Plasma 24S-hydroxycholesterol levels in elderly subjects with late onset Alzheimer's disease or vascular dementia: a case-control study

<p>Abstract</p> <p>Background</p> <p>In central nervous system cholesterol cannot be degraded but is secreted into circulation predominantly in the form of its polar metabolite 24(<it>S</it>)-hydroxycholesterol (24S-OH-Chol). Some studies suggested an association between 24S-OH-Chol metabolism and different neurological diseases including dementia. A possible decrease in 24S-OH-Chol plasma levels has been reported late onset Alzheimer's disease (LOAD) and vascular dementia (VD), but results of previous studies are partially contradictory.</p> <p>Methods</p> <p>By high-speed liquid chromatography/tandem mass spectrometry we evaluated the plasma levels of 24S-OH-Chol in a sample of 160 older individuals: 60 patients with LOAD, 35 patients with VD, 25 subjects affected by cognitive impairment no-dementia (CIND), and 40 (144 for genetics study) cognitively normal Controls. We also investigated the possible association between PPARgamma Pro12Ala polymorphism and dementia or 24S-OH-Chol levels.</p> <p>Results</p> <p>Compared with Controls, plasma 24S-OH-Chol levels were higher in LOAD and lower in VD; a slight not-significant increase in CIND was observed (ANOVA p: 0.001). A positive correlation between 24S-OH-Chol/TC ratio and plasma C reactive protein (CRP) levels was found in the whole sample, independent of possible confounders (multiple regression p: 0.04; r²: 0.10). This correlation was strong in LOAD (r: 0.39), still present in CIND (r: 0.20), but was absent in VD patients (r: 0.08). The PPARgamma Pro12Ala polymorphism was not associated with the diagnosis of LOAD, VD, or CIND; no correlation emerged between the Ala allele and 24S-OH-Chol plasma levels.</p> <p>Conclusions</p> <p>Our results suggest that plasma 24S-OH-Chol levels might be increased in the first stages of LOAD, and this phenomenon might be related with systemic inflammation. The finding of lower 24S-OH-Chol concentrations in VD might be related with a more advanced stage of VD compared with LOAD in our sample, and/or to different pathogenetic mechanisms and evolution of these two forms of dementia.</p

Accuracy and reproducibility of automated white matter hyperintensities segmentation with lesion segmentation tool: A European multi-site 3T study

Brain vascular damage accumulate in aging and often manifest as white matter hyperintensities (WMHs) on MRI. Despite increased interest in automated methods to segment WMHs, a gold standard has not been achieved and their longitudinal reproducibility has been poorly investigated. The aim of present work is to evaluate accuracy and reproducibility of two freely available segmentation algorithms. A harmonized MRI protocol was implemented in 3T-scanners across 13 European sites, each scanning five volunteers twice (test-retest) using 2D-FLAIR. Automated segmentation was performed using Lesion segmentation tool algorithms (LST): the Lesion growth algorithm (LGA) in SPM8 and 12 and the Lesion prediction algorithm (LPA). To assess reproducibility, we applied the LST longitudinal pipeline to the LGA and LPA outputs for both the test and retest scans. We evaluated volumetric and spatial accuracy comparing LGA and LPA with manual tracing, and for reproducibility the test versus retest. Median volume difference between automated WMH and manual segmentations (mL) was −0.22[IQR = 0.50] for LGA-SPM8, −0.12[0.57] for LGA-SPM12, −0.09[0.53] for LPA, while the spatial accuracy (Dice Coefficient) was 0.29[0.31], 0.33[0.26] and 0.41[0.23], respectively. The reproducibility analysis showed a median reproducibility error of 20%[IQR = 41] for LGA-SPM8, 14% [31] for LGA-SPM12 and 10% [27] with the LPA cross-sectional pipeline. Applying the LST longitudinal pipeline, the reproducibility errors were considerably reduced (LGA: 0%[IQR = 0], p < 0.001; LPA: 0% [3], p < 0.001) compared to those derived using the cross-sectional algorithms. The DC using the longitudinal pipeline was excellent (median = 1) for LGA [IQR = 0] and LPA [0.02]. LST algorithms showed moderate accuracy and good reproducibility. Therefore, it can be used as a reliable cross-sectional and longitudinal tool in multi-site studies

