Longitudinal changes in brain CT scans and development of dementia in Down's syndrome

To determine the relationship of the development of dementia to longitudinal changes in brain CT scans in patients with Down's syndrome (DS), we studied 14 Japanese DS patients at an interval of 10 years. The age at entry to the study was 35.7 +/- 9.9 (mean +/- SD) years in 1989 when we did the first CT scans. We performed the second CT scans in 1999 and quantitatively compared them with those taken in 1989. The 4 oldest of the patients (the demented group, 55.3 +/- 1.4 years of age in 1999) developed symptoms of cognitive decline before 1999. The younger 10 (the non-demented group, 41.9 +/- 9.0 years of age in 1999) remained stable in cognitive function until 1999. Despite the clear difference between the demented and the non-demented group in brain atrophy in 1999, CT measures of the demented group were similar to those of the non-demented group in 1989. These results indicate that age is a better predictor of dementia than imaging studies and that CT does not show a quantitative difference between the demented and the non-demented group before the onset of dementia.     

Extrapyramidal features in advanced Down''s syndrome: clinical evaluation and family history.

Extrapyramidal, frontal release, and other neurological signs were studied in 54 demented and non-demented patients with Down's syndrome (DS). Fourteen patients were demented and five showed extrapyramidal signs, mainly of the rigid-hypokinetic spectrum and similar to Parkinsonian features in advanced Alzheimer's disease (AD). None of the non-demented patients had Parkinsonian signs. The mean age of the demented DS patients with extrapyramidal signs was significantly higher than that of the patients without. Frontal release signs were present in demented and non-demented patients. A questionnaire showed no increase in either the proportion of early- or senile-onset dementia or Parkinsonism among first- and second-degree relatives of DS patients. Parkinsonian signs appear to be present at a lower frequency in DS than in advanced AD. A speculative hypothesis about a gene dosage effect of Cu/Zn-superoxide dismutase in preventing toxic radical formation in the substantia nigra of DS patients is presented.     

Cause of death in demented and non-demented elderly inpatients; an autopsy study of 308 cases

Few studies evaluated cause of death (COD) in elderly demented and non-demented people, the majority based on death certificates alone. The present study is based on autopsy reports with neuropathological examination of 308 inpatients (58.1% female) over age 60 years (mean: 83.5, SD: +/-8.6). CODs were classified into seven groups. The most common were bronchopneumonia (n=117; 38%) and cardiovascular disease (n=116, 37.7%). In 176 patients (57.1%) neuropathology was indicative for dementia: 76.7% Alzheimer disease (AD), 4.5% vascular dementia, 4.0% mixed type dementia (AD + vascular dementia), and 14.8% other dementias. Main COD significantly differed in demented and non-demented patients: bronchopneumonia (45.5% in demented versus 28.0% in non-demented), cardiovascular disease (46.2% in non-demented versus 31.3% in demented). Whereas there were significant differences in COD between AD patients and non-demented ones (bronchopneumonia versus cardiovascular disease), no differences were seen between the latter and patients with other types of dementia than AD. Our data emphasize the high incidence of bronchopneumonia as a COD in patients suffering from AD.     

Visual evoked potential in the diagnosis of dementia in people with down syndrome

The diagnosis of dementia in people with Down syndrome (DS) remains controversial. In this study DS patients who had a diagnosis of clinical dementia according to modified DSM-III-R criteria were assessed using the flash (P2) and pattern-reversal (P100) visual evoked potential (VEP). Abnormal VEP recordings were apparent in both demented and non-demented subjects. None of the demented subjects had the characteristic (P2–P100 latency difference) VEP changes reported in adults in the general population suffering from dementia. The VEP is unlikely to be a useful tool in the diagnosis of dementia in people with DS.     

Regional cerebral glucose metabolism in monozygotic twins discordant for Alzheimer's disease

We investigated regional cerebral glucose metabolic rates (rCMRgluc) with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) in 7 monozygotic twin pairs discordant for Alzheimer's disease (AD). Ten healthy volunteers with comparable mean age and educational level served as controls. In the hippocampus, the mean +/- SD rCMRgluc were 0.20 +/- 0.03 micromol/ml/min for the demented twins, 0.21 +/- 0.03 micromol/ml/min for their non-demented co-twins, and 0.23 +/- 0.02 micromol/ml/min for the controls. The mean hippocampal rCMRgluc was reduced in the demented twins (p = 0.006), compared with the controls. In the lateral temporal cortex, the mean +/- SD rCMRgluc were 0.27 +/- 0.05, 0.28 +/- 0.04, and 0.32 +/- 0.02 micromol/ml/min, respectively. These mean rates were reduced both in the demented (p = 0.02) and the non-demented (p = 0.01) twins, compared with the controls. In conclusion, in the demented twins, the reduction of rCMRgluc was detected in the hippocampus and lateral temporal cortex, i.e. the 2 brain areas which show early changes in pathological and imaging studies in AD. Their non-demented co-twins showed milder reductions, which may be an indication of genetic susceptibility for dementia, and an early sign of a dementing illness in them.     

