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Aging is often accompanied by changes in brain structure and executive functions, particularly in tasks involving cognitive flexibility, such as task-switching. However, substantial individual differences in the degree of cognitive impairment indicate that some individuals can cope with brain changes more effectively than others, suggesting higher cognitive reserve (CR). This study identified a neural basis for CR by examining the longitudinal relationship between task-related brain activation, structural brain changes, and changes in cognitive performance during an executive task-switching paradigm including single and dual conditions. Fifty-two older individuals were assessed at baseline and followed up after five years. Structural brain changes related to task-switching performance were analyzed using elastic net regression. Task-related functional brain activation was measured using ordinal trends canonical variate analysis (OrT CVA), capturing patterns of activation increasing from single to dual conditions. A differential task-related expression score (dOrT) was calculated as the difference in pattern expression scores between single and dual conditions at baseline. A linear regression model tested whether dOrT moderated the impact of brain changes on changes in switch cost over five years. Results showed a significant interaction between changes in brain structure and dOrT activation on switch cost change, indicating a moderation effect of task-related activation. Higher dOrT buffered the impact of brain structural decline on switch costs, enabling older adults to better cope with age-related brain structural changes and preserve cognitive flexibility. These findings suggest that these task-related activation patterns represent a neural basis for CR., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Sleep plays a crucial role in cognitive performance and cognitive changes in aging. In the current study, we investigated the role of sleep duration genetics in cognitive changes over time and the moderating effect of age., Methods: Participants were drawn from the Reference Abilities Neural Network and the Cognitive Reserve studies of Columbia University. Each participant underwent an evaluation of sleep function and an extensive neuropsychological assessment. Published GWAS summary statistics from a polygenic score for sleep duration (Sleep PGI) were used to derive Sleep PGI in our study. We examined whether this Sleep PGI is associated with cognitive changes over a 5-year follow-up and if age moderates this effect. Analysis was performed after first being adjusted for age group (young: 20-44; middle: 45-64; old: 65-80), sex, education, the first four principal components, intracranial volume (ICV), mean cortical thickness, and total gray matter volume. We included ICV, mean thickness, and total gray matter volumes as time-varying covariates. We further included interactions of time with age and the first four PCs., Results: A total of 96 white-only participants were included, aged 24 to 78 years old. In the fully adjusted model, age-specific analysis showed that in younger individuals, higher Sleep PGI was associated with lower rates of cognitive decline in speed of processing., Conclusion: Genetic variants associated with sleep duration significantly influence performance in speed of processing, with age playing a critical moderating role, over and above brain morphometry. A genetic predisposition for longer sleep duration can work as a protective factor against decline in the speed of processing in young adults.

The deposition of amyloid-β (Aβ) protein in the human brain is a hallmark of Alzheimer's disease and is related to cognitive decline. However, the relationship between early Aβ deposition and future cognitive impairment remains poorly understood, particularly concerning its spatial distribution and network-level effects. Here, we employed a cross-validated machine learning approach and investigated whether integrating subject-specific brain connectome information with Aβ burden measures improves predictive validity for subsequent cognitive decline. Baseline regional Aβ pathology measures from positron emission tomography (PET) imaging predicted prospective cognitive decline. Incorporating structural connectome, but not functional connectome, information into the Aβ measures improved predictive performance. We further identified a neuropathological signature pattern linked to future cognitive decline, which was validated in an independent cohort. These findings advance our understanding of how Aβ pathology relates to brain networks and highlight the potential of network-based metrics for Aβ-PET imaging to identify individuals at higher risk of cognitive decline., Competing Interests: Competing interest statement The authors have declared no conflicts of interest for this manuscript.

