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Background & Aims: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4 -/- /NFATc1 High )., Methods: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4 -/- /NFATc1 High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models., Results: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4 -/- /NFATc1 High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index., Conclusions: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: While it is well-known that deficits in motor performance and brain structural connectivity occur in the course of healthy aging, it is still unclear if and how these changes are related to each other. While some cross-sectional studies suggest that white matter (WM) microstructure is positively associated with motor function in healthy older adults, more evidence is needed. Moreover, longitudinal data is required to estimate whether similar associations can be found between trajectories of change in WM microstructure and motor function. The current study addresses this gap by investigating age-associations and longitudinal changes in WM microstructure and motor function, and the cross-sectional (level-level) and longitudinal (level-change, change-change) association between these two domains., Method: We used multiple-occasion data (covering 4 years) from a large sample ( N = 231) of healthy older adults from the Longitudinal Healthy Aging Brain (LHAB) database. To measure WM microstructure, we used diffusion-weighted imaging data to compute mean FA in three selected WM tracts [forceps minor (FMIN); superior longitudinal fasciculus (SLF); corticospinal tract (CST)]. Motor function was measured via two motor speed tests (grooved pegboard, finger tapping) and one motor strength test (grip force test), separately for the left and the right hand. The statistical analysis was conducted with longitudinal growth curve models in the structural equation modeling framework., Results: The results revealed longitudinal decline and negative cross-sectional age-associations for mean WM FA in the FMIN and SLF, and for motor function in all tests, with a higher vulnerability for left than right hand motor performance. Regarding cross-domain associations, we found a significant positive level-level correlation among mean WM FA in the FMIN with motor speed. Mean FA in SLF and CST was not correlated with motor performance measures, and none of the level-change or change-change associations were significant. Overall, our results (a) provide important insights into aging-related changes of fine motor abilities and FA in selected white matter tracts associated with motor control, (b) support previous cross-sectional work showing that neural control of movement in older adults also involves brain structures outside the core motor system and (c) align with the idea that, in healthy aging, compensatory mechanisms may be in place and longer time delays may be needed to reveal level-change or change-change associations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Oschwald, Mérillat, Jäncke and Seidler.)

Cross-sectional studies indicate that normal aging is accompanied by decreases in brain structure. Longitudinal studies, however, are relatively rare and inconsistent regarding their outcomes. Particularly the heterogeneity of methods, sample characteristics and the high inter-individual variability in older adults prevent the deduction of general trends. Therefore, the current study aimed to compare longitudinal age-related changes in brain structure (measured through cortical thickness) in two large independent samples of healthy older adults ( n = 161 each); the Longitudinal Healthy Aging Brain (LHAB) database project at the University of Zurich, Switzerland, and 1000BRAINS at the Research Center Juelich, Germany. Annual percentage changes in the two samples revealed stable to slight decreases in cortical thickness over time. After correction for major covariates, i.e., baseline age, sex, education, and image quality, sample differences were only marginally present. Results suggest that general trends across time might be generalizable over independent samples, assuming the same methodology is used, and similar sample characteristics are present., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jockwitz, Mérillat, Liem, Oschwald, Amunts, Jäncke and Caspers.)

