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Bengt Winblad

Publications and source records attributed to Bengt Winblad.

At least 127 records · Page 7Linked to original sources
PubMed2003

Pharmacoeconomics of mild cognitive impairment.

There is little written about the pharmacoeconomics of mild cognitive impairment (MCI), particularly with regard to intervention. The aim of the paper is to highlight methodological issues and to present some results that are of importance when drug interventions of MCI are discussed. There is a relationship between severity of dementia and costs, but to what extent such results can be extrapolated to MCI is not known. Even if it is logical to consider a postponement of the shift from MCI to dementia as cost effective, this statement must be proven, particularly in light of the insufficient knowledge about the effects of anti-dementia drugs on survival. From the Kungsholmen project in Sweden, there are indications that the postponement between MCI and manifest dementia may result in short-term benefits (a few years) of about SEK50,000 (5300 US dollars).

Canada↗
PubMed2003

What is mild cognitive impairment? Variations in definitions and evolution of nondemented persons with cognitive impairment.

Numerous studies have endeavoured to explore the nature of cognitive impairment in nondemented elderly persons. Comparison of this literature is hampered by huge variations in criteria and methodology. Despite these limitations, there are repeated reports that nondemented persons with cognitive impairment have a higher chance of progressing to dementia. Evidence also indicates higher mortality in cognitively impaired persons but there is also a chance of improvement in cognition over time. The current paper provides an overview of the various concepts and criteria proposed for cognitive impairment in nondemented persons, discusses some of the problems with current research in this field, and presents some of the findings concerning the evolution of cognitive impairment in relation to dementia, mortality and cognitive improvement.

Cognition Disorders↗
PubMed2003

The chemokine receptor CCR5 is not a necessary inflammatory mediator in kainic acid-induced hippocampal injury: evidence for a compensatory effect by increased CCR2 and CCR3.

Chemokines and their receptors have been strongly implicated in the inflammatory process. However, their roles in excitotoxic brain injury are largely unknown. In this study we used C-C chemokine receptor 5 (CCR5) knockout (KO) mice to investigate the role of CCR5 in neurodegeneration induced by intranasal administration of the excitotoxin kainic acid (KA). Although KA treatment resulted in an increased CCR5 mRNA level in the hippocampi of wild-type mice, a CCR5 deficiency in KO mice did not affect either the clinical and pathological changes in vivo or the neuronal susceptibilities to KA insult in vitro. KA treatment stimulated mRNA expression of the monocyte chemoattractant protein-2 (MCP-2) in both the wild-type and KO mice. KA treatment did not affect mRNA levels for the macrophage inflammatory protein-1alpha (MIP-1alpha) or the regulated upon activation normal T cells expressed and secreted protein (RANTES) in either wild-type or CCR5 KO mice. CCR2 mRNA expression was undetectable in the hippocampi of wild-type mice regardless of KA treatment. In contrast, CCR5 KO mice showed CCR2 mRNA expression that was remarkably increased after KA treatment. KA treatment did not affect CCR3 mRNA expression in the wild-type mice, whereas KO mice showed both a higher basal level of CCR3 mRNA expression as well as a strong upregulation following KA treatment. These results indicate that CCR5 is not a necessary inflammatory mediator in KA induced neurodegeneration. The roles of CCR5 in excitotoxic injury in CCR5 deficient mice are compensated by increased CCR2 and CCR3 expression, which share the common MCP-2 ligand with CCR5.

Animals↗
PubMed2003

Social relations as determinants of oral health among persons over the age of 80 years.

OBJECTIVE: To analyze whether social relations during a 7-year follow-up influence oral health among generally healthy, community-dwelling persons over the age of 80 years. METHOD: The present investigation is based on a subsample of 129 dentate community-dwelling individuals from The Kungsholmen Elders Oral Health Study (KEOHS), which included data from interviews and oral examinations. Social relations were measured in terms of marital status, living alone, frequency of contacts, number of confidants, and satisfaction with social contacts and with the frequency of contacts. Oral health was measured in terms of coronal caries and root caries. RESULTS: The primary findings of the adjusted multivariate logistic regression analysis were that persons who lived alone or who became alone during the 7 years prior to the dental examination had greater odds of having coronal caries (odds ratio (OR): 2.4, 95% CI: 1.0-5.7) than those who continually lived with others, and that persons who were continuously dissatisfied with the frequency of their social contacts were more likely to have root caries than those who reported a sustained satisfaction with the frequency of their social contacts (OR: 2.9, 95% CI: 1.2-7.2). CONCLUSION: This study suggests that social relations are related to the oral health status of old-old individuals. From a psychosocial perspective, our findings contribute to a deeper understanding of the background of oral health status in older adults.

