Sci. Aging Knowl. Environ., 6 April 2005
Vol. 2005, Issue 14, p. dn1
[DOI: 10.1126/sageke.2005.14.dn1]

NEURODEGENERATIVE DISEASE CASE STUDIES

Dementia of the Alzheimer's Type and Accelerated Aging in Down Syndrome

D. A. Devenny, J. Wegiel, N. Schupf, E. Jenkins, W. Zigman, S. J. Krinsky-McHale, and W. P. Silverman

The authors are at the Departments of Psychology, Developmental Neurobiology, and Cytogenetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; and the Gertrude Sergievsky Center, Columbia University, New York, NY, USA (N. S.). E-mail: dadevenny{at}aol.com

http://sageke.sciencemag.org/cgi/content/full/2005/14/dn1

Abstract: This case study, of a woman with Down syndrome and dementia of the Alzheimer's type (DAT), follows the course of her decline over an 11-year period until death at age 57. Detailed neuropathological findings are also presented. This case illustrates features of premature aging that are typically associated with Down syndrome, and the progressive changes in memory and cognition that are usually associated with DAT. Although the subject's cardiovascular condition and thyroid disorder were treated, they may have contributed to the decline of her memory. This case shows the difficulty in diagnosing dementia in an individual with mental retardation who suffered comorbid episodes of depression and psychosis.

Introduction Back to Top

Down syndrome (DS), one of the most prevalent human conditions associated with mental retardation, affects approximately one in every 800 newborns and is most often caused by trisomy of chromosome 21. In previous generations, newborns with DS were not expected to survive into adulthood, but improvements in living circumstances and in access to medical care have increased expectations of longevity dramatically. With good medical care and a supportive environment, individuals with DS can now be expected to live to the end of their sixth decade and, in some cases, beyond. Adults with DS, however, typically show declines in memory and adverse changes in their health over time, including senile cataracts, presbycusis, hypothyroidism, and early menopause in females, at ages that are consistent with premature aging. In addition, adults with DS are particularly vulnerable to Alzheimer's disease (AD) (see Honig and Chin Case Study) and some, but not all, develop dementia of the Alzheimer's type (DAT) two to three decades earlier than people in the general population. This seems to be due, at least in part, to the presence of an extra copy of the gene on chromosome 21 that encodes {beta}-Amyloid precursor protein (APP; and see the chromosome 21 map).

Overexpression of APP contributes to accumulation of diffuse, extracellular deposits of {beta}-Amyloid (A{beta}) in the brain during the second and third decades of life and the subsequent formation of fibrillar plaques by the end of the fourth decade (see "Detangling Alzheimer's Disease"). Early deposition of amyloid plaques occurs in the amygdala and hippocampus, followed by the association areas of frontal, temporal, and parietal cortex. These deposits continue to accumulate throughout adult life. Neurofibrillary tangles, another hallmark of AD neuropathology, show a slow accumulation over an estimated 19-year period until, by the fifth decade, significant pathology can be observed. Neuronal degeneration associated with neurofibrillary tangles occurs initially in the transentorhinal and entorhinal cortex (see below), followed by the cornu ammonis and subiculum of the hippocampus, the amygdala, the nucleus basalis of Meynert, and the neocortex. Neurofibrillary degeneration results in impaired neuron function and eventual cell destruction. As in the general population, overt neuroanatomical changes reflect cellular degeneration associated with AD.

We present here the case history of a woman with DS whom we followed for 11 years, from the time when she was a competent adult through her decline associated with DAT. We describe her symptoms and pattern of cognitive decline and brain pathology, and illustrate several features typical of adults with DS, including accelerated aging and an early onset of DAT. Establishing a clinical diagnosis of DAT was complicated in this individual by her life-long cognitive impairment associated with mental retardation and the development of comorbid psychiatric conditions.

Social History Back to Top

Ms. M. was the only child born to a 42-year old mother. She was delayed developmentally and first began to walk and talk at 3 years of age, and around the same age a diagnosis of DS was given. She attended a local public school in an ungraded class, but her attendance was sporadic because her parents were fearful that she might be abused. However, Ms. M. received instruction at home and learned to read and write. When Ms. M. was 22, her mother developed an incapacitating illness, and for the subsequent 5 years Ms. M. provided her mother with substantial assistance, including bathing and feeding. After her mother died, Ms. M. continued to live at home with her father, doing most of the household chores. When she was 33 years old, her father died, and Ms. M. went to live with her aunt and uncle. Ms. M. had her first experience living away from her family at age 36 when she stayed, briefly, in a community residence for adults with developmental disabilities. At age 40, she made a permanent move to this residence and began working in a sheltered workshop. For the first time, Ms. M. was given instruction in traveling independently on public transportation, and she mastered this successfully. She continued to live in the residence for the next 16 years (video clip 1).

Ms. M. was described as a friendly person who was eager to help others. She was independent in caring for her personal needs and required little help in organizing her leisure time. At age 40, she had a boyfriend, and together they went to restaurants and movies. Gradually, over the subsequent 8 years, annual reports from the residence began to describe episodes of social withdrawal, excessive slowness in complying with staff requests, and passive-aggressive behaviors. There was also an increase in atypical forms of behavior, such as hiding under the dining room table or cutting her clothes. Following a diagnosis of dementia made at age 49, Ms. M.'s schedule and living situation were modified, with an expanded social and medical support system provided to accommodate her progressive changes. By age 52, she required assistance in regulating water temperature when bathing and in dressing, and she needed supervision to carry out her household routines. Her support system was effective over the next 7 years, but in the late stages of dementia Ms. M. required nursing care and had to be transferred to a specialized residence.

