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Biomedical subjects

B Winblad

Publications and source records attributed to B Winblad.

At least 19 recordsLinked to original sources
PubMed2007

Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline.

The aim of this international guideline on dementia was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with dementia. It covers major aspects of diagnostic evaluation and treatment, with particular emphasis on the type of patient often referred to the specialist physician. The main focus is Alzheimer's disease, but many of the recommendations apply to dementia disorders in general. The task force working group considered and classified evidence from original research reports, meta-analysis, and systematic reviews, published before January 2006. The evidence was classified and consensus recommendations graded according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. The recommendations for clinical diagnosis, blood tests, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, genetic testing, tissue biopsy, disclosure of diagnosis, treatment of Alzheimer's disease, and counselling and support for caregivers were all revised when compared with the previous EFNS guideline. New recommendations were added for the treatment of vascular dementia, Parkinson's disease dementia, and dementia with Lewy bodies, for monitoring treatment, for treatment of behavioural and psychological symptoms in dementia, and for legal issues. The specialist physician plays an important role together with primary care physicians in the multidisciplinary dementia teams, which have been established throughout Europe. This guideline may contribute to the definition of the role of the specialist physician in providing dementia health care.

Alzheimer Disease↗
PubMed2006

PTEN, Akt, and GSK3beta signalling in rat primary cortical neuronal cultures following tumor necrosis factor-alpha and trans-4-hydroxy-2-nonenal treatments.

PTEN is a dual phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway important for cell survival. We determined effects of the inflammation and oxidative stresses of tumor necrosis factor-alpha (TNFalpha) and trans-4-hydroxy-2-nonenal (HNE), respectively, on PTEN, Akt, and GSK3beta signalling in rat primary cortical neurons. The inhibitors bisperoxovanadium [bpV(Pic)] and LY294002 were also used to determine PTEN and PI3K involvement in TNFalpha and HNE modulation of neuronal cell death. PTEN inhibition with bpV(Pic) alone did not affect Ser(473)Akt or Ser(9)GSK3beta phosphorylation. Instead, effects of this inhibitor were manifest when it was used together with TNFalpha and to a lesser extent with HNE. TNFalpha together with PTEN inhibition increased phosphorylation of Ser(473)Akt and Ser(9)GSK3beta. TNFalpha and HNE both gave decreased numbers of viable and increased numbers of early apoptotic neurons. PTEN inhibition partially reversed the toxic effect of TNFalpha as shown by an increased number of viable and a decreased number of early apoptotic neurons. All effects were reversed by PI3K inhibition. HNE together with inhibition of PTEN gave increased Ser(473)Akt but not Ser(9)GSK3beta phosphorylation and no effects on the number of viable or early apoptotic cells. In conclusion, PTEN inhibition gives a mild reversal of TNFalpha- but not HNE-induced cell death via the PI3K pathway.

Aldehydes↗
PubMed2006

Elevated cortical zinc in Alzheimer disease.

OBJECTIVE: To determine whether changes in brain biometals in Alzheimer disease (AD) and in normal brain tissue are tandemly associated with amyloid beta-peptide (Abeta) burden and dementia severity. METHODS: The authors measured zinc, copper, iron, manganese, and aluminum and Abeta levels in postmortem neocortical tissue from patients with AD (n = 10), normal age-matched control subjects (n = 14), patients with schizophrenia (n = 26), and patients with schizophrenia with amyloid (n = 8). Severity of cognitive impairment was assessed with the Clinical Dementia Rating Scale (CDR). RESULTS: There was a significant, more than twofold, increase of tissue zinc in the AD-affected cortex compared with the other groups. Zinc levels increased with tissue amyloid levels. Zinc levels were significantly elevated in the most severely demented cases (CDR 4 to 5) and in cases that had an amyloid burden greater than 8 plaques/mm(2). Levels of other metals did not differ between groups. CONCLUSIONS: Brain zinc accumulation is a prominent feature of advanced Alzheimer disease (AD) and is biochemically linked to brain amyloid beta-peptide accumulation and dementia severity in AD.

Age Factors↗
PubMed2006

Hyperhomocysteinemia and methylenetetrahydrofolate reductase polymorphism in patients with Parkinson's disease.