Age-related changes in plasma dehydroepiandrosterone levels in adults with Down's syndrome and the risk of dementia

People with Down's syndrome (DS) are at high risk of developing early onset dementia. Recent studies suggest a link between age-related decreases in dehydroepiandrosterone (DHEA) concentrations and dementia in the general population. The present study investigates the relationship between DHEA serum levels and age and the risk of dementia in adults with DS. The DHEA plasma concentrations of 67 adults with DS and 65 age-matched controls were determined. Participants with DS were assessed for the presence of dementia using the CAMDEX informant interview. The DHEA plasma concentrations decreased with age in subjects with DS as well as in controls. Age significantly predicted DHEA levels in both groups (B = -0.06, t = -4.536, P < 0.001 in the DS group and B = -0.04, t = -2.928, P < 0.005 in control participants). The mean ± SD DHEA level was 3.47 ± 1.41 μmol/l in controls and 2.79 ± 1.24 μmol/l in participants with DS. This difference was significant (t = -2.981, P < 0.01). Within the DS population, ancova revealed a significant relationship between DHEA concentrations and dementia (F(1,65) = 4.348, P < 0.05). We found that DHEA levels declined significantly with age in people with DS and controls and were lower, in comparison to age-matched controls, in people with DS across all ages studied. Those with DS and evidence of dementia have lower DHEA concentrations than those with DS (controlling for age) but without dementia.     

Ageing in adults with Down's syndrome in institutionally based and community-based residences

Seventy-one subjects with Down's syndrome (DS), between the ages of 29 and 68 years, and 46 matched controls (without DS) were examined for intelligence, memory (short- and long-term memory, and spatial and temporal orientation), communication (receptive, expressive and written language) and daily living skills (personal, domestic and community daily living skills). All subjects were screened on hearing and visual functions, thyroid functions; depression and dementia. DS-subjects and controls were matched on chronological age, mental age, living conditions and male/female ratio. Comparisons were made between five subgroups (I) non-demented institutionalized subjects with DS (DSI-group; n=35); (2) non-demented institutionalized controls without DS (Ci-group; n=22); (3) demented institutionalized subjects with DS (n= 10); (4) non-demented subjects with DS living in group homes (DSg; n=26); and (5) non-demented controls without DS living in group homes (Cg; n=24). Institutionalized and non-institutionalized subjects, as well as demented and non-demented subjects differed significantly on all functions measured. Multiple regression analysis was performed to examine the influence of age and sensory deficits on adaptive and cognitive functioning. In DSg subjects, significant associations were found between age and mental age, and between age and performances on written language. In (non-demented) DSi subjects, significant relations were found between age and memory functions observed in daily circumstances. Moreover, in the (non-demented) DSi elderly, visual impairment was significantly related to depressed performance on daily living skills. No age effects were seen in control subjects. Infirmities of old age like dementia and sensory deficits were far more common in people with DS than in controls. Psychiatric and diagnostic aspects of clinical depression and dementia were emphasized in particular.     

Prevalence and impact of cerebrovascular pathology in Alzheimer's disease and parkinsonism

OBJECTIVE: To study the prevalence and impact of cerebrovascular lesions (CVL) in Alzheimer's disease (AD) and their effects on cognitive impairment. MATERIAL AND METHODS: In study I, the prevalence of vascular lesions in a prospective series of 244 autopsy-proved AD cases (mean age 83.1+/-8.4 years) and 230 age-matched non-demented controls was examined using immunochemistry and current morphological diagnostic criteria. In study II, in 100 consecutive autopsy cases (mean age 84.3+/-9.3 years), the incidence of general and capillary cerebral amyloid angiopathy (CAA, CapCAA) was examined. RESULTS: In study I, AD cases showed significantly more frequent CVL than age-matched controls without differences in the Braak stages, but the severity of CAA was significantly higher in AD brain with associated vascular lesions. In study II, CAA was more frequent in demented than in non-demented patients, but did neither correlate with high-grade AD pathology nor with clinical dementia, whereas CapCAA correlated with both dementia and high Braak stages; the severity of both types of CAA showed only low correlation with each other. CONCLUSIONS: The present data and other studies confirm the importance of CVL in AD and Parkinson's disease without considerable impact on cognitive impairment in progressed stages of AD, and the close association of CapCAA but not of general CAA with clinical dementia and AD pathology.     

