[More accurate diagnosis could identify patients suitable for tacrine therapy].
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Biomedical subjects
Publications and source records attributed to B Winblad.
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OBJECTIVE: To quantify the influence of apolipoprotein E (APOE) polymorphism on cognition and survival in a population sample aged 75 years or older. DESIGN: The Kungsholmen Project established a cohort of 1810 residents in a district in Stockholm, Sweden, aged 75 years or older in 1987. Information on cognition at cohort inception is available for all subjects. Subjects were followed up for mortality to January 1, 1995. SUBJECTS: Included in this study are 1077 subjects (of 1124 genotyped for APOE) with the common epsilon 2/3, epsilon 3/3, and epsilon 3/4 APOE genotypes. RESULTS: The odds of cognitive impairment for the epsilon 3/4 vs epsilon 3/3 genotype declined with age: 4.8 for age 75 through 79 years; 1.7 for age 80 through 84 years; and 1.0 (i.e., no association) for age 85 years or older. Despite this association, APOE polymorphism did not significantly predict survival in subjects younger than 85 years, nor did it predict survival in subjects 85 years or older who were cognitively impaired. Instead, survival varied fourfold with respect to APOE polymorphism in those 85 years or older who had good cognition: Mortality in subjects with the epsilon 2/3 genotype was half that in those who carried the epsilon 3/3 genotype (hazard ratio, 0.5; 95% confidence interval, 0.2 to 0.9), and mortality in subjects with the epsilon 3/4 genotype was twice that in those who carried the epsilon 3/3 genotype (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.5). This fourfold variation resulted in 2-year differences in survival. CONCLUSIONS: The minor sequence variation in the apolipoprotein E isoforms resulted in a fourfold difference in the risk of death among the oldest old (age > or = 85 years) with good cognition. The observed variation in mortality was unlikely to have been caused by cognitive impairment, as APOE polymorphism was not a risk factor for cognitive impairment in this age group.
Oxotremorine-M stimulated [35S]GTP gamma S binding was used to assess acetylcholine muscarinic M2 receptor mediated G-protein function in superior frontal cortical, superior temporal cortical and hippocampal membranes from a series of Alzheimer's disease and matched control subjects. No significant differences were seen in basal [35S]GTP gamma S binding between the groups. The maximal level of oxotremorine-M stimulated [35S]GTP gamma S binding over basal was significantly increased in Alzheimer's disease superior temporal cortex, suggesting an enhanced muscarinic M2 receptor-G-protein coupling efficiency in this region. In contrast, the maximal level of oxotremorine-M stimulated [35S]GTP gamma S binding over basal was unaltered in Alzheimer's disease superior frontal cortex and significantly reduced in Alzheimer's disease hippocampus. Western immunoblotting using antisera towards the alpha-subunits of those G-protein types known to couple muscarinic receptors, revealed that Gq alpha and Gi alpha, but not G(o) alpha, levels were significantly reduced in Alzheimer's disease superior temporal cortex. Neither Gq alpha, Gi alpha, nor G(o) alpha levels were significantly altered in Alzheimer's disease superior frontal cortex or hippocampus. These results suggest that the efficacy of muscarinic M2 receptor G-protein coupling shows regional selective changes in Alzheimer's disease postmortem brain with deficits occurring only in a region that shows severe pathology.
We used immunoblotting and radioligand binding techniques to compare levels of the calcium-mobilizing receptor for the phosphoinositide hydrolysis-derived intracellular second messenger inositol (1,4,5)-trisphosphate (IP3) in post mortem samples from the temporal, frontal and parietal cortices of eight Alzheimer's disease (AD) and eight matched control cases. Immunoblotting with an antibody directed against the C-terminal end of the rat type I IP3-receptor showed that IP3-receptor protein levels were significantly reduced in the temporal (to 59 +/- 6% of controls, P = 0.0002) and frontal (to 62 +/- 10% of controls, P = 0.04), but not in the parietal cortices (to 63 +/- 13% of controls, P = 0.1) of the AD cases, compared to controls. The number of [3H]IP3 radioligand binding sites was significantly decreased in the temporal cortex, but not frontal and parietal cortices, of the AD brains. The decreased levels of both immunoreactive IP3-receptor protein and [3H]IP3 binding in the temporal cortex correlated with a semi-quantitative score for the severity of AD neuropathology. No significant changes were seen in the levels of glial fibrillary acidic protein, synaptophysin or phosphate-activated glutaminase, as markers for astrocytes, neuronal vesicles and mitochondria, respectively. It is concluded that in affected AD brain regions, the IP3-receptor may represent a sensitive target for proteolysis, possibly mediated by activation of the Ca(2+)-activated neutral protease calpain. These degenerative changes may in part be responsible for the disruption of Ca2+ homeostasis in AD-sensitive neurons.
