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Will the study of down syndrome solve the riddle of alzheimer disease?
CURRENT LITERATURE AND CLINICAL ISSUES
Will the study of Down syndrome solve the riddle of Alzheimer disease? Older patients with Down syndrome have a propensitY to develop a neurologic sYndrome that has striking similarities to Alzheimer disease~: dementia, identical neuropathologic abnormalities in the brain, and characteristic alterations in the concentrations of certain CNS neurotransmitters. In addition there are genetic links between Alzheimer disease and Down syndrome, and in patients or their families with both diseases there are abnormalities of the immune system and increased risks for malignancies. Discovering the means by which the presence of extra chomosomal material predisposes patients with Down syndrome to Alzheimer disease may provide important clues toward understanding the pathogenesis of Alzheimer disease. The onset of the dementia in Alzheimer disease is characterized by a gradual loss of memory for recent events. As the disease progresses, the ability to manage daily affairs is impaired because of deterioration of cognition and memory as well as personality changes. The affected individual finally loses the ability to communicate and becomes bedridden. Defining dementia in retarded individuals is somewhat more difficult, particularly in recognizing the early stages. 2,3 The dementia of Down syndrome rarely occurs before 30 years Of age, and usually after age 40 years. The dementia is characterized by deterioration of mental and emotional responses, apathy or excitement, irritability, temper tantrums, and loss of previously acquired vocabulary. The cheerfulness and affection often noted in patients with Down syndrome is replaced by solemnness. There is a decline in personal habits of cleanliness and the ability to perform activities of daily living. The dementia associated with Atzheimer disease ofte n progresses over years, whereas in Down syndrome it may run its course over months. The exact frequency of dementia in Down syndrome is uncertain, but may be in the order of 30% in older patients. Cross-sectional studies of psychometric functions in populations of patients with Down syndrome reveal deficiencies in performance in patients older than 35 years of age compared with those Younger than age 35. Declines in recent memory as well as short-term Visual retention and difficulties in object identi-
fication are noted. Patients with other forms of retardation do not show similar changes, and thus the decline in performance appears to be specifc for Down syndrome. This gradual deterioration has led some authors to suggest that all patients with Down syndrome would develop dementia if they were to live long enough. Neuropathologic changes in Alzheimer disease and Down syndrome are identical. 47 The two major changes are the presence of neuritic plaques and neurofibrillary tangles. The plaques consist of abnormal neurites, mainly unmyelinated axon terminals, associated with extracellular amyloid. Tangles are compromised of accumulations of paired helical filaments found in the Perikarya of neurons. The risk to patients with Down syndrome for developing these changes begins in early life and increases rap!dly with age. Patients with Down syndrome have a much higher incidence o f these neuropathologic changes than any other known population, and develop them at a much younger age than do patient s with Alzheimer disease. Although almost 100% of patients with Down syndrome older than 30 years have these neuropathologic changes, not all have dementia. Patients with Down syndrome and dementia have a greater density of plaques and tangles than do nondemented patients. These findings suggest that there is a correlation among dementia, density of plaques and tangles, and age. Families of patients with Alzheimer disease are at an increased risk for both secondary cases of Alzheimer disease and Down syndrome. ~,8~ The increased risk for secondary cases of Alzheimer disease is particularly high in families in whom the index case develops the disease at a young age. The risk for developing Down syndrome in relatives of Alzheimer disease probands is approximately two and one-half times that compared in control populations. Down syndrome is concentrated among families most severely affected With Alzheimer disease, particularly those with early onset and higher risks to relatives. There have been two families in which the dementia was associated with 15/21 translocation carrier state. In each family there was early onset of severe dementia in phenotypically
627
