Age-related cognitive decline and associations with sex, education and apolipoprotein E genotype across ethnocultural groups and geographic regions: a collaborative cohort study

Background The prevalence of dementia varies around the world, potentially contributed to by international differences in rates of age-related cognitive decline. Our primary goal was to investigate how rates of age-related decline in cognitive test performance varied among international cohort studies of cognitive aging. We also determined the extent to which sex, educational attainment, and apolipoprotein E ε4 allele (APOE*4) carrier status were associated with decline. Methods and findings We harmonized longitudinal data for 14 cohorts from 12 countries (Australia, Brazil, France, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, United Kingdom, United States), for a total of 42,170 individuals aged 54–105 y (42% male), including 3.3% with dementia at baseline. The studies began between 1989 and 2011, with all but three ongoing, and each had 2–16 assessment waves (median = 3) and a follow-up duration of 2–15 y. We analyzed standardized Mini-Mental State Examination (MMSE) and memory, processing speed, language, and executive functioning test scores using linear mixed models, adjusted for sex and education, and meta-analytic techniques. Performance on all cognitive measures declined with age, with the most rapid rate of change pooled across cohorts a moderate -0.26 standard deviations per decade (SD/decade) (95% confidence interval [CI] [-0.35, -0.16], p < 0.001) for processing speed. Rates of decline accelerated slightly with age, with executive functioning showing the largest additional rate of decline with every further decade of age (-0.07 SD/decade, 95% CI [-0.10, -0.03], p = 0.002). There was a considerable degree of heterogeneity in the associations across cohorts, including a slightly faster decline (p = 0.021) on the MMSE for Asians (-0.20 SD/decade, 95% CI [-0.28, -0.12], p < 0.001) than for whites (-0.09 SD/decade, 95% CI [-0.16, -0.02], p = 0.009). Males declined on the MMSE at a slightly slower rate than females (difference = 0.023 SD/decade, 95% CI [0.011, 0.035], p < 0.001), and every additional year of education was associated with a rate of decline slightly slower for the MMSE (0.004 SD/decade less, 95% CI [0.002, 0.006], p = 0.001), but slightly faster for language (-0.007 SD/decade more, 95% CI [-0.011, -0.003], p = 0.001). APOE*4 carriers declined slightly more rapidly than non-carriers on most cognitive measures, with processing speed showing the greatest difference (-0.08 SD/decade, 95% CI [-0.15, -0.01], p = 0.019). The same overall pattern of results was found when analyses were repeated with baseline dementia cases excluded. We used only one test to represent cognitive domains, and though a prototypical one, we nevertheless urge caution in generalizing the results to domains rather than viewing them as test-specific associations. This study lacked cohorts from Africa, India, and mainland China. Conclusions Cognitive performance declined with age, and more rapidly with increasing age, across samples from diverse ethnocultural groups and geographical regions. Associations varied across cohorts, suggesting that different rates of cognitive decline might contribute to the global variation in dementia prevalence. However, the many similarities and consistent associations with education and APOE genotype indicate a need to explore how international differences in associations with other risk factors such as genetics, cardiovascular health, and lifestyle are involved. Future studies should attempt to use multiple tests for each cognitive domain and feature populations from ethnocultural groups and geographical regions for which we lacked data

Asarone from Acori Tatarinowii Rhizoma Potentiates the Nerve Growth Factor-Induced Neuronal Differentiation in Cultured PC12 Cells: A Signaling Mediated by Protein Kinase A

