Diagnosis by Exclusion

Based on these criteria, the clinical diagnosis of Alzheimer's disease has been referred to as "a diagnosis by exclusion," and one that can only be made in the face of clinical deterioration over time. There is no specific clinical test or finding that is unique to Alzheimer's disease. Hence, all disorders that can bring on similar symptoms must be systematically excluded or "ruled out." This explains why diagnostic workups of individuals where the question of Alzheimer's disease has been raised can be so frustrating to patient and family alike; they are not told that Alzheimer's disease has been specifically diagnosed, but that other possible diagnoses have been dismissed, leaving Alzheimer's disease as the likely diagnosis by the process of elimination.

Some scientists think that the results from biochemical research may lead to a diagnostic "marker" for certain persons evaluated for Alzheimer's disease. For example, research has discovered a protein, called Alzheimer's Disease Associated Protein (ADAP), in the autopsied brains of Alzheimer's patients. The protein, which seems to appear only in people with Alzheimer's, is mainly concentrated in the cortex covering the front and side sections of the brain, regions involved in memory function. Researchers have found ADAP not only in brain tissue but also in spinal fluid. If they can perfect a test to detect the protein in the cerebrospinal fluid, or potentially even circulating in the blood, it may be possible to use this method of diagnosis on living patients.

Many scientists are working at developing other tests or procedures that may someday identify living persons with the disorder, perhaps even early in its course before behavioral changes become evident. Still, a reliable, specific diagnostic marker for Alzheimer's disease is not yet available.

Meanwhile, Alzheimer's disease is the most overdiagnosed and misdiagnosed disorder of mental functioning in older adults. Part of the problem, already alluded to, is that many other disorders show symptoms that resemble those of Alzheimer's disease. The crucial difference, though, is that many of these disorders--unlike Alzheimer's disease--may be stopped, reversed, or cured with appropriate treatment. But first they must be identified and not dismissed as Alzheimer's disease or senility.

Conditions that affect the brain and result in intellectual, behavioral, and psychological dysfunction are referred to as "organic mental disorders." These disorders represent a broad grouping of diseases and include Alzheimer's disease. Organic mental disorders that can cause clinical problems like those of Alzheimer's disease, but which might be reversible or controlled with proper diagnosis and treatment, include the following:

• Side Effects of Medications: Unusual reactions to medications, too much or too little of prescribed medications, combinations of medications which, when taken together, cause adverse side effects.

• Substance Abuse: Abuse of legal and/or illegal drugs, alcohol abuse.

• Metabolic Disorders: Thyroid problems, nutritional deficiencies, 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.

In addition to organic mental disorders resulting from these diverse causes, other forms of mental dysfunction or mental health problems can also be confused with Alzheimer's disease. For example, severe forms of depression can cause problems with memory and concentration that initially may be indistinguishable from early symptoms of Alzheimer's disease. Sometimes these conditions, referred to as "pseudodementia," can be reversed. Other psychiatric problems can similarly masquerade as Alzheimer's disease, and, like depression, respond to treatment.

Of course, not all memory changes or complaints in later life signal Alzheimer's disease or mental disorder. Many memory changes are only temporary, such as those that occur with bereavement or any stressful situation that makes it difficult to concentrate. In fact, older people are often accused or accuse themselves of memory changes which are not really taking place. If a person in his thirties misplaces keys or a wallet, forgets the name of a neighbor, or calls one sibling by another's name, nobody gives it a second thought. But the same normal forgetfulness for people in their seventies may raise unjustifiable concern. On the other hand, serious memory difficulties should not be dismissed as an unavoidable part of normal aging. Since rigorous studies on intelligence in later life show that healthy people who stay intellectually active maintain a sharp mind throughout the life cycle, noticeable decline in older adults that interferes with functioning should be clinically explored for an underlying problem.


The Importance of a Comprehensive Clinical Evaluation

Because of the many other disorders that can be confused with Alzheimer's disease, a comprehensive clinical evaluation is essential to arrive at a correct diagnosis of symptoms that look like those of Alzheimer's disease. Such an assessment should include at least three major components--(1) a thorough general medical workup, (2) a neurological examination, and (3) a psychiatric evaluation that may include psychological or psychometric testing. The family physician can be consulted about the best way to get the necessary examinations.


