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:

 

       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.

 

       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.

 

       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)

 

       Haloperidol (Haldol)

       Olanzapine (Zyprexa)

       Quetiapine (Seroquel)

       Risperidone (Risperdal)

 

Anti-anxiety drugs

 

       Alprazolam (Xanax)

       Buspirone (Buspar)

       Diazepam (Valium)

       Lorazepam (Ativan)

 

Antidepressants

 

       Amitriptyline (Elavil or Endep)

       Bupropion (Wellbutrin)

       Desipramine (Norpramin or Pertofrane)

       Fluoxetine (Prozac)

       Fluvoxamine (Luvox)

       Nefazodone (Serzone)

       Nortriptyline (Pamelor or Aventyl)

       Paroxetine (Paxil)

       Sertraline (Zoloft)

       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:

 

       Preclinical Testing - Phase I

       Clinical Trials - Phase II

       Clinical Trials - Phase III

       Clinical Trials - New Drug Application (NDA)

       FDA Review

       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

 

       how many participants the study will involve

       what criteria will be used for enrolling participants

       where the studies will take place

       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 Alzheimers 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.

 

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