<div><p>Acori Tatarinowii Rhizoma (ATR), the rhizome of <i>Acorus tatarinowii</i> Schott, is being used clinically to treat neurological disorders. The volatile oil of ATR is being considered as an active ingredient. Here, α-asarone and β-asarone, accounting about 95% of ATR oil, were evaluated for its function in stimulating neurogenesis. In cultured PC12 cells, application of ATR volatile oil, α-asarone or β-asarone, stimulated the expression of neurofilaments, a bio-marker for neurite outgrowth, in a concentration-dependent manner. The co-treatment of ATR volatile oil, α-asarone or β-asarone, with low concentration of nerve growth factor (NGF) potentiated the NGF-induced neuronal differentiation in cultured PC12 cells. In addition, application of protein kinase A inhibitors, H89 and KT5720, in cultures blocked the ATR-induced neurofilament expression, as well as the phosphorylation of cAMP-responsive element binding protein (CREB). In the potentiation of NGF-induced signaling in cultured PC12 cells, α-asarone and β-asarone showed synergistic effects. These results proposed the neurite-promoting asarone, or ATR volatile oil, could be useful in finding potential drugs for treating various neurodegenerative diseases, in which neurotrophin deficiency is normally involved.</p></div

Different combination ratios of α-asarone and β-asarone on increasing NF promoter activity.

<p>(A) The concentration of α-asarone of set at 5 μg/mL, and the concentration of β-asarone was varied (0.625–40 μg/mL) to form different ratios from 8:1 to 1:8. A mixture of asarone in defined ratio/concentration was applied onto pNF68/200-Luc transfected PC12 cells. The luciferase activity was determined after 48 hours. (B) The concentration of β-asarone of set at 5 μg/mL, and the concentration of α-asarone was varied (0.625–40 μg/mL) to form different ratios from 8:1 to 1:8. The cell treatment was as in (A). (C) Combination of α-asarone and β-asarone in 1:4 ratio, α-asarone or β-asarone were applied onto pNF68-Luc transfected PC12 cells in different concentrations. The luciferase activity of each sample was determined after 48 hours. (D) The treatment was as in (C) onto pNF200-Luc transfected PC12 cells. Values are expressed as percentage of increase as compared to control (without drug treatment), and in Mean ± SEM, <i>n</i> = 4, each with triplicate samples. * p < 0.05; ** p < 0.01; *** p < 0.001.</p

Inhibition of PKA suppresses neurofilament expression, induced by ATR volatile oil, α-asarone or β-asarone, in cultured PC12 cells.

<p>(A) Cultured PC12 cells were pre-treated with or without PKA inhibitor, H89 (5 μM) or KT5720 (1 μM), for 3 hours, and then treated with ATR volatile oil, α-asarone, β-asarone, at 30 μg/ mL, or NGF at 50 ng/mL, for 48 hours. The cell lysates were collected to determine the expressions of NF68, NF160, and NF200. GAPDH served as a loading control. (B) Quantification from the blots by a densitometer was shown. Values were expressed as the fold of change (x Basal) against the control (no treatment; set as 1), and in Mean ± SEM, <i>n</i> = 4, each with triplicate samples. * p < 0.05; ** p < 0.01; *** p < 0.001.</p

ATR volatile oil, α-asarone or β-asarone, induces cAMP-mediated transcriptional activity in cultured PC12 cells.

<p>(A) Cultured PC12 cells, transfected with pCRE-Luc, were treated with series concentration of forskolin for 48 hours. (B) The pCRE-Luc transfected PC12 cells were treated with series concentration of ATR volatile oil, α-asarone or β-asarone, for 48 hours. (C) The pCRE-Luc transfected PC12 cells were pre-treated with PKA inhibitor, H89 (5 μM) or KT5720 (1 μM), for 3 hours, and then treated with ATR volatile oil, α-asarone or β-asarone, at 30μg/mL, or forskolin (3 μM), for 48 hours. The cell lysates subjected to luciferase assay. Values were expressed as the fold of increase to basal reading (DMSO-treated culture as control), and in Mean ± SEM, where <i>n</i> = 4, each with triplicate samples. * p < 0.05; ** p < 0.01; *** p < 0.001 as compared to the control group.</p

ATR volatile oil, α-asarone or β-asarone, potentiates NGF-induced neurite outgrowth in PC12 cell.