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normal carriers of the translocation chromosome. Both demented patients had parents who were phenotypically normal carriers. This suggests that some small change in the amount of chromosomal material passed from the phenotypically normal carrier parent to child may have been associated with the development of dementia. An additional genetically linked similarity between the two conditions is the finding of an increased incidence of lymphoproliferative cancers among relatives of Alzheimer disease probands and an excessive incidence of leukemia among patients with Down syndrome. The hallmark of the neurotransmffter abnormalities in Alzheimer disease is a defect in cholinergic transmissi0n.L ~2-L4Brain tissue of patients with Alzheimer disease has decreased amounts of choline acetyltransferase. Studies of tissue from patients with other causes of dementia reveal normal concentrations of this enzyme. Therefore, the decrease in Choline acetyltransferase appears to be a specific finding. The finding of a low concentration of choline acetyltransferase at the time of necropsy is also predictive of that patient having suffered dementia. Thus low concentrations are not found in patients who had normal intellect, but are always associated with dementia. Additional evidence of a defect in cholinergic transmission relates to the finding of a decreased concentration of the enzyme acetylcholinesterase. Decreased concentrations of these enzymes, of a comparable magnitude, have also been found in the brains of patients with dementia and Down syndrome. Brains of demented patients with Down syndrome and Alzheimer disease also show decreased concentrations of a variety of other neurotransmitters, including norepinephrine, tyrosine, dopamine, tryptophan, 5-hydroxytryptamine, and 5-hydroxyindolacetic acid. Abnormalities in the cerebral metabolic rate for glucose as measured with positron emission tomography and flUOrine 18-labeled 2-deoxy-o-glucose is abnormal in both conditions.t. ~5 In patients with Alzheimer disease there is decreased glucose utilization. In one patient, the cerebral metabolic rate for glucose was serially studied; deficits were found in the parietal lobes before the onset of dementia, when there was only mild memory impairment. In young adults with Down syndrome, increased glucose utilization has been found, compared with that in healthy age matched young controls. Moreover, when mildly and moderately retarded groups of patients with Down syndrome were compared, the lower functioning groups had significantly higher cerebral metabolic rates of glucose utilization in the parietal lobes. Older patients with Down 9syndrome have decreased rates of glucose utilization than do younger patients with the disorder. Demented patients with Down syndrome do not have significantly different
The Journal o f Pediatrics ' April 1986
rates from older nondemented patients, but they are significantly decreased compared with those of young patients With Down syndrome. This decrease occurring during the age ganges studied does not occur between young and old age-matched controls. Thug patients with Aizheimer disease and older patients with Down syndrome both exhibit decreased cerebral metabolic rates of glucose utilization. Patients with Down syndrome have increased mortality from infectious diseases and malignancy, and an increased incidence of aut0immune disorders. This suggests the possibility of immunologic abnormalities, z6,~7 Studies of immune function have yielded Conflicting resultsl but it is generally accepted that there is dysgammagl0bulinemia, a decreased absolute number and proportion of T Cells, and an increased incidence of autoantibodies to thyroid. With the exception of the dysgammaglobulinemia manifested by increased levels of IgG and IgD, and perhaPS those related to T cell function, the immunologic deficits in Down syndrome appear t o b e similar to those s e e n during senescence in normal individuals. However, the immunologic changes of aging are seen in patients with Down syndrome 20 years earlier th~in in normal adults. The immunologic changes seen i n patients with Alzheimer disease, other than those related to aging, consist of abnormalities in H L A typing. The results have been conflicting, but those H L A phenotypes that have been found to be increased in some studies of patients with Alzheimer disease include B7, Cw3, Cw6, and DR4; typing in patients with Down syndrome has shown normal profiles, in the familial form of Alzheimer disease, which is associated with an increased incidence of Down syndrome, there is no convincing evidence of segregation With HLA. Striking similarities and relationships between Alzheimer disease and Down syndrome exist. 1,18,~9 Alzheimer dise~ise appears to be related to aging in the normal population, and the dementia of Down syndrome appears to be related to the precocious aging seen in that disorder, How does the chromosomal abnormality in Down syndrome lead to the precocious aging and dementia? Are there interactions between genetic factors and environmental agents that produce the dementia, and which may occur in the normal population with aging and prematurely in patients with Down syndrome? Various causes have been proposed for Alzheimer disease, including viral (an unusu al infective agent such as associated With CreutzfeldtJakob disease), toxic, autoimmune, and genetic factors. Coulil the extra chromosomal material in Down syndrome lead to premature aging and a defect in immune surveillance , which occur precociously in these patients and in previously normal but older individuals who are susceptible
Volume 108 Number 4
Down syndrome and Alzheimer disease
to Alzheimer disease? This might explain the postulated abnormal response to an unusual infective agent, the increased incidence of malignancy, and the increased incidence of autoimmune disorders seen in Down syndrome. The stage is set, and the scenario is enticing. One may hope that the answers will be forthcoming in the near future.
