[A simple three-step model for detection of preclinical dementia among the elderly].
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Biomedical subjects
Bengt Winblad
Publications and source records attributed to Bengt Winblad.
APP intracellular domain formation and unaltered signaling in the presence of familial Alzheimer's disease mutations.
One of the cardinal neuropathological findings in brains from Alzheimer's disease (AD) patients is the occurrence of amyloid beta-peptide (Abeta) deposits. The gamma-secretase-mediated intramembrane proteolysis event generating Abeta also results in the release of the APP intracellular domain (AICD), which may mediate nuclear signaling. It was recently shown that AICD starts at a position distal to the site predicted from gamma-secretase cleavage within the membrane. This novel site, the epsilon site, is located close to the inner leaflet of the membrane bilayer. The relationship between proteolysis at the gamma and epsilon sites has not been fully characterized. Here we studied AICD signaling in intact cells using a chimeric C99 molecule and a luciferase reporter system. We show that the release of AICD from the membrane takes place in a compartment downstream of the endoplasmic reticulum, is dependent on presenilin proteins, and can be inhibited by treatment with established gamma-secretase inhibitors. Moreover, we find that AICD signaling remains unaltered from C99 derivatives containing mutations associated with increased Abeta42 production and familial AD. These findings indicate that there are very similar routes for Abeta and AICD formation but that FAD-linked mutations in APP primarily affect gamma-secretase-mediated Abeta42 formation, and not AICD signaling.
Alzheimer Disease↗
Hints of a therapeutic vaccine for Alzheimer's?
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Alzheimer Disease↗
Partial purification and characterization of gamma-secretase from post-mortem human brain.
One characteristic feature of Alzheimer's disease is the deposition of amyloid beta-peptide (Abeta) as amyloid plaques within specific regions of the human brain. Abeta is derived from the amyloid beta-peptide precursor protein (beta-APP) by the intramembranous cleavage activity of gamma-secretase. Studies in cells have revealed that gamma-secretase is a large multimeric membrane-bound protein complex that is functionally dependent on several proteins, including presenilin, nicastrin, Aph-1, and Pen-2. However, the precise biochemical and molecular nature of gamma-secretase is as yet to be fully elucidated, and no investigations have analyzed gamma-secretase in human brain. To address this we have developed a novel in vitro gamma-secretase activity assay using detergent-solubilized cell membranes and a beta-APP-derived fluorescent probe. We report that human brain-derived gamma-secretase activity co-purifies with a high molecular weight protein complex comprising presenilin, nicastrin, Aph-1, and Pen-2. The inhibitor profile and solubility characteristics of brain-derived gamma-secretase are similar to those described in cells, and proteolysis occurs at the Abeta40- and Abeta42-generating cleavage sites. The ability to isolate gamma-secretase from post-mortem human brain may facilitate the identification of brain-specific modulators of beta-APP processing and provide new insights into the biology of this important factor in the pathogenesis of Alzheimer's disease.
Alzheimer Disease↗
Pulse pressure and risk of Alzheimer disease in persons aged 75 years and older: a community-based, longitudinal study.
BACKGROUND AND PURPOSE: Elevated blood pressure has been found to increase the risk of dementia, including Alzheimer disease. We sought to investigate whether pulse pressure was predictive of Alzheimer disease and dementia. METHODS: A community-based, dementia-free cohort (n=1270) aged > or =75 years was clinically examined twice over 6 years to detect incident dementia with the use of the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Cox proportional hazards models were used to analyze pulse pressure in association with incident Alzheimer disease and dementia after adjustment for several potential confounders, including systolic pressure and diastolic pressure. RESULTS: During the 5464.6 person-years (median, 4.7 years) of follow-up, 339 subjects developed dementia, including 256 Alzheimer disease cases. Pulse pressure as a continuous variable was not statistically related to the risk of Alzheimer disease and dementia. In the categorical analysis, however, in comparison with median tertile of pulse pressure (70 to 84 mm Hg), subjects with higher pulse pressure had adjusted relative risks (95% CI) of 1.4 (1.0 to 2.0; P=0.04) for Alzheimer disease and 1.3 (0.9 to 1.7) for dementia. The corresponding figures related to lower pulse pressure were 1.7 (1.2 to 2.3) for Alzheimer disease and 1.4 (1.0 to 1.9; P=0.03) for dementia. This association was particularly pronounced among women. CONCLUSIONS: Higher pulse pressure is associated with increased risk for Alzheimer disease and dementia in old adults, which is probably due to artery stiffness and severe atherosclerosis. Poor cerebral perfusion related to decreased pulse pressure may explain the association between lower pulse pressure and increased dementia risk.
