Biomedical subjects

Bengt Winblad

Publications and source records attributed to Bengt Winblad.

At least 91 records · Page 5Linked to original sources

PubMed2004

Serum lipids and hippocampal volume: the link to Alzheimer's disease?

The association between hippocampal volume (as a presumed index of Alzheimer's disease pathology) with serum total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was studied in 86 elderly subjects with a range of cognitive functions. High-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol or total cholesterol, was associated with hippocampal volume and dementia. This is compatible with protective effects of high-density lipoprotein cholesterol on hippocampal atrophy and Alzheimer's disease.

Aged↗

PubMed2004

Intracranial volume in mild cognitive impairment, Alzheimer's disease and vascular dementia: evidence for brain reserve?

OBJECTIVE: The possibility of brain volume reserve effects was examined in a sample of geriatric outpatients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD). The total intracranial volume (ICV) served as an estimate of the maximum attained brain volume in life. METHODS: Subjects (n = 181, mean age 60.7) were consecutive referrals to a geriatric outpatients clinic (n = 96) and a group of age-matched healthy control subjects (n = 85). ICV and brain volume were attained from T1-weighted magnetic resonance images using a stereological method. Hippocampal atrophy was assessed with a visual rating scale. RESULTS: ICV was significantly smaller in patients with AD and VaD than in control subjects, but effect size was small. After adjusting for age and gender, having ICV in the smallest quartile significantly increased the risk of cognitive impairment (either MCI or dementia). In patients with dementia, but not in MCI, severity of cognitive impairment and ICV were moderately correlated. The effect of ICV on cognition was not mediated by hippocampal atrophy. CONCLUSIONS: These findings are compatible with volume reserve effects that modify the clinical expression of symptoms in both AD and VaD. They may have implications for the design of neuroimaging studies that use ICV for normalization procedures.

Adult↗

PubMed2004

A longitudinal study integrating population, care and social services data. The Swedish National study on Aging and Care (SNAC).

BACKGROUND AND AIMS: A large, national, long-term, longitudinal, multi-purpose study has been launched in Sweden--the Swedish National study on Aging and Care (SNAC). The study involves four research centers collecting data in four different areas of Sweden. METHODS: The study consists of two parts: the population part and the care and services part. In the population part, a large, representative panel of elders in different age cohorts is followed over time to record and describe the aging process from different aspects. In the care and services part, a systematic, longitudinal, individually-based collection of data is performed concerning provision of care and services together with functional ability, specific health care problems, and living conditions of the recipients living in the area. RESULTS: The data collection in the population part of the SNAC is not yet completed. In the present article, some preliminary results are reported from the care and services part. These pertain to comparisons between the participating areas with respect to the prevalence of disability among those receiving care and social services in their ordinary homes and those receiving care in special accommodation. A comparison is also presented with regard to the amount of home help provided to subjects with a given disability. CONCLUSIONS: This project has several advantages. It is expected to generate a rich data base relevant for future research on aging and care and to have a direct impact on the future Swedish system of care and services for the elderly.

Activities of Daily Living↗

PubMed2004

Ovariectomy and gonadal hormone treatment: effects on insulin-like growth factor-1 receptors in the rat brain.

Various studies demonstrate that estradiol regulates structure and function of adult neurons. Long-term effect of estradiol in terms of neuroprotection is less documented compared to short-term one. It is well documented that estradiol interacts with insulin-like growth factor-1 (IGF-I) in the brain. The present study examines the effect of ovariectomy and two doses of ovarian hormone treatment on IGF-I receptor density in the adult rat by receptor autoradiography using (125)I-IGF-I as a ligand. Our result showed that ovariectomy decreased IGF-I receptor density in hippocampus, hypothalamus and parietal cortex compared to that of the sham-operated group. Treatment with low or high dose estrogen restored IGF-I receptor density to the control levels in nearly all areas studied in this investigation. It seems that low dose estrogen has more pronounced effect than the high dose in restoring IGF-I receptor density. On the other hand, progesterone treatment in high but not in low dose restored IGF-I receptor density to that of the control. These results demonstrate that both estrogen and progesterone significantly affects IGF-I receptor density in different areas of the brain. These effects indicate a dose-dependent modulator effect of ovarian hormones on IGF-I activity in the brain.

