Frontiers in Aging Neuroscience

BackgroundThe brainstem and its different sub-systems control essential functions such as motor agility etc. that worsen with age. The purpose of this study was: 1. To assess the impact of age-related volume loss within three brainstem sub-systems on functions supported by them. 2. To use data-driven machine learning to identify different volume loss patterns or subtypes and investigate how they are associated with function. MethodsStructural MRI and behavioral data from 674 Human Connectome Project Aging (HCA) participants was used in this project. The brainstem was extracted, internal brainstem structures segmented and the segmentations warped onto a probabilistic population atlas on which the nuclei of interest had been labeled. Jacobian deformation maps were calculated, each rois mean Jacobians extracted and converted into z-scores with and without correction for age. Linear regression analyses were used to assess volume - function (cognition, motor agility, autonomic control) associations for each roi belonging to the sub-system supporting these functions. Subtype and Stage Inference (SuStaIn) was used to identify different volume loss patterns in each sub-system. ResultsAge explained larger percentage of the variation of the behavioral variables than brainstem volumes. SuStaIn identified up to 4 subtypes, one representing typical aging and the remainder atypical aging. The subtypes did not significantly differ behaviorally with the exception of grip strength and diastolic blood pressure. ConclusionAging affects brainstem systems which contributes to the worsening of these functions with increasing age. SuStaIn detected different patterns of volume loss or subtypes within each of the brainstem systems.

Most evidence on age-related network topology derives from resting-state paradigms, leaving unclear how aging alters brain organization during naturalistic processing and whether graph-theoretical metrics relate to emotional and cognitive functioning in ecologically valid contexts. We analyzed movie-fMRI and behavioral data from 72 younger and 68 older adults, examining global (small-worldness, clustering coefficient, characteristic path length), network (participation coefficient), and nodal (degree centrality, betweenness centrality, nodal efficiency) properties. Regression models were used to test associations between nodal measures and both the Emotional Resilience Index (ERI) and the Cognitive Function Index (CFI), while mediation analyses were conducted to test whether nodal measures mediate the relationship between age and ERI. Older adults exhibited increased characteristic path length and clustering coefficient, indicating reduced global integration and greater local segregation. Although small-world organization was preserved in two groups, there was less pronounced small-world architecture in older adults compared to younger adults, suggesting a shift toward more regularized, locally clustered networks and reduced long-range connections during dynamic stimuli. Participation coefficient values were higher in the somatomotor, frontoparietal, and default mode networks, and lower in the subcortical network, among older adults reflecting greater between-network integration in cortical networks but diminished subcortical coordination in aging. Five key nodes, two thalamic regions, hippocampus, and two insular regions, showed reduced centrality and efficiency in older adults during the negative movie, indicating weakened dominance of subcortical hubs under emotional salience condition. Right thalamic nodal properties were negatively associated with ERI and CFI and served as mediators in the relationship between age and emotional resilience. These findings suggest that reduced thalamic hub centrality may reflect adaptive recalibration of salience emotional processing, linking network reorganization to improved emotional resilience in aging. Key pointsO_LIOlder adults showed higher path length and clustering, suggesting reduced integration. C_LIO_LIReduced small-worldness reflects weaker balance of segregation and integration with age. C_LIO_LIOlder adults showed higher cortical but lower subcortical participation coefficients. C_LIO_LIKey nodes showed reduced centrality during negative stimuli, indicating weaker hubs. C_LIO_LIRight thalamus changes linked to resilience, mediating age-emotion relationships. C_LI

Sensory degradation with aging can impair balance control, partly by disrupting visual contributions to self-motion estimation. We investigated how aging affects the control of frontal plane center of mass (CoM) trajectories during walking with exposure to repeated visual perturbations. We hypothesized that aging would increase responses to visual perturbations and decrease adaptation to repeated visual perturbation exposure. We applied three visual perturbations to 14 healthy older (age: 75.0{+/-}2.4) and 16 younger adults (age: 23.4{+/-}3.9) walking on a treadmill: fixating a stationary target with the background moving to the right (MB), tracking a target moving rightward over a stationary background with head rotation (MT-HR), and tracking a moving target with eye movement only (MT-EM). Deviations of CoM position and foot placement due to the visual perturbations were assessed. Over the whole trial, the older adults exhibited larger CoM position variability in MB and MT-HR conditions. During visual perturbation epochs, both age groups deviated in the same direction except MB. In MB, the older adults deviated to an opposite direction after a few perturbation repetitions. Moreover, in MT-HR and MT-EM, the older adults deviated earlier than the younger adults and they deviated more in the MT-HR condition. This indicates that older adults exhibit reduced ability to accurately estimate self-motion through correction by other sensory modalities when exposed to visual perturbations. Over repeated perturbations, the older adults showed decreased CoM deviations in MT-EM, which suggests that they still maintain the capacity to downweight visual information after repeated exposure.