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No association between polymorphisms in the neprilysin promoter region and Swedish Alzheimer's disease patients.
Amyloid beta-peptide (Abeta) deposition in brain is important in the development of Alzheimer's disease (AD). Neprilysin (NEP) appears to be the major Abeta degrading enzyme in vivo and reduced mRNA levels of NEP correlates with increased plaque density. We hypothesized that alterations in the NEP promoter region may alter NEP expression and thus be involved in the AD process. We investigated three putative important regions in the NEP promoter region; two dinucleotide-repeats (CA and GT) and a 480 base pair fragment. With fragment analysis and sequencing, 164 early-onset and 152 late-onset Swedish AD cases and 109 non-demented controls were investigated. No significant difference in the distribution of promoter polymorphisms between AD cases and controls were found in this study.
Age of Onset↗
Detection of Alzheimer's disease and dementia in the preclinical phase: population based cohort study.
OBJECTIVES: To evaluate a simple three step procedure to identify people in the general population who are in the preclinical phase of Alzheimer's disease and dementia. DESIGN: Three year population based cohort study. SETTING: Kungsholmen cohort, Stockholm, Sweden. PARTICIPANTS: 1435 people aged 75-95 years without dementia. ASSESSMENTS: Single question asking about memory complaints, assessment by mini-mental state examination, and neuropsychological testing. MAIN OUTCOME MEASURE: Alzheimer's disease and dementia at three year follow up. RESULTS: None of the three instruments was sufficiently predictive of Alzheimer's disease and dementia when administered separately. After participants had been screened for memory complaints and global cognitive impairment, specific tests of word recall and verbal fluency had positive predictive values for dementia of 85-100% (95% confidence intervals range from 62% to 100%). However, only 18% of future dementia cases were identified in the preclinical phase by this three step procedure. Memory complaints were the most sensitive indicator of Alzheimer's disease and dementia in the whole population, but only half the future dementia cases reported memory problems three years before diagnosis. CONCLUSION: This three step procedure, which simulates what might occur in clinical practice, has a high positive predictive value for dementia, although only a small number of future cases can be identified.
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Loss of muscarinic M4 receptors in hippocampus of Alzheimer patients.
We assessed muscarinic M(1), M(2) and M(4) receptor subtypes in the hippocampus of Alzheimer's and control brains by receptor autoradiography using ligands such as [(125)I]muscarinic toxin-1 ([(125)I]MT-1, M(1) selective), [(3)H]AFDX-384 (M(2) partially selective) and [(125)I]muscarinic toxin 4 ([(125)I]M(4) toxin-1, M(4) selective). Our results revealed a significant decrease in muscarinic M(4) receptor binding in the dentate gyrus and CA4 regions of brain sections from Alzheimer's patients compared to controls. No changes in the density of M(1) or M(2) receptor binding were observed. Our findings suggest that, relative to other muscarinic receptor subtypes, the M(4) receptor could be the subtype which is selectively compromised in Alzeheimer's disease (AD).
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Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study.