Neuropsychological evaluation of adults with Down's syndrome: patterns of selective impairment in non-demented old adults

A batiery of neuropsychological tests, developed to study patterns of age-related differences in adults with Down's syndrume (DS), was administered to 10 DS adults over age 35 and 19 younger DS adults. Although all adults with DS are reported to develop the neuropathoiogical changes of Alzheimer's disease by the fourth decade of life, only four of the 10 old DS adults were judged to have dementia based on clinical criteria. Demented old DS adults had global neuropsychological deficits, as indicated by significant differences on all functions tested except some simple language functions. In contrast, non-demented old adults had a selective pattern of neuropsychological reductions relative to young adults. Ability to form new long-term memories and visuospatial construction were consistently diminished, whereas immediate memory span and language were not. The global mental decline observed in demented adults suggests a stage of disease progression that corresponds to severe dementia in pre- morbidly normal adults with dementia of the Alzheimer type (DAT). The prominent long-term memory impairment with selective reductions of nonmemory functions in non-demented adults suggests a correspondence to early and intermediate DAT.     

Family, Alzheimer's disease and negative symptoms

BACKGROUND: The aim of this study is to look at the correlation between the presence of apathy measured by Marin's scale and family complaints related to withdrawal and the loss of motivation, or depression. The multicentre study was performed on 58 non-demented elderly people, 132 outpatients with Alzheimer's-type dementia, as well as their main caregiver. METHODS: After agreement of the patients and the family, the patients were assessed using different scales: Cornell's for depression, Marin's for apathy, MMS for cognitive disorders, and IRG for dependence. At the same time, two self-administered questionnaires were given to the patients' families: one concerning a list of complaints scored from 1 to 4 relating to various disorders and the other addressing the boundary ambiguities translated from Boss' questionnaire. The 58 non-demented people were 81.20 years old+/-13.75. One hundred and thirty-two demented patients were included: 39 men and 93 women. The mean age was 79.47 years+/-9.03. RESULTS: The first family complaint relates to the loss of motivation (65%). Apathy and depression occur more frequently in dementia, in particular when the MMS is degraded. Depression and apathy attracted a high complaint score. In our study the score of boundary ambiguity is higher among patients with a weak cognitive status. A high level of ambiguity is accompanied by a high score of family complaints. When the family complaint concerning the loss of motivation is present, apathy is significantly more common. Family complaints about withdrawal and loss of motivation are frequently present, and are congruent with the actual presence of apathy in the patient. It bears witness to the distress felt by families faced with the loss of ability noted in the demented person. The family's difficulties are increased by the patient's depression.     

Some morphometric observations on the brains of patients with Down's syndrome: their relationship to age and dementia

The number of senile plaques (SP) and neurofibrillary tangles (NFT) and the number and nucleolar volume of nerve cells have been estimated in certain cortical and subcortical regions in 22 patients with Down's syndrome (DS) and have been related to the patients' age and to the presence and severity of dementia. Elderly (i.e. over 50 years of age) patients showed increased densities of SP and NFT and significant reductions in number and nucleolar volume of nerve cells, when compared with patients under 50 years of age, though the extent of these changes was, in general, no greater in the non-demented elderly group than that in the demented elderly group. Of the younger, nondemented group, those patients with a limited formation of SP and NFT in their brains showed a similar number and nucleolar volume of nerve cells, as those completely devoid of SP and NFT. It is concluded that in DS, formation of SP and NFT predate any significant atrophy and loss of nerve cells and that it is only after the age of 50 years that gross atrophy and loss of neurones occurs, though the extent of this process seemingly does not predict the onset, nor the progress, of dementia.     