Elevated levels of homocysteine have been observed in Parkinson's disease (PD) patients treated with levodopa. However, it is not studied if duration of PD or PD per se is associated with hyperhomocysteinemia. In the present study, the levels of homocysteine in 99 levodopa-treated PD patients, 15 untreated PD patients and 100 controls were examined. We focused on the influence of levodopa dose, duration of therapy and disease as well as genetic (C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism) and environmental factors. We found that levodopa-treated PD patients had elevated homocysteine plasma levels as compared to controls (p < 0.05), but the levels did not depend on levodopa doses. Another factor influencing homocysteine level was the duration of PD (p < 0.001). The frequency of allele C677T of MTHFR gene did not differ between PD and controls. In conclusion, hyperhomocysteinemia is associated with the duration of PD and levodopa treatment and possibly also with PD per se.

Adult↗
PubMed2006

3-year study of donepezil therapy in Alzheimer's disease: effects of early and continuous therapy.

Delays in the diagnosis of Alzheimer's disease, and, therefore, delays in treatment, may have a detrimental effect on a patient's long-term well-being. This study assessed the effects of postponing donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer's disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer's disease. These data support the long-term efficacy and safety of donepezil.

Aged↗
PubMed2006

An estimate of the worldwide prevalence and direct costs of dementia in 2003.

Dementia disorders are today considered to be a major driver of costs in health care and social systems and worrying estimates of future dementia prevalence have been presented. It is of great interest for policy makers to have an estimate of dementia disorders' contribution to global social and health care costs, particularly in light of the demographic prognoses. The worldwide costs of dementia were estimated from prevalence figures for different regions, and cost-of-illness studies from key countries using a model based on the relationship between direct costs of care per demented and the gross domestic product per capita in each country. The worldwide direct costs for dementia in 2003 are estimated at 156 billion USD in the main scenario based on a worldwide prevalence of 27.7 million demented persons (sensitivity analysis: 129-159 billion USD). Ninety-two percent of the costs are found in the advanced economies with 38% of the prevalence. Although there are several sources of uncertainty, it is obvious that the worldwide costs are substantial and the expected increase in elderly people in the developing countries presents a great challenge.

Cost of Illness↗
PubMed2006

Genome scan on Swedish Alzheimer's disease families.

Alzheimer's disease (AD) is an age-related disease, which affects approximately 40% of the population at an age above 90 years. The heritability is estimated to be greater than 60% and there are rare autosomal dominant forms indicating a significant genetic influence on the disease process. Despite the successes in the early 1990s when four genes were identified, which directly cause the disease (APP, PSEN1 and PSEN2) or greatly increase the risk of disease development (APOE), it has proved exceedingly difficult to identify additional genes involved in the pathogenesis. However, several linkage and association studies have repeatedly supported the presence of susceptibility genes on chromosomes (chrms) 9, 10 and 12. The study populations have, however, mostly been of great genetic heterogeneity, and this may have contributed to the meagre successes in identifying the disease associated genetic variants. In this study, we have performed a genome wide linkage study on 71 AD families from the relatively genetically homogeneous Swedish population where it is also possible to study the genetic ancestry in public databases. We have performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE varepsilon4. Our results suggest that the families included in this study are tightly linked to the APOE region, but do not show evidence of linkage to the previously reported linkages on chrms 9, 10 and 12. Instead, we observed the next highest LOD score on chromosome 5q35 in the total material. Further, the data suggest that the major fraction of families linked to this region is APOE varepsilon4 positive.

Aged↗
PubMed2005

Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer's disease.

Strong evidence indicates oxidative stress in the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Abeta) has been implicated in both oxidative stress mechanisms and in neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) are antioxidants that can inhibit apoptosis signal-regulating kinase (ASK1). We examined levels of GRX1 and TRX1 in AD brain as well as their effects on Abeta neurotoxicity. We show an increase in GRX1 and a decrease in neuronal TRX1 in AD brains. Using SH-SY5Y cells, we demonstrate that Abeta causes an oxidation of both GRX1 and TRX1, and nuclear export of Daxx, a protein downstream of ASK1. Abeta toxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1. Thus, Abeta neurotoxicity might be mediated by oxidation of GRX1 or TRX1 and subsequent activation of the ASK1 cascade. Deregulation of GRX1 and TRX1 antioxidant systems could be important events in AD pathogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Clinical trials in mild cognitive impairment: lessons for the future.

Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.