BACKGROUND: Previous studies have reported a higher prevalence of dementia in persons with low blood pressure. OBJECTIVE: To examine whether low blood pressure is prospectively associated with the occurrence of Alzheimer disease and dementia in elderly people. SUBJECTS AND METHODS: A community-based, dementia-free cohort (n = 1270) aged 75 to 101 years was longitudinally examined twice within 6 years to detect incident dementia using the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria. Cox proportional hazards models were used to analyze blood pressure in association with dementia after adjustment for several potential confounders. RESULTS: During the 6-year period, 339 subjects were diagnosed with dementia, including 256 persons with Alzheimer disease. Subjects with very high systolic pressure (>180 vs 141-180 mm Hg) had an adjusted relative risk of 1.5 (95% confidence interval [CI], 1.0-2.3; P =.07) for Alzheimer disease, and 1.6 (95% CI, 1.1-2.2) for dementia. Low systolic pressure (</=140 mm Hg) was not related to incident dementia. In contrast, high diastolic pressure (>90 mm Hg) was not associated with dementia incidence, whereas extremely low diastolic pressure (</=65 vs 66-90 mm Hg) produced an adjusted relative risk of 1.7 (95% CI, 1.1-2.4) for Alzheimer disease and 1.5 (95% CI, 1.0-2.1; P =.03) for dementia. The latter association was pronounced particularly in persons who used antihypertensive drugs. CONCLUSIONS: Both low diastolic and high systolic pressure are associated with an increased risk of Alzheimer disease and dementia in this elderly population. The atherosclerotic process may explain the observed associations. In addition, low diastolic pressure may increase dementia risk by affecting cerebral perfusion.
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Lifetime principal occupation and risk of Alzheimer's disease in the Kungsholmen project.
BACKGROUND: Some studies suggest that manual work is associated with dementia. This study is aimed at identifying the specific occupational categories that may be related to dementia. METHODS: A cohort of 913 non-demented subjects aged 75 + years was longitudinally examined twice over 6 years to detect incident dementia using the DSM-III-R diagnostic criteria. The lifetime longest occupations of all subjects were divided into different categories according to the occupation-based classification system. Data were analyzed with Cox models. RESULTS: During the follow-up period, 260 subjects were diagnosed with dementia (197 with Alzheimer's disease). Manual work was associated with an increased risk of dementia, and the association was dependent on educational level. Compared with non-manual work, manual work involving goods production had a multi-adjusted relative risk (95% CI) of 1.6 (1.0-2.5, P = 0.046) for Alzheimer's disease and 1.4 (0.9-2.1) for dementia. CONCLUSIONS: An association between goods production, manual work and Alzheimer's disease found in this study suggests that factors in the mid-twentieth century goods production environment may be involved in the development of Alzheimer's disease.
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Treating the full spectrum of dementia with memantine.
An increasing number of elderly people result in increased social and economical impact of dementia, particularly its most common form Alzheimer's disease (AD). Dementia itself consists of a wide spectrum of disease, ranging from the mild cognitive impairment that progresses through several clinical milestones to advanced dementia. Drugs available at the moment on the market are approved for the treatment of mild to moderate dementia and their symptomatic effect is based on cholinergic substitution. However, the largest amount of costs utilised for dementia is institutional care for severely affected patients. At this stage of the disease both vascular and degenerative mechanisms contribute to the clinical expression of the disease. Recent clinical trials with the antiglutamatergic drug memantine have shown that cognitive benefit could be observed in patients with vascular dementia and reduced care dependence in those with moderately severe to severe form of the disease. The later findings are results from the M-BEST study, which is briefly rewieved here with some of the epidemiological, socioeconomical and clinical implications of such therapy.
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Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease.
In Alzheimer's disease (AD) brain the activity of protein phosphatase (PP)-2A is compromised and that of the extracellular signal-regulated protein kinase (ERK1/2) of the mitogen-activated protein kinase (MAPK) family, which can phosphorylate tau, is up-regulated. We investigated whether a decrease in PP-2A activity could underlie the activation of these kinases and the abnormal hyperphosphorylation of tau. Rat brain slices, 400-microm-thick, kept under metabolically active conditions in oxygenated (95% O(2), 5% CO(2)) artificial CSF were treated with 1.0 micromol/L okadaic acid (OA) for 1 hour at 33 degrees C. Under this condition, PP-2A activity was decreased to approximately 35% of the vehicle-treated control slices, and activities of PP-1 and PP-2B were not affected. In the OA-treated slices, we observed a dramatic increase in the phosphorylation/activation of ERK1/2, MEK1/2, and p70 S6 kinase both immunohistochemically and by Western blots using phosphorylation-dependent antibodies against these kinases. Treatment of 6-microm sections of the OA-treated slices with purified PP-2A reversed the phosphorylation/activation of these kinases. Hyperphosphorylation of tau at several abnormal hyperphosphorylation sites was also observed, as seen in AD brain. These results suggest 1) that PP-2A down-regulates ERK1/2, MEK1/2, and p70 S6 kinase activities through dephosphorylation at the serine/threonine residues of these kinases, and 2) that in AD brain the decrease in PP-2A activity could have caused the activation of ERK1/2, MEK1/2, and p70 S6 kinase, and the abnormal hyperphosphorylation of tau both via an increase in its phosphorylation and a decrease in its dephosphorylation.
