Biomedical subjects

B Winblad

Publications and source records attributed to B Winblad.

At least 73 records · Page 4Linked to original sources

PubMed2001

Life satisfaction among the very old: a survey on a cognitively intact sample aged 90 years or above.

The purpose of the study was to measure life satisfaction and the factors believed to influence it. The study involved 105 very old people, ninety years and above, who were not cognitively impaired, living in the inner part of Stockholm, Sweden. In order to assess life satisfaction, the Life Satisfaction Index-B (LSI-B) and Life Satisfaction Index-Z (LSI-Z) were used. Information about life events, activities, personality and social contacts were collected in order to determine their relative influence on life satisfaction. Factors associated with life satisfaction were also investigated in a content analysis to find out what the elderly themselves believe gives them life satisfaction. Results showedthat health and an emotionally stable personality were, independently of other factors, the most important factors for life satisfaction among the very old.

Aged↗

PubMed2000

Inhibition of kainic acid induced expression of interleukin-1 beta and interleukin-1 receptor antagonist mRNA in the rat brain by NMDA receptor antagonists.

The cytokines interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1ra) are rapidly induced in response to excitotoxic and ischemic brain damage. The aim of the present study was to investigate the influence of a non-competitive (dizocilpine maleate, MK-801) and a competitive ((R)-CPP) NMDA receptor antagonist on the transient cytokine expression in the rat brain induced by systemic kainic acid administration. Peripheral administration of kainic acid (10 mg/kg, i.p.) results in a transient expression of IL-1 beta and IL-1ra mRNA, mainly in microglia, in regions showing neurodegeneration such as the hippocampus, thalamus, amygdala, and certain cortical regions. In addition, a few neurons expressing IL-1ra mRNA were observed in the piriform cortex and amygdala following kainic acid injection. Administration of MK-801 (i.p.) 1 h prior to kainic acid injection reduced cytokine expression in all of these regions. MK-801 at 3.0 mg/kg decreased the IL-1 beta mRNA expression, blocked or decreased the IL-1ra mRNA expression, depending on the brain region. MK-801 at 5.0 mg/kg abolished IL-1ra mRNA expression in all of the regions, whereas the IL-1 beta mRNA expression was decreased or blocked, depending on the brain region, or the time point investigated. Peripheral administration of (R)-CPP (15 mg/kg, i.p.) 15 min prior to the kainic acid injection abolished the IL-1 beta mRNA expression. The IL-1ra mRNA expression was abolished in all regions except for a few neurons in the piriform cortex. The finding that NMDA receptor antagonists inhibit the IL-1 beta and IL-1ra mRNA synthesis induced by kainic acid suggests that NMDA receptor activation may be involved in triggering cytokine synthesis following excitotoxic brain damage.

Animals↗

PubMed2000

P0 protein peptide 180-199 together with pertussis toxin induces experimental autoimmune neuritis in resistant C57BL/6 mice.

The C57BL/6 mice strain is known to be reputedly resistant to induction of experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome in human by bovine peripheral myelin (BPM), and P2 protein or the P2 protein peptide 57-81. The P0 peptide 180-199 is a stronger neuritogenic antigen than the P2 peptide 57-81. We found that this synthetic peptide induced both clinical and pathological characteristics of an acute monophasic EAN in C57BL/6 mice. Only male mice were more sensitive to EAN induction with the P0 peptide 180-199. Intravenously administrated pertussis toxin (PT) had an adjuvant effect that increased the incidence of P0 peptide 180-199-induced EAN as well as the inflammation and demyelination in the peripheral nerves. Spontaneous and P0 peptide 180-199 stimulated proliferation of peripheral T-cells were enhanced by PT-treatment as well. The enhancing effect was lower before onset of the disease (Day 6 post immunization) (p.i.) as compared to the early phase of the disease (Day 22 p.i.). Thus, P0 peptides together with PT are able to break tolerance to myelin in C57BL/6 mice.

