In the final phase, the patient becomes aimless and may hallucinate or be restless and agitated. Language disorders can occur in late stages. Abnormal neurological reflexes, indicative of loss of higher neural inhibition, are common. Not all patients with Alzheimer-type senile dementia demonstrate the classic evolution of symptoms. Although almost all patients have some memory impairment, other focal cortical de ficits may predominate initiall y. Spatial relationship impairment is common early.
The patient may also complain of word-finding difficulty or demonstrate mild problems in speaking and understanding. In cases where damage to the frontal lobes of the brain predominates, the patient presents with judgment problems. In the absence of biological markers for the illness, it is not surprising that clinical diagnosis may be less than accurate and, in fact, may be correct in as few as one-half of Alzheimer-type senile dementia cases. Not only do cognitive changes associated with normal aging overlap those found in the early stages of dementia, but also a wide spectrum of conditions may produce dementia. In any given patient, several conditions leading to progressive cognitive decline may occur simultaneously.
The clinical diagnosis of Alzheimer-type senile dementia always requires documentation of progression. Reports from family and friends provide the most valid measures of cognitive decline in elderly persons and support the clinician’s judgment that global intellectual deterioration has occurred. Progression is usually gradual but with fluctuation of symptom severity. The patient may react very dramatically to changes in the living situation, to losses of friends or relatives, or even to admission to the hospital for evaluation.
These acute changes probably represent withdrawal of orienting stimuli and emotional distress rather than progression of the disease process. Psychometric tests may be useful in delineating patterns of cognitive deficit at various stages of severity and in identifying the qualitative aspects of performance deficit. Although laboratory tests are sometimes used to support the diagnosis of Alzheimer’s disease, the laboratory is actually more useful in excluding other causes of cognitive deterioration.
Atrophy of the cerebral cortex is often seen on computed tomography, but it is frequently overinterpreted. Alzheimer’s disease may be difficult to distinguish from the progressive dementias that are caused by many other disease conditions. For example, dementia is common in patients with terminal cancer and may result from a variety of causes. The evaluation of a patient presenting with dementia often reveals untreatable causes, but treatable dementia is discovered in 20–25 percent of such patients. Of the many treatable causes of dementia, multi-infarct dementia may be the most difficult to differentiate from Alzheimer’s disease. Risk factors for stroke should be evaluated and controlled when possible in every patient with early dementia. Depression is the most common treatable illness that may masquerade as Alzheimer-type senile dementia.
Cognitive abilities return to baseline levels when depression is treated. Because some patients with early dementia have secondary depression, dementia and pseudodementia may be difficult to differentiate. The depression that occurs in the early stages of Alzheimer-type senile dementia tends to resolve as the disease progresses. Pseudodemented, depressed patients are apt to have poor attention, inconsistent cognitive changes, absence of cortical signs, weight loss, sleep disturbance, guilt, poor self-esteem, a past personal family psychiatric history, and a more rapid onset. In contrast, patients with cortical dementia of the Alzheimer type often show insidious onset, slow progression, early loss of insight, amnesia for remote and recent events, spatial disorientation, reduction in spontaneous speech, and occasionally aphasia.
Agnosia, apraxia, increased muscular tension, and abnormal neurological reflexes may also be present. A wide variety of gross morphological and microscopic changes occur in the brains of patients with Alzheimer’s disease. Unfortunately, many of these changes are difficult to distinguish from alterations that occur in the brains of normal elderly persons, who also show some atrophy of white matter and, to a lesser extent, gray matter.
Although it is generally recognized that genetic influences are important in Alzheimer’s disease, the exact nature of these genetic influences also remains unclear. Some families have a large number of members with the clinical or pathological diagnosis of Alzheimer ’s disease. The most important practical point regarding these kindreds is that most of them meet criteria for autosomal dominant inheritance. Penetrance of the gene exceeds 90 percent in most of these families. As a result, the children of an affected person have a 50 percent risk of developing dementia if they survive to the age at which dementia begins in that family. The exact proportion of familial cases is unknown, but they may account for as many as 10 percent of all cases of Alzheimer-type dementia.