Alzheimer Disease↗
Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease.
The ribosomal S6 protein kinase p70 S6 kinase is known for its role in modulating cell-cycle progression, cell size, and cell survival. In response to mitogen stimulation, p70 S6 kinase activation up-regulates ribosomal biosynthesis and enhances the translational capacity of the cell. In Alzheimer's disease (AD), there is a marked increase in total tau protein in the form of abnormally hyperphosphorylated tau (PHF-tau) in neurons with neurofibrillary tangles (NFTs). In the present study, we investigated whether p70 S6 kinase activation is associated with PHF-tau accumulation in AD. By immunohistochemistry, we found that the levels of phosphorylated p70 S6 kinase (at Thr389 or at Thr421/Ser424) were increased in accordance with the progressive sequence of neurofibrillary changes according to Braak's criteria. Confocal microscopy showed that in AD brain, phosphorylated p70 S6 kinase appeared especially in neurons that are known to later develop NFTs. This pattern of neurons showed dot-like structures of phosphorylated p70 S6 kinase and hyperphosphorylated tau, which partially correlated with rab5 (endosome marker), lamp-1 (lysosome marker), and ubiquitin (ubiquitin-proteasomal system marker). By indirect enzyme-linked immunosorbent assay, phosphorylated p70 S6 kinase (Thr389 or Thr421/Ser424), total tau, and PHF-tau were found to be significantly increased in AD brain as compared to control cases. The levels of total p70 S6 kinase and p70 S6 kinase phosphorylated at Thr421/Ser424 showed significant correlations with the levels of both total tau and PHF-tau. Regression analyses revealed a significant dependence of total tau or PHF-tau on p70 S6 kinase phosphorylated at Thr421/Ser424 rather than at Thr389. The levels of ribosomal protein S6 as well as the levels of markers for the proteolytic system were also significantly increased in AD as compared to control brain. Using a SH-SY5Y neuroblastoma cell model, we found that 100 micro mol/L zinc sulfate could induce p70 S6 kinase phosphorylation and activation, in particular at Thr421/Ser424. This up-regulation of the activated kinase resulted in an increased expression and phosphorylation of tau. Pretreatment of cells with rapamycin (an inhibitor of FRAP/mTOR which is the immediate upstream kinase of the p70 S6 kinase) attenuated the effects induced by zinc. In primary cultured neurons of rat cortical cortex, zinc sulfate treatment could repeat p70 S6 kinase phosphorylation and activation at Thr421/Ser424, followed by increased expression and phosphorylation of tau. Taken together, these data suggest that activated p70 S6 kinase could mediate an up-regulation of tau translation. The partial co-localization of phosphorylated p70 S6 kinase with rab5, lamp-1 and ubiquitin, or PHF-tau with ubiquitin suggests that the activated proteolytic system might not be sufficient to degrade the over-produced and over-phosphorylated tau protein. A p70 S6 kinase modulated up-regulation of tau translation might contribute to PHF-tau accumulation in neurons with neurofibrillary changes.
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Women are more disabled in basic activities of daily living than men only in very advanced ages: a study on disability, morbidity, and mortality from the Kungsholmen Project.
OBJECTIVE: We explored the effect of morbidity, mortality, and occurrence of new disability on gender differences in activities of daily living (ADL) functioning in different age groups in the elderly population. METHODS: All 77+-year-old members of a community-based cohort were clinically examined by physicians, assessed by psychologists, and interviewed by nurses at baseline and after a 3-year interval. Diseases were diagnosed according to ICD-9 and the DSM-III-R criteria for dementia. The Katz index of ADL was used to measure basic functional status. RESULTS: After adjustment for socio-demographic characteristics, the oldest women (90+ years) had higher disability prevalence and a tendency for higher long-term disability incidence. Women aged 85+ years also had higher morbidity prevalence. Mortality among disabled subjects was similar for both genders, whereas higher mortality was found in younger nondisabled men (77-84 years). CONCLUSION: We conclude that gender differences in disability, morbidity, and mortality vary with age in the elderly population. Gender differences in morbidity and basic functional dependence were evident only in the oldest old. Based on current and previous findings, we speculate that more women may be at higher risk of developing severe disability than men in the advanced ages due to longer survival with slight disability earlier in adult life.