Aged↗
PubMed2005

Flow cytometry as a method for studying effects of stressors on primary rat neurons.

The mechanisms associated with cell death have been an important focus for neurobiology research. In the present study, the methodology of flow cytometry was used to optimize quantification of the toxic effects of tumor necrosis factor-alpha (TNF-alpha), trans-4-hydroxy-2-nonenal (4-HNE), and aged amyloid-beta (Abeta1-42) on rat primary cortical neurons. The fluorescent dyes annexin V-FITC and propidium iodide (PI) were used to identify populations of viable, early apoptotic, necrotic and late apoptotic cells by flow cytometry. Prior to exposure, the primary cultures showed 83% cell viability. Flow cytometry following labeling of cells with a specific neuronal marker, TUJ-1, revealed 82% pure neuronal populations, whereas approximately 7% were astrocytic as shown by glial fibrillary acidic protein positivity. Exposure of primary cultures to TNF-alpha, 4-HNE, and aged Abeta1-42 gave an increased number of early apoptotic cells. We show that flow cytometry is a suitable method for quantifying effects of different stressors on neurons in primary cultures. This technique could be useful for screening and testing of pharmacological compounds relevant to neurodegenerative disorders.

Aldehydes↗
PubMed2004

Effects of high cholesterol diet on gliosis in apolipoprotein E knockout mice. Implications for Alzheimer's disease and stroke.

Hypercholesterolemia has been suggested as a risk factor for Alzheimer's disease (AD). A genetic risk factor for AD is the E4 allele of apolipoprotein E (apoE). ApoE is the major lipoprotein transporter in the brain, and is mainly produced by glial cells. The present study is focussed on analysing the effects of high cholesterol (HC) diet, duration 9 months, on glial activation in the brain, both in wild type (WT) mice and in mice with a null mutation in the apoE gene (knock-out, KO) mice. The activation of astrocytes and microglia was analysed after immunohistochemical labelling of glial fibrillary acidic protein (GFAP), and F4/80, respectively. In addition, the expression of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1) was analysed. There was a marked stimulation of astrocyte and microglial activation as well as induced expression of NQO1 in the hippocampus and cerebral cortex upon HC diet. Furthermore, there was significant astrocyte activation in the apoE KO mice, as compared to the WT mice, on ND. The long time exposure to HC diet combined with apoE deficiency resulted in a synergistic effect on the expression of NQO1 in the brain.

Animals↗
PubMed2004

Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study.

BACKGROUND: Research on diabetes mellitus as a risk factor for dementia and its main subtypes has produced conflicting results. The authors investigated the relationship between diabetes mellitus and risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD). METHODS: A dementia-free cohort of 1,301 community dwellers aged 75 years and older in Stockholm, Sweden, was longitudinally examined twice over 6 years to detect dementia cases (Diagnostic and Statistical Manual of Mental Disorders-III-R diagnostic criteria). Cox proportional hazards models were used to analyze the data with adjustment for several potential confounders. RESULTS: During the 5,584 person-years of follow-up, 350 subjects developed dementia, including 260 AD and 49 VaD cases. Diabetes mellitus was associated with hazard ratios (HR) of 1.5 (95% CI 1.0 to 2.1, p = 0.04) for dementia, 2.6 (95% CI 1.2 to 6.1) for VaD, and 1.3 (95% CI 0.9 to 2.1) for AD. Patients who were treated with oral antidiabetic medications had HRs of 1.7 (95% CI 1.0 to 2.8, p = 0.04) for dementia and 3.6 (95% CI 1.3 to 9.5) for VaD. There were significant interactions of diabetes with severe systolic hypertension (> or =180 mm Hg) on dementia and its main subtypes, and of diabetes with heart disease on VaD. CONCLUSIONS: Diabetes mellitus increases the risk of dementia, and VaD in particular, in very old people. The risk for dementia and VaD is especially high when diabetes mellitus occurs together with severe systolic hypertension or heart disease.

Aged↗
PubMed2004

APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging.

