| 1. |
- Alafuzoff, Irina, et al.
(author)
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The need to unify neuropathological assessments of vascular alterations in the ageing brain : Multicentre survey by the BrainNet Europe consortium
- 2012
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In: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 47:11, s. 825-833
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Journal article (peer-reviewed)abstract
- Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.
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| 2. |
- Benedict, Christian, et al.
(author)
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Intranasal insulin as a therapeutic option in the treatment of cognitive impairments
- 2011
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In: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 46:2-3, s. 112-115
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Journal article (peer-reviewed)abstract
- The brain is a major target of circulating insulin. Enhancing central nervous insulin action has been shown to improve memory functions in animals as well as in humans, benefitting in particular hippocampus-dependent (declarative) memory. As Alzheimer's disease (AD) is associated with reduced central nervous insulin signaling and attenuated permeation of blood-borne insulin across the blood-brain-barrier, the cognitive decline in AD patients may at least in part be derived from impaired brain insulin signaling. Thus, therapeutic strategies to overcome central nervous system insulin deficiency and resistance might be an attractive option in the treatment of cognitive impairments like AD. Insulin can be effectively delivered directly to the brain via the intranasal route that enables the hormone to bypass the blood-brain barrier and modulate central nervous functions. This review summarizes a series of studies demonstrating beneficial effects of intranasal insulin on memory functions both in healthy humans and in patients with cognitive impairments such as AD. These experiments in humans consistently indicate that enhancing brain insulin signaling by intranasal administration of the hormone improves hippocampus-dependent memory in the absence of adverse side effects. Considering that insulin also acts as a neuroprotective signal, up-regulating brain insulin levels by intranasal insulin administration appears to be a promising approach in the treatment and prevention of central nervous system insulin deficiency and resistance as found in AD.
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| 3. |
- Bruno, Davide, et al.
(author)
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Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants.
- 2012
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In: Experimental gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 47:5, s. 347-52
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Journal article (peer-reviewed)abstract
- Neurofilament light (NFL) proteins in cerebrospinal fluid (CSF) are a marker of neuronal damage, especially subcortical axonal injury and white matter disease. Subjects with Alzheimer's disease (AD) have shown elevated levels of CSF NFL as compared to controls. However, the presence of the APOE ε4 allele, an established risk factor for AD, was not found to associate with higher CSF NFL concentrations. We examined whether TOMM40 variants, which have been reported to influence age of onset of AD and are in linkage disequilibrium with APOE, have an effect on CSF NFL levels, in 47 healthy, cognitively intact individuals with or without APOE ε4. Our results show that the presence of APOE ε4 alone does not affect CSF NFL levels significantly; however APOE and TOMM40 appear to interact. Subjects with APOE ε4 have higher CSF NFL levels than non-ε4 carriers, only when they do not carry a short poly-T variant of TOMM40, which is associated with later age of onset of AD, and may act as protective against the dose effect of ε4.
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| 4. |
- Cacciani, Nicola, et al.
(author)
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Age related differences in diaphragm muscle fiber response to mid/long term controlled mechanical ventilation
- 2014
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In: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 59, s. 28-33
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Journal article (peer-reviewed)abstract
- BACKGROUND: Critically ill intensive care patients are subjected to controlled mechanical ventilation (CMV) which has an important association in triggering the impaired muscle function and the consequent delayed weaning from the respirator. AIM: The main aim of this study was to measure the effects of age and CMV over a period up to 5days on rat diaphragm muscle fibers, more specifically focusing on the changes in fiber structure and function. METHODS: Diaphragm muscle fiber cross-sectional area (CSA) and force generating capacity were measured in young (6months) and old (28-32months) rats in response to five days of CMV. To investigate the biological age of the old rats in this rat strain (F344 BN hybrid), a second set of experiments comparing muscle fiber size and specific force (maximum force normalized to CSA) was investigated in fast- and slow-twitch distal hind limb muscles in 3 different age groups: young adults (6months), middle aged (18months) and old rats (28months). RESULTS: This study shows an unexpected response of the diaphragm fibers to 5days CMV, demonstrating an increased CSA (p<0.001) in both young and old animals. Furthermore, an observed decreased maximum force of 39.8-45.2% (p<0.001) in both young and old animals compared with controls resulted in a dramatic loss of specific force. We suggest that this increase in CSA and decrease in specific force observed in both the young and old diaphragm fibers is an ineffective compensatory hypertrophy in response to the CMV. These results demonstrate an important mechanism of significant importance for the weaning problems associated with mechanical ventilation.
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| 5. |
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| 6. |
- Cedernaes, Jonathan, et al.
(author)
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Efficacy of antibody-based therapies to treat Alzheimer's disease : Just a matter of timing?