Adjuvants, Immunologic↗

PubMed2000

Incidence of stroke in relation to cognitive function and dementia in the Kungsholmen Project.

OBJECTIVE: To investigate whether cognitive function is related to incidence of stroke. METHODS: A population-based cohort of 1551 subjects with no clinical history or signs of stroke, age 75 years and over at baseline, were followed up for 3 years. Individuals with a first-ever stroke event that was recorded in the Stockholm inpatient register after the date of baseline interview were considered as incident stroke patients. Diagnosis of stroke followed the International Classification of Disease, 9th Revision (ICD-9). Diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (DSM-III-R). Cognitive functioning was assessed with the Mini-Mental State Examination. RESULTS: During the 4102 person-years of follow-up, 110 events were recorded, giving an overall incidence of stroke of 26.8 per 1000 person-years. Subjects with mild dementia had a relative risk of 2.6 (95% CI, 1.2 to 5.7) of developing stroke after controlling for the potential confounders. The corresponding figure for subjects with cognitive impairment was 2.0 (95% CI, 1.0 to 3.8; p = 0.05). There was a tendency for subjects who developed stroke to be more likely to have vascular factors (systolic blood pressure >180 mm Hg, heart disease, or diabetes mellitus) than those who did not. CONCLUSIONS: Mild dementia and cognitive impairment are associated with an increased incidence of stroke among subjects age 75 years old and over. Because stroke increases risk of dementia and prior stroke increases risk of a subsequent stroke, mild dementia and cognitive impairment may be a manifestation of clinically unrecognized stroke.

Aged↗

PubMed2000

Increased expression of mRNA encoding interleukin-1beta and caspase-1, and the secreted isoform of interleukin-1 receptor antagonist in the rat brain following systemic kainic acid administration.

Kainic acid, an analogue of glutamate, injected systemically to rats evokes seizures that are accompanied by nerve cell damage primarily in the limbic system. In the present study, we have analyzed the temporal profile of the expression of the cytokines interleukin-1beta (IL-1beta) and IL-1 receptor antagonist (IL-1ra), and the related IL-1beta-converting enzyme (ICE/caspase-1), in different regions of the rat brain in response to peripheral kainic acid administration (10 mg/kg, i.p.). In situ hybridization histochemistry experiments revealed that IL-1beta mRNA-expressing cells, morphologically identified as microglial cells, were mainly localized to regions showing pronounced neuronal degeneration; hippocampus, thalamus, amygdala, and certain cortical regions. The strongest expression of IL-1beta mRNA was observed after 12 hr in these regions. A weak induction of the IL-1beta mRNA expression was observed already at 2 hr. Similar results were obtained by RT-PCR analysis, showing a significantly increased expression of IL-1beta mRNA in the hippocampus and amygdala after 12 hr. In addition, RT-PCR analysis revealed that IL-1ra mRNA, and specifically mRNA encoding the secreted isoform of IL-1ra (sIL-1ra), was strongly induced in the hippocampus and amygdala at 12 and 24 hr post-injection. RT-PCR analysis of mRNA encoding caspase-1 showed a significantly increased expression in the amygdala after 12 hr. In conclusion, in response to systemic kainic acid injection IL-1beta mRNA is rapidly induced and followed by induction of IL-1ra mRNA and caspase-1 mRNA, supporting a role of the IL-1 system in the inflammatory response during excitotoxic damage.

Animals↗

PubMed2000

Influence of social network on occurrence of dementia: a community-based longitudinal study.