Telomere Length and Mental Well-Being in Elderly Men from the Netherlands and Greece

Telomeres, repetitive DNA sequences that promote chromosomal stability, have been related to different measures of mental well-being and self-rated health, but mainly in women during adulthood. We aimed to investigate whether accelerated telomere shortening is associated with poor mental well-being and poor self-rated health in community-dwelling elderly men. Leukocyte telomere length was measured using quantitative PCR in two different samples of 203 elderly men (mean age 78 years) from the Netherlands in 1993, and 123 elderly men (mean age 84 years) from Greece in 2000. We also obtained follow-up data in 2000 from 144 Dutch subjects, of whom 75 had paired telomere length data in 1993 and 2000. Mental well-being was conceptualized as dispositional optimism, depressive symptoms, cognitive functioning, and loneliness. Linear regression analyses were used to study the association between telomere length, measures of mental well being, and self-rated health, while adjusting for potential confounders. In cross-sectional analyses, leukocyte telomere length was not associated with measures of mental well-being and self-rated health, neither in the Netherlands nor in Greece. Also, the rate of leukocyte telomere shortening (mean decrease: 0.28 kbp over 7 years) in the 75 Dutch participants with longitudinal data was not associated with changes in different measures of mental well-being and self-rated health. Thus, our results provide no support for a relationship between leukocyte telomere length and mental well-being in elderly community-dwelling men

Exp Gerontol

The importance of the endocrine environment in the initiation of the ageing process has been elucidated in several in vivo and in vitro studies. Changes in endocrine pathways accompany healthy ageing, these include the growth hormone/insulin-like growth factor-I axis (somatopause) and that of sexual hormones, namely estradiol (menopause), testosterone (andropause), and dehydroepiandrosterone and its sulphate (adrenopause). The clinical significance of these changes is variable and results in morphological and functional alterations of all organ systems including the skin and the central nervous system. Moreover, the pathogenesis of age-associated diseases such as epithelial skin cancer and neurodegenerative diseases has been partly attributed to the lack of hormones. Several studies have been conducted in an attempt to reverse the ageing process and clinical signs by substitution of the serum hormone levels in older individuals, however the benefits of hormone replacement therapy, if any, are still controversial. On the other hand, recent data suggest that skin is a window to the human organism and represents an adequate model for ageing research, also implying the use of skin samples for evaluating the ageing status of the central nervous system

In vivo

Introduction: AAES is a powdered form of Biostymina, herbal medicinal product of Phytopharm Klęka S.A., a water extract of Aloe arborescens Mill. leaves. Aloe arborescens Mill. (woody aloe, tree-like aloe) is known to have several traditional medicinal properties including anti-inflammatory, immunomodulatory, antiviral and antimicrobial activity. Objective: The aim of this work was to study the in vivo effect of AAES on cellular (leukocyte-induced cutaneous angiogenesis, LIA test, and proliferative response to PHA) and humoral (anti-SRBC antibody response)immunity in mice. Methods: Balb/c mice were fed AAES from 0.5 to 75 mg/kg body mass for seven days before grafting their splenocytes intradermally to F1 (Balb/cxC3H) recipients (LIA test). Neovascular reaction was evaluated 72 h later in dissection microscope. Spleen cell cultures were incubated with 0.5, 1 and 2 µg/ml of PHA. After 48 h of incubation, tritiated thymidine was added. After further 24 h, cells were harvested (Skatron) and incorporation of tritiated thymidine was measured using Beta-scintillation counter. Balb/c mice were fed for 7 days with AAES, then immunized intraperitoneally with 5% SRBC suspension and 7 days later the antibody response was measured with hemagglutination test. Results: Neovascular reaction was significantly higher in groups grafted with splenocytes collected from all AAES fed donors than from the controls. The proliferation of splenocytes taken from mice fed AAES at doses ranging from 0.5 mg/kg to 7.5 mg/kg was stimulated in all cultures. Suppression of proliferation was observed in cell cultures derived from mice fed with higher doses of AAES. Stimulation of anti-SRBC antibody production was seen in mice fed both 2.5 and 7.5 mg/kg dose of AAES. Conclusion: Powdered form of Biostymina (AAES) might be useful in the treatment of patients with ischaemia of tissues and organs (myocardial infarction, stroke, necrosis) and in deficiency in the production of immune cells and growth factors (infections, chronic wound healing, ulceration and bone fusion)