Healthy young and older adults completed two randomized sessions of split-belt treadmill walking, with and without a concurrent cognitive task. When the single-task session occurred first, both age groups showed savings in step length asymmetry during re-adaptation one week later. However, performing the dual-task session first reduced savings, and this order-effect was greater in older adults compared to young adults. These findings suggest that cognitive load during initial motor adaptation interferes with savings, but once stored, locomotor readaptation is resilient to dual-tasking.

Risky decision-making under uncertainty reflects complex cognitive processes supported by distributed brain networks that are vulnerable to aging. However, it remains unclear whether risk-taking behavior can serve as a behavioral marker of brain aging. In the present study, we combined behavioral tasks, computational modeling, and structural magnetic resonance imaging to investigate the relationship between risky decision-making, chronological age, and brain age. A total of 55 young adults and 112 healthy older adults completed the Iowa Gambling Task (IGT) and the Balloon Analogue Risk Task (BART), along with neuropsychological assessments and neuroimaging scanning. Decision processes were quantified using computational models, including the Value-Plus-Perseveration model and Exponential-Weight Mean-Variance. Brain age was estimated from gray matter volume. The results showed significant age-related alterations in parameters reflecting feedback sensitivity, learning rate, and loss aversion in both tasks. Within older adults, several decision parameters were significantly associated with both chronological age and brain age. Regression analyses further showed that computational parameters significantly predicted chronological age and brain age, whereas traditional cognitive screening measures did not show significant predictive effect. Structural brain analyses indicated that IGT-related parameters were primarily associated with the basal ganglia, while BART-related parameters were linked to a broader network including prefrontal, cingulate, and temporal regions. These findings suggest that computational markers of risk-taking behavior capture subtle age-related changes in cognitive processes and brain deterioration. Therefore, risk-taking parameters may serve as reliable functional markers of brain aging, providing critical insights into the mechanisms underlying successful aging.

Motoric Cognitive Risk (MCR) syndrome, defined by subjective cognitive complaints and slow gait speed, identifies older adults at increased risk of major neurocognitive disorders (NCDs). Yet, gait speed reflects a composite output shaped by heterogeneous neuromusculoskeletal and cognitive processes, limiting its clinical specificity. This study aimed to refine the motor signature of MCR by quantifying domain-specific gait deviations relative to a normative reference cohort using an anomaly detection approach. Ninety-seven adults ([≥] 55 years) completed two 3-minute treadmill walking bouts at their preferred speed. Participants were categorized into three groups: older adults with MCR (n = 20), healthy older adults with slow gait (sHOA; n = 20) matched to MCR for age and gait speed, and healthy older adults (HOA; n = 57). Linear spatiotemporal and nonlinear trunk acceleration-derived variables were organized into ten functional gait domains, conceptually grouped into gait pattern (pace, rhythm, phases, postural control, symmetry), fluctuation amplitude (variability), and temporal structure of fluctuations (regulation, signal complexity, divergence of movement trajectories, and attractor complexity). For each domain, a Gaussian mixture model trained on HOA data defined a normative reference space, from which individual anomaly scores quantified deviations across groups. Both sHOA and MCR showed higher deviations in gait pattern domains (pace and phases) than HOA, consistent with their slower gait speed. Only MCR exhibited additional deviations in domains related to fluctuation amplitude and temporal structure, reflected by increased step-to-step variability and trunk acceleration fluctuations that were more divergent, more predictable, and less complex. These findings reveal a multidimensional motor signature of MCR. Domain-specific anomaly scores may provide individualized, clinically interpretable biomarkers to support early detection and monitoring of older adults at increased risk of major NCDs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/716304v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@3b2e52org.highwire.dtl.DTLVardef@15e4101org.highwire.dtl.DTLVardef@fdb9c4org.highwire.dtl.DTLVardef@1af0d03_HPS_FORMAT_FIGEXP M_FIG C_FIG