BACKGROUND: Few data are available on the effect of social ties on dementia development. This study explored whether single social network components and different degrees of the social connections affect dementia incidence. METHODS: A community-based cohort of 1203 non-demented people, living at home in the Kungsholmen district of Stockholm, Sweden, and who had good cognition, was followed for an average period of 3 years. On the basis of medical and psychological data, 176 patients were diagnosed with dementia according to the criteria of the third edition revision of the Diagnostic and Statistical Manual of Mental Disorders. Information on social network was obtained by personal interview by trained nurses at baseline. The covariates included in the analysis were age, sex, education, cognitive and functional status, depressive symptoms, and vascular diseases. FINDINGS: Those individuals living alone, and those without any close social ties, both had an adjusted relative risk for developing dementia of 1.5 (95% CI 1.0-2.1 and 1.0-2.4, respectively). Compared with married people living with someone, single people and those living alone had an adjusted relative risk of 1.9 (95% CI 1.2-3.1). Infrequent contacts with network resources did not increase the risk of the disease if such contacts were experienced as satisfying. When all components were combined in an index, a poor or limited social network increased the risk of dementia by 60% (95% CI 1.2-2.1), and a significant gradient was found for the four degrees of social connections (p=0.0009). INTERPRETATION: An extensive social network seems to protect against dementia. Confirmation of this finding and further investigation to clarify the mechanisms are worthwhile due to the implications for prevention.

Aged↗

PubMed2000

Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women.

Estrogens may be implicated in the development of Alzheimer's disease (AD). Most of their effects are mediated via receptors whose function and expression may be modified by DNA polymorphisms. Here the estrogen receptor 1 gene (ESR1) polymorphisms XbaI and PvuII were analyzed in 214 AD patients and 290 controls. In logistic regression analysis, a significantly increased risk of familial AD due to interaction between the ESR1 xx genotype and the apolipoprotein E epsilon4 allele was observed in women in a Swedish clinic-based sample, taking subjects who had neither the xx genotype nor epsilon4 as reference (OR 11.3, 95% CI 2.9-43.8). The risk of AD was more pronounced in early-onset (OR 22.0, 95% CI 3. 7-132.7) than in late-onset (OR 6.0, 95% CI 1.2-29.7) female patients. For women carrying the pp genotype together with epsilon4 the risk of AD was similarly elevated. Likewise in a Swedish community-based set of women, an increased risk of familial AD was observed in subjects who had either the ESR1 xx or pp genotype together with epsilon4. Furthermore, the Pp genotype frequency was found to be significantly increased in Finnish women with sporadic AD. We, thus, conclude that the ESR1 gene may have a role in the development of AD in females.

Age of Onset↗

PubMed2000

Levels of alpha- and beta-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimer's disease patients.

Alternative cleavage of the amyloid precursor protein (APP) results in generation and secretion of both soluble APP (sAPP) and beta-amyloid (Abeta). Abeta is the main component of the amyloid depositions in the brains of Alzheimer's disease (AD) patients. Using Western blotting, we compared the levels of alpha-secretase cleaved sAPP, beta-secretase cleaved sAPP and total sAPP, in cerebrospinal fluid (CSF) from 13 sporadic AD patients and 13 healthy controls. Our findings show significant amounts of beta-secretase cleaved sAPP in CSF. There was no statistically significant difference in the levels of beta-secretase cleaved sAPP between AD patients and controls. The levels of alpha-secretase cleaved sAPP and total sAPP were, however, found to be significantly lower in the AD patients than in the controls.

Aged↗

PubMed2000

The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample.

OBJECTIVES: To examine the ability of the total score and individual items from the Mini-Mental State Examination in predicting the development of Alzheimer disease (AD) across a 3- and 6-year period in a population-based sample, and to describe the longitudinal changes in these measures across the same follow-up periods. DESIGN: Prospective follow-up of a community-based cohort, with 3 times of testing across a 6-year period. At each time of measurement, participants were clinically examined by physicians to identify demented and nondemented participants according to Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria. PARTICIPANTS: The study population consisted of all participants who were nondemented at the first follow-up and participated in the second follow-up examination. Among those, 459 remained nondemented and 73 developed AD during the second follow-up period. RESULTS: Baseline differences in the total Mini-Mental State Examination score and the delayed memory item were seen 6 years before eventual dementia diagnosis (P<.01). Analysis of the longitudinal changes showed no differences in the rate of decline for the incident AD or nondemented group between time 1 and time 2 (P>.10). However, the incident AD group exhibited precipitous declines in 8 of the 10 subscales between time 2 and time 3, the point at which they were clinically diagnosed (P<.01). Logistic regression analyses showed that only the delayed memory item was a significant predictor of who would develop AD, independent of age, sex, and years of education, at both of the first 2 times of measurement (P<.001). CONCLUSIONS: The diagnosis of AD is preceded by a long preclinical phase in which deficits in memory performance are most common. These deficits remain relatively stable up until the time that a dementia diagnosis can be rendered. Arch Neurol. 2000.