Cognitive Function Back to Top

At age 36, Ms. M. had a full-scale IQ score of 67 (verbal score 66; performance score 72) on the Wechsler Intelligence Scale for Adults--Revised, placing her within the level of mild mental retardation. Ms. M. had reading ability at 3rd grade level: She was able to read a newspaper, could tell the time, and had rudimentary math and writing skills. Her social maturity was equivalent to that of a 9-year-old. In general, her overall intellectual level and academic achievements placed Ms. M. high in the range of abilities expected for individuals with DS, particularly for her birth cohort, whose members had limited opportunities for education and support.

Medical History Back to Top

At age 39, Ms. M. weighed 105 lbs and was 4'11" tall. Her body mass index of 21.2 kg/m2 was in the normal range. She also had normal hearing and vision (with corrective lenses). Her hair had begun to gray. Chromosome testing showed a karyotype with a complete triplication of chromosome 21, the most prevalent DS karyotype. She had an apolipoprotein E (APOE) genotype of 3/3 (i.e., two copies of the {epsilon}3 allele), indicating no additional increased genetic risk for the early onset of DAT beyond her chromosome 21 trisomy status. Although her health was generally good, amenorrhea began at age 32 with a follicle-stimulating hormone level of 86.4, indicating early menopause. At age 40, Ms. M. had an elevated thyroid-stimulating hormone level and was successfully treated with the synthetic thyroid hormone drug Synthroid. A functional systolic heart murmur with episodes of sinus bradycardia resulted in implantation of a pacemaker during the same year. Ms. M. had successful surgery for the removal of cataracts, also at the age of 40. Her cholesterol levels and blood pressure remained within normal limits throughout her life.

When she was age 45, reports by caregivers indicated that Ms. M. was showing behaviors such as stealing from a local store, social withdrawal, and an eating disorder (in which she engaged in secretive nighttime eating, had rigid food preferences, and had episodes of binge eating followed by dieting). Although these behaviors were problematic, a neurologist felt that her changes in functioning did not warrant a diagnosis of dementia. Initially, her behavioral changes were interpreted in the context of what caregivers felt to be her eccentric personality. From around age 48 and onward, behavioral changes were present that were eventually associated with DAT, including episodes of getting lost in the neighborhood, using cooking oil as detergent, and throwing her blood pressure monitor in the garbage. Caregivers reported further regression in her daily living activities, including the loss of her ability to travel independently on public transportation. Increased emotional isolation was noted by her caregivers. In group settings, Ms. M. was observed to be self-occupied, playing with and picking at her fingers, and ignoring staff and peers. A caregiver observed that "she appears unaware of her surroundings, but it is difficult to judge whether she is truly disoriented or pretending." In a report from a day treatment center it was noted that Ms. M. now had impaired hearing, but no documentation was provided, and mention of this did not appear in subsequent reports. Although Ms. M. was responsive to verbal communication, the presence of hearing loss likely contributed to her social isolation, at least in some settings. At age 49, she was hospitalized for recurrent suicidal ideation and depression, and was treated with antidepressant and antipsychotic medications for the next 15 months. She was initially placed on Prozac and Haldol for 8 months, then switched to Stelazine and Pamelor for the following 7 months. Stelazine was terminated at age 50, but treatment with an antidepressant (Vivavtil) continued through age 52.

Eight months after Ms. M.'s hospitalization, she was given a diagnosis of DAT. This diagnosis was given by a neurologist, after a comprehensive evaluation that included psychiatric and EEG examinations by a clinical team experienced in assessing adults with intellectual disability had ruled out other primary causes for the observed cognitive and behavioral decline.

When Ms. M. was between the ages of 50 and 56, caregiver reports described a progressive increase in her confusion and forgetfulness and a deterioration in her ability to conduct the activities of daily living. On the Dementia Scale for Down Syndrome (Gedye, 1995), Ms. M. reached the criteria for cognitive decline that is consistent with early-stage dementia at age 49, middle-stage dementia at age 50, and late-stage dementia at age 55. During this time period, Ms. M. was hospitalized for virulent skin infections that resulted in cellulitis and pneumonia. By age 56, her abilities were profoundly diminished and Ms. M. was totally dependent on caregivers (Table 1). Ms. M. died at age 57 at an advanced stage of dementia, in which she no longer recognized family or caregivers and had no volitional abilities.

Cognitive Assessment Back to Top

Ms. M. began participating in a longitudinal study of aging in adults with developmental disabilities at age 46. At this time, her caregivers harbored no suspicions of Ms. M.'s decline. For the next 11 years, Ms. M. was tested at intervals ranging from 4 to 15 months using a comprehensive battery of cognitive assessment tests, but by age 56 she was no longer able to participate in any test activities. In the four test sessions that preceded a diagnosis of dementia, her performance on the tests was characterized by declines in measures of memory and visuospatial organization, but also by considerable variability in performance.

Ms. M.'s episodic memory was tested with an adaptation of the Selective Reminding Test. This test consists of presenting eight items within a single category (animals or foods), followed by 10 trials of free recall by the subject. After trial one, only those items not recalled on the preceding trial are re-presented for the next and each subsequent trial. Decline on this measure preceded the diagnosis of dementia in Ms. M. by 2 years (Fig. 1). Memory decline continued to be consistent and gradual, with the exception of one test session at age 52 when, following two hospitalizations, her score dropped to 12 out of 80. Ms. M. was retested 4 months later, and her performance returned to a level comparable to that prior to her hospitalization (video clip 2).



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Fig. 1. Ms. M.'s performance on the Selective Reminding Test as a function of age. The score on this test is the total number of items recalled over 10 trials; the maximum score is 80. The vertical line marks the age at which Ms. M. received a diagnosis of dementia.

