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Alzheimer's Disease
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Alzheimer's disease

Introduction:

Alzheimer's disease (AD) is a progressive disease of the brain that is characterized by impairment of memory and a disturbance in at least one other thinking function, for example, language or perception of reality. Many scientists believe that AD results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) that leads to nerve cell death. Loss of nerve cells in strategic brain areas, in turn, causes deficits in the neurotransmitters, which are the brain's chemical messengers. Alzheimer's disease is not a normal part of aging and is not something that inevitably happens in later life. Rather, it is one of the dementing disorders, which are a group of brain diseases that result in the loss of mental and physical functions.

Risk Factors of Alzheimer's Disease: The main risk factor for Alzheimer's Disease is increased age. As the population ages, the frequency of AD continues to increase. 10 % of people over age 65 and 50 % of those over 85 have Alzheimer's Disease. The number of individuals with AD is expected to be 14 million by the year 2050.

There are also genetic risk factors for AD. The presence of several family members with AD has suggested that, in some cases, heredity may influence the development of AD. A genetic basis has been identified through the discovery of mutations in several genes that cause AD in a small subgroup of families in which the disease has frequently occurred at relatively early ages (beginning before age 50). Some evidence points to chromosome 19 as implicated in certain other families in which the disease has frequently developed at later ages. Studies of aging and dementia (general mental deterioration) in the general population have identified three groups of subjects:

  • Persons who are not demented
  • Those who are demented
  • And individuals who cannot be classified because they have a cognitive (thinking, memory) impairment, but do not meet the criteria for dementia.

The Symptoms Of Alzheimer's Disease: The onset of Alzheimer's Disease is usually very slow and gradual. Over time, however, it follows an increasingly more serious course. Among the symptoms that typically develop, none is unique to AD at its various stages. It is important that suspicious changes be thoroughly evaluated before they become inappropriately or neglectfully labeled AD.

Warning Signs of Alzheimer's Disease Warning signs of Alzheimer's Disease are given blow, these include common symptoms of AD. Individuals who exhibit several of these symptoms should see a physician for a complete evaluation. 1. Memory loss that affects job skills 2. Difficulty performing familiar tasks 3. Problems with language 4. Disorientation to time and place 5. Poor or decreased judgment 6. Problems with abstract thinking 7. Misplacing things 8. Changes in mood or behavior 9. Changes in personality 10. Loss of initiative Problems of memory, particularly recent or short-term memory, are general early in the course of AD. For example, the individual may, on repeated occasions, forget to turn off the iron or fail to recall which of the morning's medicines were taken. Mild personality changes, such as less spontaneity, or a sense of apathy and a tendency to withdraw from social interactions, may occur early in the illness. As the disease progresses, problems in abstract thinking or in intellectual functioning develop. The person may begin to have trouble with figures when working on bills, with understanding what is being read, or with organizing the day's work. Further disturbances in behavior and appearance may also be seen at this point, such as agitation, irritability, and a diminishing ability to dress appropriately. Later in the course of the disorder, affected individuals may become confused or disoriented about what month or year it is, be unable to describe accurately where they live, or be capable of correctly naming a place being visited. Eventually, patients may wander, be unable to engage in conversation, seem inattentive and erratic in mood, appear uncooperative, and lose bladder and bowel control. In extreme cases, persons may become totally incapable of caring for themselves, if the final stage is reached. Death then follows, perhaps from pneumonia or some other problem that occurs in severely deteriorated states of health. The average course of the disease from the time it is recognized to death is about 6 to 8 years, but it may range from under 2 to over 20 years. Those who develop the disorder later in life may die from other illnesses, before AD reaches its final and most serious stages. Mild Cognitive Impairment

In recent years, more attention has turned to the transitional period of cognitive (thinking, memory) impairment between normal aging and early AD. This condition is referred to as mild cognitive impairment. Affected individuals have problems with memory but are otherwise able to function well. The criteria for mild cognitive impairment are as follows:

  • Memory complaint, preferably corroborated by a family member.
  • Objective memory impairment (as determined by a formal test of memory).
  • Normal general cognitive function (Abilities to think and function are normal.)
  • Intact activities of daily living.