Animals↗

PubMed2004

Reduced susceptibility to kainic acid-induced excitoxicity in T-cell deficient CD4/CD8(-/-) and middle-aged C57BL/6 mice.

Kainic acid (KA)-induced hippocampal injury is a good model for studying human neurodegenerative diseases. To investigate the roles of immune cells and age related changes in neurodegeneration, we used this model to assess reactions in young and middle-aged wild-type and CD4/CD8(-/-) mice by intranasal administration of KA. We found that CD4/CD8-deficiency resulted in a significant reduction of the severity of clinical signs and pathological changes in KA-treated young, but not in KA-treated middle-aged mice. Middle-aged wild-type mice had a similar reaction to KA insult as young and middle-aged CD4/CD8(-/-) mice. CD4/CD8(-/-) mice exhibited decreased locomotor and rearing activities as they approached to middle-aged state, which was not seen in wild-type mice. In addition, CD4/CD8-deficiency and increased age prevented KA-induced increase of both locomotor and rearing activities. The results suggest that a decline of immunological function is associated with aging, and both of them may contribute to the relative resistance to KA-induced neurotoxicity.

Aging↗

PubMed2004

Neuronal expression of caspase-1 immunoreactivity in the rat central nervous system.

Caspase-1/interleukin-1beta (IL-1beta)-converting enzyme (ICE) cleaves IL-1beta and IL-18 precursor proteins to the active forms of these proinflammatory cytokines. Since both cytokines are constitutively expressed in the brain, we investigated whether this is also the case for caspase-1. Using an antibody raised against the p10-subunit of the active enzyme, constitutive expression of caspase-1 immunoreactivity was found in nerve cells in the arcuate nucleus and in nerve fibres throughout the brain. Co-localisation with alpha-melanocyte stimulating hormone was demonstrated. The distribution pattern of caspase-1 immunoreactive structures is consistent with a role to produce mature IL-1beta in regions where IL-1beta mediates fever and sleep.

Animals↗

PubMed2004

CCR5 deficiency does not prevent P0 peptide 180-199 immunized mice from experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyelinating disease of peripheral nervous system (PNS) and represents an animal model of Guillain-Barré syndrome (GBS) in man. The inflammatory cell infiltrating into the PNS is a prerequisite for developing EAN. To explore the role of CC chemokine receptor 5 (CCR5) in the inflammatory process of EAN, we induced EAN in CCR5-deficient (CCR5(-/-)) mice with P0 protein peptide 180-199. We found that CCR5(-/-) mice showed a similar EAN clinical course and severity as well as profile of infiltrating macrophages and T cells in cauda equina (CE) of EAN and the same levels of spleen mononuclear cell (MNC) response to antigen and mitogen when compared with CCR5(+/+) control mice. However, increased IP-10 and MIP-1beta production in sciatic nerves were seen in CCR5(-/-) mice. These results suggest that CCR5 deficiency does not prevent P0 peptide 180-199-immunized mice from EAN. Increased MIP-1beta and IP-10 in sciatic nerves may compensate the CCR5 deficiency and contribute to inflammatory cells infiltrating to the PNS.

Animals↗

PubMed2004

IL-12p35 deficiency alleviates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice.

The role of IL-12 in excitotoxic neurodegeneration of brain is largely unknown. To address this issue, we used the model of kainic acid (KA)-induced hippocampal injury in IL-12p35 knockout (KO) mice, a well-characterized model for human neurodegenerative diseases. After KA treatment, hippocampal neurodegeneration was significantly less severe in the IL-12p35 KO mice than in wild-type mice as demonstrated by reduced pathological changes and astrogliosis. One day after KA treatment, levels of F4/80 and CD86 expression on microglia were significantly lower in IL-12p35 KO mice than in wild-type mice analyzed by flow cytometry, indicating that IL-12p35 deficiency resulted in lower levels of microglial activation. Five days after KA treatment, CD86 expression on microglia of wild-type mice was still higher, whereas F4/80 expression in wild-type mice decreased and was similar to that in IL-12p35 KO mice. Because microglial activation is necessary for KA-induced neurodegeneration, the lower level of microglial activation in the absence of IL-12p35 may alleviate hippocampal injury in KO mice. In summary, this study indicates that IL-12 may play a critical role in excitotoxin-induced brain injury.

