disease, such as age and family history. The Alzheimer's Association
has established a list of ten warning signs to look for when attempting to
detect Alzheimer's in a patient, before the disease noticeably progresses to
the advanced stages.
The actual
diagnostic work-up involves several steps an initial evaluation, including a
medical history, a mental status evaluation, a clinical examination, and
laboratory tests each outlined in the Differential Diagnosis of AD Algorithm.
Physicians and the care team should disclose the diagnosis to the individual
with Alzheimer's disease because of the individuals moral and legal right to
know. The diagnosis may have to be disclosed to the families first in cases
where the person with Alzheimer's may have difficulty understanding. Disclosing
the diagnosis early in the disease process allows the individual to continue to
live a life of quality and play an active role in planning for the future. If
disclosure of the diagnosis is made after the dementia has advanced, it may no
longer be warranted or meaningful to the affected individual.
If the individual
is informed of the diagnosis early on, he or she can also be involved in
communicating and planning for end-of-life decisions. These plans can apply to
issues such as life-prolonging measures and consenting to participate in
Alzheimer research, and can be expressed through legal documents called advance
directives. A joint meeting with the individual and the family members should
be arranged to disclose the diagnosis. Telling families the diagnosis is
Alzheimer's can be difficult, since there is currently no promising prognosis
for those affected. The initial meeting can be overwhelming, therefore, a
follow-up meeting to continue discussion on the diagnosis and available support
services may need to be scheduled. After disclosing the diagnosis, expect
various responses from the individual and family, such as acceptance of what
was suspected, relief at learning what is causing behavioural changes, denial
or depression.
Consider the
following before communicating the diagnosis
Gain an
understanding of family dynamics and cultural values. When possible, include
all of the professionals (nurses, social workers, psychologists, etc.) involved
in determining the diagnosis in the joint meeting to answer questions and
provide specific recommendations. Allow sufficient time to answer questions
from the individual and family. A follow-up meeting may need to be scheduled to
continue discussion. Discuss how the disease might progress and agree upon a
specific care plan that considers the person's values and beliefs. Provide
written educational materials and a list of available community resources
including the Alzheimer's Association.
The individual
and family should understand the following
Alzheimer's
disease is not a normal part of aging, but a degenerative disease of the brain
that results in impaired memory, thinking and behaviour. Alzheimer's disease
affects every individual differently, so there is no exact way to determine how
the disease will progress. While there is no cure for the disease, some of its
symptoms can be treated by medications and behavioural approaches. Disclosure
of the diagnosis allows the individual to maximize quality of life and empowers
him or her by being involved in planning future care decisions. Assistance is
available from the Alzheimer's Association and other resources. Progress is
being made in the area of research. One way to help that progress is by
participating in clinical drug trials. To locate the clinical drug trials being
conducted in the area, contact the local chapter of the Alzheimer's
Association.
Throughout the
diagnostic evaluation and treatment planning, physicians should involve the
family and caregiver. As the disease progresses and patients become
increasingly dependent upon their caregivers, these individuals will become the
physician's primary informant of the patient's daily mental and physical
health. In addition, the primary caregiver and other members of the family also
suffer from the stress that accompanies care giving and need information and
support, as well as attention to their own health needs.
Treating
cognitive symptoms Alzheimer's disease is most often characterized by loss of
memory and decline in cognitive abilities. Two drugs that have been approved by
the Food and Drug Administration (FDA) to treat these symptoms are tacrine
(Cognex), available by prescription since 1993, and donepezil (Aricept),
available since 1996. Tacrine and donepezil are both cholinesterase inhibitors;
neither will cure Alzheimer's, nor do they stop the progression of the disease.
Both are indicated for the treatment of mild to moderate Alzheimer's and may
not be as effective for those in the advanced stages of the disease.
These two drugs
can be useful in the management of cognitive losses and behavioural changes,
and in improving a patient's abilities to perform the activities of daily
living. However, there is no known way to predict whether or not a patient with
Alzheimer's will benefit from these drugs. Therefore, it is important to have a
thorough discussion with the patient and his or her family about the possible
results of treatment, and potential benefits, risks, and costs associated with
the use of these drugs. It is also important to observe patients who may be
suffering from co-morbidity urinary tract infections, pulmonary problems, etc.
and treat them accordingly.