 
The Block Design subtest from the Wechsler Intelligence Scale for Children--Revised was used to measure visuospatial abilities with minimal demands made on memory. This task involves reproducing a design from a model using red and white colored blocks. Ms. M.'s performance on this task also showed a general trajectory of progressive decline with some variability (Fig. 2).



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Fig. 2. Performance as a function of age on the Block Design subtest of the Wechsler Intelligence Scale for Children--Revised. The vertical line marks the age at which Ms. M. received a diagnosis of dementia.

 
Working memory, as measured by the Digit Span subtest of the Wechsler Intelligence Scale for Children--Revised, did not begin to show a decline until age 52, 3 years after Ms. M. was diagnosed with dementia.

Orientation was tested with the Institute for Basic Research Evaluation of Mental Status (an adaptation of the Mini-Mental State Examination). This test includes questions related to knowledge of time, place, and person, the naming of colors and objects, counting forward and backward, reciting the alphabet, and printing numbers. Orientation to time was the first domain to show a change, evident when Ms. M. was aged 50, whereas orientation to person and place remained intact until age 53. Initially, Ms. M. could answer all questions on this test correctly, but by age 55 she was able to answer only three of the five questions related to person and none related to time and place, and she could recognize the name of only one color and name only 1 out of 10 objects.

Neurological Examination Back to Top

Neurological examinations carried out at the ages of 48 and 49 showed Ms. M. to be an alert individual with good orientation to time, place, and person, normal cranial nerve function, and normal muscle tone and strength. Reflexes were present and symmetrical. A follow-up neurological examination at age 49.5, prompted by caregiver concerns about regression in activities of daily living, showed frontal release signs. By the age of 55, Ms. M.'s spontaneous language and social interactions were severely impaired. A neurological examination at this time found a masklike facial expression, bradykinesia, and some impairment of gross and fine motor movements. The presence of slight hypertonia, hyperreflexia, and an equivocal plantar response (downward movement of the toes in response to scraping the sole of the foot) were also present. At age 55, Ms. M. had a grand mal seizure and was initially placed on phenytoin, an anticonvulsant medication, but because of its toxicity for people with DS her medication was changed to Depakote one month later. A CT scan at this time showed mild cerebral atrophy and scattered calcification of the basal ganglia.

Neuropathological Examination Back to Top

Methods

All necessary consents were obtained for tissue donation for research, and the brain was removed 5 hours after death. The left hemisphere was fixed in 4% paraformaldehyde, cryoprotected in sucrose, frozen, and cut into 50-µm thick sections. Brain sections were immunolabeled with monoclonal antibodies detecting A{beta} [4G8; New York State Institute for Basic Research (IBR)], abnormally phosphorylated tau protein in neurofibrillary tangles (Tau-1; IBR), microglial cells (CD45; Dako), astrocytes [antibody against glial fibrillar acidic protein (GFAP); Boehringer], or {alpha}-synuclein in Lewy bodies (NCL-ASYN; Novocastra). Morphometric methods were used to detect changes in the volume of brain structures and number of neurons.

Gross brain examination at autopsy

Gross examination indicated a reduced brain weight of 860 g, as compared to a female control subject aged 52, who did not suffer from mental retardation (1140 g) (death in the control case was due to pneumonia; tissue had been preserved within 4 hours after death). The weight of Ms. M.'s cerebellum was also reduced, at 52 g compared to 71 g for the control. The brain was small and rounded, a characteristic typical of DS, with a brain anterior-posterior axis measuring 145 mm, compared to 153 mm in the control. The size of the brain hemispheres, brainstem, and cerebellum are illustrated in Fig. 3. A dissection of the left hemisphere in 10-mm-thick frontal slices revealed a reduction in both gray and white matter, a narrowing of the gyri (ridges), a widening of sulci (grooves) and fissures, and substantial enlargement of the ventricles indicating severe brain atrophy (Fig. 4). Frontal and temporal lobes were more affected by atrophic changes than other brain regions. Volume differences between the brain of Ms. M. and the control case are likely to result from multiple factors, including (i) size differences between individuals (Ms. M. was of the relatively small stature typical of DS and probably began adult life with a smaller brain volume); (ii) developmental changes associated with DS; (iii) accelerated aging; and (iv) progressive degeneration associated with amyloidosis and neurofibrillary degeneration. Other possible contributing factors, such as hypoxia from her heart condition, oxidative stress from thyroid treatment, and effects of medication, cannot be excluded.



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Fig. 3. Gross appearance of Ms. M.'s brain. Lateral (A) and medial (B) surface of the left hemisphere, showing the abnormal round shape of the brain (i.e., a reduction of the anterior-posterior axis) and marked atrophy. Narrowing of gyri is more significant in frontal (arrow) and temporal (two arrows) lobe than in other brain regions. The lateral ventricle (v) is enlarged.

 


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Fig. 4. Atrophy of Ms. M.'s brain. Coronal sections through (A) the anterior pole of the temporal lobe, (B) the amygdala and entorhinal cortex, (C) the body of the hippocampus, and (D) the calcarina in the occipital pole of the hemisphere, showing atrophy with loss of gray and white matter and enlargement of ventricles (v). A thin entorhinal cortex (arrow), reduced size of the amygdala (two arrows) and the body of the hippocampus (arrowhead), and narrowing of gyri (double arrowheads) are other hallmarks of brain atrophy.

 
Histopathology

Microscopic examination revealed extensive brain amyloidosis, neurofibrillary degeneration, and neuronal loss in Ms. M., consistent with AD. The majority of amyloid deposits in the hippocampus, amygdala, and neocortex were fibrillar plaques (Fig. 5).