The mouse skull serves as the coordinate framework for stereotaxic neurosurgery, yet whether aging alters surgically critical calvarial geometry has not been examined. We measured three parameters in large cohorts of young (2-3 months) and aged (23-30 months) male and female C57BL/6J mice: bregma-lambda distance and the dorsoventral depth at rostral-lateral (X = {+/-} 2.5 mm, Y = 0) and caudal-lateral (X = {+/-} 2.5 mm, Y = -0.65 mm) calvarial sites. Bregma-lambda distance was significantly reduced with aging in both sexes. Similarly, the rostral-lateral calvaria showed age-related flattening in both male and female mice. The more caudal-lateral site showed smaller but significant age-related flattening, with males exhibiting significantly greater reductions than females. Aging increased caudal-lateral shape variability while reducing bregma-lambda distance variability in males. On the contrary, aging reduced rostral-lateral shape variability in females. These findings demonstrate that the mouse skull undergoes significant, spatially non-uniform, and sexually dimorphic remodeling into old age, where skull shrinks along the midline and flattens more significantly at the rostral than caudal plane. Stereotaxic protocols designed for young adult mice may systematically misestimate skull geometry in aged animals. Age-stratified reference data should be incorporated into stereotaxic practice for aged rodent models.

Healthy aging is associated with progressive structural brain decline, yet the loss of functional abilities varies across individuals, which has been linked to reserve mechanisms. Within the framework of complex systems theory, reserve is thought to manifest as resilience when the system is challenged by stressors, such as increases in task difficulty. The cerebellum has been proposed as a potential source of motor reserve, but empirical evidence linking cerebellar structure, function, and resilience remains limited. We conducted a cross-sectional study including 50 young, 80 older, and 30 older-old adults to examine resilience to increasing task demands across cerebellar-specific and general outcomes. Participants completed three motor tasks (pure elbow motion, motor timing, postural stability) and two cognitive tasks (mental rotation, spatial working memory). Structural MRI was acquired to quantify cerebellar grey matter volume within functionally defined regions. Cerebellar-specific motor measures (anticipatory muscle activation and timing variability) were preserved across age groups and remained resilient under increased task demands, including in adults over 80 years of age. In contrast, general sensorimotor performance (postural sway) declined with age and showed reduced resilience. Within the cognitive domain, both cerebellar-specific and general measures showed comparable age-related declines and reduced resilience. Resilience measures were not correlated across tasks, indicating that resilience is task- and domain-specific. Furthermore, cerebellar grey matter volume did not predict resilience in motor or cognitive outcomes. These findings support the cerebellar motor reserve hypothesis, suggesting that cerebellar-dependent motor processes remain resilient despite age-related structural decline. However, resilience appears to be function-specific rather than a generalized individual trait. Overall, the results highlight dissociations between brain structure, function, and resilience, underscoring the selective contribution of the cerebellum to motor preservation in healthy aging.

Freezing of gait is a disabling episodic symptom of Parkinson's disease, typically emerging during complex locomotor tasks such as turning, obstacle negotiation, and gait initiation. These tasks require effective motor planning and proactive visual search of the intended walking route. Current evidence suggests that people with Parkinson's disease and freezing of gait show different patterns of visual search compared to those without freezing of gait and healthy older adults. However, existing reports are based on relatively simple tasks that lack common triggers for freezing of gait and do not adequately control for other factors likely to influence visual search, such as motor symptom severity and balance ability. This study examined visual search behaviour in 24 healthy older adults and 37 people with Parkinson's disease (21 with freezing of gait, 16 without) during a complex walking task requiring repeated turning and navigation through narrow spaces. Visual search characteristics were compared between people with Parkinson's disease and healthy controls, and relationships between visual search, freezing of gait, motor symptom severity, and balance ability were explored within the Parkinson's disease group. Compared with healthy controls, people with Parkinson's disease showed significantly fewer fixations toward areas outside the walking path, longer average fixation durations, and reduced saccade amplitudes, with no differences in proactive visual planning of the intended route. No relationship was found between visual search outcomes and freezing of gait. Reduced fixations to outside-path areas were associated with poorer functional balance independently of motor symptom severity. These findings indicate that restricted visual sampling in Parkinson's disease is primarily associated with balance impairment rather than freezing of gait or motor symptom severity.