Recent advancements in connectome analyses have enabled more precise measurements of brain network integrity. Identifying neural measures that can operate as mechanisms of cognitive reserve (CR) is integral for the study of individual variability in age-related cognitive changes. In the present study, we tested the hypothesis that network resilience, or the network's ability to maintain functionality when facing internal or external perturbations that cause damage or error, can function as a CR candidate, modifying the relationship between cognitive and brain changes in a lifespan cohort of cognitively healthy adults. One hundred cognitively healthy older adults from the Reference Ability Neural Network (RANN) longitudinal lifespan cohort (50-80 years) underwent resting-state fMRI and neuropsychological testing at baseline and five-year follow-up. Using undirected weighted adjacency matrices created from the Schaefer et al. (2018) 400-parcellation atlas and 19 additional subcortical regions (419 nodes in total), whole-brain network resilience was assessed through a targeted attack approach, where nodes were sequentially removed by nodal strength and resilience defined as the iteration of the steepest slope in the largest connected component (LCC) decay. We observed that brain resilience (BR) moderated the effect of cortical thickness (CT) changes on longitudinal changes in Fluid Reasoning performance, even after adjusting for baseline differences, demographic factors, and the initial LCC of the unlesioned matrix, indicating that individuals with greater resilience were less sensitive to the effect of cortical thickness changes on changes in cognition. These findings support the use of targeted attack as a measure of cognitive reserve, suggesting that higher brain network resilience may allow individuals with reduced brain integrity to better cope with structural loss and maintain cognitive function., Competing Interests: Conflict of interest The authors confirm that they have no conflict of interest to declare.

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1 + CD56 + NK cell subset. The study estimated "Immunological Age" (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimer's disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.

Some theories of aging have linked age-related cognitive decline to a reduction in distinctiveness of neural processing. Observed age-related correlation increases among disparate cognitive tasks have supported the dedifferentiation hypothesis. We previously showed cross-sectional evidence for age-related correlation decreases instead, supporting an alternative disintegration hypothesis. In the current study, we extended our previous research to a longitudinal sample. We tested 135 participants (20-80 years) at two time points-baseline and 5-year follow-up-on a battery of 12 in-scanner tests, each tapping one of four reference abilities. We performed between-tasks correlations within domain (convergent) and between domain (discriminant) at both the behavioral and neural level, calculating a single measure of construct validity (convergent - discriminant). Cross-sectionally, behavioral construct validity was significantly different from chance at each time point, but longitudinal change was not significant. Analysis by median age split revealed that older adults showed higher behavioral validity, driven by higher discriminant validity (lower between-tasks correlations). Participant-level neural validity decreased over time, with convergent validity consistently greater than discriminant validity; this finding was also observed at the cross-sectional level. In addition, a disproportionate decrease in neural validity with age remained significant after controlling for demographic factors. Factors predicting longitudinal changes in global cognition (mean performance across all 12 tasks) included age, change in neural validity, education, and National Adult Reading Test (premorbid intelligence). Change in neural validity partially mediated the effect of age on change in global cognition. Our findings support the theory of age-related disintegration, linking cognitive decline to changes in neural representations over time., (© 2024 Massachusetts Institute of Technology.)

Cognition and gait share brain substrates in aging and dementia. Cognitive reserve (CR) allows individuals to cope with brain pathology and delay cognitive impairment and dementia. Yet, evidence for that CR is associated with age-related cognitive decline is mixed, and evidence for that CR is associated with age-related gait decline is limited. In 1,079 older (M Age = 75.4 years; 56.0% women) LonGenity study participants without dementia at baseline and up to 12 years of annual follow-up (M follow-up = 3.9 years, SD = 2.5 years), high CR inferred from cognitive (education years), physical (number of blocks walked per day; weekly physical activity days), and social (volunteering/working; living with someone) proxies were associated with slower rates of age-related decline in global cognition - not gait speed decline. Thus, cognitive, physical, and social CR proxies are associated with cognitive decline in older adults without dementia. The multifactorial etiology and earlier decline in gait than cognition may render it less modifiable by CR proxies later in life., (Copyright © 2024 Elsevier Inc. All rights reserved.)