Healthy aging is associated with changes in cognitive performance and functional brain organization. In fact, cross-sectional studies imply lower modularity and significant heterogeneity in modular architecture across older subjects. Here, we used a longitudinal dataset consisting of four occasions of resting-state-fMRI and cognitive testing (spanning 4 years) in 150 healthy older adults. We applied a graph-theoretic analysis to investigate the time-evolving modular structure of the whole-brain network, by maximizing the multilayer modularity across four time points. Global flexibility, which reflects the tendency of brain nodes to switch between modules across time, was significantly higher in healthy elderly than in a temporal null model. Further, global flexibility, as well as network-specific flexibility of the default mode, frontoparietal control, and somatomotor networks, were significantly associated with age at baseline. These results indicate that older age is related to higher variability in modular organization. The temporal metrics were not associated with simultaneous changes in processing speed or learning performance in the context of memory encoding. Finally, this approach provides global indices for longitudinal change across a given time span and it may contribute to uncovering patterns of modular variability in healthy and clinical aging populations., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Healthy aging is associated with weaker functional connectivity within resting state brain networks and stronger functional interaction between these networks. This phenomenon has been characterized as reduced functional segregation and has been investigated mainly in cross-sectional studies. Here, we used a longitudinal dataset which consisted of four occasions of resting state fMRI and psychometric cognitive ability data, collected from a sample of healthy older adults (baseline N = 232, age range: 64-87 y, age M = 70.8 y), to investigate the functional segregation of several well-defined resting state networks encompassing the whole brain. We characterized the ratio of within-network and between-network correlations via the well-established segregation index. Our findings showed a decrease over a 4-year interval in the functional segregation of the default mode, frontoparietal control and salience ventral attention networks. In contrast, we showed an increase in the segregation of the limbic network over the same interval. More importantly, the rate of change in functional segregation of the frontoparietal control network was associated with the rate of change in processing speed. These findings support the hypothesis of functional dedifferentiation in healthy aging as well as its role in cognitive function in elderly., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Age-related differences in white matter (WM) microstructure have been linked to lower performance in tasks of processing speed in healthy older individuals. However, only few studies have examined this link in a longitudinal setting. These investigations have been limited to the correlation of simultaneous changes in WM microstructure and processing speed. Still little is known about the nature of age-related changes in WM microstructure, i.e., regionally distinct vs. global changes. In the present study, we addressed these open questions by exploring whether previous changes in WM microstructure were related to subsequent changes in processing speed: (a) 1 year later; or (b) 2 years later. Furthermore, we investigated whether age-related changes in WM microstructure were regionally specific or global. We used data from four occasions (covering 4 years) of the Longitudinal Healthy Aging Brain (LHAB) database project ( N = 232; age range at baseline = 64-86). As a measure of WM microstructure, we used mean fractional anisotropy (FA) in 10 major WM tracts averaged across hemispheres. Processing speed was measured with four cognitive tasks. Statistical analyses were conducted with bivariate latent change score (LCS) models. We found, for the first time, evidence for lagged couplings between preceding changes in FA and subsequent changes in processing speed 2 years, but not 1 year later in some of the WM tracts (anterior thalamic radiation, superior longitudinal fasciculus). Our results supported the notion that FA changes were different between regional WM tracts rather than globally shared, with some tracts showing mean declines in FA, and others remaining relatively stable across 4 years., (Copyright © 2019 Oschwald, Mérillat, Liem, Röcke, Martin and Jäncke.)

Normal aging is accompanied by an interindividually variable decline in cognitive abilities and brain structure. This variability, in combination with methodical differences and differences in sample characteristics across studies, pose a major challenge for generalizability of results from different studies. Therefore, the current study aimed at cross-validating age-related differences in cognitive abilities and brain structure (measured using cortical thickness [CT]) in two large independent samples, each consisting of 228 healthy older adults aged between 65 and 85 years: the Longitudinal Healthy Aging Brain (LHAB) database (University of Zurich, Switzerland) and the 1000BRAINS (Research Centre Jülich, Germany). Participants from LHAB showed significantly higher education, physical well-being, and cognitive abilities (processing speed, concept shifting, reasoning, semantic verbal fluency, and vocabulary). In contrast, CT values were larger for participants of 1000BRAINS. Though, both samples showed highly similar age-related differences in both, cognitive abilities and CT. These effects were in accordance with functional aging theories, for example, posterior to anterior shift in aging as was shown for the default mode network. Thus, the current two-study approach provides evidence that independently on heterogeneous metrics of brain structure or cognition across studies, age-related effects on cognitive ability and brain structure can be generalized over different samples, assuming the same methodology is used., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

The notion of bilingual advantages in executive functions (EF) is based on the assumption that the demands posed by cross-language interference serve as EF training. These training effects should be more pronounced the more cross-language interference bilinguals have to overcome when managing their two languages. In the present study, we investigated the proposed link between linguistic and EF performance using the similarity between the two languages spoken since childhood as a proxy for different levels of cross-language interference. We assessed the effect of linearly increasing language dissimilarity on linguistic and EF performance in multiple tasks in four groups of young adults (aged 18-33): German monolinguals ( n = 24), bidialectals ( n = 25; German and Swiss German dialect), bilinguals speaking two languages of the same Indo-European ancestry ( n = 24; e.g., German-English), or bilinguals speaking two languages of different ancestry ( n = 24; e.g., German-Turkish). Bayesian linear-mixed effects modeling revealed substantial evidence for a linear effect of language similarity on linguistic accuracy, with better performance for participants with more similar languages and monolinguals. However, we did not obtain evidence for the presence of a similarity effect on EF performance. Furthermore, language experience did not modulate EF performance, even when testing the effect of continuous indicators of bilingualism (e.g., age of acquisition, proficiency, daily foreign language usage). These findings question the theoretical assumption that life-long experience in managing cross-language interference serves as EF training.