Activities of Daily Living↗
PubMed2003

Molecular identification of AMY, an Alzheimer disease amyloid-associated protein.

One of the neuropathological lesions characteristic of Alzheimer disease (AD) is the cerebral accumulation of the amyloid beta-peptide (A beta). Although numerous studies have demonstrated that A beta spontaneously forms amyloid in vitro, the molecular events underlying A beta amyloid formation in vivo are less well understood. Immunohistochemical studies have shown that other proteins colocalize with A beta in amyloid deposits in brain. The identity of one of these proteins, AMY, has so far remained elusive; therefore we attempted to purify AMY. The AMY protein was found to co-purify with A beta in insoluble fractions from human AD brain, and was absent in brains from control subjects. AMY immunoreactivity was primarily restricted to a 50-kDa and 100-kDa protein species. Interestingly, the chromatographic and immunological profile of AMY resembled the recently identified amyloid-associated protein CLAC, derived from a transmembrane collagen-like precursor, CLAC-P. Antibodies against AMY recognized CLAC-P expressed in mammalian cells. In addition, side-by-side comparisons of AD brain sections and extracts, using antibodies against both AMY and CLAC, respectively, resulted in almost identical staining patterns. Therefore, we conclude that the AMY immunoreactivity seen in association with amyloid in AD brain is due to the presence of the CLAC protein.

Aged↗
PubMed2003

An economic evaluation of donepezil in mild to moderate Alzheimer's disease: results of a 1-year, double-blind, randomized trial.

The costs and consequences of donepezil versus placebo treatment in patients with mild to moderate Alzheimer's disease (AD) were evaluated as part of a 1-year prospective, double-blind, randomized, multinational clinical trial. Patients received either donepezil (n = 142; 5 mg/day for 28 days followed by 10 mg/day according to the clinician's judgement) or placebo (n = 144). Unit costs were assessed in 1999 Swedish kronas (SEK) and converted to US dollars (USD). Donepezil-treated patients gained functional benefits relative to placebo on the Progressive Deterioration Scale (p = 0.042) and Instrumental Activities of Daily Living scale (p = 0.025) at week 52. Caregivers of donepezil-treated patients spent an average of 400 h less annually providing care than caregivers of placebo-treated patients. Mean annual healthcare costs were SEK 137,752 (USD 16,438) per patient for the donepezil group and SEK 135,314 (USD 16,147) in the placebo group. With the average annual cost of donepezil at SEK 10,723 (USD 1,280) per patient, the SEK 2,438 (USD 291) cost difference represented a 77% cost offset. When caregiver time and healthcare costs were included, mean annual costs were SEK 209,244 (USD 24,969) per patient in the donepezil group and SEK 218,434 (USD 26,066) in the placebo group, a total saving associated with donepezil treatment of SEK 9,190 (USD 1,097) per patient [95% CI of SEK -43,959 (USD -5,246), SEK 25,581 (USD 3,053); p = 0.6]. The positive effects on the efficacy outcome measures combined with no additional costs from a societal perspective indicate that donepezil is a cost-effective treatment, representing an improved strategy for the management of patients with AD.

Aged↗
PubMed2003

Amyloid beta pathology in Alzheimer's disease and schizophrenia.

OBJECTIVE: Severe cognitive impairment is common in elderly patients with schizophrenia. Alzheimer's disease is the main cause of dementia among the elderly. Biochemical and genetic studies suggest that amyloid beta-peptide is central in Alzheimer's disease. The authors examined the possible involvement of amyloid beta-peptide in cognitive impairment in schizophrenia. METHOD: Specific antibodies against two major forms of amyloid beta-peptide, Abetax-40 and Abetax-42, were used in sandwich enzyme-linked immunosorbent assays to determine the levels of amyloid beta-peptide in postmortem brain samples from Alzheimer's disease patients (N=10), normal elderly comparison subjects (N=11), and schizophrenia patients with (N=7) or without (N=26) Alzheimer's disease. RESULTS: The levels of amyloid beta-peptide were highest in the Alzheimer's disease patients, followed by the patients with schizophrenia and comparison subjects. The mean Abetax-42 level in the schizophrenia patients without Alzheimer's disease was similar to that in the comparison subjects, but the level in the schizophrenia patients with Alzheimer's disease was significantly higher than in those without Alzheimer's disease or the comparison subjects. The Abetax-42 level in the schizophrenia patients with Alzheimer's disease was significantly lower than the level in the Alzheimer's disease cohort. CONCLUSIONS: In contrast to elderly schizophrenia patients with Alzheimer's disease pathology, those without Alzheimer's disease had amyloid beta-peptide levels that were not significantly different from those of normal subjects; hence amyloid beta-peptide does not account for the cognitive deficits in this group. These results suggest that the causes of cognitive impairment in "pure" schizophrenia are different from those in Alzheimer's disease.