Meningeal lymphatic vessels (mLV) play essential roles in draining cerebrospinal fluid (CSF) into peripheral blood. The mLVs are hypothesized to be supportive structures to the glymphatic system, which is thought to remove metabolic byproducts from brain parenchyma and has been most directly studied in rodent models. Previous rodent studies have indicated a correlation between mLV function and cognitive performance, but this relationship in humans remains unexplored. Age-related declines in glymphatic system efficiency in humans and cognitive performance have been observed separately. This study investigates age- and sex-related differences in CSF production via choroid plexus volumes, mLV characteristics, and glymphatic system efficiency, overall elucidating the implication of cerebral lymphatic function on cognition. We recruited 26 healthy adults from Dallas-Fort Worth and acquired magnetic resonance images. mLVs along the sagittal sinus were visualized and segmented from T2-FLAIR images. The glymphatic system was evaluated by measuring diffusivity along the perivascular space. Choroid plexus volume and brain volume were estimated from T1-MPRAGE. Neuropsychological tests were conducted to assess cognitive function. Our findings indicate that glymphatic function diminishes with age, while mLV and choroid plexus volumes increase. Males displayed greater mLV volume than females, yet no sex differences were found in glymphatic function or choroid plexus volume. Notably, mLV volume increased as glymphatic function declined, independent of age. Moreover, a glymphatic-mLV latent variable significantly predicted processing speed, underscoring the influence of cerebral lymphatics on cognition. In conclusion, this study highlights a decline in glymphatic function with age, accompanied by increased mLV volumes and altered processing speed. These lymphatic system changes may underlie or contribute to the cognitive declines observed in healthy and pathological aging. Significance StatementThe glymphatic system and meningeal lymphatic vessels play crucial roles in removing brain cell waste. The relationship between these systems and their effect on human cognition, particularly processing speed, is unknown. We demonstrate that these systems change with advancing age. Variations in cerebral lymphatic function contribute to differences in processing speed independent of age, ultimately affecting higher-order cognitive function. The findings presented have implications for cognitive function in both healthy and diseased states.

Emerging preclinical and clinical evidence suggests that low frequency hemodynamic oscillations drive CSF flow, which in turn mediates glymphatic clearance. The current study investigated whether CO2-induced low frequency hemodynamic oscillations during magnetic resonance imaging would increase clearance of proteins (glial fibrillary acidic protein, neurofilament light chain, ptau217 and brain-derived tau) from brain to blood, and temporarily improve cognitive performance in individuals with chronic traumatic brain injury (TBI) and age/sex-matched healthy controls. Results indicated that cerebrovascular reactivity, normalized CSF volume, and predicted brain age significantly differed between chronic TBI and controls, while bulk CSF flow differed only at trend levels. Multiple protein concentrations were significantly increased at [~]45 minutes post-hypercapnia, decreased at [~]90 minutes, and returned to pre-hypercapnia levels by [~]150 minutes. Protein efflux was more strongly associated with total CSF volume and total white matter volume rather than cerebrovascular reactivity or bulk CSF flow. Both groups exhibited reduced cognitive interference post-hypercapnia, and hypercapnia associated symptoms quickly returned to baseline levels. In conclusion, hypercapnia temporarily increases clearance of multiple neural abundant proteins into blood, and this effect is moderated by atrophy. Current results suggest that hypercapnia may therapeutically combat pathological protein aggregation post-trauma, and prophylactically during normal aging.