Marvin A. Fishman M.D. Professor of Pediatrics and Neurology Director, Section of Child Neurology Baylor College o f Medicine Chief, Neurology Service Texas Children's Hospital Houston, Texas 77030 REFERENCES
I. Cutler NR, Heston LL, Davies P, Haxby JV, Schapiro MB. Alzheimer's disease and Down's syndrome: new insights. Ann intern Med 1985;103:566-578. 2. Dalton A J, Crapper DR, Sch!otterer GR. Alzheimer's disease in Down's syndrome:visual retention deficits. Cortex 1974; 10:366-377. 3. Thase ME, Tigner R, Smeltzer D J, Liss L. Age-related neuropsychologic/d deficits in Down's syndrome. Biol Psychiatry 1984i19:571-585. 4. Ropper AH, Williams RS. Relationship between plaques, tangles and dementia in Down syndrome. Neurology 1980; 30:639-644. 5. Ball M J, Nuttall K. Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down syndrome: quantitative comparison with Alzheimer-dementia. Ann Neurol 1980; 7:462-465. 6. Mann DMA, Yates PO, Marcyniuk B. Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of
7.
8.
9.
10.
11. 12.
13.
14.
15.
16. 17. 18. 19.
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pathological changes. Neuropathol Appl Neurobiol 1984; 10:185-207. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol 1985;17:278-282. Heston LL_ Alzheimer's disease, trisomy 21, and myeloproliferative disorders: associations suggesting a genetic diathesis. Science 1976;196:322-323. Heston LL. Alzheimer's dementia and Down's syndrome: genetic evidence suggesting an association. Ann N Y Acad Sci 1982;396:29-37. Heymari A, Wilkinson WE, Hurwitz BJ, Schmechel D, Sigmon AH, Weinberg T, Helms M J, Swift M. Alzheimer's disease: genetic aspects and associated clinical disorders. Ann Neurol 1983;14:507,515. Heston LL. Down's syndrome and Alzheimer's dementia: defining an association. Psychiatr Dev 1984;4:287-294. Yates CM, Simpson J, Maloney AFJ, Gordon A, Reid AH. Alzheimer-fike cholinergic deficiency in Down synizlrome. Laiacet 1980;2:979. ~(ates CM, Ritchie IM, Simpson J, Maloney AFJ, Gordon A. Noradrenaline in Alzheimer-type dementia and Down syndrome. Lancet 1981 ;2:39-40. Nyberg P, Carlsson A, Winblad B. Brain monoamines in cases with Down's syndrome with and without dementia. J Neural Transm 1982;55:289-299. Sizhwartz M, Duara R, Haxby J, Grady C, White BJ, Kessler RM, Kay AD, Cutler NR, Rapoport SI. Down's syndrome in adults: brain metabolism. Science 1983;221:781-783. Thase ME. Longevity and mortality in Down's syndrome. J Ment Defic Res 1982;26:177-192. Walford RL. Immunological studies of Down's syndrome and Alzheimer's disease. Ann N Y Acad Sci 1982;396:95-t 06. L0tt IT. Down's syndrome, aging, and Alzheimer's disease: a clinical review. Ann NY Acad Sci 1982;396:15-27. Price DL, Whitehonse P J, Struble RG, Coyle JT, Clark AW, Delong MR, Cork LC, Hedreen JC. Alzheimer's disease and Down's syndrome. Ann NY Acad Sci 1982;396:145:164.