Aged↗
PubMed2003

Resource utilisation and cost analysis of memantine in patients with moderate to severe Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a devastating illness that causes enormous emotional stress to affected families and is associated with substantial medical and nonmedical costs. OBJECTIVE: To determine the effects of 28 weeks of memantine treatment for patients with AD on resource utilisation and costs. STUDY DESIGN AND METHODS: Multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial performed in the US. The Wilcoxon-Mann-Whitney test was used to examine the resource utilisation variables and logistic regression models were used for multivariate resource utilisation analyses. Analysis of covariance (ANCOVA) models (log and non-log) were computed to examine costs from a societal perspective. All costs were calculated in 1999 US dollars. STUDY POPULATION: Outpatients with moderate to severe AD. Overall, 252 patients received randomised treatment, and 166 patients (placebo n = 76, memantine n = 90) formed the treated-per-protocol (TPP) subset for the health economic analyses, on which the main cost analysis was based. MAIN OUTCOME MEASURE: Resource Utilisation in Dementia (RUD) scale, measuring patient and caregiver resource utilisation, and various sources for cost calculations. RESULTS: Controlling for baseline differences between the groups, significantly less caregiver time was needed for patients receiving memantine than for those receiving placebo (difference 51.5 hours per month; 95% CI -95.27, -7.17; p = 0.02). Analysis of residential status also favoured memantine: time to institutionalisation (p = 0.052) and institutionalisation at week 28 (p = 0.04 with the chi-square test). Total costs from a societal perspective were lower in the memantine group (difference dollars US 1089.74/month [non-overlapping 95% CI for treatment difference -1954.90, -224.58]; p = 0.01). The main differences between the groups were total caregiver costs (dollars US-823.77/month; p = 0.03) and direct nonmedical costs (dollars US-430.84/month; p = 0.07) favouring memantine treatment. Patient direct medical costs were higher in the memantine group (p < 0.01), mainly due to the cost of memantine. CONCLUSION: Resource utilisation and total health costs were lower in the memantine group than the placebo group. The results suggest that memantine treatment of patients with moderate to severe AD is cost saving from a societal perspective.

Activities of Daily Living↗
PubMed2003

Therapeutic strategies for Alzheimer's disease based on new molecular mechanisms.

BACKGROUND AND OBJECTIVE: Alzheimer's disease (AD)--the main cause of dementia--is characterized by the presence of neuritic plaques containing the amyloid-beta peptide (A beta) and an intraneuronal accumulation of tubule-associated protein called tau. The current and future therapeutic strategies for AD will be discussed. Currently available treatment used in AD is based on acetylcholinesterase inhibitors, since in the course of AD there is a substantial loss in cholinergic neurons. Another registered drug used in more severe AD is NMDA antagonist--memantine. Available strategies for AD include vitamin supplementation for reducing homocysteine levels, statins and non-steroidal anti-inflammatory drugs. The big hope of the last few years--vitamin E and estrogen supplementation have not been proved efficient, but more studies are needed. There are several strategies aimed at acting directly on A beta or amyloid precursor protein (APP) processing: vaccination with A beta peptide, A beta passive immunization, beta and gamma secretases inhibitors. Nerve growth factors and neurotrophines could also be targeted by new therapies. CONCLUSIONS: A better understanding of the role of APP processing and folate and homocysteine in neuronal homeostasis throughout life consist revealing novel and relatively inexpensive approaches for preventing and treating AD.

Alzheimer Disease↗
PubMed2002

Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease.

The abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) has been proposed to involve the extracellular-signal-regulated protein kinase (ERK) of the mitogen-activated protein (MAP) kinase family. ERK is phosphorylated and thereby activated by MAP kinase kinase (MEK). In the present study, we determined the intracellular and regional distribution of the active forms of both MEK1/2 and ERK1/2, i.e. p-MEK1/2 and p-ERK1/2 in the entorhinal, hippocampal, and temporal cortices of 49 brains staged for neurofibrillary changes according to Braak and Braak's protocol. We found that p-MEK1/2 and p-ERK1/2 were present in the initial stages of neurofibrillary degeneration in the projecting neurons in the transentorhinal region, and extended into other brain regions co-incident with the progressive sequence of neurofibrillary changes up to and including Braak stage VI. It appeared that the accumulation of p-MEK1/2 and p-ERK1/2 was initiated in the cytoplasm of pretangle neurons in varying size granules, which grew into large aggregates co-existing with the progressive development of neurofibrillary tangles. Accumulation of p-MEK1/2 and p-ERK1/2 was found in cases with stages I-III neurofibrillary degeneration, which were devoid of amyloid deposition. These data provide direct in situ evidence consistent with the possible involvement of MAP kinase pathway in the hyperphosphorylation of tau and the presence of this lesion before deposition of beta-amyloid in AD.