Aged↗

PubMed2000

Lead concentrations in elderly urban people related to blood pressure and mental performance: results from a population-based study.

BACKGROUND: The Kungsholmen project is a longitudinal study of ageing and dementia conducted in Stockholm in 1987. In a 1994-96 follow-up, 804 subjects had their blood samples analyzed for lead. METHODS: Lead concentration in blood in an elderly population aged 75+ (mean age of 88.4 years) was studied in relation to age, blood pressure (BP), body mass index (BMI), cognitive function measured with Mini-Mental State Examination (MMSE), gender, and smoking. RESULTS: The mean blood lead level (n = 762) was 3.7 microg/dL (0.18 micromol/L) whole blood with a standard deviation of 2.3, (0.11). There was a contribution of gender with men having higher blood lead levels than women (beta = -0.20; P = 0.000001) but not of smoking habits (beta = 0.07; P = 0.08) when these variables were entered into a multiple regression model with lead as the dependent variable (R = 0.22; P < 0.000001). Different multiple regression models were tested with lead as the dependent variable. No relation was found between lead concentrations and age, BMI, systolic BP, diastolic BP, or MMSE. Systolic and diastolic BP were correlated to BMI (R = 0.10; P = 0.01 and R = 0.22; P = 0.000 001, respectively). CONCLUSIONS: In this elderly population from a specified area of Stockholm it is unlikely that lead exposure affects BP or cognition. However, high lead levels in blood may reflect earlier occupational exposure or life style factors.

Age Factors↗

PubMed2000

The interplay of institution and family caregiving: relations between patient hassles, nursing home hassles and caregivers' burnout.

This population-based study investigated the relationship between stresses (hassles) and burnout for 30 family caregivers and their institutionalized demented elderly. The Burnout Measure, the Patient Hassles Scales and the Nursing Home Hassles Scale were used. Hassles included: patient hassles (cognitive, behavior, basic ADL) and nursing home hassles (caregiver - staff, patient - staff, practical/logistical). The caregiver's characteristics are described in relation to burnout and the caregiver's most frequent hassles are discussed. All subscales except basic ADL were correlated to burnout. However, regression analysis showed the nursing home hassles to be the most important stresses explaining variance in burnout among family caregivers.

Aged↗

PubMed2000

Expression of interleukin 1 alpha and beta, and interleukin 1 receptor antagonist mRNA in the rat central nervous system after peripheral administration of lipopolysaccharides.

