In: L. Nadel & Donna Rosenthal (Eds.). Down Syndrome: Living and Learning in the Community.
Copyright ©1995, pp. 58-64.
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CASE HISTORY: DAVID
Mr. and Mrs. Davis of Indianapolis, Indiana, have recently described a lifetime of affectionate caring and support for David, their 46-year-old son with Down syndrome, who is now suffering from some of the signs of Alzheimer disease (Davis, 1992). David showed the first signs when he was about 33 years of age. He was slowing down and unable to perform in the workshop program the way he used to. He developed difficulties in bowling, one of his favorite leisure activities. He then developed seizures which, at first, were poorly controlled by medication that caused unexpectedly serious side effects. He now needs more or less continuous care, is disoriented, and no longer seems to enjoy watching television. His mood changes suddenly and his vision is becoming poor. He has hearing difficulties that make it hard to communicate with him. He now has dental, digestive, and elimination problems. For his parents, David has become more than they can cope with. They feel the agonizing impact of their own diminishing stamina at this stage in their lives. This story is gradually becoming more common as individuals with Down syndrome live longer and healthier lives under the care of their family or service providers and, consequently, face an increased risk of Alzheimer disease. Unfortunately, our understanding of the causes, diagnosis, treatment and prevention of Alzheimer disease and its relationships with Down syndrome are very limited at the present time.
ALZHEIMER DISEASE: WHAT IS IT?
Alzheimer disease is a fatal, progressive, degenerative disease of the brain that affects about 11% of all individuals over the age of 60 years (Terry, 1976). There are distinctive changes in the brain of affected individuals, including the loss of millions of nerve cells and the widespread appearance of senile plaques and neurofibrillary tangles, which have been described by many investigators (for example, Wolstenholme and O'Connor, 1970; Katzman et al., 1978). Over a period of years, these physical changes in the brain cause significant deterioration of its intellectual and communication capabilities and the skills of daily life, and, ultimately, all of its other functions. The most evident symptoms of Alzheimer disease may appear as barely subtle changes in memory followed by increasing difficulties in language and orientation and decline in mobility. These signs may then be followed by changes in personality and a gradual deterioration in many other functions over a period lasting from as little as a year to longer than 20 years. However, each person affected with Alzheimer disease will show only some of the signs, these will be different from person to person and they will not necessarily appear in the same sequence as the disease progresses.
SUSCEPTIBILITY OF PERSONS WITH DOWN SYNDROME TO ALZHEIMER DISEASE
Individuals with Down syndrome are uniquely susceptible to Alzheimer disease. It has been known for more than 60 years that the brains of nearly all individuals with Down syndrome who die after the age of 40 years show clear-cut evidence of Alzheimer disease (Struwe, 1929). However, there are a few exceptions. Whalley (1982) reported the absence of any pathology in the brain of a 49-year-old woman with Down syndrome and a similar report has been made by Janota (in an article by Sylvester, 1984) from examination of the brain of a 4-year-old person with Down syndrome.
There is a large gap in our knowledge about the characteristics of the clinical manifestations and course of Alzheimer disease in persons with Down syndrome (Dalton, 1992). The clinical signs and symptoms of Alzheimer disease in persons with Down syndrome were first described in English by Jervis (1948), and reviews of the current status of knowledge are numerous (see, for example, Lott, 1982; Sinex and Merril, 1982; Dalton and Crapper-McLachian, 1986; Dalton and Wisniewski, 1990; Schupf et al., 1990; Dalton et al., 1993). The symptoms, though difficult to observe for many reasons, seem to be similar in persons with Down syndrome when compared to those from the general population who develop Alzheimer disease. The chief difference seems to be the age of onset. Persons with Down syndrome develop symptoms 20-25 years earlier. While it is generally assumed that the brains of most (if not all) individuals with Down syndrome will have the characteristic brain lesions of Alzheimer disease, it is equally apparent that not all of them will develop the clinical manifestations of dementia. Explanations for this situations have been numerous and many speculations have been offered (see reviews by Rabe et al., 1990; Oliver and Holland, 1986; Wisniewski and Rabe, 1986). To complicate matters further, it has not been conclusively shown that the brain pathology and the possible factors that produce it are identical in persons with Down syndrome and those with Alzheimer disease without Down syndrome.
CAUSES OF ALZHEIMER DISEASE: UNKNOWN
The loss of millions of brain cells is the most dramatic physical evidence of the disease. The process whereby these nerve cells die in such numbers and the significance of the selective losses in particular regions (such as the nucleus basalis) and the death of specific types of nerve cells are not known. The search for infectious or transmissible agents, genetic or inherited abnormalities, and environmental toxins have yielded a large and important body of knowledge but no specific cause(s) for Alzheimer disease has been established. No infectious or viral agent has yet been identified and there have been no reported instances of one affected person transmitting the disease to any other. The neurofibrillary tangles and the senile plaques which are found in widespread regions of the brains of affected individuals have been the subject of intense research over many years (see recent reviews by Iqbal et al., 1993; Wisniewski and Wisniewski, 1992) and data from such studies hold promise for the development of potential bio-markers useful in diagnosis and rational approaches to drug therapies. Unfortunately, it is not clear whether the neurofibrillary tangles and/or the senile plaques are causes of Alzheimer disease or whether they simply represent the debris or consequences of some as yet undetermined process of unidentified causative event. The possibility of a genetic basis for Alzheimer disease has received a significant boost since the discovery of a location on chromosome 21 for the genetic blueprint for an important protein associated with deposits of betaamyloid in senile plaques and blood vessels of the brain (Robakis et al., 1987). While this gene may lead to the overproduction of beta-amyloid, there is no proof that it causes Alzheimer disease either. Understanding the molecular events involved in the production, breakdown, modification, and regulation of beta-amyloid may yield important new treatment strategies.