Adult↗
PubMed2002

Role of protein kinase B in Alzheimer's neurofibrillary pathology.

Protein kinase B (PKB) is an important intermediate in the phosphatidylinositol-3 kinase signaling cascade that acts to phosphorylate glycogen synthase kinase-3 (GSK-3) at its serine 9 residue, thereby inactivating it. Activated GSK-3 has been previously shown to be preferentially associated with neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. In the present study, we performed immunohistochemistry with an antibody to the active form of PKB in brains with different stages of neurofibrillary degeneration. We found that the amount of activated PKB (p-Thr308) increased in correlation to the progressive sequence of AT8 immunoreactivity and neurofibrillary changes assessed according to Braak's criteria. By confocal microscopy, activated PKB (p-Thr308) was found to appear in particular in neurons that are known to later develop NFTs in AD. Western blotting showed that activated PKB was increased by more than 50% in the 16,000- g supernatants of AD brains as compared with normal aged and Huntington's disease controls. This increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site. These studies suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.

Adult↗
PubMed2002

Environmental manipulation differentially alters c-Fos expression in amygdaloid nuclei following aversive conditioning.

This study analyzes the impact of environmental complexity in adult rats on their emotional behavior and c-Fos expression (a transcription factor protein implicated in neuronal plasticity) in various subdivisions of amygdala, as well as selected parts of the thalamus and hypothalamus. The animals were housed for 60 days in either enriched or impoverished conditions and then one group of rats was tested in an open field test, and a second group of rats was treated to footshock-motivated aversive training. Two and 24 h later, the animals from the second group, along with the appropriate controls, were sacrificed and their brains were used for the immunocytochemical analysis of c-Fos levels. We found that this long-term environmental manipulation exerts significant effects on animals' emotionality and this behavioral difference is accompanied by the differential c-Fos activation (at 2 h after the aversive training) in the amygdala, a brain structure believed to subserve emotional reactions. On the other hand, no difference was found in c-Fos expression between both groups of animals in the thalamus and hypothalamus. At 24 h after the training, c-Fos levels were down to the values observed in naive rats that did not differentiate between enriched versus impoverished breeding conditions. These results may help to explain differential emotional aspects of behavior that arise following differential housing conditions of adult animals.

Amygdala↗
PubMed2002

Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) was recently described as a heterogeneous group with a variety of clinical outcomes and high risk to develop Alzheimer's disease (AD). Regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) was used to study the heterogeneity of MCI and to look for predictors of future development of AD. METHODS: rCBF was investigated in 54 MCI subjects using Tc-99m hexamethylpropyleneamine oxime (HMPAO). An automated analysis software (BRASS) was applied to analyze the relative blood flow (cerebellar ratios) of 24 cortical regions. After the baseline examination, the subjects were followed clinically for an average of two years. 17 subjects progressed to Alzheimer's disease (PMCI) and 37 subjects remained stable (SMCI). The baseline SPECT ratio values were compared between PMCI and SMCI. Receiver operating characteristic (ROC) analysis was applied for the discrimination of the two subgroups at baseline. RESULTS: The conversion rate of MCI to AD was 13.7% per year. PMCI had a significantly decreased rCBF in the left posterior cingulate cortex, as compared to SMCI. Left posterior cingulate rCBF ratios were entered into a logistic regression model for ROC curve calculation. The area under the ROC curve was 74%-76%, which indicates an acceptable discrimination between PMCI and SMCI at baseline. CONCLUSION: A reduced relative blood flow of the posterior cingulate gyrus could be found at least two years before the patients met the clinical diagnostic criteria of AD.

Alzheimer Disease↗
PubMed2002

Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen project.