The significance of early detection and ability to treat mild cognitive impairment and thus delay the progression of this condition to AD would be of great benefit. Several studies have recently addressed this issue and estimated the risk of progression from mild cognitive impairment to AD as being between 6% and 25% per year. This means that between 6% and 25% of those with mild cognitive impairment will develop AD in any given year.

Causes of Alzheimer's Disease:

  • With the exception of rare cases of familial AD, in whom the disease is caused by mutations (changes in the DNA) of a single gene, most cases of AD are probably caused by a variety of factors acting together.
  • Cases without a family history are called "sporadic." The study of familial AD, however, has uncovered several proteins that are not only important for familial, but also for sporadic AD.
  • These are the amyloid precursor protein (APP) and two presenilins. APP is a major component of plaques (abnormal deposits of proteins in the brain).
  • Mutations in the genes that encode APPs and the presenilins can cause AD. This means that individuals carrying these mutations have a very high probability of developing Alzheimer's Disease.
  • Changes in other genes may not cause AD, but they may increase the risk of developing AD. The best-studied "risk" gene is the one that encodes apolipoprotein E (apoE). Certain forms (alleles) of this gene can increase the risk for AD.
  • The apoE gene has three different forms (alleles) -- apoE2, apoE3, and apoE4. ApoE3 is the most common form in the general population. However, apoE4 occurs in approximately 40 % of all late-onset AD patients. People who inherit two apoE4 alleles (one from the mother and one from the father) are several times more likely to develop AD than those who have two of the more common E3 version. The least common allele, E2, lowers the risk of AD. People with one E2 and one E3 gene have only one-fourth the risk of developing Alzheimer's as do people with two E3 genes.

Since the 1970's, abnormalities in the brain's chemical messengers, called neurotransmitters, have been identified in patients with AD. Acetylcholine is a critical neurotransmitter in the process of forming memories. This chemical messenger is abundant in the nerve cells of the hippocampus and cerebral cortex, the regions that are devastated by AD.

In addition to the known risk factors of age and family history, several other possible risk factors have been identified. Some studies have found that AD occurs more often among people who suffered traumatic head injuries earlier in life. Women may have a higher risk of the disease, although their higher rates may only reflect the effects of age, because women have longer life spans on average than do men. In addition, lower educational levels may increase the risk. It is not know whether this reflects a decreased "cognitive reserve" or other factors associated with a lower educational level.

The Diagnosis of Alzheimer's Disease: Clinical Features of Alzheimer's Disease

The 'clinical' features of AD, as opposed to the 'tissue' changes, are threefold:
1. Dementia - general mental deterioration, including the significant loss of intellectual abilities, such as memory capacity, that are severe enough to interfere with social or occupational functioning. 2. Insidious (gradual and subtle) onset of symptoms - subtle, progressive, and irreversible course with documented deterioration over time.
3. Exclusion of all other specific causes of dementia- by history, physical examination, laboratory tests, psychometric, and other studies. The essential feature of dementia is impairment in short and long-term memory that is associated with deficits in abstract thinking, impaired judgment, or personality change. Theses disturbance are severe enough to interfere significantly with work, usual social activities, or relationships with others.

What Other Conditions Should Be Screened For?

There are many conditions that affect the brain and result in intellectual, behavioral, and psychological dysfunction. These disorders represent a broad grouping of diseases and include AD. Some of these disorders that can cause clinical problems similar to those of AD may be reversible or controlled with proper diagnosis and treatment. These other conditions include:

  • Side effects of medications: Unusual reactions to medications, too much or too little of prescribed medications, and combinations of medications which, when taken together, can cause adverse side effects.
  • Psychiatric disorders: Severe forms of depression can cause problems with memory and concentration that initially may be indistinguishable from the early symptoms of AD. Sometimes, these conditions, referred to as pseudodementia, can be reversed. Other psychiatric problems can similarly masquerade as AD, and, like depression, respond to treatment. Studies have shown that persons with depression and coexistent cognitive (thinking, memory) impairment are highly likely to have an underlying dementia when followed for several years.
  • Substance Abuse: Abuse of legal and/or illegal drugs and alcohol abuse.
  • Metabolic Disorders: Thyroid problems, nutritional deficiencies such as vitamin B 12 deficiency, anemias, etc.
  • Circulatory Disorders: Heart problems, strokes, etc.
  • Neurological Disorders: Normal-pressure hydrocephalus, multiple sclerosis, etc.
  • Infections: Especially viral or fungal infections of the brain.
  • Trauma: Injuries to the head.
  • Toxic Factors: Carbon monoxide, methyl alcohol, etc.
  • Tumors: Any type within the skull, whether originating or metastasizing there.
  • Syphilis: Screening for this disease in a patient with dementia is only recommended if the patient has some specific risk factor or evidence of a prior syphilitic infection, or if the patient resides in one of the few areas in the U.S. with high numbers of syphilis cases (i.e., southern states and Midwest).
The Importance of Comprehensive Clinical Evaluation

Because of the many other disorders that can be confused with AD, a comprehensive clinical evaluation is essential in arriving at a correct diagnosis of symptoms that resemble those of AD. Such an assessment should include at least three major components:

  1. Thorough general medical workup
  2. Neurological examination
  3. Psychiatric evaluation that may include psychological and memory testing.

The family physician can be consulted about the best way to get the necessary examination.

Despite many attempts, identification of a blood test to diagnose AD has remained elusive. There has been intense interest in developing markers for AD in the blood and particularly in the cerebrospinal fluid (CSF) (the fluid surrounding the brain and the spinal cord). CSF b-amyloid 1-42, CSF tau, CSF AD7C-NTP have all been studied, but are currently not routinely recommended in determining the diagnosis of AD at this time.

What is the Prognosis for a Person with Alzheimer's Disease? Though the changes just described represent the general range of symptoms for AD, the specific problems, along with the rate and severity of decline, can vary considerably in different individuals. Indeed, most persons with AD can function at a reasonable level and remain at home far into the course of the disorder. Moreover, throughout much of the course of the illness, individuals maintain the capacity for giving and receiving love, sharing warm interpersonal relationships, and participating in a variety of meaningful activities with family and friends. A person with AD may no longer be able to do math, but still be able to read a magazine with pleasure for months or years to come. Playing the piano might become too stressful in the face of increasing mistakes, but singing along with others may still be satisfying. The chessboard may have to be put away, but playing tennis may still be enjoyable. Thus, despite the many exasperating moments in the lives of Alzheimer patients and their families, many opportunities remain for positive interactions. Challenge, frustration, closeness, anger, warmth, sadness, and satisfaction may all be experienced by those who work to help the person with AD. The reaction of an individual to the illness, and his or her capacity to cope with it, also vary and may depend on such factors as lifelong personality patterns and the nature and severity of stress in the immediate environment. Depression, severe uneasiness, paranoia, or delusions may accompany or result from the disease, but these conditions can often be improved by appropriate treatments. Although there is no cure for AD, treatments are available to alleviate many of the symptoms that cause suffering. Some people have the disease only for the last 5 years of life, while others may have it for as many as 20 years. The most common cause of death in AD patients is infection.

What treatment and management options are available for Alzheimer's disease? The management of AD consists of medication-based and non-medication based treatments. Treatments aimed at changing the underlying course of the disease (delaying or reversing the progression) have so far been largely unsuccessful. Medicines that restore the deficit (defect), or malfunctioning, in the chemical messengers of the nerve cells, such as the cholinesterase inhibitors, have been shown to improve symptoms. Finally, medications are available that deal with the psychiatric manifestations of AD. Various other agents have been tried in an attempt to modify the course of AD, including ginkgo biloba, anti-inflammatory agents, and prednisone. However, the use of these agents is so far not supported by adequate available evidence. Estrogen should not be routinely prescribed to treat AD.