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We examined the relationship between low levels of serum vitamin B12 (< 200 pmol/L) and folic acid (< 11 nmol/L), separately or combined, and episodic memory performance in very old age. Participants with low serum vitamin values were compared with a control group matched for age and educational level. Participants (N = 250) were selected from a group of nondemented, community-dwelling persons ages 75-96. Episodic memory was tested by means of free recall and recognition of slowly and rapidly presented words. Results indicated a deterioration in both free recall and recognition as a function of serum vitamin status. However, no linear effects of vitamin levels on memory were observed, indicating that vitamin B12 and folic acid status may effect memory only among individuals at the low end of the distribution. We speculate that the vitamin-related memory deficit may reflect encoding problems, possibly due to alterations in brain metabolism.
This study illustrates some characteristics of the quality of life in old age when ageing is seen as a continued human development. In the Kungsholmen Project 87 healthy elderly persons were asked about the quality of their lives. Allardt's definition of quality of life was used as the conceptual framework for the content analysis. The findings indicate that the dimensions of loving and being, as Allardt describes them, take on a different meaning and the material things in the having dimension become less important. The differences point to another meaning of the quality of life in old age. The emphasis is on health and independence, contentment and a peaceful life, personal integrity in terms of a moral and a caring attitude. The findings tend to be in accordance with the successful ageing as described in Erikson's theory of psychosocial development and in Tornstam's theory of gerotranscendence. To gain a deeper understanding of this complex phenomenon, qualitative methods which go beyond definitions are required.
OBJECTIVE: To describe the use of cardiovascular drugs in an older population with respect to age, sex, housing type, and creatinine clearance. DESIGN: A cross-sectional survey. PARTICIPANTS: All residents of a district of Stockholm (Kungsholmen), Sweden, aged 75 and older, living in institutions or at home. MEASUREMENTS: Cardiovascular drug use, serum creatinine, electrolytes, height, weight, and symptoms. RESULTS: A total of 43 cardiovascular (CV) drugs were used. The most common drugs were digoxin (used by 18.2%), furosemide (16.4%), and glyceryl trinitrate (12.4%). Drugs with an antihypertensive effect accounted for 61% of all CV drugs. CV drug use increased with age for cardiac glycosides and diuretics, but decreased with age for calcium antagonists and beta-blockers. Drug doses tended to be less than the recommended daily dose except for a few drugs, e.g., furosemide. There was a trend toward decreasing dose with increasing age, but this was not significant. Diuretics were the only CV drugs used more often in women. People living in institutional care used the least amount of CV drugs. The dose of drugs taken did not appear to be related to estimated creatinine clearance. Comparisons between drug use and complaint of symptoms showed a strong correlation between the use of cardiac glycosides and anorexia, calcium antagonists and constipation, and nitrates and vertigo. There were weaker correlations with cardiac glycosides and visual disturbances and with potassium sparing diuretics and a high potassium. CONCLUSIONS: CV drugs are used commonly in older people. We suggest that the symptoms correlating with cardiac glycoside use may be signs of unrecognized toxicity, and this may relate to our finding that drug use is often not tailored to renal function as measured by creatinine clearance.
This state of the art document is the result of the conference held in Stockholm on March 9-10, 1995, initiated by the Swedish Medical Research Council. The conference brought together researchers from basic science and clinic to different disciplines. Response to questions was given in small groups and the answers were presented and discussed with all the participants. The final consensus was formulated in this larger group and comprises the state of the art document.
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OBJECTIVES: To study differences in nutritional, dental status and oral function between institutionalised patients with Alzheimer's disease and cognitively healthy elderly people living in the community. DESIGN: Comparison was made between two groups. Alzheimer's disease sufferers and healthy controls, using established criteria for anthropometric, mental and dental state. SETTING: An institution and residential area in Stockholm, Sweden. SUBJECTS: Forty patients with Alzheimer's disease living in a nursing home and 40 age- and gender-matched control subjects living independently. INTERVENTION: Dental status and anthropometric variables. RESULTS: Overnutrition was less frequent among the demented than the controls and more demented were undernourished. Dental status was similar in the two groups with few edentulous subjects but only 2 of 7 edentulous subjects with Alzheimer's disease wore dentures. Having natural teeth and many functional oral zones is important for food consistency choice, but not for nutritional status. In the Alzheimer group, the stage of dementia has a strong association to the ability to eat unaided and an association with dental status. CONCLUSION: There are differences in nutritional status between Alzheimer's patients in institutions and cognitively healthy elderly living at home. The choice of food consistency is correlated to dental status but nutritional status is not shown to be influenced by dental status. However, the ability to eat unaided is strongly correlated to cognitive status.