Animals↗

PubMed2004

Kainic acid-induced excitotoxic hippocampal neurodegeneration in C57BL/6 mice: B cell and T cell subsets may contribute differently to the pathogenesis.

The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in C57BL/6 mice lacking specific T cell populations (CD4, CD8, and CD4/CD8 cells) and B cells [Igh-6(-/-)]. At 48 mg/kg of KA administrated intranasally, KA-induced convulsions were seen in all groups. However, CD4/CD8(-/-) mice exhibited the mildest seizures; the responses of CD8(-/-), Igh-6(-/-) and wild-type mice were intermediate, whereas CD4(-/-) mice displayed much more severe clinical signs and 100% early mortality, indicating that a deficiency of CD4 T cells obviously increased susceptibility to KA-induced brain damage. Histopathological analysis of the mice that survived 7 days after KA administration revealed that CD4/CD8(-/-) mice had the fewest pathologic changes but Igh-6(-/-) mice showed more severe lesions in area CA3 of the hippocampus than CD8(-/-) and wild-type mice. Reactive astrogliosis were prominent in all KA-treated mice. Locomotor activity as assessed by open-field test increased after KA administration in Igh-6(-/-) and wild-type mice only. These results denote the influence of the adaptive immune response on KA-induced hippocampal neurodegeneration and suggest that B cell and T cell subsets may contribute differently to the pathogenesis.

Animals↗

PubMed2004

An active and socially integrated lifestyle in late life might protect against dementia.

The recent availability of longitudinal data on the possible association of different lifestyles with dementia and Alzheimer's disease (AD) allow some preliminary conclusions on this topic. This review systematically analyses the published longitudinal studies exploring the effect of social network, physical leisure, and non-physical activity on cognition and dementia and then summarises the current evidence taking into account the limitations of the studies and the biological plausibility. For all three lifestyle components (social, mental, and physical), a beneficial effect on cognition and a protective effect against dementia are suggested. The three components seem to have common pathways, rather than specific mechanisms, which might converge within three major aetiological hypotheses for dementia and AD: the cognitive reserve hypothesis, the vascular hypothesis, and the stress hypothesis. Taking into account the accumulated evidence and the biological plausibility of these hypotheses, we conclude that an active and socially integrated lifestyle in late life protects against dementia and AD. Further research is necessary to better define the mechanisms of these associations and better delineate preventive and therapeutic strategies.

Aged↗

PubMed2004

Co-expressed presenilin 1 NTF and CTF form functional gamma-secretase complexes in cells devoid of full-length protein.

The enzyme gamma-secretase catalyzes the intramembrane proteolytic cleavage that generates the amyloid beta-peptide from the beta-amyloid precursor protein. The presenilin (PS) protein is one of the four integral membrane protein components of the mature gamma-secretase complex. The PS protein is itself subjected to endoproteolytic processing, generating stable N- and C-terminal fragment (NTF and CTF, respectively) heterodimers. Here we demonstrate that coexpression of PS1 NTF and CTF functionally mimics expression of the full-length PS1 protein and restores gamma-secretase activity in PS-deficient mammalian cells. The coexpressed fragments re-associate with each other inside the cell, where they also interact with nicastrin, another gamma-secretase complex component. Analysis of gamma-secretase activity following the expression of mutant forms of NTF and CTF, under conditions bypassing endoproteolysis, indicated that the putatively catalytic Asp257 and Asp385 residues have a direct effect on gamma-secretase activity. Moreover, we demonstrate that expression of the wild-type CTF rescues endoproteolytic cleavage of C-terminally truncated PS1 molecules that are otherwise uncleaved and inactive. Recovery of cleavage is critically dependent on the integrity of Asp385. Taken together, our findings indicate that ectopically expressed NTF and CTF restore functional gamma-secretase complexes and that the presence of full-length PS1 is not a requirement for proper complex assembly.