Incomplete letter recognition tasks are frequently used to detect visual deficits arising from neurodegenerative syndromes, including Posterior Cortical Atrophy (PCA; visual-variant Alzheimers disease). A recent development of this approach is the Graded Incomplete Letters Test (GILT), which measures recognition thresholds for letters degraded by removing pixelated sections (decreasing completeness). Although GILT thresholds are strongly elevated in PCA relative to typical adults, the precise cortical visual impairments underlying these deficits are unclear, as is the potential contribution from age-related optical limitations. We compared candidate cortical factors (crowding and global integration) with optical limitations (blur and low contrast) by simulating these factors in typical adults (n=6) viewing incomplete letter stimuli. Participants identified foveally presented letters (12 alternatives), with completeness varied using QUEST. At baseline, thresholds averaged [~]5% completeness. Optical factors were simulated by separately applying blur and lowered contrast. These factors had minimal effect on thresholds, except where blur/contrast levels approached visibility limits, where thresholds rose modestly but remained far below clinical levels in PCA. Cortical factors were simulated by increasing crowding (disruptions from clutter) through peripheral presentation, with global-integration impairments simulated by varying pixel size to alter the distribution of degradation (limiting spatial integration) or degrading letters dynamically with limited-lifetime pixels (limiting temporal integration). These manipulations substantially elevated thresholds, with combined crowding and global-integration impairments increasing thresholds to levels comparable with PCA. We conclude that impaired incomplete letter recognition is driven primarily by cortical rather than optical factors, and that neurodegenerative deficits may reflect the combined impact of multiple cortical limitations.

Insulin-like growth factor-1 (IGF-1) plays a critical role in neuronal signaling. Disrupted insulin/IGF-1 signaling is implicated in Alzheimers disease, among other conditions, yet its specific influence on glutamate receptor-mediated calcium responses remains unclear. We examined the impacts of IGF-1 on glutamate receptor function in primary rat neurons monitored for intraneuronal calcium following stimulation with glutamate, AMPA, or NMDA/glycine. Pharmacological blockers (CNQX for AMPA receptors, APV for NMDA receptors, and nimodipine for L-type calcium channels) were applied to define receptor-specific contributions. In hippocampal neurons, IGF-1 and insulin altered responses to glutamate in different directions, with IGF-1 tending to evoke and enhanced response. In neocortical neurons, by contrast, IGF-1 consistently reduced glutamate- and AMPA-evoked calcium peaks, suggesting an inhibitory effect on AMPA receptors. To rule out effects on voltage-gated calcium channels downstream of AMPA receptors, we tested effects of IGF-1 on depolarization with potassium chloride; calcium elevation in this case was unaffected by IGF-1. Likewise, IGF-1 did not inhibit responses to NMDA/glycine; and IGF-1 did not affect glutamate responses in the presence of CNQX, a selective AMPA receptor blocker. These findings, combined with the observation that IGF-1 effects persisted in the presence of APV (an NMDA receptor antagonist), indicate that the inhibition of glutamate responses by IGF-1 is mediated by suppression of AMPA receptor activity. IGF-1 may thus contribute to normal neurophysiology, and given the role that glutamate receptors play in excitotoxicity, IGF-1 may confer neuroprotection in the neocortex. Disruption of IGF-1 signaling, as seen in states resembling insulin resistance, may therefore worsen glutamate-driven excitotoxicity and contribute to adverse outcomes.

Abstract Background: Biological systems exhibit dynamic patterns over multiple temporal scales -from minutes to months- that are poorly captured by conventional cross-sectional or low-frequency longitudinal studies. These patterns, including circadian and ultradian rhythms, may be critical determinants of health, resilience, and disease risk in aging. Existing longitudinal studies in older adults lack high-frequency, multimodal measurements that integrate molecular, physiological, and digital health data streams. Objectives: The TIME Study aims to: (i) Characterize temporal patterns in molecular, physiological, and digital health measures in healthy older adults; (ii) determine how these patterns vary across biological domains and relate to each other; and (iii) assess how physiological systems respond to defined perturbations (oral glucose tolerance and maximal exercise). Methods: TIME is a single-site, observational, longitudinal study enrolling up to 150 adults aged [≥] 55 years. Over an 11-week main phase, participants complete seven weekly low-frequency visits, two perturbation challenge visits, and two, two-day high-frequency sampling epochs. Biospecimens, clinical measures, cognitive and physical performance tests, and continuous digital health data are collected. Follow-up visits occur at 6 and 12 months. Expected Impact: By integrating multimodal, temporally resolved data, TIME will provide a foundational dataset for understanding the role of biological rhythms in aging and inform future precision health strategies.