OBJECTIVE: To investigate whether presence of the APOE epsilon4 allele is related to the pathologic progression of preclinical Alzheimer disease (AD), as reflected by change in Mini-Mental State Examination (MMSE) scores among persons in the preclinical phase of AD, and cognitively intact adults confirmed as dementia-free during the 6-year assessment period. METHOD: In a population-based sample, participants were stratified according to APOE genotype (epsilon4 or non-epsilon4) and whether they received a diagnosis of AD at the end of either a 3- or 6-year assessment period. Participants were aged 75 years and older, and were nondemented at baseline. At the end of the 3-year period, 17.2% of non-epsilon4 and 26.7% of epsilon4 carriers became demented. For the 6-year period those percentages were 11.2% for non-epsilon4 carriers and 16.9% for epsilon4-carriers. RESULTS: Individuals in the preclinical phase of AD showed greater decline on the MMSE as compared to nondemented adults. However, the decline was most marked in the 3 years prior to clinical diagnosis. Further, APOE-epsilon4 genotype did not modify the rate of decline among to-be-demented participants, as well as individuals who would remain free of AD. CONCLUSIONS: Although possession of the APOE epsilon4 allele is a risk factor for AD in old age, it does not modify the progression of the disease during the preclinical period. Further, in the absence of preclinical dementia, APOE did not influence global cognitive change in nondemented persons.

Aged↗
PubMed2004

Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment.

The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.

Aged↗
PubMed2004

Mild cognitive impairment: a cross-national comparison.

OBJECTIVE: The main aim of this collaborative study was to assess the comparability of the most commonly used criteria for mild cognitive impairment (MCI) by comparing the cognitive performance of patients with MCI from the Mayo Clinic (USA) and the Karolinska Institutet (Sweden). METHODS: Standardised neuropsychological test scores were used to compare the two samples from the two institutions with regard to the number of cognitive domains in which performance was below 1.5 SD. Possible predictors for the conversion from MCI to Alzheimer's disease (AD) were assessed. RESULTS: When the two institutions were considered together in the Cox proportional hazard model, the number of affected cognitive domains below 1.5 SD was a significant predictor of time to AD diagnosis with age, education, and APOE epsilon4 genotype entered into the same model as covariates. The number of affected cognitive areas remained as a significant predictor when the institutions were considered separately. The logistic regression model of conversion to AD showed that only tests assessing learning and retention were predictors of developing AD. CONCLUSIONS: Differences in population as well as in methodology of case ascertainment as well as other aspects may account for the observed variability between samples of patients with MCI. The number of impaired cognitive factors at baseline can predict the progression from MCI to AD. Furthermore, tests assessing learning and retention are the best predictors for progression to AD.

Aged↗
PubMed2004

Risk and protective effects of the APOE gene towards Alzheimer's disease in the Kungsholmen project: variation by age and sex.

BACKGROUND: The risk effect of APOE epsilon 4 allele for Alzheimer's disease is acknowledged, whereas the putative protective effect of epsilon 2 allele remains in debate. OBJECTIVES: To investigate whether those inconsistent findings may be attributable to differences in age and sex composition of the study populations. METHODS: A community dementia free cohort (n = 985) aged > or =75 years was followed up to detect Alzheimer's disease cases (DSM-III-R criteria). Data were analysed using Cox models with adjustment for major potential confounders. RESULTS: Over a median 5.6 year follow up, Alzheimer's disease was diagnosed in 206 subjects. Compared with APOE epsilon 3/epsilon 3 genotype, the relative risk (RR) of Alzheimer's disease was 1.4 (95% confidence interval (CI), 1.0 to 2.0; p = 0.03) for heterozygous epsilon 4 allele and 3.1 (95% CI, 1.6 to 5.9) for homozygous epsilon 4 allele. The association between epsilon 4 allele and Alzheimer's disease risk was stronger in men than in women (RR related to the interaction term epsilon 4 allele by sex, 0.4; 95% CI, 0.2 to 0.9). The epsilon 4 allele accounted for one third of Alzheimer's disease cases among men, but only one tenth among women. The epsilon 2 allele was related to a reduced Alzheimer's disease risk mainly in people aged <85 years (RR, 0.4; 95% CI, 0.2 to 0.8). The RR of Alzheimer's disease related to the interaction term of epsilon 2 allele by age was 2.4 (95% CI, 1.0 to 6.0; p = 0.06). CONCLUSIONS: The APOE genotype specific effects on Alzheimer's disease vary by age and sex, in which the epsilon 4 allele has a stronger risk effect in men, and the epsilon 2 allele confers a protective effect only in younger-old people.

Age Factors↗