Growth models (GM) of the mixed-effects and latent curve varieties have become popular methodological tools in lifespan research. One of the major advantages of GM is their flexibility in studying ...individual differences in change. We scrutinized the change functions of GM used in five years of publications on cognitive aging. Of the 162 publications that we identified, 88% test linear or quadratic polynomials, and fewer than 5% apply functions that are nonlinear in their parameters, such as exponential decline. This apparent bias in favor of polynomial decomposition calls for exploring what conclusions about individual differences in change are likely to be drawn if one applies linear or quadratic GMs to data simulated under a conceptually and empirically plausible model of exponential cognitive decline from adulthood to old age. Hence, we set up a simulation that manipulated the rate of exponential decline, measurement reliability, number of occasions, interval width, and sample size. True rate of decline and interval width influenced results strongly, number of occasions and measurement reliability exerted a moderate effect, and the effects of sample size appeared relatively minor. Critically, our results show that fit statistics generally do not differentiate misspecified linear or quadratic models from the true exponential model. Moreover, power to detect variance in change for the linear and quadratic GMs is low, and estimates of individual differences in level and change can be highly biased by model misspecification. We encourage researchers to also consider plausible nonlinear change functions when studying behavioral development across the lifespan.
Amyloid-β (Aβ) is the main constituent of amyloid deposits in Alzheimer's disease (AD). The neuropathology is associated with neuroinflammation. Here, we investigated effects of systemic ...lipopolysaccharide (LPS)-treatment on neuroinflammation and Aβ deposition in AβPP-mice and double-transgenic mice with brain expression of AβPP and heparanase, an enzyme that degrades HS and generates an attenuated LPS-response. At 13 months of age, the mice received a single intraperitoneal injection of 50 µg LPS or vehicle, and were sacrificed 1.5 months thereafter. Aβ in the brain was analyzed histologically and biochemically after sequential detergent extraction. Neuroinflammation was assessed by CD45 immunostaining and mesoscale cytokine/chemokine ELISA. In single-transgenic mice, LPS-treatment reduced total Aβ deposition and increased Tween-soluble Aβ. This was associated with a reduced CXCL1, IL-1β, TNF-α-level and microgliosis, which correlated with amyloid deposition and total Aβ. In contrast, LPS did not change Aβ accumulation or inflammation marker in the double-transgenic mice. Our findings suggest that a single pro-inflammatory LPS-stimulus, if given sufficient time to act, triggers Aβ-clearance in AβPP-transgenic mouse brain. The effects depend on HS and heparanase.
Expanded hemodialysis (HDx) provides increased clearance of conventional and large middle molecules through innovative medium cutoff (MCO) membranes. However, there is a paucity of real‐world data ...regarding the benefits and safety of HDx. This large observational study evaluated outcomes among patients in Colombia undergoing HDx at a extended dialysis clinical services provider. This was a prospective single cohort study of prevalent patients who were treated with HDx; baseline information was collected from the most recent data before patients were started on HDx. Patients were followed prospectively for 1 year for changes in serum albumin and other laboratory parameters compared with the baseline. Survival, hospitalization and safety were assessed from the start of HDx. A total of 1000 patients were invited to enroll; 992 patients met the inclusion criteria for data analysis and 638 patients completed the year of follow‐up. Seventy‐four (8%) patients died during 866 patient‐years (PY) of follow‐up; the mortality rate was 8.54 deaths/100 PY (95% confidence interval CI, 6.8‐10.7). There were 673 hospitalization events with a rate of 0.79 events/PY (95% CI, 0.73‐0.85) with 6.91 hospital days/PY (95% CI, 6.74‐7.09). The observed variability from baseline and maximum average change in mean serum albumin levels were −1.8% and −3.5%, respectively. No adverse events were related to the MCO membrane. HDx using an MCO membrane maintains stable serum albumin levels and is safe in terms of nonoccurrence of dialyzer related adverse events.
Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-β (Aβ) deposits in Alzheimer disease brain and in Aβ precursor protein (AβPP) transgenic mouse models. Heparanase is an ...endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of Aβ pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human AβPP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect AβPP processing because the steady-state levels of Aβ1–40, Aβ1–42, and soluble AβPP β were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the Aβ burden, measured by Aβx-40 and Aβx-42 immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the Aβx-42 burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated Aβ1–42-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing Aβ fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with Aβ-HSPG interactions might be a potential strategy for Alzheimer disease treatment.
Background: Heparan sulfate colocalizes with amyloid-β in senile plaques of Alzheimer disease.
Results: Overexpression of the heparan sulfate-degrading enzyme (heparanase) lowers the amyloid burden in a transgenic mouse model of Alzheimer disease.
Conclusion: Heparan sulfate modulates amyloid-β deposition.
Significance: We present the first direct in vivo proof that heparan sulfate actively participates in senile plaque formation.