Recent findings suggest that a rich social network may decrease the risk of developing dementia. The authors hypothesized that such a protective effect may be due to social interaction and intellectual stimulation. To test this hypothesis, data from the 1987-1996 Kungsholmen Project, a longitudinal population-based study carried out in a central area of Stockholm, Sweden, were used to examine whether engagement in different activities 6.4 years before dementia diagnosis was related to a decreased incidence of dementia. Dementia cases were diagnosed by specialists according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria. After adjustment for age, sex, education, cognitive functioning, comorbidity, depressive symptoms, and physical functioning at the first examination, frequent (daily-weekly) engagement in mental, social, or productive activities was inversely related to dementia incidence. Adjusted relative risks for mental, social, and productive activities were 0.54 (95% confidence interval (CI): 0.34, 0.87), 0.58 (95% CI: 0.37, 0.91), and 0.58 (95% CI: 0.38, 0.91), respectively. Similar results were found when these three factors were analyzed together in the same model. Results suggest that stimulating activity, either mentally or socially oriented, may protect against dementia, indicating that both social interaction and intellectual stimulation may be relevant to preserving mental functioning in the elderly.

Aged↗
PubMed2002

Up-regulation of cell division cycle (cdc) 2 kinase in neurons with early stage Alzheimer's disease neurofibrillary degeneration.

The major component of Alzheimer's disease (AD) neurofibrillary tangles (NFTs) is abnormally hyperphosphorylated tau aggregated as paired helical filaments (PHFs). Cell division cycle (cdc) 2 kinase is one of the main candidate kinases that phosphorylates normal tau in vitro at several sites seen in PHF-tau. Using brains staged according to Braak and Braak criteria, we investigated the role of cdc2 in neurofibrillary changes in the hippocampal formation, and the entorhinal and temporal cortices. Neurons with tangle-like inclusions positive for active cdc2 were found to appear first in the Pre-alpha layer of the entorhinal cortex, and then extend to other brain regions co-incident with the progressive sequence of neurofibrillary changes. This predictable progressive pattern is not associated with amyloid. The intraneuronal accumulation of active cdc2 appeared to precede the deposition of PHF-tau phosphorylated at Ser 202/Thr 205 sites. These data are consistent with the notion that cdc2 might be involved in the abnormal hyperphosphorylation of tau and consequently aggregation of tau into PHF at an early stage and that increased cdc2 activity is not consequent to the deposition of beta-amyloid in AD brain.

Adult↗
PubMed2002

Excitotoxic neurodegeneration induced by intranasal administration of kainic acid in C57BL/6 mice.

Glutamate excitotoxicity plays a key role in inducing neuronal cell death in many neurological diseases. In mice, administration of kainic acid, an analogue of the excitotoxin glutamate, results in hippocampal cell death and seizures. Kainic-acid-induced seizures in mice provide a well-characterized model for studies of human neurodegenerative diseases. However, C57BL/6 mice, which are often used for genetic analyses and transgenic and knockout studies, are resistant to excitotoxicity induced by subcutaneous administration of kainic acid. In the present study, kainic acid administered by the intranasal route was shown to result in continuous tonic-clonic seizures in C57BL/6 mice. These seizures continued for 1-5 h and successfully induced selective lesions in area CA3 of the hippocampus. The survival rate was high even after mice experienced severe seizures. The hippocampal lesions were associated with a high level of cyclooxygenase-2 production as well as astrogliosis. Administration of kainic acid also altered behavioral responses, with mice showing a significant increase in locomotion and rearing activity as indicated by an open-field test. This animal model could provide a valuable tool for exploring the role of excitotoxicity in neuropathological conditions and should be further evaluated in gene-targeting studies of neurodegenerative diseases.

Administration, Intranasal↗
PubMed2002

CD4 and CD8 T cells, but not B cells, are critical to the control of murine experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune disease of the peripheral nervous system that duplicates the clinical, pathological, and electrophysiological features of Guillain-Barré syndrome in humans. However, the molecular pathogenesis of EAN remains controversial. Therefore, for this study, we induced EAN with P0 protein peptide 180-199 in CD4(-/-), CD8(-/-), CD4(-)8(-), and B cell knockout (microMT) mice to further investigate the roles of these cells in EAN. Our results showed that the severity of clinical signs and histopathological manifestations of EAN and the T cell response to P0 peptide 180-199 in CD4(-/-) mice were significantly lower than those in their wild-type counterparts. CD8(-/-) mice also had a milder clinical course, less histopathological change, and a diminished T cell response to P0 peptide 180-199. However, more severe clinical and histopathological manifestations, a stronger T cell response to P0 peptide 180-199, and enhanced IFN-gamma production in the spleen were observed in the EAN of CD4(-)8(-) and microMT mice, but these were not obviously different from those of wild-type mice. Levels of IgG production were similar in sera from CD4(-/-), CD8(-/-), and CD4(-)8(-), and wild-type mice. These findings suggest that the induction and control of murine EAN are dependent on both CD4(+) and CD8(+) T cells and that B cells apparently do not perpetuate the related inflammatory demyelination.

Animals↗