White matter hyperintensities (WMH) are associated with cortical thinning. Although they are primarily detected in older participants, these lesions can appear in younger and midlife individuals. Here, we tested whether WMH are associated with cortical thinning in relatively younger (26-50 years) and relatively older (58-84) participants who were free of dementia, and how these associations are moderated by WMH localization. WMH were automatically quantified and categorized according to the localization of three classes of white matter tracts: association, commissural and projection fibers. Mediation analyses were used to infer whether differences in cortical thickness between younger and older participants were explained by WMH. Our results revealed that total WMH explained between 20.6 % and 65.5 % of the effect of age on cortical thickness in AD-signature regions including the lateral temporal lobes and supramarginal gyrus, among others. This mediation was slightly stronger for projection WMH, although it was still significant for association and commissural WMH. These results suggest that there is an interplay between vascular and AD causes of cognitive impairment that starts at younger ages., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives: Cognitive reserve (CR) is a property of the brain that allows for better-than-expected cognitive performance relative to the degree of brain change over the course of life. However, neurophysiological markers of CR remain under-investigated. Electroencephalography (EEG) features may function as suitable neurophysiological markers of CR. To assess this, we investigated whether the dorsal attention network (DAN) and ventral attention network (VAN) activities, as measured during resting-state EEG, moderate the relationship between hippocampal volume and episodic memory., Methods: Participants were recruited as part of the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes. Hippocampal volume was determined using magnetic MRI, and episodic memory was measured using word lists. After testing the effect of hippocampal volume on memory performance using multiple regression analysis, we evaluated the interactions between hippocampal volume and DAN and VAN network activities. We further used the Johnson-Neyman technique to quantify the moderating effects of DAN and VAN network activities on the relationship between hippocampal volume and word list memory, as well as to identify specific ranges of DAN and VAN network activity with significant hippocampal-memory association., Results: A total of 449 participants were included in this study. Our analysis revealed significant moderation of DAN with a slope of β = -0.00012 (95% CI: -0.00024; -0.00001, p = 0.040), and VAN with a slope of β = 0.00014 (95% CI: 0.00001; 0.00026, p = 0.031). Further, we found that a larger hippocampal volume was associated with improved memory performance, and that this association became stronger as the DAN activity decreased until a limit of DAN activity of 944.9, after which the hippocampal volume was no longer significantly related to word-list memory performance. For the VAN, we found that a higher hippocampal volume was more strongly associated with better memory performance when VAN activity was higher. However, when VAN activity extended beyond -914.6, the hippocampal volume was no longer significantly associated with word-list memory., Discussion: Our results suggest that attentional networks help to maintain memory performance in the face of age-related structural decline, meeting the criteria for the neural implementation of cognitive reserve., 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 © 2024 Katayama, Stern, Habeck, Coors, Lee, Harada, Makino, Tomida, Morikawa, Yamaguchi, Nishijima, Misu, Fujii, Kodama and Shimada.)

Greater engagement in cognitively stimulating activities (CSA) during adulthood has been shown to protect against neurocognitive decline, but no studies have investigated whether CSA during childhood protects against effects of brain changes on cognition later in life. The current study tested the moderating role of childhood CSA in the relationships between brain structure and cognitive performance during adulthood. At baseline (N=250) and 5-year follow-up (N=204) healthy adults aged 20-80 underwent MRI to assess four structural brain measures and completed neuropsychological tests to measure three cognitive domains. Participants were categorized into low and high childhood CSA based on self-report questionnaires. Results of multivariable linear regressions analyzing interactions between CSA, brain structure, and cognition showed that higher childhood CSA was associated with a weaker relationship between cortical thickness and memory at baseline, and attenuated the effects of change in cortical thickness and brain volume on decline in processing speed over time. These findings suggest higher CSA during childhood may mitigate the effects of brain structure changes on cognitive function later in life., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier Inc.)