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Fig. 5. Micrographs illustrate topographic relationships between the main components of cored amyloid plaques. (A) Staining of amyloid [using monoclonal antibody (mAb) 4G8] reveals a dense amyloid core (arrow) and amyloid wisps dispersed at a classical plaque corona (two arrows). The elongated nucleus of a microglial cell attached to the amyloid core is marked with an arrowhead. (B) Staining of microglia (mAb CD45) shows infiltration of plaque with activated microglial cells, including small amoeboid cells (arrow) and cells with numerous cytoplasmic processes (single arrowheads). (C) Staining of astrocytes (mAb GFAP) shows a ring of activated astrocytes (single arrowheads) with numerous processes penetrating into the plaque. (D) Staining of abnormally phosphorylated tau (mAb Tau-1) reveals enlarged dystrophic neurites (arrowhead) at the plaque perimeter and neurons with neurofibrillary tangles (arrow). Nuclei were stained with cresyl violet.

 
In AD, neurofibrillary degeneration generally starts in the transentorhinal cortex and spreads in a time-dependent manner to the entorhinal cortex, which provides a major input to the hippocampus, a key component of the brain's memory system (see Fig. 1 in Bizon Review). In Ms. M.'s brain, the volume of the entorhinal cortex was 75% less than that of the control brain. The presence of neurofibrillary changes in 80% of the remaining neurons (Fig. 6) indicated that neurofibrillary degeneration was a major cause of severe neuronal loss in the entorhinal cortex, whereas a relatively low amyloid load (7%) suggested that A{beta} pathology may have been less of a factor in this region (Table 2).



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Fig. 6. Photomicrograph of the stellate cells in the second layer of the entorhinal cortex of Ms. M.'s brain, showing a dramatic reduction in the number of neurons. The majority of neurons still present at this stage of Alzheimer's disease are affected by neurofibrillary degeneration (arrow). A dense network of neuropil threads reflects severe abnormal tau protein phosphorylation in neuronal processes (arrowhead).

 
The hippocampus is among the brain structures most severely affected by AD in the general population. In the brain of Ms. M., all three subdivisions of the hippocampus (cornu ammonis, subicular complex, and dentate gyrus) were affected with {beta}-amyloidosis (Fig. 7A) and severe neurofibrillary degeneration (Fig. 7B). In this individual with DS, the volume of the cornu ammonis was 613 mm3, a 71% reduction compared to the control case of 2100 mm3. The total number of neurons in the CA 1 to 4 sectors was reduced by 86% (2.4 million compared to 16.8 million in Ms. M. and the control case, respectively). Moreover, 55% of the neurons present were affected by neurofibrillary degeneration. Amyloid load, however, was relatively low (6% of hippocampal volume) (Fig. 8), indicating that neurofibrillary degeneration was the main cause of loss of neurons in this region. In the subicular complex, there was also a severe loss of volume (85%) and neuronal loss (78%) and a large percentage of neurons with neurofibrillary changes, but a moderate amyloid load (11%). In the dentate gyrus, AD pathology typically develops much later than in the cornu ammonis or subiculum, but it eventually reaches the degree of severity seen in structures affected earlier in the disease. In the dentate gyrus of Ms. M., 21% of granule cells were affected by neurofibrillary changes. Amyloid plaques were arranged characteristically in the superficial two-thirds of the molecular layer, the projection area of neurons of the entorhinal cortex. Because the entorhinal cortex was so severely affected in this case, the dentate gyrus would receive little or no effective input, thus leading to functional deterioration of the memory system.



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Fig. 7. Evidence of amyloid deposition in Ms. M.'s hippocampus. (A) Immunostaining with mAb 4G8 reveals numerous amyloid plaques in all sectors of the cornu ammonis (CA1 to 4), a row of plaques in the molecular layer of the dentate gyrus (DG, arrow), severe amyloidosis in the pyramidal layer in the subiculum proper (SUB), presubiculum (PrSUB), and parasubiculum (PaSUB), and in the parahippocampal gyrus (PARG). Diffuse amyloid deposits in the parvopyramidal layer of the presubiculum are marked with an arrowhead. (B) Immunostaining with mAb Tau-1 shows a very strong reaction in all sectors of the cornu ammonis, subicular complex, and parahippocampal gyrus.

 


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Fig. 8. A higher magnification view showing amyloid deposition in the CA1 sector of Ms. M.'s hippocampus. Staining for {beta}-amyloid (mAb 4G8) shows (A) plaques (arrow) in the stratum pyramidale. Immunostaining with mAb Tau-1 (B) reveals severe neurofibrillary degeneration with formation of NFTs in neurons (arrow), numerous neurofibrillary threads (arrowhead), and Tau-positive dystrophic neurites in plaques (two arrowheads). Immunostaining with mAb GFAP (C) reveals severe astrocytosis in the stratum pyramidale, with an increase in the number of activated astrocytes (single arrows).

 
The nucleus basalis of Meynert (NBM) is the main source of cholinergic innervation in the cerebral cortex and hippocampus. In this structure, Ms. M. had 82% fewer neurons than the control case, and the presence of neurofibrillary tangles (NFTs) in 13% of the remaining neurons implied that neurofibrillary degeneration was involved in this loss of neurons. Here again, a low amyloid load (5%) suggested a limited contribution of {beta}-amyloidosis to structural and functional deterioration of the NBM.

Severe {beta}-amyloidosis was present throughout the neocortex, with an accumulation of clusters of microglial cells in plaques and activated astrocytes at the periphery of plaques, as well as severe neurofibrillary degeneration (Fig. 9). In contrast to the severe brain amyloidosis observed, vascular amyloidosis was minimal.