Amyloid Precursor Protein Secretases↗

PubMed2004

Tooth loss and caries prevalence in very old Swedish people: the relationship to cognitive function and functional ability.

OBJECTIVE: To analyse whether cognitive function and functional ability are related to oral health among community-dwelling older people over the age of 80 years. BACKGROUND: This cross-sectional study is based on the Kungsholmen Elders Oral Health Survey (KEOHS). The study included oral examinations carried out in two local clinics by standardised examiners and interviews using structured questionnaires. MATERIALS AND METHODS: Altogether 159 individuals were included in this study. Coronal caries and root caries were assessed using the National Institute of Dental and Craniofacial Research (NIDCR) diagnostic criteria. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) index and functional ability was assessed by a global measure of self-reported changes. RESULTS: Older adults with a low MMSE score (< or = 23) tended to have a higher risk of coronal caries than those with higher scores. Participants with mild cognitive decline (MMSE = 24-26) and with a decrease in functional ability had a significantly higher risk of root caries. These associations changed little when adjusted by the covariates. In addition, people with a low MMSE (0-23) had a four times higher risk of not using dental services regularly. This result was unchanged after adjusting for the variables studied. CONCLUSIONS: This study revealed associations between the cognitive and functional status of the individual and aspects of oral health, that may contribute to a deeper understanding of the background of oral health status in older adults.

Activities of Daily Living↗

PubMed2004

Increased susceptibility to experimental autoimmune neuritis after upregulation of the autoreactive T cell response to peripheral myelin antigen in apolipoprotein E-deficient mice.

Experimental autoimmune neuritis (EAN), an acute demyelinating inflammatory disease of the peripheral nervous system (PNS), is a good model for the human counterpart, Guillain-Barré syndrome. Apolipoprotein E (ApoE), a 34 kDa glycosylated protein with multiple biological properties, has been linked both with the innate immune response of mice and with neurological disease. The present study investigated the previously unexplored role of ApoE in autoimmune-mediated demyelination. ApoE-deficient (apoE -/-) mice exhibited a greater susceptibility to EAN induced by the PNS myelin P0 protein peptide 180-199, as compared to wild type (apoE +/+) mice. The augmented susceptibility seen in apoE -/- mice was associated with increased inflammatory cell infiltrates in the PNS during the effector phase. Although the 2 groups of mice exhibited no quantitative or proportional differences in splenic lymphocyte populations, the apoE -/- mice showed enhanced antigen-specific proliferation of T cells of spleen, which is related to modified macrophage function, upregulation of Th1 and downregulation of Th2-autoreactive responses to P0 peptide. These effects were shown as increased numbers of IFN-gamma expressing cells in the spleen and of IFN-gamma, IL-12 and TNF-alpha expressing cells in the PNS, as well as a decreased IL-10 production by splenic cells in apoE -/- mice. In addition, apoE -/- mice had enhanced antigen-specific antibody responses, which might have contributed to their aggravated EAN. These data provide strong evidence that apoE acts as an inhibitor of this inflammatory and demyelinating disease by upregulating IL-10, as well as by inhibiting Th1 responses and antigen-specific antibody formation. These data may aid the development of new and more effective therapeutic strategies for inflammatory and demyelinating diseases such as Guillain-Barré syndrome.

Analysis of Variance↗

PubMed2004

Occupational exposure to electromagnetic fields and risk of Alzheimer's disease.