Institutionalization risk amongst people with dementia supported by family carers in a Scottish city

We studied 114 community-resident demented older people living at home with the support of a family carer and a matched sample of 114 non-demented older people to determine the factors predictive of institutionalization. We interviewed elders and carers for presence and severity of dementia, characteristics of elder and carer, service use, and carers' perceptions of needs and attitudes to care. Subjects were followed up over a 2-year period. Eleven demented and 10 non-demented elders were lost to follow-up. Forty-nine of 103 demented and 7 of 104 non-demented elders were institutionalized. Demented elders were 8.21 times more likely to be institutionalized than non-demented elders, adjusting for age and sex (95% CI 3.69-18.23). Using Cox's Proportional Hazards Model, factors which predicted institutionalization amongst demented elders were: Mini Mental State Examination Score (RR 0.87, 95% CI 0.80-0.96), carers' perceived problems in relation to the elders' physical disabilities (need for 1-3 hours per week vs no need, RR 6.10, 95% CI 2.34-15.89), behavioural problem score (7-13 vs 6, RR 5.67, 95% CI 1.47-21.88) and carers' willingness to continue caring (willing vs totally willing RR 4.46, 95% CI 1.41-14.10). Our study confirms the high risk of institutionalization amongst demented older people. Early institutionalization of demented elders can be predicted and should be planned for, to help elders and carers cope with the process of adjustment. Where carers are totally committed to continuing care, intensive community support may be required for problems associated with advanced dementia.     

Psychiatric aspects of Down's syndrome

In a survey study of psychiatric morbidity, based on a representative sample from the Danish mental retardation register, 44 adults with Down's syndrome (DS) were compared with 258 other mentally retarded adults. Assessed by the parameters psychiatric disorder, behaviour problems, neurotic traits, and deviant social interaction, the DS group functioned better on all parameters. However, male and female DS patients were very different, the females constituting a superior well-functioning group while the males had major problems in every area. High prevalence rates of dementia and infantile autism were found in the DS group. General function rapidly decreased with age in DS patients.     

Immediate causes of death of demented and non-demented elderly

Objective – To investigate the immediate causes of death, in autopsied demented and non-demented elderly. Design – Retrospective clinicopathologic correlations. Setting – Acute and intermediate care geriatric hospital. Participants – 342 hospitalized demented and non-demented elderly (mean age 84.94±6.9 years) who underwent consecutive post-mortem examinations: 120 demented patients with either vascular dementia (VaD, n =34), mixed dementia (MD, n =65) or Alzheimer's disease (AD, n =21) neuropathologically confirmed and 222 non-demented elderly. Results – Primary causes of death were similar in both demented and non-demented patients; the commonest were cardiovascular disease and bronchopneumonia. Cardiac causes of death and especially cardiac failure were more frequent in VaD than in AD or MD (respectively P =0.027 and 0.005). Dementia was an underlying but never a primary cause of death. Conclusions – Immediate causes of death are similar in elderly demented and non-demented patients.     

Temporal lobe-oriented CT scanning and dementia in Down's syndrome

BACKGROUND: Although individuals with Down's syndrome (DS) are uniquely at risk of developing Alzheimer's disease, the diagnosis of dementia in DS is problematic because of the difficulty in detecting cognitive decline in individuals with pre-existing learning disability. AIM: To determine if dementia in DS is associated with Medial Temporal Lobe (MTL) atrophy as measured by temporal lobe-oriented CT scanning. METHOD: Ten individuals with DS who were experiencing functional decline had CT scans with temporal lobe-oriented views. All individuals were assessed for the presence of dementia according to modified DSM-IIIR criteria. The minimal thickness of the MTL, corrected for age-related atrophy was measured using a computer calipers at the level of the mid-brainstem by a radiologist blind to the dementia diagnosis. RESULTS: All six individuals who met modified DSM-IIIR criteria for dementia showed significant MTL atrophy. CONCLUSIONS: The utility of temporal lobe-oriented CT scanning as an adjunct to the diagnosis of dementia in DS appears promising and warrants further study.     

Down syndrome, Alzheimer's disease and seizures

Neuropathologically, Alzheimer-type abnormalities are demonstrated in patients with Down syndrome (DS), both demented and nondemented and more than a half of patients with DS above 50 years develop Alzheimer's disease (AD). The apolipoprotein E epsilon4 allele, oestrogen deficiency, high levels of Abeta1-42 peptide, elevated expression of BACE2, and valine polymorphism of prion protein gene are associated with earlier onset of dementia in DS individuals. Advanced AD alone may be an important risk factor for new-onset seizures in older adults and age above 60 years is a recognized risk factor for poor outcome from convulsive and nonconvulsive status epilepticus. DS patients aged over 45 years are significantly more likely to develop Alzheimer's disease than those less than 45 years and up to 84% demented individuals with DS develop seizures. Late-onset epilepsy in DS is associated with AD, while early-onset epilepsy is associated with an absence of dementia. In AD patients with a younger age of dementia onset are particularly susceptible to seizures. DS adults with epilepsy score significantly higher overall on the adaptive behaviour profile. Language function declined significantly more rapidly in AD patients with seizures and there is a good correlation between the severity of EEG abnormalities and cognitive impairment whereas in DS slowing of the dominant occipital rhythm is related to AD and the frequency of the dominant occipital activity decreases at the onset of cognitive deterioration.     