Cognitive reserve explains differential susceptibility of cognitive performance to neuropathology. We investigated whether certain personality traits underlie cognitive reserve and are accordingly associated with better cognition and less cognitive decline in the presence of age-related brain changes. We included healthy adults aged 19-80 years for cross-sectional (N=399) and longitudinal (N=273, mean follow-up time=5 years, SD=0.7 years) analyses. Assessment of the BIG5 personality traits openness, conscientiousness, extraversion, agreeableness, and neuroticism was questionnaire-based. Each cognitive domain (perceptual speed, memory, fluid reasoning, vocabulary) was measured with up to six tasks. Cognitive domain-specific brain status variables were obtained by combining 77 structural brain measures into single scores using elastic net regularization. These brain status variables explained up to 43.1% of the variance in cognitive performance. We found that higher openness was associated with higher fluid reasoning and better vocabulary after controlling for brain status, age, and sex. Further, lower brain status was associated with a greater decline in perceptual speed only in individuals with low openness. We conclude that high openness benefits cognitive reserve., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cognitive reserve (CR) explains differential susceptibility of cognitive performance to neuropathology. However, as brain pathologies progress, cognitive decline occurs even in individuals with initially high CR. The interplay between the structural brain health (= level of brain reserve) and CR-related brain networks therefore requires further research. Our sample included 142 individuals aged 60-70 years. National Adult Reading Test intelligence quotient (NART-IQ) was our CR proxy. On an in-scanner Letter Sternberg task, we used ordinal trend (OrT) analysis to extract a task-related brain activation pattern (OrT slope) for each participant that captures increased expression with task load (one, three, and six letters). We assessed whether OrT slope represents a neural mechanism underlying CR by associating it with task performance and NART-IQ. Additionally, we investigated how the following brain reserve measures affect the association between NART-IQ and OrT slope: mean cortical thickness, total gray matter volume, and brain volumes proximal to the areas contained in the OrT patterns. We found that higher OrT slope was associated with better task performance and higher NART-IQ. Further, the brain reserve measures were not directly associated with OrT slope, but they affected the relationship between NART-IQ and OrT slope: NART-IQ was associated with OrT slope only in individuals with high brain reserve. The degree of brain reserve has an impact on how (and perhaps whether) CR can be implemented in brain networks in older individuals., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The relationship between tau deposition and cognitive decline in cognitively healthy older adults is still unclear. The tau PET tracer 18 F-MK-6240 has shown favorable imaging characteristics to identify early tau deposition in aging. We evaluated the relationship between in vivo tau levels ( 18 F-MK-6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, a set of regions of interest (ROIs) was selected a priori based on previous literature: (1) total-ROI comprising selected areas, (2) medial temporal lobe-ROI, and (3) lateral temporal lobe-ROI and cingulate/parietal lobe-ROI. Higher tau burden in most ROIs was associated with a steeper decline in memory and speed. There were no associations between tau and reasoning change. The novelty of this finding is that tau burden may affect not only episodic memory, a well-established finding but also processing speed. Our finding reinforces the notion that early tau deposition in areas related to Alzheimer's disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample with low amyloid-β pathology., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Neurodegeneration and structural changes in the brain due to amyloid deposition have been observed even in individuals with mild cognitive impairment (MCI). EEG measurement is considered an effective tool because it is noninvasive, has few restrictions on the measurement environment, and is simple and easy to use. In this study, we investigated the neurophysiological characteristics of community-dwelling older adults with MCI using EEG., Methods: Demographic characteristics, cognitive function, physical function, resting-state MRI and electroencephalogram (rs-EEG), event-related potentials (ERPs) during Simon tasks, and task proportion of correct responses and reaction times (RTs) were obtained from 402 healthy controls (HC) and 47 MCI participants. We introduced exact low-resolution brain electromagnetic tomography-independent component analysis (eLORETA-ICA) to assess the rs-EEG network in community-dwelling older adults with MCI., Results: A lower proportion of correct responses to the Simon task and slower RTs were observed in the MCI group (p < 0.01). Despite no difference in brain volume between the HC and MCI groups, significant decreases in dorsal attention network (DAN) activity (p < 0.05) and N2 amplitude of ERP (p < 0.001) were observed in the MCI group. Moreover, DAN activity demonstrated a correlation with education (Rs = 0.32, p = 0.027), global cognitive function (Rs = 0.32, p = 0.030), and processing speed (Rs = 0.37, p = 0.010) in the MCI group. The discrimination accuracy for MCI with the addition of the eLORETA-ICA network ranged from 0.7817 to 0.7929, and the area under the curve ranged from 0.8492 to 0.8495., Conclusions: The eLORETA-ICA approach of rs-EEG using noninvasive and relatively inexpensive EEG demonstrates specific changes in elders with MCI. It may provide a simple and valid assessment method with few restrictions on the measurement environment and may be useful for early detection of MCI in community-dwelling older adults., (© 2023. The Author(s).)