Interleukin 1alpha (IL-1alpha) and IL-1beta, and the endogenous IL-1 receptor antagonist (IL-1ra) are known members of the IL-1 family. Using in situ hybridization histochemistry we demonstrated that following endotoxin injection (lipopolysaccharides, LPS, 2.0 mg/kg, i.p.) a time dependent expression and partly different expression patterns of the cytokines occurred within the rat brain and pituitary gland. All cytokines were observed in the choroid plexus. In addition, IL-1ra mRNA expressing cells were observed scattered in the brain parenchyma, whereas scattered IL-1beta mRNA expressing cells were restricted to central thalamic nuclei, the dorsal hypothalamus, and cortical regions, such as the parietal and frontal cortex. A strong IL-1beta mRNA expression was found in the circumventricular organs. In the pituitary gland, a low IL-1alpha and a high IL-1beta mRNA expression was observed, with the highest density of cytokine-expressing cells seen in the posterior pituitary. The cell types expressing the mRNA's of IL-1alpha, IL-1beta and IL-1ra were identified as monocytes in the circumventricular organs and the pituitary gland, and as microglia in the brain parenchyma. In conclusion, the present findings revealed that cytokine production in response to a peripheral endotoxin challenge mainly occurs in peripherally derived monocytes in the circumventricular organs and the pituitary gland. IL-1beta is the predominant form expressed, whereas the expression of IL-1alpha mRNA and IL-1ra mRNA is lower. Our observations support the view that peripherally derived IL-1 may play a role in the induction of centrally mediated illness symptoms.

Animals↗

PubMed2000

nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer's disease.

The immunocytochemical distribution of the neuronal form of nitric oxide synthase (nNOS) was compared with neuropathological changes and with cell death related DNA damage (as revealed by in situ end labeling, ISEL) in the hippocampal formation and entorhinal cortex of 12 age-matched control subjects and 12 Alzheimer's disease (AD) patients. Unlike controls, numerous nNOS-positive reactive astrocytes were found in AD patients around beta-amyloid plaques in CA1 and subiculum and at the places of clear and overt neuron loss, particularly in the entorhinal cortex layer II and CA4. This is the first evidence of nNOS-like immunoreactivity in reactive astrocytes in AD. In contrast to controls, in all but one AD subject, large numbers of ISEL-positive neuronal nuclei and microglial cells were found in the CA1 and CA4 regions and subiculum. Semiquantitative analysis showed that neuronal DNA fragmentation in AD match with the distribution of nNOS-expressing reactive astroglial cells in CA1 (r = 0.74, P < 0.01) and CA4 (r = 0.58, P < 0.05). A portion of the nNOS-positive CA2/CA3 pyramidal neurons was found to be spared even in the most affected hippocampi. A significant inverse correlation between nNOS expression and immunoreactivity to abnormally phosphorylated tau proteins (as revealed by AT8 monoclonal antibody) in perikarya of these CA2/3 neurons (r = -0.85, P < 0.01) suggests that nNOS expression may provide selective resistance to neuronal degeneration in AD. In conclusion, our results imply that an upregulated production of NO by reactive astrocytes may play a key role in the pathogenesis of AD.

Aged↗

PubMed2000

Growth-associated protein GAP-43 in the frontal cortex and in the hippocampus in Alzheimer's disease: an immunohistochemical and quantitative study.

We studied the growth-associated protein, GAP-43 (also called neuromodulin and B-50) in post-mortem brain tissue using immunohistochemistry and quantitative Western blotting, from patients with Alzheimer's disease (AD) and age-matched control subjects. By immunohistochemistry, we found a clear reduction of GAP-43 in the frontal cortex, while in the hippocampus, there was a marked reduction in some areas (dentate molecular layer, stratum moleculare and radiale of CA1 and CA4), while not in other areas (stratum lacunosum, pyramidale and oriens of CA1). Moreover, in the hippocampus, neuritic staining was prominent, and was often associated with senile plaques. Quantitative analysis showed that GAP-43 was significantly reduced in AD, both in the frontal cortex (70% of the control value, p < 0.01) and in the hippocampus (81% of the control value, p < 0.05). In the frontal cortex, there was a significant negative correlation between GAP-43 and duration of dementia (r = -0.58; p < 0.02) and a positive correlation between GAP-43 and the synaptic vesicle-specific protein rab3a (r = 0.62; p < 0.05), while no such correlation were found in the hippocampus. In contrast, a significant positive correlation was found between GAP-43 and the number of senile plaques in the hippocampus (r = 0.64; p < 0.05), but not in the frontal cortex. GAP-43 is known to be involved in maintenance of synapses and in neuritic regeneration. Our findings may suggest that in the frontal cortex, GAP-43 levels decline as a consequence of the synaptic degeneration, while in the hippocampus, sprouting processes, involving GAP-43, are active.