Will the study of Down syndrome solve the riddle of Alzheimer disease? Older patients with Down syndrome have a propensitY to develop a neurologic sYndrome that has striking similarities to Alzheimer disease~: dementia, identical neuropathologic abnormalities in the brain, and characteristic alterations in the concentrations of certain CNS neurotransmitters. In addition there are genetic links between Alzheimer disease and Down syndrome, and in patients or their families with both diseases there are abnormalities of the immune system and increased risks for malignancies. Discovering the means by which the presence of extra chomosomal material predisposes patients with Down syndrome to Alzheimer disease may provide important clues toward understanding the pathogenesis of Alzheimer disease. The onset of the dementia in Alzheimer disease is characterized by a gradual loss of memory for recent events. As the disease progresses, the ability to manage daily affairs is impaired because of deterioration of cognition and memory as well as personality changes. The affected individual finally loses the ability to communicate and becomes bedridden. Defining dementia in retarded individuals is somewhat more difficult, particularly in recognizing the early stages. 2,3 The dementia of Down syndrome rarely occurs before 30 years Of age, and usually after age 40 years. The dementia is characterized by deterioration of mental and emotional responses, apathy or excitement, irritability, temper tantrums, and loss of previously acquired vocabulary. The cheerfulness and affection often noted in patients with Down syndrome is replaced by solemnness. There is a decline in personal habits of cleanliness and the ability to perform activities of daily living. The dementia associated with Atzheimer disease ofte n progresses over years, whereas in Down syndrome it may run its course over months. The exact frequency of dementia in Down syndrome is uncertain, but may be in the order of 30% in older patients. Cross-sectional studies of psychometric functions in populations of patients with Down syndrome reveal deficiencies in performance in patients older than 35 years of age compared with those Younger than age 35. Declines in recent memory as well as short-term Visual retention and difficulties in object identi-
fication are noted. Patients with other forms of retardation do not show similar changes, and thus the decline in performance appears to be specifc for Down syndrome. This gradual deterioration has led some authors to suggest that all patients with Down syndrome would develop dementia if they were to live long enough. Neuropathologic changes in Alzheimer disease and Down syndrome are identical. 47 The two major changes are the presence of neuritic plaques and neurofibrillary tangles. The plaques consist of abnormal neurites, mainly unmyelinated axon terminals, associated with extracellular amyloid. Tangles are compromised of accumulations of paired helical filaments found in the Perikarya of neurons. The risk to patients with Down syndrome for developing these changes begins in early life and increases rap!dly with age. Patients with Down syndrome have a much higher incidence o f these neuropathologic changes than any other known population, and develop them at a much younger age than do patient s with Alzheimer disease. Although almost 100% of patients with Down syndrome older than 30 years have these neuropathologic changes, not all have dementia. Patients with Down syndrome and dementia have a greater density of plaques and tangles than do nondemented patients. These findings suggest that there is a correlation among dementia, density of plaques and tangles, and age. Families of patients with Alzheimer disease are at an increased risk for both secondary cases of Alzheimer disease and Down syndrome. ~,8~ The increased risk for secondary cases of Alzheimer disease is particularly high in families in whom the index case develops the disease at a young age. The risk for developing Down syndrome in relatives of Alzheimer disease probands is approximately two and one-half times that compared in control populations. Down syndrome is concentrated among families most severely affected With Alzheimer disease, particularly those with early onset and higher risks to relatives. There have been two families in which the dementia was associated with 15/21 translocation carrier state. In each family there was early onset of severe dementia in phenotypically
627
628
Fishrnan
