Propensity for somatic expansion increases over the course of life in Huntington disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Kacher R
PROVIDER: S-EPMC8118653 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description: Not available
| S-EPMC9308656 | biostudies-literature
Project description:Amyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312(+) dystrophic neurites, GFAP(+) reactive astrocytes, and IBA1(+) and CD68(+) activated microglia in randomly selected dense-core (Thioflavin-S(+)) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques. Dystrophic neurites (Kendall ? = 0.34, P = 0.001), reactive astrocytes (Kendall ? = 0.30, P = 0.003), and CD68(+) (Kendall ? = 0.48, P < 0.0001), but not IBA1 microglia (Kendall ? = 0.045, P = 0.655), exhibited a significant positive correlation with symptom duration. When excluding control subjects, only the positive association between CD68(+) microglia and symptom duration remained significant (Kendall ? = 0.39, P = 0.0003). The presence of the APOE?4 allele did not affect these results. We conclude that plaques exert an increasing toxicity in the surrounding neuropil over the clinical course of AD, thereby potentially contributing to cognitive decline.
| S-EPMC4729270 | biostudies-other
Project description:Using nineteen panels of the 1979 National Longitudinal Survey of Youth (NLSY-79), we construct life-lines characterizing women's childless expectations and fertility behavior. One-quarter of women in the NLSY-79 cohort ever reported an expectation for childlessness but only 14.8 percent of women remain childless. Childless women follow two predominant life course paths: (1) repeated postponement of childbearing and the subsequent adoption of a childless expectation at older ages or (2) indecision about parenthood signaled through vacillating reports of childless expectations across various ages. We also find that more than one in ten women became a mother after considering childlessness: an understudied group in research on childlessness and childbearing preferences. These findings reaffirm that it is problematic to assign expected and unexpected childlessness labels to the reproductive experience of childless women. In addition, despite their variability over time, childless expectations strongly predict permanent childlessness, regardless of the age when respondents offer them. Longitudinal logistic regression analysis of these childless expectations indicates a strong effect of childbearing postponement among the increasingly selective group of childless women. However, net of this postponement, few variables commonly associated with childlessness are associated with reports of a childless expectation. We thus conclude that the effects of socio-demographic and situational factors on childless expectations are channeled predominantly through repeated childbearing postponement.
| S-EPMC6659743 | biostudies-literature
Project description:Background and aimsAlcohol consumption changes markedly over the life course, with important implications for health and social development. Assessment of these patterns often relies on cross-sectional data, which cannot fully capture how individuals' drinking changes as they age. This study used data from 18 waves of a general population panel survey to measure drinking trajectories over the life course in Australia.Design and settingLongitudinal survey data from the Household, Income and Labour Dynamics in Australia (HILDA) survey between 2001 and 2018.ParticipantsA total of 20 593 individuals ages 15 or above in two samples assessing quantity-frequency (n = 20 569, 52.0% female) and risky single occasion drinking (RSOD), respectively, (n = 17 340, 52.5% female), interviewed as part of HILDA.MeasurementsUsual quantity of alcohol consumed per drinking occasion; frequency of drinking occasions per week; average daily consumption, calculated by combining reported usual quantity and frequency; and average reported frequency of RSOD per week.FindingsMultilevel, mixed effects models run with fractional polynomial terms found similar male and female alcohol consumption trajectories for quantity-frequency and RSOD measures. Usual quantity of alcohol consumed per drinking occasion (5.4 drinks for men, 3.8 for women) and RSOD frequency (0.56 occasions/week for men, 0.38 for women) peaked in young adulthood, whereas frequency of drinking occasions (2.5 occasions/week for men, 1.7 for women) peaked in middle age. Middle-age drinkers had the highest average daily consumption of alcohol (1.4 drinks/day for 54-year-old men, 0.6 drinks for 57-year-old women) and engaged in RSOD slightly less than young adults.ConclusionsAlcohol consumption in Australia appears to vary substantially over the life course, with usual quantity per drinking occasion and frequency of risky single occasion drinking peaking during early adulthood and average daily consumption and frequency of consumption peaking in middle age.