Aged↗

PubMed2000

Social and emotional loneliness among non-demented and demented elderly people.

There is a lack of studies about loneliness and cognitive functioning among elderly people and, above all, among those with cognitive impairment. The aim of this study is to investigate loneliness, both social and emotional, in non-demented and demented elderly people. The study is based on 589 persons, who answered the question about social loneliness (often being lonely) in the Kungsholmen longitudinal project. All subjects were examined extensively to reach a diagnosis and to determine the dementia level. Data were collected through structured interviews on subjective social loneliness as well as emotional loneliness (feelings of loneliness, from often to never) and background variables (age, sex, housing and housing conditions). Non-demented elderly subjects reported themselves to be lonely significantly less often compared to demented subjects, but there were no differences in the emotional experience of loneliness. Social loneliness was more common in the different levels of dementia and increased with reduced cognitive functioning, while emotional loneliness decreased. Living together with someone and living in one's own apartment showed a positive influence on feelings of loneliness.

Journal Article↗

PubMed2000

Apolipoprotein E varepsilon4 allele has an impact on vascular reactivity in Alzheimer's disease.

Seventeen otherwise healthy, non-smoking patients with probable Alzheimer's disease (AD) and 11 healthy, non-smoking, age-matched controls participated in a study of vascular reactivity. Three substances were iontophoresed into the skin: sodium nitroprusside (SNP) delivered at the cathode, and acetylcholine chloride and isoprenaline sulphate delivered at the anode. The resultant vasodilation was mapped through a laser Doppler perfusion imager. The patients harbouring the Apolipoprotein E varepsilon4 allele (ApoE4) (n=9) showed significantly greater vasodilation compared both with patients without the ApoE4 and with controls (one control possessed the ApoE4) when SNP was delivered at the cathode. An additional study of ten of the AD patients and ten controls suggested that the enhanced reactivity in the patients with the ApoE4 depended on a greater sensitivity to the iontophoretic current itself at the cathode rather than to SNP. The quotient between total cholesterol and high-density lipoprotein-cholesterol was higher in the patients with the ApoE4 compared both with patients without the ApoE4 and with controls. A dysfunction of voltage-dependent ion channels and/or other membrane abnormalities in AD patients possessing the ApoE4 is suggested.

Journal Article↗

PubMed2000

Alzheimer's disease presenilin-1 exon 9 deletion and L250S mutations sensitize SH-SY5Y neuroblastoma cells to hyperosmotic stress-induced apoptosis.