normal carriers of the translocation chromosome. Both demented patients had parents who were phenotypically normal carriers. This suggests that some small change in the amount of chromosomal material passed from the phenotypically normal carrier parent to child may have been associated with the development of dementia. An additional genetically linked similarity between the two conditions is the finding of an increased incidence of lymphoproliferative cancers among relatives of Alzheimer disease probands and an excessive incidence of leukemia among patients with Down syndrome. The hallmark of the neurotransmffter abnormalities in Alzheimer disease is a defect in cholinergic transmissi0n.L ~2-L4Brain tissue of patients with Alzheimer disease has decreased amounts of choline acetyltransferase. Studies of tissue from patients with other causes of dementia reveal normal concentrations of this enzyme. Therefore, the decrease in Choline acetyltransferase appears to be a specific finding. The finding of a low concentration of choline acetyltransferase at the time of necropsy is also predictive of that patient having suffered dementia. Thus low concentrations are not found in patients who had normal intellect, but are always associated with dementia. Additional evidence of a defect in cholinergic transmission relates to the finding of a decreased concentration of the enzyme acetylcholinesterase. Decreased concentrations of these enzymes, of a comparable magnitude, have also been found in the brains of patients with dementia and Down syndrome. Brains of demented patients with Down syndrome and Alzheimer disease also show decreased concentrations of a variety of other neurotransmitters, including norepinephrine, tyrosine, dopamine, tryptophan, 5-hydroxytryptamine, and 5-hydroxyindolacetic acid. Abnormalities in the cerebral metabolic rate for glucose as measured with positron emission tomography and flUOrine 18-labeled 2-deoxy-o-glucose is abnormal in both conditions.t. ~5 In patients with Alzheimer disease there is decreased glucose utilization. In one patient, the cerebral metabolic rate for glucose was serially studied; deficits were found in the parietal lobes before the onset of dementia, when there was only mild memory impairment. In young adults with Down syndrome, increased glucose utilization has been found, compared with that in healthy age matched young controls. Moreover, when mildly and moderately retarded groups of patients with Down syndrome were compared, the lower functioning groups had significantly higher cerebral metabolic rates of glucose utilization in the parietal lobes. Older patients with Down 9syndrome have decreased rates of glucose utilization than do younger patients with the disorder. Demented patients with Down syndrome do not have significantly different
The Journal o f Pediatrics ' April 1986
rates from older nondemented patients, but they are significantly decreased compared with those of young patients With Down syndrome. This decrease occurring during the age ganges studied does not occur between young and old age-matched controls. Thug patients with Aizheimer disease and older patients with Down syndrome both exhibit decreased cerebral metabolic rates of glucose utilization. Patients with Down syndrome have increased mortality from infectious diseases and malignancy, and an increased incidence of aut0immune disorders. This suggests the possibility of immunologic abnormalities, z6,~7 Studies of immune function have yielded Conflicting resultsl but it is generally accepted that there is dysgammagl0bulinemia, a decreased absolute number and proportion of T Cells, and an increased incidence of autoantibodies to thyroid. With the exception of the dysgammaglobulinemia manifested by increased levels of IgG and IgD, and perhaPS those related to T cell function, the immunologic deficits in Down syndrome appear t o b e similar to those s e e n during senescence in normal individuals. However, the immunologic changes of aging are seen in patients with Down syndrome 20 years earlier th~in in normal adults. The immunologic changes seen i n patients with Alzheimer disease, other than those related to aging, consist of abnormalities in H L A typing. The results have been conflicting, but those H L A phenotypes that have been found to be increased in some studies of patients with Alzheimer disease include B7, Cw3, Cw6, and DR4; typing in patients with Down syndrome has shown normal profiles, in the familial form of Alzheimer disease, which is associated with an increased incidence of Down syndrome, there is no convincing evidence of segregation With HLA. Striking similarities and relationships between Alzheimer disease and Down syndrome exist. 1,18,~9 Alzheimer dise~ise appears to be related to aging in the normal population, and the dementia of Down syndrome appears to be related to the precocious aging seen in that disorder, How does the chromosomal abnormality in Down syndrome lead to the precocious aging and dementia? Are there interactions between genetic factors and environmental agents that produce the dementia, and which may occur in the normal population with aging and prematurely in patients with Down syndrome? Various causes have been proposed for Alzheimer disease, including viral (an unusu al infective agent such as associated With CreutzfeldtJakob disease), toxic, autoimmune, and genetic factors. Coulil the extra chromosomal material in Down syndrome lead to premature aging and a defect in immune surveillance , which occur precociously in these patients and in previously normal but older individuals who are susceptible
Volume 108 Number 4
Down syndrome and Alzheimer disease
to Alzheimer disease? This might explain the postulated abnormal response to an unusual infective agent, the increased incidence of malignancy, and the increased incidence of autoimmune disorders seen in Down syndrome. The stage is set, and the scenario is enticing. One may hope that the answers will be forthcoming in the near future.