| S-EPMC9311147 | biostudies-literature
Project description:College graduates earn higher wages than high school graduates by age 30. Among women, the advantages of a college degree decline somewhat as they age, although they are still substantial at age 50; for men, the advantage of a college degree grows throughout the life cycle. Most previous research on returns to higher education has focused on income at a single point in time or averaged over multiple years; our contribution is to study how returns vary by age. We also document how these patterns vary by the propensity of graduating from college. We find modest wage returns for mid-propensity college graduates, but large returns for low-propensity and, for men, high-propensity college graduates. Our results rely on propensity score–based matching combined with multilevel growth curve models applied to data from the National Longitudinal Survey of Youth 1979 cohort.
| S-EPMC8673759 | biostudies-literature
Project description:BackgroundComprehensive conjoint characterization of long-term trajectories representing several biological systems is lacking.MethodsWe measured serially indicators representing 14 distinct biological systems in up to 3,453 participants attending four Framingham Study examinations: bone mineral density, body mass index (BMI), C-reactive protein, glomerular filtration rate, forced vital capacity (FVC), 1 second forced expiratory volume/FVC ratio (FEV1/FVC), gait speed, grip strength, glycosylated hemoglobin (HbA1c), heart rate, left ventricular mass, Mini-Mental State Examination (MMSE), pulse pressure, and total/high-density lipoprotein cholesterol ratio (TC/HDL).ResultsWe observed that correlations among the 14 sex-specific trajectories were modest (r < .30 for 169 of 182 sex-specific correlations). During follow-up (median 8 years), 232 individuals experienced a cardiovascular disease (CVD) event and 393 participants died. In multivariable regression models, CVD incidence was positively related to trajectories of BMI, HbA1c, TC/HDL, gait time, and pulse pressure (p < .06); mortality risk was related directly to trajectories of gait time, C-reactive protein, heart rate, and pulse pressure but inversely to MMSE and FEV1/FVC (p < .006). A unit increase in the trajectory risk score was associated with a 2.80-fold risk of CVD (95% confidence interval [CI], 2.04-3.84; p < .001) and a 2.71-fold risk of death (95% CI, 2.30-3.20; p < .001). Trajectory risk scores were suggestive of a greater increase in model c-statistic compared with single occasion measures (delta-c compared with age- and sex-adjusted models: .032 vs .026 for CVD; .042 vs .030 for mortality).ConclusionsBiological systems age differentially over the life course. Longitudinal data on a parsimonious set of biomarkers reflecting key biological systems may facilitate identification of high-risk individuals.
| S-EPMC7357457 | biostudies-literature
Project description:To make early diagnosis of IT15 gene mutation in a Wuhan juvenile-onset Huntington disease (HD) family, for providing them with genetic counseling, and making preparation for the further research on pathogenesis and experimental therapy of HD.According to the principle of informed consent, we extracted genomic DNA from peripheral blood samples and carried genetic diagnosis of pathogenic exon 1 of IT15 gene by modified touchdown PCR and DNA sequencing methods.Eight of twenty-five family members carried abnormal allele: III(10), III(12), III(14), IV(3), and V(2) carried (CAG) (48), IV(11) and IV(12) carried (CAG) (67), and IV(14) carried (CAG) (63), in contrast with the 8-25 CAG trinucleotides in the members of control group. IV(14) carried 15 more CAG trinucleotides than her father III(10).The results definitely confirm the diagnosis of HD and indicate the CAG trinucleotide repeat expansion of IT15 gene in this HD family. In addition, CAG expansion results in juvenile-onset and anticipation (characterized by earlier age of onset and increasing severity) of the patient IV(12).
| S-EPMC5550581 | biostudies-other
Project description:BackgroundHuntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes.MethodsThe sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses.FindingsUsing data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI = 1·94 to 4·80, p = 1·3 × 10-6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 × 10-6), MLH3 (pFDR = 8·0 × 10-4), MLH1 (pFDR = 0·004) and MSH3 (pFDR = 0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines.InterpretationThese data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders.FundingCHDI Foundation.