Genome-wide association studies have discovered common genetic variants associated with cognitive performance. Polygenic scores that summarize these discoveries explain up to 10% of the variance in cognitive test performance in samples of adults. However, the role these genetics play in cognitive aging is not well understood. We analyzed data from 168 cognitively healthy participants aged 23-77 years old, with data on genetics, neuropsychological assessment, and brain-imaging measurements from two large ongoing studies, the Reference Abilities Neural Networks, and the Cognitive Reserve study. We tested whether a polygenic index previously related to cognition (Cog PGI) would moderate the relationship between age and measurements of the cognitive domains extracted from a neuropsychological evaluation: fluid reasoning, memory, vocabulary, and speed of processing. We further explored the relationship of Cog PGI and age on cognition using Johnson-Neyman intervals for two-way interactions. Sex, education, and brain measures of cortical thickness, total gray matter volume, and white matter hyperintensity were considered covariates. The analysis controlled for population structure-ancestry. There was a significant interaction effect of Cog PGI on the association between age and the domains of memory (Standardized coefficient = -0.158, p -value = 0.022), fluid reasoning (Standardized coefficient = -0.146, p -value = 0.020), and vocabulary (Standardized coefficient = -0.191, p -value = 0.001). Higher PGI strengthened the negative relationship between age and the domains of memory and fluid reasoning while PGI weakened the positive relationship between age and vocabulary. Based on the Johnson-Neyman intervals, Cog PGI was significantly associated with domains of memory, reasoning, and vocabulary for younger adults. There is a significant moderation effect of genetic predisposition for cognition for the association between age and cognitive performance. Genetics discovered in genome-wide association studies of cognitive performance show a stronger association in young and midlife older adults.

Recent attention has been given to topological data analysis (TDA), and more specifically persistent homology (PH), to identify the underlying shape of brain network connectivity beyond simple edge pairings by computing connective components across different connectivity thresholds (see Sizemore et al., 2019). In the present study, we applied PH to task-based functional connectivity, computing 0-dimension Betti (B 0 ) curves and calculating the area under these curves (AUC); AUC indicates how quickly a single connected component is formed across correlation filtration thresholds, with lower values interpreted as potentially analogous to lower whole-brain system segregation (e.g., Gracia-Tabuenca et al., 2020). One hundred sixty-three participants from the Reference Ability Neural Network (RANN) longitudinal lifespan cohort (age 20-80 years) were tested in-scanner at baseline and five-year follow-up on a battery of tests comprising four domains of cognition (i.e., Stern et al., 2014). We tested for 1.) age-related change in the AUC of the B 0 curve over time, 2.) the predictive utility of AUC in accounting for longitudinal change in behavioral performance and 3.) compared system segregation to the PH approach. Results demonstrated longitudinal age-related decreases in AUC for Fluid Reasoning, with these decreases predicting longitudinal declines in cognition, even after controlling for demographic and brain integrity factors; moreover, change in AUC partially mediated the effect of age on change in cognitive performance. System segregation also significantly decreased with age in three of the four cognitive domains but did not predict change in cognition. These results argue for greater application of TDA to the study of aging., Competing Interests: Declaration of Competing Interest We have no interests to declare., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Age-related cognitive changes can be influenced by both brain maintenance (BM), which refers to the relative absence over time of changes in neural resources or neuropathologic changes, and cognitive reserve (CR), which encompasses brain processes that allow for better-than-expected behavioral performance given the degree of life-course-related brain changes. This study evaluated the effects of age, BM, and CR on longitudinal changes over 2 visits, 5 years apart, in 3 cognitive abilities that capture most of age-related