Marvin A. Fishman M.D. Professor of Pediatrics and Neurology Director, Section of Child Neurology Baylor College o f Medicine Chief, Neurology Service Texas Children's Hospital Houston, Texas 77030 REFERENCES
I. Cutler NR, Heston LL, Davies P, Haxby JV, Schapiro MB. Alzheimer's disease and Down's syndrome: new insights. Ann intern Med 1985;103:566-578. 2. Dalton A J, Crapper DR, Sch!otterer GR. Alzheimer's disease in Down's syndrome:visual retention deficits. Cortex 1974; 10:366-377. 3. Thase ME, Tigner R, Smeltzer D J, Liss L. Age-related neuropsychologic/d deficits in Down's syndrome. Biol Psychiatry 1984i19:571-585. 4. Ropper AH, Williams RS. Relationship between plaques, tangles and dementia in Down syndrome. Neurology 1980; 30:639-644. 5. Ball M J, Nuttall K. Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down syndrome: quantitative comparison with Alzheimer-dementia. Ann Neurol 1980; 7:462-465. 6. Mann DMA, Yates PO, Marcyniuk B. Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of
7.
8.
9.
10.
11. 12.
13.
14.
15.
16. 17. 18. 19.
629
pathological changes. Neuropathol Appl Neurobiol 1984; 10:185-207. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol 1985;17:278-282. Heston LL_ Alzheimer's disease, trisomy 21, and myeloproliferative disorders: associations suggesting a genetic diathesis. Science 1976;196:322-323. Heston LL. Alzheimer's dementia and Down's syndrome: genetic evidence suggesting an association. Ann N Y Acad Sci 1982;396:29-37. Heymari A, Wilkinson WE, Hurwitz BJ, Schmechel D, Sigmon AH, Weinberg T, Helms M J, Swift M. Alzheimer's disease: genetic aspects and associated clinical disorders. Ann Neurol 1983;14:507,515. Heston LL. Down's syndrome and Alzheimer's dementia: defining an association. Psychiatr Dev 1984;4:287-294. Yates CM, Simpson J, Maloney AFJ, Gordon A, Reid AH. Alzheimer-fike cholinergic deficiency in Down synizlrome. Laiacet 1980;2:979. ~(ates CM, Ritchie IM, Simpson J, Maloney AFJ, Gordon A. Noradrenaline in Alzheimer-type dementia and Down syndrome. Lancet 1981 ;2:39-40. Nyberg P, Carlsson A, Winblad B. Brain monoamines in cases with Down's syndrome with and without dementia. J Neural Transm 1982;55:289-299. Sizhwartz M, Duara R, Haxby J, Grady C, White BJ, Kessler RM, Kay AD, Cutler NR, Rapoport SI. Down's syndrome in adults: brain metabolism. Science 1983;221:781-783. Thase ME. Longevity and mortality in Down's syndrome. J Ment Defic Res 1982;26:177-192. Walford RL. Immunological studies of Down's syndrome and Alzheimer's disease. Ann N Y Acad Sci 1982;396:95-t 06. L0tt IT. Down's syndrome, aging, and Alzheimer's disease: a clinical review. Ann NY Acad Sci 1982;396:15-27. Price DL, Whitehonse P J, Struble RG, Coyle JT, Clark AW, Delong MR, Cork LC, Hedreen JC. Alzheimer's disease and Down's syndrome. Ann NY Acad Sci 1982;396:145:164.