BACKGROUND: Extremely-low-frequency magnetic field (ELF-MF) exposure is suspected to increase the risk of Alzheimer's disease. Such fields are present in the vicinity of electrical motors and other electric appliances containing coils. METHODS: We investigated lifetime occupational ELF-MF exposure in relation to Alzheimer's disease and dementia among a community dementia-free cohort (n = 931) age 75 years and older in Stockholm, Sweden. This cohort was followed from 1987-1989 until 1994-1996 to detect dementia cases (Diagnostic and Statistical Manual of Mental Disorders, revised 3rd edition criteria). Information on lifetime job history was obtained by interview, usually of next of kin. ELF-MF exposure was assessed using a job-exposure matrix, measurement on historical equipment, and expert estimation. We analyzed the data with Cox models controlling for potential confounders. RESULTS: Dementia was diagnosed in 265 subjects, including 202 with Alzheimer's disease. Among men, ELF-MF exposure > or=0.2 microT in lifetime principal job was related to multivariate-adjusted relative risks of 2.3 (95% CI = 1.0-5.1) for Alzheimer's disease and 2.0 (1.1-3.7) for dementia. We found no association among women. A similar sex-specific pattern was seen for the associations with average ELF-MF exposure throughout the work life. A dose-response relation was suggested in men, with multivariate-adjusted relative risks of 2.4 (0.8-6.8) for Alzheimer's disease and 2.5 (1.1-5.6) for dementia for the upper tertile of lifetime average exposure. CONCLUSIONS: Long-term occupational exposure to a higher ELF-MF level may increase the risk of Alzheimer's disease and dementia in men. Similar patterns were not seen in women, which may in part be the result of a greater exposure misclassification in women than in men.

Aged↗

PubMed2004

Impact of donepezil treatment for Alzheimer's disease on caregiver time.

OBJECTIVE: To assess the impact of donepezil treatment compared with placebo on caregiver time spent assisting patients with Alzheimer's disease (AD). RESEARCH DESIGN AND METHODS: Patient and caregiver data were collected as part of a 1-year, prospective, double-blind, randomized, placebo-controlled trial. The Resource Utilization in Dementia (RUD) questionnaire was used to record caregiver time at study baseline and at Weeks 12, 24, 36, and 52. This analysis focuses solely on those caregivers who were actively (> 0 h/day reported on the RUD) providing care at study baseline. MAIN OUTCOME MEASURES: The change in time relative to baseline that caregivers spent assisting patients over the course of the study. RESULTS: The active caregiver population was composed of 96 caregivers of donepezil-treated patients and 94 caregivers of patients receiving placebo. Over the course of the 1-year study, and as the condition of the AD patients deteriorated, it was expected that caregiver time would increase. As expected, after 52 weeks, caregivers of placebo patients were providing almost 2 h each day (106.8 min) more care than they had done at study baseline. For those caregivers of donepezil-treated patients, although they were spending more time caring than they had done at study baseline, their time burden had only increased by 42.6 min more each day. This difference in caring time between the 2 groups, relative to baseline at Week 52, was 1.1 h (64.2 min) each day, and was significant (p = 0.03). CONCLUSION: Caregiver time devoted to helping an AD patient typically increases with the severity of the disease. By helping the patient maintain his/her ability to perform activities of daily living for longer, treatment with donepezil is not only beneficial to the patient, but also has positive time-burden implications for the caregiver.

Activities of Daily Living↗

PubMed2003

Gamma-secretase activity of presenilin 1 regulates acetylcholine muscarinic receptor-mediated signal transduction.