variability., Methods: Participants included 254 healthy adults aged 20-80 years at recruitment. Potential BM was estimated using whole-brain cortical thickness and white matter mean diffusivity at both visits. Education and intelligence quotient (IQ; estimated with American National Adult Reading Test) were tested as moderating factors for cognitive changes in the 3 cognitive abilities., Results: Consistent with BM-after accounting for age, sex, and baseline performance-individual differences in the preservation of mean diffusivity and cortical thickness were independently associated with relative preservation in the 3 abilities. Consistent with CR-after accounting for age, sex, baseline performance, and structural brain changes-higher IQ, but not education, was associated with reduced 5-year decline in reasoning (β = 0.387, p = .002), and education was associated with reduced decline in speed (β = 0.237, p = .039)., Discussion: These results demonstrate that both CR and BM can moderate cognitive changes in healthy aging and that the 2 mechanisms can make differential contributions to preserved cognition., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brain-segregation attributes in resting-state functional networks have been widely investigated to understand cognition and cognitive aging using various approaches [e.g., average connectivity within/between networks and brain system segregation (BSS)]. While these approaches have assumed that resting-state functional networks operate in a modular structure, a complementary perspective assumes that a core-periphery or rich club structure accounts for brain functions where the hubs are tightly interconnected to each other to allow for integrated processing. In this article, we apply a novel method, persistent homology (PH), to develop an alternative to standard functional connectivity by quantifying the pattern of information during the integrated processing. We also investigate whether PH-based functional connectivity explains cognitive performance and compare the amount of variability in explaining cognitive performance for three sets of independent variables: (1) PH-based functional connectivity, (2) graph theory-based measures, and (3) BSS. Resting-state functional connectivity data were extracted from 279 healthy participants, and cognitive ability scores were generated in four domains (fluid reasoning, episodic memory, vocabulary, and processing speed). The results first highlight the pattern of brain-information flow over whole brain regions (i.e., integrated processing) accounts for more variance of cognitive abilities than other methods. The results also show that fluid reasoning and vocabulary performance significantly decrease as the strength of the additional information flow on functional connectivity with the shortest path increases. While PH has been applied to functional connectivity analysis in recent studies, our results demonstrate potential utility of PH-based functional connectivity in understanding cognitive function., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objectives: This series of experiments explores whether flexibility in strategy shifting might function as an expression of cognitive reserve (CR)., Methods: A reasoning task was designed using matrix reasoning stimuli that each required 1 of 2 specific solution strategies: logicoanalytic and visuospatial. It was formatted as a task-switching paradigm, assessing the ability to switch between solution strategies as measured by switch costs. Study 1 was done on Amazon Mechanical Turk and included an assessment of CR proxies. Study 2 used participants who had been studied extensively with neuropsychological assessments and structural neuroimaging., Results: Study 1 found that switch costs increased with aging. In addition, a relationship between switch costs and CR proxies was noted, suggesting a relationship between the flexibility of strategy shifting and CR. The results of Study 2 again indicated that age negatively affected strategy-shifting flexibility, but that individuals with higher CR as measured with standard proxies performed better. The flexibility measure accounted for additional variance in cognitive performance over that explained by cortical thickness, suggesting that it may contribute to CR., Discussion: Overall, the results are consistent with the idea that flexibility in strategy shifting might be 1 cognitive process that underlies cognitive reserve., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)