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Fig. 9. Characteristics of late-stage Alzheimer's disease in Ms. M.'s brain. (A) Severe {beta}-amyloidosis, revealed by staining with mAb 4G8, and (B) neurofibrillary degeneration, revealed by staining with mAb Tau-1, are evident in the neocortex (frontal cortex) of the brain.

 
In the brain of Ms. M., the volume of the substantia nigra was smaller by 55%, and the number of pigmented neurons lower by 68%, as compared to the control case. Staining for {alpha}-synuclein, a marker of Lewy bodies, was negative in Ms. M's substantia nigra (Lewy bodies are a hallmark of Parkinson's disease; see Posner Case Study and Constantino and Honig Case Study). The absence of Lewy bodies, the relatively low percentage of neurons with NFTs (6%), and the trace amounts of amyloid present (0.05% amyloid load) suggest that other mechanisms were responsible for the severe loss of pigmented neurons in this individual.

The caudate nucleus and putamen represent two major components of the basal ganglia, and in Ms. M.'s brain large neurons of both structures were affected with neurofibrillary degeneration, whereas small neurons were not affected. Amyloid was deposited almost exclusively in the form of diffuse plaques, free of neuronal dystrophy and glial activation. These plaques are typically unrelated to disruption of neural processes, suggesting that A{beta} pathology did not play a major role in the loss of these neurons.

The cerebellum was affected, with significant {beta}-amyloidosis, numerous diffuse plaques in the molecular layer of the cerebellar cortex, and a few fibrillar plaques in the border between the molecular and granule cell layers. Diffuse plaques in the molecular layer were free of dystrophic changes in neurons, activated microglial cells, and astrocytes (Fig. 10). In AD as observed in the general population, the cerebellum is not vulnerable to neurofibrillary changes, and this was also true in the case of Ms. M.



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Fig. 10. Diffuse {beta}-amyloid deposits in the molecular layer of Ms. M.'s cerebellar cortex. Immunostaining with mAb 4G8 shows (A) amyloid deposits in diffuse plaques (arrow). However, immunostaining with mAb CD45 (B) shows no signs of microglial cell proliferation (arrowhead) or activation in diffuse plaques.

 

Discussion Back to Top

Ms. M., a woman with DS and DAT studied in middle age, showed behavioral and cognitive declines that were similar in type and progression to those associated with DAT in individuals from the general population, although her decline occurred at an earlier age.

Ms. M. received a diagnosis of dementia relatively late in her decline. Although there were several behavioral concerns reported by caregivers in the years prior to her diagnosis, these signs were interpreted in the context of her lifelong cognitive impairment, eccentric personality, and psychiatric concerns. It has only recently been recognized that an onset of a new maladaptive behavior, or an increase of or change in pre-existing behaviors, may be an indication of diminished inhibition and an early sign of AD in individuals with DS. Because Ms. M. had relatively mild mental retardation, she may have been able to compensate for changes in memory during everyday activities, at least during the initial period of her decline. It is unlikely that she was asked to self-report on changes in her mental abilities, a source of diagnostic information in the general population.

Testing during a research protocol indicated declines in episodic memory and visuospatial organization approximately 2 years prior to Ms. M.'s diagnosis, whereas declines in working memory and orientation were not observed until 2 to 5 years later. This profile of cognitive changes associated with DAT is similar to that found in the general population. Although these findings could have been informative in the diagnostic process, because they were obtained as part of a research protocol they were not part of her clinical file. The neuropsychological documentation of her decline is unusual for an individual with DS and reflects the increased interest in aging processes in this population at the time she was first tested. This case also illustrates the importance of establishing baseline levels of memory and cognitive abilities in individuals with mental retardation, because a premorbid level of performance cannot be assumed, as it is in the general population.

Ms. M. seemed to progress rapidly through early and middle-stage dementia. This may have been related to a delay in diagnosis, given that retrospective findings indicated that she had had behavioral changes several years prior to age 49. If her diagnosis had been established soon after behavioral changes appeared, then the documentation of her rate of progression would have been similar to that typically found for AD. Clinical assessments capable of detecting the rather subtle signs of early-stage AD are available for the general population but are just beginning to be developed for individuals with mental retardation. At present, it is typical for a clinician to depend on the reports of caregivers to indicate when a significant change in daily functioning has occurred, and in this population concern is often not raised until behaviors develop to unmanageable levels. This case illustrates the importance of developing clinical diagnostic tools for adults with mental retardation that are sensitive to the subtle cognitive and behavioral changes associated with dementia.

The diagnosis of AD in Ms. M. at age 49 was consistent with a broader profile of accelerated aging. Other evidence for premature aging included an onset of menopause at age 32 and the development of hypothyroidism and cataracts by the age of 40. Studies have indicated that early onset of menopause is related to earlier onset and increased risk of dementia in individuals with DS. Premature aging is typical of adults with DS, but there is considerable variability in the presentation of the signs of aging and in the age at which they occur. The signs of aging appeared unusually early in Ms. M., even for an individual with DS.

Ms. M. had a grand mal seizure during late-stage dementia. The onset of a seizure disorder associated with AD is characteristic of individuals with DS. While in the general population there is an increased risk associated with AD for the occurrence of generalized- and partial-onset unprovoked seizures (occurring in ~10 to 20% of patients with AD) (Hesdorffer et al., 1996; Mendez & Lim, 2003), late-onset seizures are more common in individuals with DS and DAT. Individuals with DS treated with phenytoin for late-onset seizures often experience debilitating side effects (Tsiouris et al., 2002), and alternative medications for seizure control are recommended. Ms. M. was treated with phenytoin prior to the publication of the study regarding side effects of this drug, but she was soon changed to an alternative medication. Ms. M. survived for 8 years following her diagnosis of dementia, and at the time of her death had very advanced dementia consistent with late-stage AD.