George tried to get Mary Ellen to see their family physician but she refused. Finally, he suggested that they both go in to have their blood pressure checked. The doctor was shocked at the deterioration in Mary Ellen's personality and scheduled a complete physical examination for her. He also made an appointment with a neurologist for further neurological examination, including a CAT scan. A psychiatrist working in the same office conducted a psychiatric evaluation. George helped by giving them many details of Mary Ellen's history. A tentative diagnosis of Alzheimer's disease was made, and George was instructed to bring Mary Ellen back in 6 months for further evaluation. George still hoped that Mary Ellen's condition was temporary and told no one of his distress. When their two daughters called, he always made excuses as to why their mother did not answer the telephone. He neglected his writing as more of his time was taken up with household tasks that Mary Ellen no longer even tried to do.

 

The Search For The Cause Of Alzheimer's Disease

Alzheimer's disease has emerged as one of the great mysteries in modern day medicine, with a growing number of clues but still no answers as to its cause. The quest to uncover its cause has the air of a veritable whodunit saga. Though none of the leading theories about the genesis of Alzheimer's disease has resolved the mystery, each has led to certain intriguing findings that suggest further investigation is needed. It is important to examine these theories, not only to understand current thinking on Alzheimer's disease, but also to learn what popular ideas have proved to be incorrect. There have been at least five prominent theories about the cause of Alzheimer's disease:


1. Chemical Theories

(Deficiencies and Toxic Excesses)

A. Biochemical Changes in Growth (Trophic) Factors: Much research is taking place in the examination of naturally occurring substances that may affect the nervous system and that may contribute to the dysfunction or death of brain cells in Alzheimer's. It is possible that one reason for nerve cell death in Alzheimer's patients is a decline in growth-promoting factors that maintain the functioning of brain cells, or, conversely, a spontaneous increase in factors that are toxic to brain cells.

A naturally occurring substance of interest is nerve growth factor (NGF). Experiments in aged rats indicate that specific nerve growth factors can stimulate the growth of new synaptic connections in the hippocampus and, as a result, restore some memory loss. Although there could be neurotoxic as well as growth-enhancing effects in the use of NGF, scientists are investigating methods of safely introducing NGF into the brain, possibly through the transplant of genetically engineered cells.

Other research is exploring whether changes or an imbalance in the metabolism of certain elements like calcium in brain cells may be part of the process by which the cells degenerate and die in Alzheimer's disease.

B. Chemical Deficiencies: One of the ways in which brain cells communicate with one another is through chemicals called neurotransmitters. Studies of Alzheimer's disease brains have uncovered diminished levels of various neurotransmitters that are thought to influence intellectual functioning and behavior. For example, reduced levels of the neurotransmitter acetylcholine (ACh) have been found in Alzheimer's disease. This finding has been coupled with observations that drugs whose side effects lower ACh levels in the brain can cause reversible memory problems. These findings have led to a number of drug studies employing pharmacologic agents to elevate ACh in patients. The treatments have included lecithin, choline, physostigmine, deprenyl, tacrine hydrochloride (THA), and others, used alone or in different combinations with one another. The results of these experiments are difficult to interpret. In some of these studies, a few Alzheimer's disease patients seem to show minor improvement over a brief but not sustained period of time. Typically, any improvement may be on certain narrow test measures--and not usually on significant activities of daily living which would be more important to the person's family and physician. Nonetheless, the researchers' enthusiasm is understandable, for they are dealing with the potential modifiability of underlying physiological phenomena that influence the Alzheimer's disease symptoms. The drugs they are studying now may not be the right ones, but they may point the way to the discovery of more effective pharmacologic agents.

One drug in particular, THA or tacrine (trade name, Cognex), has been studied extensively. Early studies indicated that THA appeared to have a slightly positive effect on patient functioning, but assessment by a skilled observer showed no overall improvement. More recent studies conducted on patients with mild or moderate Alzheimer's, using a higher dosage of tacrine than the earlier studies, showed a statistically significant improvement, both in clinical and caregiver evaluations and in quality of life measurements. These results caused the Food and Drug Administration in the fall of 1993 to approve the drug. Tacrine can, however, have side effects, including elevation of liver functioning tests. The family of the patient should be aware that the patient must take the medication 4 times a day, that blood must be drawn weekly during the dose adjustment phase, and that a third of patients experience significant adverse effects. As is always the case, but particularly while better drugs are being developed, caregivers and patients will have to weigh the possible benefits of the available drug against the cost and the potential problems incurred.

C. Toxic Chemical Excesses: Although some researchers have found increased levels of aluminum, mercury, or other metals in the brains of Alzheimer's disease victims, others have not. And while some investigators have hypothesized that aluminum may play a role in the genesis of Alzheimer's disease, most have regarded aluminum as an effect of the disorder rather than its cause. In other words, instead of aluminum's acting to induce brain tissue changes in Alzheimer's disease, it more likely accumulates in response to such changes. Research continues in an effort to better understand this phenomenon and to determine whether the aluminum deposits are a cause or a consequence of the disease, and, if the latter, whether they contribute further to the impairment already experienced.