There is some familial clustering in families without dominant inheritance. It appears that concordance for dementia is somewhat higher in monozygotic versus dizygotic twins, suggesting genetic factors. On the other hand, concordance is not 100 percent, so environmental factors must have a role. Because age of onset varies within a twin pair, it may be difficult to be certain whether a given pair is truly discordant. An association has been shown also between Alzheimer’s disease and families that produce children with Down syndrome.
Further support for a link between Down syndrome and Alzheimer’s disease is provided by the fact that patients with Down syndrome tend to demonstrate neuropathological findings consistent with Alzheimer-type senile dementia if they live to adult life. Because Down syndrome represents a disorder of chromosome 21, a point of origin for the search for the genetic determinants of Alzheimer’s disease is suggested. Recent data favor the hypothesis of a genetically induced overproduction of amyloid protein as a factor in the cause of Alzheimer’s disease.
When families request genetic counseling, one can explain only what is known about the genetic factors. In a family with a single Alzheimer victim, the lifetime risk for a close relative also to develop dementia is approximately 10 percent. Because most dementia develops after the age of 70, this is a relatively small probability.
In families with dementia occurring over several generations, an autosomal dominant inheritance is probable, and the risk for children of an affected parent may approach 50 percent. In these families, optimum health management indicates the suspicion of dementia in every elderl y person with altered environmentalsocial interactional skills, multiple physical complaints in the absence of objective disease, or vague and unclear history.
Autopsy can be suggested to confirm diagnosis to trace the pedigree more accurately. Environmental causes for Alzheimer’s disease have also been suggested. Some investigators have linked focal intranuclear accumulation of aluminum to the presence of neurofibrillary degeneration in hippocampal neurons.
The relationship of aluminum to Alzheimer-type senile dementia, however, is not well accepted. General decline of immunologic competence with aging suggests an autoimmune mechanism. Although elevated levels of brain antibody have been demonstrated in Alzheimer ’s disease, antineuronal antibodies have not been demonstrated in the central nervous system. Serum protein abnormalities have been demonstrated, notably changes in haptoglobin functions. Finally, a viral cause has been proposed but not substantiated.
Alzheimer’s disease remains a major challenge not only to modern medicine but also to the health care delivery system and to society at large. Not only is further research necessary in the diagnosis and management of the disease itself, but also major changes are necessary in the health care delivery system if patients afflicted with this illness are to get the care that they need.
History
Although Alzheimer’s disease has only recently become widely known, it doubtless has a long history under such rubrics as “senility,” “hardening of the arteries,” and “dementia,” to name but a few.Certainly senility and dementia are conditions that have been recognized for millennia. The Assyrians, Greeks, and Romans all knew and described them. J. Esquirol, however, has been credited for the first modern description, in 183 8, of what seems to have been Alzheimer’s disease. Esquirol wrote of a “senile dementia” that increases with age. Seven years later, Wilhelm Griesinger published a textbook on mental disease that clearly recognized the condition of “presenile dementia” caused by brain atrophy found at autopsy.
Neither of these reports, however, seems to have had much influence on investigators at the time. It was during the latter half of the nineteenth century that public as well as scientific concern for problems of the elderly increased considerably. With that concern came the birth of the field of geriatrics and increasing attention paid to dementia in the elderly. Much of the effort during these decades focused on whether it was an inevitable product of aging or an actual disease. Emil Kraepelin, one of the founders of modern psychiatry, pointed out the difficulty in separating normal senility from senile dementia. In applying the new technique of silver staining, Alzheimer, his student, identified a new neuropathological marker of dementia in the brain of a patient who had died at age 55 after a 4-year illness.
This marker was the neurofibrillary tangle, which he speculated was the marker of a dead cell. Alzheimer thus made the first correlation between clinical characteristics of dementia in a patient and pathological lesions in the brain. Kraepelin later named the illness “Alzheimer’s disease” in honor of his former pupil. The question then became one of determining if this disease was the same as senile dementia. It revolved around the ancient problem of what pathological changes can be attributed to aging as opposed to other causes.