<p>(A) Cultures were co-treated with ATR volatile oil, α-asarone or β-asarone, at 30 μg/mL with NGF (0.5 ng/mL) for 48 hours. NGF at 50 ng/mL served as a control. Then, the cells were fixed with ice-cold 4% PFA. Scale bar = 10 μm. Representative images were shown. The percentage of differentiated cells (B) and length of neurite (C) were counted as described in Method section. Values were expressed as % of cells in 100 counted cells, Mean ± SEM, <i>n</i> = 4. Each with triplicate samples. * p < 0.05; ** p < 0.01; *** p < 0.001 as compared to the control group.</p

ATR volatile oil, α-asarone or β-asarone, induces the transcriptional activation of neurofilament promoters in cultured PC12 cells.

<p>(A) PC12 cells were transfected with pNF68/pNF200-Luc promoter and treated with series dose of NGF for 48 hours. (B & C) ATR volatile oil, α-asarone or β-asarone, was applied onto the cells after transfected with pNF68/200-Luc, as in (A) for 48 hours. The cell lysates were collected to determine the luciferase activity. NGF at 50 ng/ mL served as a control. Values are Means ± SEM, <i>n</i> = 3, each with triplicate samples.</p

ATR volatile oil, α-asarone or β-asarone, induces phosphorylation of CREB in cultured PC12 cells.

<p>(A) Cultured PC12 cells, serum starved for 5 hours, were treated with NGF at high concentration at 50 ng/mL, or low concentration at 0.5 ng/mL. (B) ATR volatile oil, α-asarone or β-asarone, at 30 μg/mL, with or without NGF at 0.5 ng /mL, for different time. (C) Cultured PC12 cells, serum starved for over 5 hours, were pre-treated with or without PKA inhibitor, H89 (5 μM) or KT5720 (1 μM), for 3 hours prior to the treatment with NGF (50 ng/mL), or ATR volatile oil, or α-asarone, or β-asarone, for 10 minutes. Total CREB and phosphorylated CREB (~42 kDa) were revealed by using specific antibodies (upper panel). Quantification plot is shown in histograms (lower panel). Data are expressed as the fold of change (x Basal) against the control (no treatment; set as 1), Mean ± SEM, <i>n</i> = 5, each with triplicate samples. Statistical comparison was made with the H89-treated or KT5720-treated group; * p < 0.05; ** p < 0.01; *** p < 0.001.</p

Metabolomics Analysis Reveals Specific Novel Tetrapeptide and Potential Anti-Inflammatory Metabolites in Pathogenic Aspergillus species

Infections related to Aspergillus species have emerged to become an important focus in infectious diseases, as a result of the increasing use of immunosuppressive agents and high fatality associated with invasive aspergillosis. However, laboratory diagnosis of Aspergillus infections remains difficult. In this study, by comparing the metabolomic profiles of the culture supernatants of 30 strains of six pathogenic Aspergillus species (A. fumigatus, A. flavus, A. niger, A. terreus, A. nomius and A. tamarii) and 31 strains of 10 non-Aspergillus fungi, eight compounds present in all strains of the six Aspergillus species but not in any strain of the non-Aspergillus fungi were observed. One of the eight compounds, Leu–Glu–Leu–Glu, is a novel tetrapeptide and represents the first linear tetrapeptide observed in Aspergillus species, which we propose to be named aspergitide. Two other closely related Aspergillus-specific compounds, hydroxy-(sulfooxy)benzoic acid and (sulfooxy)benzoic acid, may possess anti-inflammatory properties, as 2-(sulfooxy)benzoic acid possesses a structure similar to those of aspirin [2-(acetoxy)benzoic acid] and salicylic acid (2-hydroxybenzoic acid). Further studies to examine the potentials of these Aspergillus-specific compounds for laboratory diagnosis of aspergillosis are warranted and further experiments will reveal whether Leu–Glu–Leu–Glu, hydroxy-(sulfooxy)benzoic acid and (sulfooxy)benzoic acid are virulent factors of the pathogenic Aspergillus species