The neuropathological examination of the brain of Ms. M. indicated substantial neuronal loss in all areas examined. Severe fibrillar {beta}-amyloidosis, neurofibrillary degeneration, and neuronal loss are consistent with the clinical diagnosis of AD. The pattern of neuropathological changes suggests that neurofibrillary degeneration was an important factor in neuronal loss in some, but not all, brain subdivisions.

The qualitative and quantitative findings of brain amyloidosis, neurofibrillary degeneration, and neuronal loss in this case are typical for AD in an individual with DS. In contrast to sporadic AD found in the general population, in people with DS the extent of neurofibrillary degeneration, neuronal loss, and the number of cortical plaques correlates with age. The impact of early, diffuse, nonfibrillar amyloid deposits on neuronal function appears to be clinically undetectable in young and early middle-aged individuals with DS. At ages above 50 years, the functional impairment that is frequently identified appears to be related to (i) progression of neurofibrillary degeneration leading to neuronal loss and (ii) development of the very numerous neocortical fibrillar plaques that are associated with degeneration of neuronal processes and synapses in the plaque perimeter. Despite the early onset of amyloidosis and neurofibrillary degeneration, clinical signs of dementia usually appear about 15 years later, indicating a slower progression in structural and functional deterioration associated with AD in individuals with DS than is observed in sporadic AD in the general population.