Cholinesterase inhibitors (ChEIs) ChEIs are the only agents that are approved by the FDA for the treatment of AD. ChEIs are medicines that restore the defect, or malfunctioning, in the chemical messengers of the nerve cells. These chemical messengers are referred to as nerve cells(neurotransmitters). ChEIs impede the action of an enzyme that inactivates the chemical messengers. Therefore, in the presence of ChEI medicines, more chemical messengers are available to transmit the messages of the nerves in the brain. Four ChEIs have been approved; tacrine (Cognex), donepezil hydrochloride (Aricept), rivastigmine, and galantamine. Significant treatment effects have been demonstrated indicating that this class of agents is consistently better than a placebo. However, the disease eventually continues to progress despite treatment and the average effect on mental functioning has only been modest. ChEIs have effects on many aspects of daily living. Head-to-head comparative trials evaluating the relative usefulness of ChEIs have not been conducted. Available data do not suggest major differences in the effectiveness among different ChEIs, although side-effects may vary slightly. The principal side effects of ChEIs involve the gastrointestinal system and include nausea, vomiting, cramping, and diarrhea. Tacrine is the only agent that is associated with liver toxicity and the use of this agent requires close hematologic (blood test) monitoring, including liver function tests every other week during the period of dose escalation and every 3 months thereafter. Rivastigmine has been associated with weight loss and the monitoring of the patient's weight is recommended when using this drug. The occurrence of side effects for ChEIs is related to the rate of dose increase. Therefore, doctors gradually increase the dose at intervals until the optimal therapeutic dosage has been reached. The interval between dose increases may be extended or the dose step size may be reduced accordingly if side effects occur. Between 75% and 90% of patients will tolerate therapeutic doses of ChEIs.

Initiating, Maintaining, and Terminating Treatment Treatment with ChEIs should be initiated at the time the diagnosis of AD is established. In other words, treatment should not be delayed until more severe deterioration has occurred. Evidence from studies in which the start of treatment has been delayed suggests that such delay reduces the maximum possible response to ChEIs. Patients should be treated for 3 to 5 years until the severity of clinical deficit is such that little therapeutic benefit is likely. Treatment trials using ChEIs in patients residing in nursing homes demonstrate that patients with moderately severe dementia continue to show cognitive and behavioral responses. The placement of the patient in a nursing home or the emergence of moderately severe dementia are not in themselves reasons for discontinuing ChEIs. Interruptions in ChEIs therapy should be minimized. There is evidence that the response following reinitiation of ChEIs after a period without therapy is less that obtained with the first start of treatment. When continuing benefit is in doubt or when the family or medical practitioner desires to discontinue treatment with ChEIs, the agent should be withdrawn with close observation. The therapeutic dose can be reduced by 50% every 2 weeks. The patient should be monitored at the time of dose reduction. If there is deterioration in cognition, behavior, or function, thereby suggesting that the patient is continuing to benefit from the treatment, then an optimal dosage should be restored. Switching from one ChEI to another has not been well studied. The prescribing of two ChEIs at the same time is not recommended because there may be side effects. Doctors' experience with many different patients indicates that those who fail to respond to one ChEI may respond to another. There is substantial individual variability in a patient's response to ChEIs and predictors of this variability are being actively investigated. Patients with low MMSE (mental exam) scores have larger cognitive responses (ability to think), and patients with more severe behavioral disturbances also demonstrate a greater benefit when treated with ChEIs. Recent clinical trials have begun to include additional features, such as secondary effects on caregivers, delay to nursing home placement, pharmacoeconomic outcomes (cost of drug treatments), and impact on quality of life, as measures for the potential use of ChEIs. These studies may further influence the use of ChEIs in clinical practice.

Treatment of Psychiatric Symptoms The principal treatable neuropsychiatric disturbances in AD are:

  • Agitation
  • Depression
  • Psychosis
  • Anxiety
Patients with AD may respond well to antipsychotics, antidepressants, anticonvulsants, and other psychopharmacological (medicines for the treatment of psychiatric disturbances) agents. Target symptoms should be clearly specified and documented and the treatment response should be evaluated regularly. Agitation occurs in as many as 70% of patient with AD and is more common as the disease progresses. Classes of agents used to treat agitation include antipsychotics, mood-stabilizing anticonvulsants, trazodone, anxiolytics, and beta-blockers. Available evidence suggests that antipsychotics, trazodone, or anticonvulsants have the greatest effectiveness in reducing agitation. Atypical antipsychotic agents such as clozapine, risperidone, olanzapine, quetiapine, and ziprasidone appear to have advantages over the older antipsychotic agents based on their side effect profiles and the patients' ability to tolerate them. Psychosis is common in AD, with a frequency of about 50% over the lifetime of an AD patient. Atypical antipsychotics are the treatment of choice. Risperidone and olanzapine have an established benefit in this regard and quetiapine and ziprasidone may be useful. Sedation (dullness, calmness) is the most common side effect noted in patients receiving antipsychotics. Depressive symptoms are frequent in AD and occur in as many as 50% of patients. Major depression is more unusual. The treatment of depressive symptoms commonly consists of selective serotonin reuptake inhibitors (SSRIs), such as sertraline, citalopram, or fluoxetine. Full doses of the SSRIs are generally tolerated in the elderly, which is unlike most other psychotropic agents wherein lower doses are typically used. Alternatively, tricyclic antidepressants with few anticholinergic (dry mouth, constipation, memory problems) side effects, such as nortriptyline, or combined noaradrenergic and serotonergic reuptake inhibitors, such as venlafaxine, have been used. Anxiety is a common symptom in AD and affects 40% to 50% of patients at some point in the course of the illness. Most patients do not require medicines for the treatment of their anxiety. For those requiring medicines, benzodiazepines are best avoided because of their potential adverse effects on the thinking process. Nonbenzodiazepine anxiolytics, such as buspirone or SSRIs, are preferred. Difficulty sleeping (insomnia) occurs in many patients with AD at some point in the course of their disease. Agents that are useful in treating insomnia in AD patients include moderately short-acting benzodiazepines, such as temazepam, nonbenzodiazepine sedative hypnotics, such as zolpidem or zaleplon, or sedating antidepressants, such as trazodone. Sleep improvement measures, such as sunlight, adequate treatment of pain, and limiting nighttime fluids, should also be implemented.

Potential and future therapies for AD

Advances in our understanding of the brain abnormalities that occur in AD will provide the framework for new targets of treatment that are more focused on altering the course of the disease. Many compounds, including anti-inflammatory agents, are being actively investigated. Clinical trials using specific cyclooxygenase inhibitors (COX-2), such as rofecoxib and celecoxib, are underway.

Preliminary animal experiments using immunization with beta-amyloid antibodies (amyloid vaccine) have shown very promising results. Clinical trials for patients with AD are underway and results will be highly anticipated.

Caring for the caregiver and Alzheimer's disease resources

Caring for the caregiver is an essential element of managing the patient with AD. Caregiving is a distressing experience. On the other hand, caregiver education delays nursing home placement of AD patients. The 3Rs - Repeat, Reassure, and Redirect - can help caregivers reduce troublesome behaviors and limit the use of pharmacological (medicines) intervention. The short-term educational programs are well liked by family caregivers and can lead to a modest increase in disease knowledge and greater confidence among caregivers. Educational training for staffs of long-term care facilities can decrease the use of antipsychotics in AD patients. Caregivers should be directed to support services, particularly the Alzheimer's Association (1-800-272-3900, www.alz.org/chapter/).

Alzheimer's Disease At A Glance

  • Alzheimer's disease is a brain disease of unknown cause that leads to dementia.
  • Most patients with Alzheimer's disease are over 65 years of age.
  • There are some classic warning signs of Alzheimer's disease: memory loss that affects job skills, difficulty performing familiar tasks, problems with language, disorientation to time and place, poor or decreased judgment, problems with abstract thinking, misplacing things, changes in mood or behavior, changes in personality, and loss of initiative.
  • Patients with symptoms of dementia should be thoroughly evaluated before they become inappropriately or negligently labeled Alzheimer's disease.
  • Although there is no cure for Alzheimer's disease, treatments are available to alleviate many of the symptoms that cause suffering.
  • The management of AD consists of medication-based and non-medication based treatments organized to care for the patient and family. Treatments aimed at changing the underlying course of the disease (delaying or reversing the progression) have so far been largely unsuccessful. Medicines that restore the defect, or malfunctioning, in the chemical messengers of the nerve cells have been shown to improve symptoms. Finally, medications are available that deal with the psychiatric manifestations of AD.
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