DIAGNOSIS OF ALZHEIMER DISEASE
There is no test or procedure that can identify the presence of Alzheimer disease before the onset of clinical manifestations. Furthermore, there is no test that adequately monitors the total range of deficits induced by Alzheimer disease and no single test is useful throughout the entire course of the disease (Dalton et al., 1993). Of particular significance, diagnosis of individuals with Down syndrome must rely on procedures that have been developed for individuals who do not have Down syndrome. Some of these procedures can be expected to yield incorrect information because many diagnosticians do not have sufficient experience with individuals with Down syndrome. Therefore, follow-up evaluations conducted at appropriate intervals may be particularly important to help improve the accuracy of diagnosis. Because there is no specific test for Alzheimer disease, evaluation must be sufficiently extensive to rule out every other possible explanation. A "tentative" diagnosis of Alzheimer disease can then be given on the basis of exclusion. These procedures rely heavily on the report of behavioral, psychological, and other changes reported by family members or care and service providers who have constant association with the affected individual. The diagnostic procedures may involve several stages spread over several weeks or months and include a visit to a neurologist specializing in the functions and disorders of the brain. Laboratory studies of blood specimens will be required to rule out a long list of possibilities. An electrocardiogram to assess heart function, an electroencephalogram to assess abnormal electrical brain activity, imaging studies using a computerized brain scan (CTT) or magnetic resonance image (MRI) to assess the possibility of brain tumors or other physical abnormality in the brain, and neuropsychological evaluations to assess learning, memory, intellectual. and other aspects of psychological function may also be included in the evaluation. An accurate diagnosis is very important because the prognosis for Alzheimer disease is so poor and there are many conditions that resemble Alzheimer disease but could be effectively treated if detected and correctly identified. Some of these problems have been addressed recently in a review of the clinical aspects of the association between Alzheimer disease and Down syndrome (Dalton et al., 1993). Diagnosis of Alzheimer disease among persons with Down syndrome is difficult to make. Many treatable conditions, such as thyroid abnormality, vitamin deficiency, or depression, can be confused with Alzheimer disease. Moreover, some conditions occur more often not because the individual is growing older but because of the extra chromosome 21 present in each cell. Examples of such conditions include sleep apnea, cataracts, susceptibility to influenza and other infections, as well as epilepsy. Increased aggressiveness and acting-out behaviors may not be related to Alzheimer disease. While all individuals with Down syndrome are at risk, some are known to have lived as long as 82 years of age and retained all of the functional competencies they possessed throughout their lifetime. The Office of Mental Retardation of the State of New York has information on more than 230 living persons with Down syndrome living in New York State who are 60 years of age or older and, of these, more than 50 persons are over 70 years of age at the present time. Unfortunately, the current health status of these individuals, including the incidence and prevalence of Alzheimer disease, is not known. Preliminary data bearing on this issue has been described in a recent survey conducted in New York State. In a recent survey in New York State 244 (1.6%) out of 6840 individuals with Down syndrome over 40 years of age who are receiving services from New York State institutions and not-for-profit service providers have been diagnosed or suspected of having Alzheimer disease (Janicki and Dalton, 1993). Half of those suspected or diagnosed with Alzheimer disease were individuals with Down syndrome, indicating that this diagnosis is four to five times more common among individuals with Down syndrome than other developmentally handicapped individuals of comparable age, level of function, health, and lifestyle factors.
This report has focused on Alzheimer disease because it is one of the most important health problems of growing older with Down syndrome. Unfortunately, the existing knowledge on the subject has been almost entirely published in technical journals, which are easily accessible only to those who can find their way through the complexities of information retrieval systems of university libraries. Public awareness has heightened to such an extent in the past 15 years that Alzheimer disease has become a household word and a term that may be incorrectly assigned to an older person with Down syndrome who is showing any change in conduct or behavior. Our incomplete understanding of Alzheimer disease and its connection with Down syndrome has a major impact on everyone affected as well as their families and care providers. Accurate diagnosis is particularly crucial because of the complex interplay of the life-long impact of the trisomy condition, with its more familiar age-related changes in sensory, motor, language, communication, and intellectual abilities, with the subtle, insidious alterations in functions caused by Alzheimer disease. Proper recognition, sensitivity, and greater attention to the individual's needs are essential elements in maintenance of quality of life at this time in the life of the aging person with Down syndrome as well as lessening the impact on family members and caring service providers. Inaccurate diagnosis also hampers research studies that seek to establish the incidence and prevalence of Alzheimer disease, to identify as yet unknown risk factors, and to establish patterns of disease frequency and severity among family members and relatives.
This report was supported in part by NIA grant 5ROI-AGO8849 and a grant from the Velleman Foundation.
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