April 6, 2005

Abbreviations: Accelerated aging. Physical and/or cognitive changes that are typically associated with advanced aging, either occurring at an earlier chronological age or showing a faster rate of progression than expected with reference to individuals in the general population. • Alzheimer's disease. Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive and irreversible loss of neurons, leading first to memory loss and then to dementia. Changes observed in the brain include the accumulation of extracellular amyloid plaques in the walls of small blood vessels, and neurofibrillary degeneration in neurons associated with loss of synaptic contacts between neurons and with cell death. • Amygdala. An almond-shaped mass of subcortical gray matter within the tip of the temporal lobe of the brain, with olfactory, limbic, thalamic, and hypothalamic connections. The amygdala receives highly preprocessed sensory impressions from other parts of the brain and is responsible for the initiation and integration of somatic and autonomic responses. It is associated with affective behavior.{beta}-Amyloid. {beta}-Amyloid (A{beta}) is produced by proteolytic processing of {beta}-amyloid precursor protein (APP), encoded by a gene on chromosome 21. Cleavage of APP by {beta}- and {gamma}-secretases generates 40 or 42 amino acid {beta}-peptides, which aggregate in vivo to produce insoluble {beta}-pleated sheet structures within extracellular amyloid deposits in plaques and blood vessels. A{beta} deposition in fibrillar plaques is associated with local neuronal degeneration. • Apolipoprotein E. Apolipoprotein E (APOE) is a plasma protein that participates in the normal transportation of cholesterol and lipids, maintenance of nerve cell membranes, growth and remodeling of neuronal processes, and synaptogenesis. APOE is encoded by alleles of the APOE gene located on human chromosome 19, which exist in three types. The most common {epsilon}3 allele has a frequency of about 74% in the normal population, with the {epsilon}4 allele being present in 15% and the {epsilon}2 allele in 11% of individuals. Inheritance of APOE {epsilon}4 has been associated with an earlier age at onset of Alzheimer's disease. • Basal ganglia. The basal ganglia (consisting of the caudate nucleus, putamen, globus pallidus, and nucleus accumbens) are brain structures involved in the programming and execution of movements, and the timing of complex body movements. They are the center for regulation of posture or postural reflexes. Each subunit of the basal ganglia processes a vast array of highly differentiated information forwarded by the cortex, thalamus, amygdaloid body, and hippocampus. • Block Design. A subtest of the Wechsler Intelligence Scale for Children--Revised. It consists of asking the subject to reproduce a model using blocks that have sides of either red, white, or red and white together divided by a diagonal. This subtest measures an aspect of visuospatial organization that requires the ability to analyze and then re-assemble a spatial pattern. • Bradycardia. Slowing of the heartbeat to less than 60 beats per minute in an adult. • Community residence. Homes within the community where up to 15 individuals with developmental disabilities live under supervision. These residences are owned and managed either by private nonprofit organizations or by state agencies. • Dementia. The loss of cognitive and intellectual capacities, characterized by deficits in memory, attention, orientation, language, judgment, motor and spatial skills, and by altered emotional behavior and personality. Although dementia can have many etiologies, when it is thought to result from Alzheimer's disease it is termed dementia of the Alzheimer's type (DAT). • DAT. A diagnosis of dementia of the Alzheimer's type (DAT) is given when the presumed cause of dementia is Alzheimer's disease and other possible causes of dementia are ruled out. A definitive diagnosis of Alzheimer's disease is based on neuropathological findings after death. • Dementia scale for Down syndrome. An informant-based scale developed by A. Gedye that identifies behaviors associated with early-, middle-, and late-stage dementia in individuals with Down syndrome (Gedye, 1995). • Dentate gyrus. The dentate gyrus is a part of the brain involved in transfer of information from the entorhinal cortex to the cornu ammonis and subiculum. The entorhinal cortex receives information from the neocortex and subcortical regions. Numerous fibers of the entorhinal cortex reach the stratum moleculare of the dentate gyrus and form synapses on dendrites of granular cells. Granular cells stimulate the dendrites of neurons in sectors CA3 and CA4. • Developmental disabilities. Cognitive, sensory or physical disabilities beginning prior to 22 years of age that result in intellectual impairment and/or compromised vocational, economic, or socially independent functioning. • Diffuse plaques. Diffuse (or nonfibrillar) A{beta} deposits appear in the brains of people with Down syndrome more than 20 years before the onset of fibrillar brain amyloidosis. In the cerebellar cortex, caudate/putamen, and part of the presubiculum, diffuse A{beta} deposits are present up to the end stage of Alzheimer's disease. Because diffuse deposits are almost free of fibrillar amyloid, neurodegenerative changes and activated microglia, they are considered a benign form of brain amyloidosis. • Digit Span. A subtest of the Wechsler Intelligence Scale for Children--Revised. This is a test of working memory and consists of presenting sequences of numbers for immediate repetition both forward and backward. Initially, forward number sequences begin with 3 test items and increase by one number every two trials; backward number sequences begin with 2 test items and increase by one number every two trials. • Down syndrome. Down syndrome (DS) is the most frequent genetic cause of mental retardation in humans and is the developmental consequence of an extra copy of chromosome 21 (trisomy 21) in the majority of affected individuals (~92%). DS can also result from an unbalanced translocation involving chromosome 21 (3 to 5% of affected individuals), from mosaicism in which only some cells have trisomy 21 (2 to 3%) or, in a small number of individuals, from partial trisomy 21 (Dykens et al., 2000). Neurological abnormalities have three major clinical manifestations in DS: hypotonia in the newborn child and infant, developmental and mental retardation throughout life, and the progressive accumulation of neuropathology associated with Alzheimer's disease beginning in the third decade of life. Although the neuropathology of Alzheimer's disease is evident by the fourth decade of life, clinical signs and symptoms of dementia are typically not seen until 10 to 20 years later. • Episodic memory. The system of memory related to the acquisition of information associated with a specific time and place. List-learning tasks are frequently used as a measure of episodic memory, in which selected test items are uniquely combined to be learned and remembered during a particular test session that, typically, spans a time interval of minutes. For adults with Down syndrome, this type of task is less dependent on language and narrative ability (areas in which they have considerable difficulty) than a story-recall test, another approach to testing episodic memory. • Fibrillar plaques. Fibrillar plaques consist of a fibrillar amyloid core surrounded by several activated microglial cells, degenerated neuronal processes and synapses, and amyloid wisps dispersed between astrocytic processes. Because of the degeneration seen in neuronal processes in direct contact with fibrillar A{beta}, cored plaques are considered to be brain lesions resulting in functional deterioration. • Frontal release signs. The emergence of developmental or primitive reflexes (snout, rooting, sucking, glabellar tap, palmomental, grasping) and paratonia, signaling the presence of diffuse cortical atrophy with resultant weakening of cortical inhibition. Frontal release signs are found more frequently in patients with a clinical diagnosis of dementia of the Alzheimer's type than in elderly members of the general population. • Hippocampus. A brain structure consisting of the hippocampus proper (cornu ammonis), the subicular complex, and the dentate gyrus. Based on cytoarchitectonic criteria (size, shape, distribution, and connections of neurons), the cornu ammonis is divided into four sections (CA 1, 2, 3, and 4). The subiculum consists of the subiculum proper, presubiculum, and parasubiculum. All these subdivisions of the hippocampal formation are linked by prominent and largely unidirectional connections that appear to unite them as a functional entity. The hippocampal formation plays a prominent role in the formation of enduring memories. Alzheimer's disease is associated with four neuropathological correlates in the hippocampal formation: neuronal cell loss, neurofibrillary tangles, neuritic plaques, and granulovacuolar degeneration. • Hypertonia. Abnormal increase in muscle tone or