2. The Genetic Theory

Genetic aspects of many diseases are confusing. For example, a disorder can occur more frequently in certain families than in others, but still not be genetic. Since family members living together are exposed to the same environment, they would all be at increased risk if an environmental toxin or infectious agent were the causative factor in a particular disease. Furthermore, a disorder can be congenital and not hereditary--that is, prenatal problems can cause developmental defects not brought on by heredity. And an illness can be hereditary but remain in a latent state if some other disease factor does not occur to trigger its onset.

Several connections between Alzheimer's disease and Down's syndrome led researchers initially to look for genetic factors in Alzheimer's disease on chromosome 21--the chromosome that is affected in Down's syndrome. At the present time, several genetic markers have been identified on chromosomes 21 and 14 in that small number of families where Alzheimer's disease has occurred with unusual frequency at relatively early ages. In families where the disease has tended to develop at later ages, other studies suggest that Alzheimer's disease is unusually frequent in persons who have a particular form of the apolipoprotein E (ApoE) gene found on chromosome 19. Only a minority of the general population show this version (ApoE4) of the gene, out of several variants that occur.

Despite these findings, the extent of genetic and hereditary involvement in Alzheimer's disease remains unclear. There are a vast number of people affected with this disorder who are not part of a strong family pattern. Furthermore, the genetic factors associated with the disease clearly vary for different families. This has led some investigators to postulate that there may be a number of subtypes of Alzheimer's disease, with differing risk factors and causes.

The National Institute of Mental Health (NIMH) is supporting research to locate the genes that cause Alzheimer's disease, schizophrenia, and manic depression. Ten diagnostic centers, three of which study Alzheimer's, provide genetic material to a central gene bank. Scientists at the centers use identical diagnostic tests, chosen for their sensitivity and reliability, to select members of families whose blood is sent to the gene bank for processing, storage, and distribution. Participating families must have several members affected by one of the diseases. The centers studying Alzheimer's are: The Johns Hopkins University, Baltimore, Maryland; Massachusetts General Hospital, Boston, Massachusetts; and University of Alabama, Birmingham, Alabama.


3. The Autoimmune Theory

The body's immune system, which protects against potentially harmful foreign invaders, may erroneously begin to attack its own tissues, producing antibodies to its own essential cells. This is called an autoimmune response, and it may take place in the brain. Some scientists speculate that certain late life changes in aging neurons (the major nerve cells of the brain) might be triggering an autoimmune response that evokes symptoms of Alzheimer's disease in vulnerable individuals. Curiously, some antibrain antibodies have been identified in the brains of those with Alzheimer's disease. Their significance, though, is not known, especially since some antibrain antibodies have also been identified in aging brains without Alzheimer's disease. Moreover, even if changes are occurring in brain neurons to trigger an autoimmune response, what originally induces these brain cell changes is not known.


4. The Slow Virus Theory

Because a slow-acting virus has been identified as a cause of some brain disorders that closely resemble Alzheimer's disease (for example, Creutzfeldt-Jakob disease), a slow virus has been postulated in Alzheimer's disease. Various researchers have suggested that suspicious brain tissue changes in Alzheimer's disease victims may be caused by a virus. However, to date a virus has not been isolated from the brains of those with Alzheimer's disease, and no immune reaction has been found in the brains of Alzheimer's patients, comparable to that found in patients with other viral dementias. At present, the possibility of a viral cause of Alzheimer's cannot be either decisively eliminated or confirmed.


5. The Blood Vessel Theory

Defects in blood vessels supplying blood to the brain have been studied as a possible cause of Alzheimer's disease. Hardening of the brain's arteries, also known as cerebroarteriosclerosis, proved not to be a cause of Alzheimer's disease. Thus, the hyperbaric oxygen chamber treatment proved ineffective as a therapy for Alzheimer's.

Stroke, another blood vessel problem that most often occurs later in life, can cause symptoms like those of Alzheimer's disease. But this condition, called multi-infarct dementia, differs from Alzheimer's disease. More recently, the blood vessel theory has been expanded to hypothesize potential defects in the blood-brain barrier, a protective membrane-like mechanism that guards the brain from foreign bodies or toxic agents circulating in the blood stream outside the brain.

There have been several reports of a possible association between serious head injuries involving a loss of consciousness and later onset of Alzheimer's disease. One theory as to why this connection might occur has to do with possible breaks in the blood-brain barrier as a result of these injuries to the brain.