Mutations in the presenilin-1 (PS1) and presenilin-2 (PS2) genes account for the majority of early-onset familial Alzheimer's disease cases. Recent studies suggest that presenilin gene mutations predispose cells to apoptosis by mechanisms involving altered calcium homeostasis and oxidative damage. In the present study, we determined whether PS1 mutations also sensitize cells to hyperosmotic stress-induced apoptosis. For this, we established SH-SY5Y neuroblastoma cell lines stably transfected with wild-type PS1 or either the PS1 exon 9 deletion (deltaE9) or PS1 L250S mutants. Cultured cells were exposed to an overnight (17 h) serum deprivation, followed by a 30 min treatment with either 20 mM glucose, 10 nM insulin-like growth factor-1 or 20 mM glucose + 10 nM insulin-like growth factor-1. Cells were then cultured for a further 3, 6 or 24 h and stained for apoptotic condensed nuclei using propidium iodide. Confirmation that cells were undergoing an active apoptotic process was achieved by labelling of DNA strand breaks using the terminal dUTP nick end labelling (TUNEL) technique. We also determined cell viability using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Propidium iodide staining revealed that all cell lines and controls showed an increased number of apoptotic cells appearing with condensed nuclei at 24 h compared with 6 h and 3 h. High glucose-induced hyperosmotic stress resulted in significantly more apoptotic cells in the PS1 deltaE9 and PS1 L250S mutation cell lines at 24 h, compared with the wild-type PS1 lines (P < 0.001, ANOVA for both comparisons). Mean values (+/-S.D.) for the percentage number of apoptotic cells at 24 h following high glucose treatment were 16.1 +/- 3.5%, 26.7 +/- 5.5% and 31.0 +/- 5.7% for the wild-type PS1, PS1 deltaE9 and PS1 L250S lines, respectively. The pro-apoptotic effects of high glucose treatment were reversed by 10 nM insulin-like growth factor-1, although to a lesser extent in the mutation cell lines (5.8 +/- 2.4%, 15.2 +/- 7.3% and 13.2 +/- 2.0% for the wild-type PS1, PS1 deltaE9 (P < 0.01 for comparison with wild-type PS1) and PS1 L250S (P < 0.01 for comparison with wild-type PS1) transfected lines, respectively. TUNEL labelling of cells at 24 h following treatment gave essentially the same results pattern as obtained using propidium iodide. The percentage number of apoptotic cells with DNA strand breaks (means +/- S.D.) following high glucose treatment was 15.4 +/- 2.6% for the wild-type PS1, 26.8 +/- 3.2% for the PS1 deltaE9 (P < 0.001 for comparison with wild-type PS1) and 29.7 +/- 6.1% for the PS1 L250S transfected lines (P < 0.001 for comparison with wild-type PS1). The PS1 deltaE9 and PS1 L250S transfected lines also showed a higher number of apoptotic cells with DNA strand breaks at 24 h following high glucose plus insulin-like growth factor-1 treatment (11.4 +/- 2.0% and 14.3 +/- 2.8%, respectively), compared with values for the wild-type PS1 lines (8.5 +/- 2.4%). These differences were significant (P < 0.01) for the comparison of wild-type PS1 and PS1 L250S, but not PS1 deltaE9 lines. The mutation-related increases in number of apoptotic cells at 24 h following high glucose treatment were not accompanied by significant differences in cell viability at this time-point. Our results indicate that PS1 mutations predispose to hyperosmotic stress-induced apoptosis and that the anti-apoptotic effects of insulin-like growth factor-1 are compromised by these mutations. Perturbations of insulin-like growth factor-1 signalling may be involved in PS1 mutation-related apoptotic neuronal cell death in Alzheimer's disease.

Alzheimer Disease↗

PubMed2000

Density profiles of Alzheimer disease regional brain pathology for the huddinge brain bank: pattern recognition emulates and expands upon Braak staging.

Density profiles of Alzheimer's disease (AD) regional brain pathology were constructed for 249 subjects in the Huddinge Brain Bank. Counts per square millimeter for neurofibrillary tangles (NFT), diffuse plaques (DP), and neuritic plaques (NP) in 38 areas were investigated using a pattern recognition technique called GoM. The seven distributional profiles of AD neuropathology emulated and expanded upon Braak staging illustrating induction (Groups 1-3) and clinical progression (Groups 4-7). Normal aging represented limited AD changes, few NFT in the entorhinal cortex and hippocampal CA1 (Group 1). The threshold for possible AD was NFT in the subiculum (Group 2), found with DP in the neocortex. Temporal medial NFT was the threshold for probable AD (Group 4). The 'oldest-old', often demented without brain atrophy, had extensive entorhinal/CA1 NFT and cortical DP, but few cortical NFT or NP (Group 5). A second subtype 'disconnection' (Group 6) lacked AD pathology for a specific set of subcortical and cortical areas. Accumulation of NFT in first-affected areas continued through end-stage disease (Group 7), with apparent rapid transition of DP to NP in the cortex during clinical progression. The evolution of AD is a highly ordered sequential process. Pattern recognition approaches such as GoM may be useful in better defining the process.

Alzheimer Disease↗