tension. • Hyperreflexia. Abnormal increase in reflexes. • Hypothyroidism. Insufficiency of thyroid hormones. Hypothyroidism is common in older adults with Down syndrome and is responsive to treatment with synthetic thyroid hormones. Untreated, hypothyroidism can cause symptoms that are difficult to distinguish from those related to dementia of the Alzheimer's type. Hypothyroidism may contribute to other age-associated changes in adults with Down syndrome, but these have yet to be determined. • Institute for Basic Research Evaluation of Mental Status. An adaptation of the Mini-Mental Status Examination (Folstein et al., 1975) for individuals with mental retardation. It tests orientation to person (5 items), place (5 items), and time (5 items); naming objects (10 items) and colors (4 items); reciting the alphabet; counting forward to and backward from 20; printing letters (A to E) and numbers (1 to 5); and drawing simple geometric figures (3 items). • Lewy bodies. Lewy bodies are a manifestation of neurodegeneration seen in pigmented neurons in the substantia nigra of individuals with Parkinson's disease. They are composed of {alpha}-synuclein protein, assembled in fibrils. • Microglial cells. During development, cells of the monocyte lineage penetrate the wall of brain capillaries, reside for a short period of time in the basal lamina of brain capillaries (where they are known as perivascular cells) or on the external surface of capillary walls (perivascular microglial cells), and migrate into the gray matter where they become resting microglial cells. When pathology is present, these cells become macrophages and remove cellular debris. In Alzheimer's disease they are an integral component of fibrillar plaques. A lack of evidence for A{beta} internalization and degradation suggests that microglia do not remove fibrillar amyloid in cored plaques. It has been proposed that microglia contribute to fibrillar A{beta} deposition in plaques. • Neurofibrillary tangles. A slow process is observed in which abnormal phosphorylation of microtubule-associated protein (MAP) tau protein takes place, leading to an accumulation of paired helical filaments (PHFs) and the formation of neurofibrillary tangles (NFTs) within the neuronal cytoplasm. After about 4 years of neurofibrillary degeneration, neurons die, leaving only a "ghost tangle" as a remnant. The number of neurons with neurofibrillary degeneration increases as Alzheimer's disease progresses, and correlates with the degree of dementia observed. The progression of degeneration begins with the development of NFTs and neuropil threads occurring selectively in the transentorhinal and entorhinal cortex (known as the transentorhinal stage). Subsequently, the progression extends according to a predictable pattern into the hippocampus (the limbic stage) and gradually into the neocortex (the neocortical stage). These stages of neurofibrillary degeneration occur in sporadic Alzheimer's disease, early-onset Alzheimer's disease, and also in people with Down syndrome. • Neuropil threads. Neuronal processes accumulating abnormally phosphorylated tau and paired helical filaments in neurons affected with neurofibrillary degeneration. • Nucleus basalis of Meynert. The nucleus basalis of Meynert (NBM) is one of four groups of neurons within the nucleus basalis complex, with 90% of the neurons being cholinergic. The NBM acts as a cholinergic relay for transmitting limbic information to the neocortex in a fashion that influences learning and memory and also integrated motor and emotional responses. • Presbycusis. Hearing loss associated with normal aging. The hearing loss is sensorineural and affects high frequencies first. It is often accompanied by a loss of auditory discrimination of speech sounds. • Selective Reminding Test. A list-learning task developed by H. Buschke for the general population (Buschke, 1973) and adapted for individuals with intellectual disability. This test consists of eight items from a single category (animals or foods). The list of items is read aloud by the examiner, and the subject is required to name the items in any order, as in a standard free-recall task. After each of the nine subsequent trials, the examiner presents only those items not recalled in the immediately preceding trial. The score is the total number of items recalled. This test has been employed in a longitudinal study of older adults with DS, in which it was found that small declines are associated with "normal" aging. However, a decline of 20% or greater from an individual's highest score on two successive evaluations is strongly associated with the onset of dementia of the Alzheimer's type in this population (Devenny et al., 1996; Devenny et al., 2000; Krinsky-McHale et al., 2002). • Sheltered workshop. Community-based facilities that provide work for individuals with developmental disabilities in a supported environment. • Substantia nigra. An area of the brain that consists of two subdivisions, the pars compacta and pars reticulata. Pigmented neurons of the pars compacta send the major ascending dopaminergic inputs to the striatum (caudate nucleus and putamen). They are involved in initiating the motor response. Degeneration of dopaminergic neurons in the substantia nigra results in Parkinson's disease involving tremor, a masklike facial expression, flexed posture, and paucity and slowness of movement. • Tau. Under normal circumstances, brain tau--also known as microtubule-associated Protein (MAP) tau--promotes assembly of tubulin into microtubules and maintains microtubular structures required for axonal transport. However, an abnormal increase in tau phosphorylation (from 2 to 3 up to 5 to 9 moles of phosphate per mole of tau protein) results in disassembly of normal microtubules, leading to formation of abnormal paired helical filaments (PHFs) and neurofibrillary pathology. • Transentorhinal cortex. A transition zone of cortical gray matter, forming a bridge from the phylogenetically older three-layered entorhinal cortex to the newer six-layered neocortex. • Trisomy of chromosome 21. The majority of people with Down syndrome (DS) have a complete third copy of chromosome 21, which carries approximately 350 genes. A critical region of chromosome 21 consists of 39 genes, and this region is known to be responsible for full expression of the complex DS phenotype. Of these key genes, for example, an extra copy of the gene encoding minibrain kinase/Dyrk1A may have a major role in abnormal brain development; an additional copy of the gene encoding superoxide dismutase-1 may lead to accelerated aging; and a third copy of the gene encoding {beta}-amyloid precursor protein likely contributes to the early onset of Alzheimer's disease pathology in people with DS. • Wechsler Intelligence Scale for Children--Revised. The Wechsler Intelligence Scale for Children--Revised (WISC) is a standardized measure of intellectual ability (Wechsler, 1974). In our study of adults with Down syndrome, we employed this scale as an omnibus measure of cognition rather than the adult version of the test (WAIS), because for some of our participants even the simplest items on the adult test would be too difficult. Performance on the subtests was recorded in the form of raw scores. • Wechsler Intelligence Scale for Adults--Revised. The Wechsler Intelligence Scale for Adults--Revised (WAIS) is a standardized measure of intellectual ability (Wechsler, 1981). It is constructed such that the mean score of the general population is 100, with a standard deviation of ±15. Subtests can also be performed to provide verbal IQ and performance (nonverbal) IQ scores. • Working memory. Memory for information that is held in awareness for a brief period of time before either being converted into a more enduring memory or forgotten. Working memory also includes the processes that maintain this information in a temporary store so that it can be manipulated during comprehension, learning, and reasoning. Unlike many other components of memory, working memory is of limited capacity.

Suggested ReadingBack to Top

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  • The authors thank the family of Ms. M. for their cooperation and generous support of our research and the Builders of Family and Youth, who gave us their space and staff time so we could conduct our research. We also thank S. Vietze for her careful work in collecting and organizing the behavioral information, I. Kuchna and K. Nowicki for their work in morphometry, and R. Freedland and Jarek Wegiel for their work in editing the graphs and images. This study was supported by funds from the New York State Office of Mental Retardation and NIH grants AG 14771 (D.A.D.), HD043960 (J.W.), AG14673 (N.S.), HD37425 (W.Z.), HD35897 (W.S.), and AG11531 (H. M. Wisniewski).
Citation: D. A. Devenny, J. Wegiel, N. Schupf, E. Jenkins, W. Zigman, S. J. Krinsky-McHale, W. P. Silverman, Dementia of the Alzheimer's Type and Accelerated Aging in Down Syndrome. Sci. Aging Knowl. Environ. 2005 (14), dn1 (2005).








Science of Aging Knowledge Environment. ISSN 1539-6150