In vivo immuno - and angiomodulatory effects of Aloe arborescens folii recentis extractum siccum (AAES) in mice

Introduction: AAES is a powdered form of Biostymina, herbal medicinal product of Phytopharm Klęka S.A., a water extract of Aloe arborescens Mill. leaves. Aloe arborescens Mill. (woody aloe, tree-like aloe) is known to have several traditional medicinal properties including anti-inflammatory, immunomodulatory, antiviral and antimicrobial activity. Objective: The aim of this work was to study the in vivo effect of AAES on cellular (leukocyte-induced cutaneous angiogenesis, LIA test, and proliferative response to PHA) and humoral (anti-SRBC antibody response)immunity in mice. Methods: Balb/c mice were fed AAES from 0.5 to 75 mg/kg body mass for seven days before grafting their splenocytes intradermally to F1 (Balb/cxC3H) recipients (LIA test). Neovascular reaction was evaluated 72 h later in dissection microscope. Spleen cell cultures were incubated with 0.5, 1 and 2 µg/ml of PHA. After 48 h of incubation, tritiated thymidine was added. After further 24 h, cells were harvested (Skatron) and incorporation of tritiated thymidine was measured using Beta-scintillation counter. Balb/c mice were fed for 7 days with AAES, then immunized intraperitoneally with 5% SRBC suspension and 7 days later the antibody response was measured with hemagglutination test. Results: Neovascular reaction was significantly higher in groups grafted with splenocytes collected from all AAES fed donors than from the controls. The proliferation of splenocytes taken from mice fed AAES at doses ranging from 0.5 mg/kg to 7.5 mg/kg was stimulated in all cultures. Suppression of proliferation was observed in cell cultures derived from mice fed with higher doses of AAES. Stimulation of anti-SRBC antibody production was seen in mice fed both 2.5 and 7.5 mg/kg dose of AAES. Conclusion: Powdered form of Biostymina (AAES) might be useful in the treatment of patients with ischaemia of tissues and organs (myocardial infarction, stroke, necrosis) and in deficiency in the production of immune cells and growth factors (infections, chronic wound healing, ulceration and bone fusion)

Cold Acclimation of the Thermoacidophilic Red Alga Galdieria sulphuraria: Changes in Gene Expression and Involvement of Horizontally Acquired Genes

Galdieria sulphuraria is a unicellular red alga that lives in hot, acidic, toxic metal-rich, volcanic environments, where few other organisms survive. Its genome harbors up to 5% of genes that were most likely acquired through horizontal gene transfer. These genes probably contributed to G.sulphuraria's adaptation to its extreme habitats, resulting in today's polyextremophilic traits. Here, we applied RNA-sequencing to obtain insights into the acclimation of a thermophilic organism towards temperatures below its growth optimum and to study how horizontally acquired genes contribute to cold acclimation. A decrease in growth temperature from 42C/46C to 28C resulted in an upregulation of ribosome biosynthesis, while excreted proteins, probably components of the cell wall, were downregulated. Photosynthesis was suppressed at cold temperatures, and transcript abundances indicated that C-metabolism switched from gluconeogenesis to glycogen degradation. Folate cycle and S-adenosylmethionine cycle (one-carbon metabolism) were transcriptionally upregulated, probably to drive the biosynthesis of betaine. All these cold-induced changes in gene expression were reversible upon return to optimal growth temperature. Numerous genes acquired by horizontal gene transfer displayed temperature-dependent expression changes, indicating that these genes contributed to adaptive evolution in G.sulphuraria

Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET

A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimer's disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis. (C) 2002 Elsevier Science (USA)