Apolipoprotein E, cognitive function, and dementia in a general population aged 85 years and over

We examined 510 subjects representing 83.2% of all citizens of a Finnish city aged 85 years or over. Mini-Mental State Examination (MMSE) scores, diagnosis of dementia by DSM-III-R criteria, and Apo-E genotype were determined. The prevalence of dementia was 38.6%. The odds ratio (OR) of the Apo-E epsilon4 carriers (with the reference population of people with the genotype epsilon3/epsilon3) for dementia was 2.36 (95% CI 1.58 - 3.53). There was a significant sex difference: The OR in women was 3.23 (95% CI 2.02 - 5.17) whereas among men it was insignificant. The mean MMSE score (+/- SD) among the Apo-E epsilon4 carriers (15.0 +/- 10.0) and noncarriers (18.7 8.6) (p < .001) differed among the whole population, but not within the demented or nondemented subjects analyzed separately. This study does not support the hypothesis that the Apo-E epsilon4 allele impairs cognitive functions of nondemented elderly, at least in those surviving to very old age.     

Length of stay in skilled nursing facilities is longer for patients with dementia

Studies estimate prolonged stays in acute and sub-acute facilities for patients with dementia. Actuarial projections suggest prolonged stays in long term care facilities for patients with dementia. To test these predictions, we assessed whether patients with dementia stay in skilled nursing facilities (SNF) longer than patients without dementia. We obtained medical records of 5,373 residents discharged from a SNF between 1996 and 2001. Residents were identified as having dementia by ICD-9 codes. Age, sex and length of stay (LOS), measured in days from admission to discharge or death, were gathered. Mean LOS for patients with dementia (92.7 +/- 313.0, n = 758) was significantly longer than non-demented patients (29.7 +/- 136.8, n = 4615, p < 0.001). In a subset of individuals who stayed until death, the mean LOS for patients with dementia (202.9 +/- 528.6, n = 195) also was significantly longer than for non-demented patients (91.8 +/- 300.5, n = 610, p < 0.001). LOS was increased for demented patients even within age groups. Thus, patients with dementia stay in SNFs significantly longer from entry until discharge or death. It is likely that demented patients enter for non-physical, cognitive related reasons. These results may help families and institutions plan for long-term care.     

Alzheimer's disease in adults with Down's syndrome: the relationship between regional cerebral blood flow equivalents and dementia.

Twenty adult patients suffering from Down's syndrome (DS) were recruited from hospitals and the community, together with 14 age- and sex-matched controls of normal intelligence. Dementia was diagnosed in patients using a structured psychiatric and physical examination as well as a carer interview and case notes. All patients and controls were imaged using single photon emission computerized tomography with 99mTc-exametazime. Four patients were clinically demented and all of them showed regional cerebral blood flow (rCBF) changes commonly found in patients with Alzheimer's disease, namely bilateral temporo-parietal deficits. These changes were also observed in about half of the patients without clinical evidence of dementia, but in none of the healthy controls. Across the group of patients, temporo-parietal rCBF deficits were associated with evidence of deterioration, but not with advancing age.     

The natural history of dementia in Down's syndrome

In a prospective longitudinal study with death as the end point in 17 middle-aged patients with Down's syndrome, dementia was clinically diagnosed in 15 patients, by means of careful observations in daily circumstances. Autopsies were performed in 10 cases: 8 demented patients and 2 nondemented patients. Neuropathologically, Alzheimer-type abnormalities were demonstrated in 9 patients, both demented and nondemented, and combined Alzheimer-type abnormalities with infarctions were demonstrated in 1 patient. In the 14 demented patients who did not show evidence of cerebrovascular or systemic vascular disease, dementia had an early onset and was rapidly progressive (mean age at onset, 51.3 years in the moderately retarded patients and 52.6 years in the severely retarded patients; mean duration of symptoms, respectively, 4.9 and 5.2 years). Cognitive and behavioral decline corresponded to symptoms of dementia of the Alzheimer's type in patients without Down's syndrome, but often were not recognized early. In the present group of patients, there was a remarkably high incidence of gait and speech deterioration. Also, the incidence of epileptic seizures and myoclonus was about eightfold, as compared with dementia of the Alzheimer's type in patients without Down's syndrome.