Activities of Daily Living↗
Voxel- and VOI-based analysis of SPECT CBF in relation to clinical and psychological heterogeneity of mild cognitive impairment.
This study aimed to explore the heterogeneity of mild cognitive impairment (MCI) and detect differences in regional cerebral blood flow (rCBF) and cognitive function between progressive mild cognitive impairment (PMCI) and stable mild cognitive impairment (SMCI) in order to identify specific changes useful for early diagnosis of dementia. SPECT was performed in 82 MCI subjects and 20 controls using Tc-99m hexamethylpropyleneamine oxime. Cognitive functions were tested in five domains which included episodic memory, semantic memory, visuospatial function, attention, and general cognitive function. After the initial examination, MCI subjects were clinically followed for an average of 2 years. Twenty-eight subjects progressed to dementia and were defined as PMCI at baseline and 54 subjects remained stable and were defined as SMCI at baseline. The baseline rCBF and cognitive function of PMCI, SMCI, and controls were compared. PMCI had decreased relative rCBF in the parietal lobes and increased relative rCBF in prefrontal cortex compared to SMCI and controls at baseline. The cognitive function of PMCI was more severely impaired compared to SMCI with respect to episodic memory and visuospatial and general cognitive function. Both SPECT and neuropsychological tests had moderate discriminant function between PMCI and SMCI at baseline with the area under the receiver operating characteristic (ROC) curve at 75-77%. The combination of these two methods improved the diagnostic accuracy with the area under the ROC curve at 82-84%. Semantic memory and attention were negatively correlated with left prefrontal relative rCBF among the study population. The results show that the clinical heterogeneity of MCI is reflected in different patterns of psychological and CBF changes. Combined SPECT investigation and neuropsychological testing might predict the future development of dementia in patients with MCI.
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Societal burden and economics of vascular dementia: preliminary results from a Swedish-population-based study.
Knowledge about the health economic implications of vascular dementia (VaD) is insufficient. The impact of cardiovascular comorbidities must also be taken into consideration when resource utilization and costs in patients with VaD are analyzed. It is also of great importance that the analysis be done from a societal perspective. In the rural Nordanstig cohort of the Kungsholmen project in Sweden, the major cost drivers in the RUD (Resource Utilization in Dementia) instrument were used. The cost from a societal perspective was 23% higher for patients with VaD compared with patients with Alzheimer's disease ( p = .02).
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Preface: mild cognitive impairment.
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Aging↗
Treatment of mild cognitive impairment: rationale, present and future strategies.
Mild cognitive impairment (MCI) is a condition with a high conversion rate to Alzheimer's disease (AD), which justifies early diagnostic and therapeutic interventions. At the moment, treatment strategies for AD could be extrapolated to interventional strategies in MCI. This article reviews currently available symptomatic treatments with acetylcholinesterase inhibitors, putative treatments such as antiglutamatergic drugs, nootropics, antioxidants, anti-inflammatory drugs and still controversial estrogen replacement therapy, and visionary treatments targeting neuropathological substrates of the disease, such as amyloid production and aggregation, phosphorylation of tau, formation of neurofibrillary tangles and apoptosis. Findings from epidemiological studies have expanded our knowledge on risk as well as possible neuroprotective factors and given means to develop preventive strategies with antihyperlipidaemic drugs such as statins. A wide range of suggested treatments and their possible combinations necessitate their efficacy assessment in well-designed randomized clinical trials where the crucial prerequisites are selection of the treatment population and definitions of outcome measures. Prevention and disease-modifying strategies are raising ethical questions because interventions are focused on non-diseased elderly at risk, which means that emphasis should be not only on efficacy but also on long-term safety.
Animals↗