Treating
behavioural symptoms
Behavioural
symptoms become problematic when patients are suffering from extreme
discomfort, or are at risk of causing harm to themselves, their caregivers, or
other family members. Alzheimer's can instigate a variety of behavioural
symptoms, including anxiety, agitation, aggression, depression, delusions,
hallucinations, insomnia, and wandering. Changes in behaviour may be prompted
by several factors physical discomfort or pain that cannot be expressed, fear
of unfamiliar surroundings and loud noises that accompany active environments,
frustration resulting from an inability to communicate with others, or the
inability to perform activities of daily living (e.g., bathing, dressing,
eating).
When a patient
exhibits a problematic behaviour, he or she needs to be evaluated for potential
underlying causes. Some behavioural symptoms may result from physical
discomfort or pain, medication side effects, chronic pain, infection,
nutritional deficiencies, dehydration, or impaired vision or hearing.
Behavioural symptoms of Alzheimer's can occur intermittently or consistently
and can be problematic to varying degrees of severity. Treatment plans need to
be modified as symptoms progress or decline.
Non-drug
treatment of behavioral problems are recommended as a first option
It is important to
discuss with caregivers and families all behavioural symptoms exhibited by the
patient, and help them identify the underlying cause(s). Many times behavioural
problems can be alleviated by modifying a patients surroundings, such as
adjusting lighting, removing clutter, and monitoring noise levels. Agitated
behaviours also may be avoided by eliminating cause for accidents by providing
safety within the environment (e.g., removing hazardous chemicals or objects,
adjusting hot water temperature to prevent burns, locking doors to prevent
wandering). More effective communication with patients also can be helpful in
easing agitation and frustration. Keeping conversation simple and direct can be
effective, while arguing, dictating, and overloading patients with information
may cause confusion, fear and anxiety.
A family's
understanding of the disease process and how their loved one is and will
continue to be affected is essential. Professional advice, education, and
support can help caregivers and families become better prepared to handle
difficult situations, especially as the disease progresses.
In some cases,
severe behavioural problems may be best treated with medication
Several drugs are
available for treating behavioural symptoms and many more are being researched
for specific use in managing patients with Alzheimer's disease. Often, drugs
that are available for the treatment of cognitive symptoms, such as donepezil
(Aricept) or tacrine (Cognex), also may improve behavioural problems. Patients
suffering from depression, anxiety, delusions or hallucinations may benefit
most from drug treatments indicated specifically for those conditions.
Because older
patients may be more sensitive to drug side effects, or may be taking several
medications simultaneously, the lowest possible dosage of medication should be
used initially when treating patients with Alzheimer's. In order to determine
treatment efficacy, patients should be monitored periodically to identify
whether the problem has improved or become worse.
Try to administer
treatments that may cause the least amount of problems in patients with
dementia, because many antipsychotics, anxiolytics and antidepressants can
cause undesirable side effects. Since patients with Alzheimer's may have
difficulty identifying medication side effects, educate caregivers and families
about what to expect and warning signs to watch for with any drug that is
administered.
Other proposed
treatments Within the last year, researchers have studied several other
proposed treatments for Alzheimer's disease. The use of these treatments in
patients with Alzheimer's is still experimental, although many physicians have
recommended and administered these treatments to their patients. Most of these
drugs have shown improved cognition or behaviour for at least some individuals,
with few side effects when taken in moderation. Nevertheless, further research
is needed in order to determine the exact benefits and risks of the following
drugs when prescribed to patients with Alzheimer's disease.
Anti-oxidants,
such as vitamin E or selegiline (Eldepryl, Deprenyl), which is commonly used
for the treatment of Parkinson's disease, may help reduce oxidative damage
to nerve cells. In a two-year study, researchers found that high dosages of
vitamin E (2000 I.U.s) helped middle-stage Alzheimer patients maintain longer
their ability to perform daily activities, such as bathing, dressing, etc. The
patients did not show significant improvement, but their deterioration was
slowed.
Non-steroidal
anti-inflammatory drugs (NSAIDs) may aid in preventing or delaying the onset of
Alzheimer's by protecting nerve cells in the brain from inflammation that may
contribute to nerve cell damage. Studies have shown that individuals who have
taken NSAIDs, such as ibuprofen, for pain relief in the past may be at lower
risk for developing AlzheimerÔs disease in the future.
Estrogen may
counteract the damage inflicted by Alzheimer's by performing several positive
functions: increasing the amount of acetylcholine in the brain, enhancing the
brains anti-oxidant properties, and increasing nerve cell growth. In some
studies, estrogen has been shown to improve cognition in those with
Alzheimer's, and may have a protective effect in asymptomatic individuals.