- 2014
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In: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 57, s. 104-106
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Journal article (peer-reviewed)abstract
- A pharmaceutical intervention that has received great attention in recent years for treating Alzheimer's disease (AD) is the use of antibodies targeting amyloid beta (A beta) in the brain, as the formation of A beta plaques is considered as being the driving force for the development and progression of AD. Recently, a Phase III trial in patients with mild-to-moderate AD has provided ambivalent evidence for the efficacy of this intervention. In this trial, the intravenous administration of bapineuzumab, a monoclonal antibody targeting A beta in the brain, for 78 weeks led to a reduction of cerebrospinal fluid levels of phosphorylated tau and evidence for lower A beta accumulation in the brain of AD patients who carried APOE epsilon 4. However, this treatment did not improve clinical outcomes (e.g. the rate of cognitive decline) in these patients. Similar null results with respect to the rate of cognitive decline were found in a separate Phase III clinical trial after treatment with solanezumab. Based on these findings, one conclusion could be that antibodies targeting A beta in the brain may unfold their highest efficacy when given before the development of clinical AD symptoms, i.e. during a period where neurodegeneration but not cognitive loss represents the major pathology. Another conclusion could be that antibody-based pharmaceutical interventions may fail to slow the progress of cognitive loss in patients who have AD because of their solely pharmaceutical therapeutic approach. Leisure activities that require patients' mental and physical abilities (e.g. exercise) are associated with a reduced risk of developing dementia. In the same manner, they may help to curb the progress of this devastating disease. Thus, combining the use of antibodies targeting A beta with therapeutic strategies that require patients' mental and physical abilities might help tackle the neurodegenerative dynamics and cognitive loss both in patients with AD, and its prodromal state, mild cognitive impairment.
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| 7. |
- Gardner, Michael, et al.
(author)
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Gender and telomere length : Systematic review and meta-analysis
- 2014
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In: Experimental Gerontology. - : Elsevier. - 0531-5565 .- 1873-6815. ; 51, s. 15-27
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Research review (peer-reviewed)abstract
- Background: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions: Telomere length is longer in females thanmales, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required. (C) 2013 Published by Elsevier Inc.
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| 8. |
- Hampel, Harald, et al.
(author)
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Total and phosphorylated tau protein as biological markers of Alzheimer's disease.
- 2010
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In: Experimental gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 45:1, s. 30-40
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Journal article (peer-reviewed)abstract
- Advances in our understanding of tau-mediated neurodegeneration in Alzheimer's disease (AD) are moving this disease pathway to center stage for the development of biomarkers and disease modifying drug discovery efforts. Immunoassays were developed detecting total (t-tau) and tau phosphorylated at specific epitopes (p-tauX) in cerebrospinal fluid (CSF), methods to analyse tau in blood are at the experimental beginning. Clinical research consistently demonstrated CSF t- and p-tau increased in AD compared to controls. Measuring these tau species proved informative for classifying AD from relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) differentiated between AD and frontotemporal dementia, tau phosphorylated at serine 181 (p-tau181) enhanced classification between AD and dementia with Lewy bodies. T- and p-tau are considered "core" AD biomarkers that have been successfully validated by controlled large-scale multi-center studies. Tau biomarkers are implemented in clinical trials to reflect biological activity, mechanisms of action of compounds, support enrichment of target populations, provide endpoints for proof-of-concept and confirmatory trials on disease modification. World-wide quality control initiatives are underway to set required methodological and protocol standards. Discussions with regulatory authorities gain momentum defining the role of tau biomarkers for trial designs and how they may be further qualified for surrogate marker status.
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| 9. |
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| 10. |
- Koistinen, Arto P, et al.
(author)
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Short-term exercise-induced improvements in bone properties are for the most part not maintained during aging in hamsters.
- 2014
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In: Experimental Gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 51, s. 46-53
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Journal article (peer-reviewed)abstract
- Physical exercise during growth affects composition, structure and mechanical properties of bone. In this study we investigated whether the beneficial effects of exercise during the early growth phase have long-lasting effects or not. Female Syrian golden hamsters (total n=152) were used in this study. Half of the hamsters had access to running wheels during their rapid growth phase (from 1 to 3months of age). The hamsters were sacrificed at the ages of 1, 3, 12, and 15months. The diaphysis of the mineralized humerus was analyzed with microCT and subjected to three-point-bending mechanical testing. The trabecular bone in the tibial metaphysis was also analyzed with microCT. The collagen matrix of the humerus bone was studied by tensile testing after decalcification. The weight of the hamsters as well as the length of the bone and the volumetric bone mineral density (BMDvol) of the humerus was higher in the running group at the early age (3months). Moreover, the mineralized bone showed improved mechanical properties in humerus and had greater trabecular thickness in the subchondral bone of tibia in the runners. However, by the age of 12 and 15months, these differences were equalized with the sedentary group. The tensile strength and Young's modulus of decalcified humerus were higher in the runners at early stage, indicating a stronger collagen network. In tibial metaphysis, trabecular thickness was significantly higher for the runners in the old age groups (12 and 15months). Our study demonstrates that physical exercise during growth improves either directly or indirectly through weight gain bone properties of the hamsters. However, the beneficial effects were for the most part not maintained during aging.
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