| S-EPMC6838430 | biostudies-literature
Project description:Conifer somatic embryogenesis (SE) is a process driven by exogenously supplied plant growth regulators (PGRs). Exogenous PGRs and endogenous phytohormones trigger particular ontogenetic events. Complex mechanisms involving a number of endogenous phytohormones control the differentiation of cells and tissues, as well as the establishment of structures and organs. Most of the mechanisms and hormonal functions in the SE of conifers have not yet been described. With the aim to better understand these mechanisms, we provided detailed analysis of the spectrum of endogenous phytohormones over the course of SE in Norway spruce (Picea abies). Concentrations of endogenous phytohormones including auxins, cytokinins (CKs), abscisic acid (ABA), jasmonates, and salicylic acid (SA) in somatic P. abies embryos were analyzed by HPLC-ESI-MS/MS. The results revealed that the concentrations of particular phytohormone classes varied substantially between proliferation, maturation, desiccation, and germination. Endogenous ABA showed a maximum concentration at the maturation stage, which reflected the presence of exogenous ABA in the medium and demonstrated its efficient perception by the embryos as a prerequisite for their further development. Auxins also had concentration maxima at the maturation stage, suggesting a role in embryo polarization. Endogenous jasmonates were detected in conifer somatic embryos for the first time, and reached maxima at germination. According to our knowledge, we have presented evidence for the involvement of the non-indole auxin phenylacetic acid, cis-zeatin- and dihydrozeatin-type CKs and SA in SE for the first time. The presented results represent the currently most comprehensive overview of plant hormone levels in embryos throughout the whole process of conifer SE. The differences in concentrations of various classes of phytohormones over the proliferation, maturation, desiccation, and germination in somatic P. abies embryos clearly indicate correlations between endogenous phytohormone profiles and particular developmental stages of the SE of conifers.
| S-EPMC6136392 | biostudies-literature
Project description:ImportanceEarlier identification of high coronary artery disease (CAD) risk individuals may enable more effective prevention strategies. However, existing 10-year risk frameworks are ineffective at earlier identification. Understanding the variable importance of genomic and clinical factors across life stages may significantly improve lifelong CAD event prediction.ObjectiveTo assess the time-varying significance of genomic and clinical risk factors in CAD risk estimation across various age groups.Design setting and participantsA longitudinal study was performed using data from two cohort studies: the Framingham Offspring Study (FOS) with 3,588 participants aged 19-57 years and the UK Biobank (UKB) with 327,837 participants aged 40-70 years. A total of 134,765 and 3,831,734 person-time years were observed in FOS and UKB, respectively.Main outcomes and measuresHazard ratios (HR) for CAD were calculated for polygenic risk scores (PRS) and clinical risk factors at each age of enrollment. The relative importance of PRS and Pooled Cohort Equations (PCE) in predicting CAD events was also evaluated by age groups.ResultsThe importance of CAD PRS diminished over the life course, with an HR of 3.58 (95% CI 1.39-9.19) at age 19 in FOS and an HR of 1.51 (95% CI 1.48-1.54) by age 70 in UKB. Clinical risk factors exhibited similar age-dependent trends. PRS significantly outperformed PCE in identifying subsequent CAD events in the 40-45-year age group, with 3.2-fold more appropriately identified events. The mean age of CAD events occurred 1.8 years earlier for those at high genomic risk but 9.6 years later for those at high clinical risk (p<0.001). Overall, adding PRS improved the area under the receiving operating curve of the PCE by an average of +5.1% (95% CI 4.9-5.2%) across all age groups; among individuals <55 years, PRS augmented the AUC-ROC of the PCE by 6.5% (95% CI 5.5-7.5%, p<0.001).Conclusions and relevanceGenomic and clinical risk factors for CAD display time-varying importance across the lifespan. The study underscores the added value of CAD PRS, particularly among individuals younger than 55 years, for enhancing early risk prediction and prevention strategies.
| S-EPMC10635271 | biostudies-literature