Familial Alzheimer's disease (FAD) presenilin 1 (PS1) mutations give enhanced calcium responses upon different stimuli, attenuated capacitative calcium entry, an increased sensitivity of cells to undergo apoptosis, and increased gamma-secretase activity. We previously showed that the FAD mutation causing an exon 9 deletion in PS1 results in enhanced basal phospholipase C (PLC) activity (Cedazo-Minguez, A., Popescu, B. O., Ankarcrona, M., Nishimura, T., and Cowburn, R. F. (2002) J. Biol. Chem. 277, 36646-36655). To further elucidate the mechanisms by which PS1 interferes with PLC-calcium signaling, we studied the effect of two other FAD PS1 mutants (M146V and L250S) and two dominant negative PS1 mutants (D257A and D385N) on basal and carbachol-stimulated phosphoinositide (PI) hydrolysis and intracellular calcium concentrations ([Ca2+]i) in SH-SY5Y neuroblastoma cells. We found a significant increase in basal PI hydrolysis in PS1 M146V cells but not in PS1 L250S cells. Both PS1 M146V and PS1 L250S cells showed a significant increase in carbachol-induced [Ca2+]i as compared with nontransfected or wild type PS1 transfected cells. The elevated carbachol-induced [Ca2+]i signals were reversed by the PLC inhibitor neomycin, the ryanodine receptor antagonist dantrolene, the general aspartyl protease inhibitor pepstatin A, and the specific gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. The cells expressing either PS1 D257A or PS1 D385N had attenuated carbachol-stimulated PI hydrolysis and [Ca2+]i responses. In nontransfected or PS1 wild type transfected cells, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester and pepstatin A also attenuated both carbachol-stimulated PI hydrolysis and [Ca2+]i responses to levels found in PS1 D257A or PS1 D385N dominant negative cells. Our findings suggest that PS1 can regulate PLC activity and that this function is gamma-secretase activity-dependent.

Amyloid Precursor Protein Secretases↗

PubMed2003

Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.

24S-hydroxycholesterol is a side-chain oxidized oxysterol formed in the brain that is continuously crossing the blood-brain barrier to reach the circulation. There may be an opposite flux of 27-hydroxycholesterol, which is formed to a lower extent in the brain than in most other organs. Here we measured cholesterol, lathosterol, 24S- and 27-hydroxycholesterol, and plant sterols in four different brain areas of deceased Alzheimer's disease (AD) patients and controls. 24S-hydroxycholesterol was decreased and 27-hydroxycholesterol increased in all the brain samples from the AD patients. The difference was statistically significant in four of the eight comparisons. The ratio of 27-hydroxycholesterol to 24S-hydroxycholesterol was significantly increased in all brain areas of the AD patients and also in the brains of aged mice expressing the Swedish Alzheimer mutation APP751. Cholesterol 24S-hydroxylase and 27-hydroxylase protein was not significantly different between AD patients and controls. A high correlation was observed between the levels of 24S-hydroxycholesterol and lathosterol in the frontal cortex of the AD patients but not in the controls. Most probably the high levels of 27-hydroxycholesterol are due to increased influx of this steroid over the blood-brain barrier and the lower levels of 24S-hydroxycholesterol to decreased production. The high correlation between lathosterol and 24-hydroxycholesterol is consistent with a close coupling between synthesis and metabolism of cholesterol in the frontal cortex of the AD brain.

Aged↗

PubMed2003

Combined effects of APOE genotype, blood pressure, and antihypertensive drug use on incident AD.

OBJECTIVE: To study the hypotheses that APOE-epsilon4 allele may interact with blood pressure to affect Alzheimer's disease (AD) occurrence and that antihypertensive therapy could modify such an effect. METHODS: A dementia-free cohort of 966 community-dwelling persons aged 75 years and older in Stockholm, Sweden was followed to detect patients with AD using the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) diagnostic criteria. Data were analyzed using Cox proportional hazards models with adjustment for several potential confounders. RESULTS: During a 6-year follow-up period, AD was diagnosed in 204 persons. APOE-epsilon4 allele, high systolic pressure (> or = 140 mm Hg), and low diastolic pressure (<70 mm Hg) were associated with an increased risk of AD. APOE-epsilon4 allele combined with low diastolic pressure greatly increased the risk of AD independent of antihypertensive drug use. Antihypertensive therapy significantly reduced the risk of AD regardless of APOE-epsilon4 status and counteracted the combined risk effect of the epsilon4 allele with high systolic pressure on the disease. CONCLUSIONS: Elderly people with genetic susceptibility for Alzheimer's disease may experience a further increased disease risk if they have either high systolic pressure or low diastolic pressure. Antihypertensive therapy decreases the risk of Alzheimer's disease exerted by the APOE-epsilon4 allele.

Aged↗