Overweight and cognition NILSSON, LARS-GÖRAN; NILSSON, ERIK
Scandinavian journal of psychology,
December 2009, Letnik:
50, Številka:
6
Journal Article
Recenzirano
Odprti dostop
There is a growing concern among health authorities that an increasing number of people in the Western world become overweight and even obese. It is well known that obesity is related to several ...diseases (e.g., diabetes, stroke, and high blood pressure) and that such diseases related to obesity lead to early death. It has also been discussed whether overweight and obesity in themselves or in relation to such diseases lead to cognitive decline. On the basis of data from a large, population‐based, prospective study we examined three cognitive domains: episodic memory, semantic memory, and spatial ability. Two body measures were used to define normal weight and overweight, body‐mass index and waist/hip ratio. Although these two body measures reveal quite different prevalence data of overweight, the associations between overweight and cognition are similar. For episodic memory, overweight interacts with age, but when controlling for hypertension, stroke and diabetes, this interaction disappears. For semantic memory, normal weight participants outperform overweight participants even after controlling for these diseases. For spatial ability, the well‐established advantage for men holds for young‐old and old‐old normal‐weight participants. For overweight participants, this advantage holds for middle‐age participants only. We conclude that there is a weight‐cognition relationship even after controlling for obesity‐related diseases. The results are discussed in terms of possible biological mechanisms.
Self-disorders have been hypothesized to be an underlying and trait-like core feature of schizophrenia-spectrum disorders and a certain degree of temporal stability of self-disorders would therefore ...be expected. The aim of the study was to examine the persistence of self-disorders measured by the Examination of Anomalous Self Experiences over a time span of 5 years. 48 patients with schizophrenia-spectrum disorders were thoroughly assessed for psychopathology at baseline and 5 years later. Self-disorders were assessed by the Examination of Anomalous Self Experiences. The level of self-disorders was same at the two occasions for the full Examination of Anomalous Self Disorders and for four out of the five domains. For one domain, the level of self-disorders increased slightly from baseline to follow-up. The correlations between baseline and follow-up were moderate. 9 out of the 13 most-frequently rated items at baseline showed equal frequencies at follow-up. The baseline level of self-disorders predicted global symptomatic, but not functional outcome. Self-disorders measured by the Examination of Anomalous Self Experiences show a high level of temporal persistence over 5 years and predict symptomatic outcome.
In the early 1990s, breakthrough discoveries on the genetics of Alzheimer's disease led to the identification of missense mutations in the amyloid-β precursor protein gene. Research findings quickly ...followed, giving insights into molecular pathogenesis and possibilities for the development of new types of animal models. The complete toolbox of transgenic techniques, including pronuclear oocyte injection and homologous recombination, has been applied in the Alzheimer's disease field, to produce overexpressors, knockouts, knockins and regulatable transgenics. Transgenic models have dramatically advanced our understanding of pathogenic mechanisms and allowed therapeutic approaches to be tested. Following a brief introduction to Alzheimer's disease, various nontransgenic and transgenic animal models are described in terms of their values and limitations with respect to pathogenic, therapeutic and functional understandings of the human disease.
Knowledge regarding unbound concentrations is of vital importance when exploring the PK and PD of a drug. The accurate and reproducible determination of plasma protein binding and unbound ...concentrations for a compound/drug is a serious challenge for the bioanalytical laboratory. When the drug is in equilibrium with the binding protein(s), this equilibrium will shift when physiological conditions are not met. Furthermore, the true unbound fraction/concentration is unknown, and there are numerous publications in the scientific literature reporting and discussing data that have been produced without sufficient control of the parameters influencing the equilibrium. In this Review, different parameters affecting the equilibrium and analysis are discussed, together with suggestions on how to control these parameters in order to produce as trustworthy results for unbound concentrations/fractions as possible.
Objectives
To examine the association between self‐reported memory failures and incident dementia in individuals aged 60 and older.
Design
Longitudinal, community based.
Setting
Betula Prospective ...Cohort Study, a population‐based study in Umeå, Sweden.
Participants
Individuals with a mean age of 71.5 ± 8.8 (range 60–90) (N = 1,547).
Measurements
Participants rated the frequency of everyday memory failures using the 16‐item Prospective and Retrospective Memory Questionnaire (PRMQ) and underwent objective memory testing at baseline. Participant self‐reports of complaints of poor memory by family and friends were evaluated. Dementia status was followed‐up for 10 to 12 years.
Results
Over the study period, 225 participants developed dementia (132 with Alzheimer′s disease (AD)). In Cox proportional hazard regression models adjusted for demographic factors, PRMQz‐scores predicted incident dementia (hazard ratio (HR) = 1.21 for all‐cause dementia; HR = 1.25 for AD, Ps < .01). The significant associations remained when depressive symptoms and objective memory performance were adjusted for, when low performers on objective memory (≥1 standard deviations below the age group mean) were excluded, and in analyses with delayed entry (survival time ≥ 5 years). Similar patterns were observed for the prospective and retrospective subscales, although including how often participants self‐reported that others complained about their poor memory eliminated the association between PRMQ scores and dementia and itself emerged as a significant predictor.
Conclusion
Self‐reported memory failure predicted future dementia or AD independent of objective memory performance. Subjective reports of complaints by family and friends appear to be an even more‐important indicator of preclinical impairments, and physicians should not ignore them, even in the absence of objective memory deficits.
Renewable energy can become the major energy supply option in low-carbon energy economies. Disruptive transformations in all energy systems are necessary for tapping widely available renewable energy ...resources. Organizing the energy transition from non-sustainable to renewable energy is often described as the major challenge of the first half of the 21st century. Technological innovation, the economy (costs and prices) and policies have to be aligned to achieve full renewable energy potentials, and barriers impeding that growth need to be removed. These issues are also covered by IPCC’s special report on renewable energy and climate change to be completed in 2010. This article focuses on the interrelations among the drivers. It clarifies definitions of costs and prices, and of barriers. After reviewing how the third and fourth assessment reports of IPCC cover mitigation potentials and commenting on definitions of renewable energy potentials in the literature, we propose a consistent set of potentials of renewable energy supplies.
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