BACKGROUND AND PURPOSE: We investigated apolipoprotein E polymorphism stroke risk in a population sample of 1810 persons aged 75 years or more in Stockholm (the Kungsholmen Project). Information on cognition at cohort inception (from 1987 to 1989) and on stroke occurrence (from 1969 to 1994) is available for the cohort. In the cohort, cognitive impairment is associated with the epsilon 4 allele, and longer survival in subjects aged > or = 85 years with good cognition is associated with the epsilon 2 allele and the absence of epsilon 4. METHODS: We compared stroke incidence in the 1077 of 1124 genotyped subjects who carried epsilon 2/3, epsilon 3/3, or epsilon 3/4 and estimated the proportion of cognitive impairment attributable to stroke. RESULTS: Risk of stroke did not vary with apolipoprotein E polymorphism (P = .82): 24% of 87 incident stroke patients during follow-up compared with 25% of 827 subjects with normal cognition and no stroke diagnosis at baseline carried the epsilon 3/4 genotype. An estimated 9% of cognitive impairment was attributable to stroke. Notably, a reduced epsilon 3/4 frequency of 20% was found in subjects who survived a prior stroke and were included in the cohort, and risk of hemorrhagic stroke tended to be associated with the presence of the epsilon 3/4 genotype and the absence of epsilon 2/3. CONCLUSIONS: This population-based study indicates that apolipoprotein E polymorphism is not a risk factor for ischemic stroke in subjects aged > or = 75 years (although it might possibly influence survival after stroke occurrence and be a risk factor for infrequent hemorrhagic stroke) and that approximately 10% of cognitive impairment in this age group is attributable to stroke.
OBJECTIVE: The aim of the study is to test the hypothesis that freehand human-figure drawing (HFD), can be used as a complementary screening instrument to differentiate between demented elderly people and healthy elderly controls in population based studies. METHOD: HFD was examined in 668 elderly ( > or = 75 years of age) participants from an epidemiological study in Stockholm, who were asked to draw a human figure. The drawings were analysed on the content of body details and structural characteristics. RESULT: The results show quite clearly that the body details and the height decrease with decreasing cognitive function, whereas the centredness (the distance in cm from the centre of the figure to the centre of the paper) increases with decreasing cognitive functioning. Demented people place their figures in the upper left corner of the sheet, compared with the mostly well centred figures of non-demented people. Age, on the other hand, has an influence on the HFD as after 90 years of age most of the variables show regressive changes. CONCLUSION: The HFD can help to differentiate between demented and non-demented subjects as well as between dementia of different severity. The HFD does not help us, however, to discriminate between Alzheimer's disease and vascular dementia. Age has an influence on the HFD in the sense that after 90 years most of the variables regress to a smaller or more primitive form.
Before the implementation of the health care reform of 1992 (The Adel Reform), a study of the frequency of mental impairment of people in different residential and care services was conducted in a parish of Stockholm. All residents, 65 years or older, registered with Primary Care Centres, Geriatric Hospitals and other institutions were assessed with respect to cognitive function according to the seven stage "Global Deterioration Scale" (GDS). The age-specific frequencies of mental impairment were similar to prevalences reported in earlier studies. The frequency of cognitive dysfunction of non-institutionalized and institutionalized elderly was 42% and 52%, respectively, and higher for women than for men. There was considerable variation in the prevalence of cognitive dysfunction among subjects in different types of accommodation. For the different stages of mental impairment the average age was about the same. With increasing need and demand for services, and limited resources, these variations in cognitive dysfunction have important implications for structuring appropriate support systems in a population with a rapidly rising proportion of elderly people.
Amyloid (A beta) deposition was investigated in cases of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch type, due to mutations in the amyloid precursor protein (APP) gene using the end-specific monoclonal antibodies BA27 and BC05 that recognize A beta 40 or A beta 42(43), respectively. In cases of APP717 mutation the predominant A beta species within plaques terminate at A beta 42(43) with relatively little A beta 40 being present. The total amount of A beta deposited as A beta 42(43) is significantly greater than in sporadic Alzheimer's disease, consistent with the suggestion that this mutation might influence the processing of APP so as to produce more of the highly aggregatable form, A beta 1-42. In cases of APP670/671 mutation the major peptide in plaques is also A beta 42(43), although the proportion of plaques containing A beta 40, and the total A beta load is similar to that in sporadic Alzheimer's disease. As in sporadic Alzheimer's disease, the vascular amyloid in APP670/671 and APP717 and in cases of hereditary cerebral hemorrhage with amyloidosis, Dutch type is predominantly A beta 40 in this latter disorder, however, parenchymal deposits are exclusively A beta 42(43). Although the various APP mutations may influence the type, quantity, and location of A beta deposited, the predominant, and possibly the initial, species deposited in the brain parenchyma is A beta 42(43).
The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-containing plaques and neurofibrillary tangles. The main constituent of senile plaques is amyloid beta-peptide (A beta) and in recent years, pathogenic mutations in the amyloid precursor protein (APP) gene have been discovered in some AD families. The APP670/671 mutation, found in a Swedish AD family, has revealed over-production of A beta as one pathogenic mechanism for the development of AD. In the present study we have used an immunoassay to measure A beta levels in cerebrospinal fluid (CSF) from APP670/671 mutation-carriers and non-carriers. A correlation was seen between decrease in A beta levels and duration of disease although no difference was found in levels of A beta between the groups (14.5 +/- 3.3 ng/ml versus 14.9 +/- 2.3 ng/ml).
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