Kraepelin had emphasized the presenile nature of Alzheimer’s disease, yet because of its similarity to senile dementia some investigators suggested that Alzheimer’s disease might be caused by “a premature onset of the aging process.” Also confusing the picture was the nineteenth century notion that extended also into the twentieth century: that cerebral arteriosclerosis might be the cause of senile dementia. By the late 1920s, there had been a sufficient accumulation of case descriptions of dementia among the elderly that statistical analysis could be brought to bear on the problem. It was found that most of the cases did in fact occur between the ages of 50 and 60, sustaining the notion of its presenile nature. In 1955 Martin Roth showed that mental changes could be triggered by a variety of both “functional” and “organic” diseases, and by the 1960s two major groups of researchers were at work on Alzheimer’s disease.
One, headed by Robert Terry, was based at Albert Einstein University, and the other, headed by Bernard Tomlinson, Gary Blessed, and Roth, was located at Newcastle upon Tyne. From their work and from other studies, it became apparent, among other things, that the changes in the brain found in cases of presenile dementia were the same as those in senile dementia. The discovery broadened the definition of Alzheimer’s disease and thereby increased enormously the number of individuals viewed as victims of it.
It also created major semantic problems. Previously, the presenile nature of Alzheimer’s disease was a de fining factor. Now the illness, shown to be a major affliction of the elderly population, was called senile dementia of the Alzheimer type (SDAT), which psychiatrists call “primary degenerative dementia.” Senile dementia has been used to mean either SDAT or Alzheimer’s disease, but it may also refer to other forms of dementia in the elderly. In addition, Alzheimer’s disease and senile dementia were often lumped together as senility or as cerebral arteriosclerosis.
This latter concept proved to be so tenacious that even as late as the middle 1970 s it was called “probably the most common medical misdiagnosis” of the cause of mental deterioration in the elderly. In the early 1980s, Alzheimer’s disease was defined as an “age-associated cognitive decline of gradual onset and course, accompanied by Alzheimer-type neuropathologic brain changes” with “no distinction with respect to age of onset,” and was thought to be responsible for 50 percent or more of all dementias. Experts at a 1990 conference on the illness believed that Alzheimer’s disease is being diagnosed correctly in about 80 percent of cases, even though such diagnoses can be con firmed only after death, and even though the etiology and epidemiology of the disease remain obscure. It may well be determined that Alzheimer’s disease is not a single disease but, rather, many different diseases with multiple causes ranging from genetics to exogenous toxins.
The extent to which age and aging will rank among those causes remains a subject of debate. Reports of the condition among individuals in their 30s have been used to support the contention that the disease is unrelated to aging. On the other hand, there is a rising prevalence with age, such that by age 85 and over, some 20 percent or more are demented. If, of course, Alzheimer’s disease is a specific disease or diseases (as opposed to an inevitable product of the aging process for some 5–7 percent of the population over age 65), then, of course, there is hope for a cure. The question, however, of why Alzheimer’s disease has been called the disease of this century – one that has only recently burst upon the developed world in epidemic proportions – is certainly bound up with advancing age for many and with the demographic changes that this has wrought. In 1900, there were only 3 million Americans aged 65 or older.
Today there are more than 27 million, and it has been estimated that in the year 2030 there will be 50 million. Given the fact that an individual who lives to be 80 has an almost 1:4 chance of developing Alzheimer’s disease or a related disorder, estimates suggest that the number of these victims will increase to about 4 million by the turn of the century. As the 1990s began, it was further estimated that fully half of all nursing home patients in the United States were Alzheimer victims.
The implications of the growing number of these victims for health care delivery systems are staggering. In 1967 a White House conference on aging resulted in the creation of the National Institute on Aging, which greatly facilitated research on Alzheimer’s disease. In 1983, a Task Force on Alzheimer’s Disease was created by the Department of Health and Human Services, which has emphasized the need for increased research and increased research funding, and in 1987 the international journal Alzheimer’s Disease and Associated Disorders was founded to report such research. As more and more resources are brought to bear, the outlook for breakthroughs in understanding the causes of Alzheimer’s disease and treating it are more optimistic than in former times. But it remains a devastating disease whose etiology is unknown.
Joseph A. Kwentus
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