Using data from a randomized clinical trial, we examined whether daily biofeedback training that modulates heart rate oscillations is associated with changes in microstructural brain texture in Alzheimer's disease signature cortical (ADSC) and hippocampal regions. Younger and older adults were randomly assigned to one of two daily biofeedback practices for five weeks: slow-paced breathing designed to increase heart rate oscillations (Osc+) or self-selected strategies aimed at decreasing oscillations (Osc-). Intervention effects were observed in both ADSC and hippocampus regions and were confined to a composite texture factor dominated by uniformity and entropy. Across regions, effects were expressed primarily as Time x Condition interactions, indicating differential texture trajectories between Osc+ and Osc-. In the hippocampus, this pattern was further qualified by a Time x Condition x Age Group interaction, reflecting more pronounced effects in older adults, whereas younger adults showed no reliable texture modulation. Partial least squares correlation analyses further demonstrated that training-related texture changes in the left hippocampus, right fusiform gyrus, and right entorhinal cortex covaried with concurrent changes in plasma AD-related biomarkers, with tau- and p-tau related measures contributing most strongly to the multivariate association. Together, these findings suggest that HRV biofeedback may selectively influence specific dimensions of brain microstructural texture and that such changes are meaningfully coupled with plasma AD-related biomarker profiles.

BACKGROUND: Aging and Parkinsons disease (PD) reduce gait automaticity and increase cognitive demand during walking. Although dual task (DT) paradigms investigate cognitive motor interference, evidence remains limited by heterogeneous tasks, predominant focus on prefrontal cortex (PFC) activity, and variability in functional near infrared spectroscopy (fNIRS) methods. This study investigates whether longitudinal changes in cortical activation during DT walking differ among young adults, older adults, and individuals with PD, and how these changes relate to DT costs over 5 years. METHODS: This longitudinal observational study follows STROBE and fNIRS guidelines and will be conducted in a controlled laboratory (Rede Amparo, CEPID NeuroMat, University of Sao Paulo). Participants will be evaluated annually under three randomized conditions: motor single-task walking, cognitive single task phonemic verbal fluency and DT walking with phonemic verbal fluency, each repeated 10 times. The primary outcome measure will be longitudinal changes in cortical activation during DT walking, quantified by oxygenated hemoglobin (HbO) signals measured with fNIRS in prefrontal and premotor cortical regions. The main predictors of interest will be motor and cognitive DT costs. Covariates will include age, sex, education, cognition, balance, mood, and disease severity in the PD group. Spatiotemporal gait parameters, including gait speed, step length, stride length, step time, base of support, double support, stance phase, and variability, will be recorded using the GAITRite system, and DT costs will be calculated for selected parameters. Cortical activation will be assessed using a 66 channel wearable fNIRS system with short separation channels. DISCUSSION: By combining randomized task blocks, separate motor and cognitive conditions, broader cortical coverage, and concurrent neural and gait assessment across three groups annually, this protocol is expected to provide a comprehensive characterization of cognitive motor interference during walking and its evolution, supporting interpretation of cortical and behavioral responses. The study may help distinguish age related adaptations from PD specific alterations and clarify whether increased cortical recruitment during DT gait reflects compensation, reduced neural efficiency, or ceiling effects, refining understanding of gait automaticity decline and informing rehabilitation and non invasive brain stimulation approaches.

Tauopathies, including Alzheimers disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tauR406W. Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy.

Healthy aging is accompanied by subtle difficulties in language production. While behavioral and neuroimaging studies suggest that older adults rely on acute semantic access to maintain language abilities, the underlying neurophysiological mechanisms remain poorly understood. In particular, it is still unclear how large-scale brain dynamics reorganize to support naturalistic sentence generation with age. In this study, we investigated the spatiotemporal brain-state dynamics during covert sentence generation (GE2REC protocol) in younger and older adults using magnetoencephalography (MEG). Source-reconstructed MEG signals were analyzed using a Hidden Markov Model which identified five recurrent brain states, encompassing language-semantic, language-control, sensorimotor, and visual domains. Latent modeling was then used to relate the spectral and temporal properties of these brain states to age and language performance. Spectrally, older adults appear to redistribute oscillatory activity from sensorimotor-related states toward semantic-related states across alpha, beta, and low-gamma frequency bands. Temporally, older adults exhibit a more segmented processing sequence between semantic and sensorimotor processing which interfaces with visuo-posterior processing. These changes robustly covaried with age and better verbal fluency (semantic & lexical). Taken together, these results suggest that the older adult brain undergoes a coordinated time-frequency reorganization to support sentence production. Individuals likely establish an embodied semantic strategy in aging that involves "chunking" the processing stages of sentence production via visuo-posterior information processing. We speculate that this may help shape a resource-efficient, predictive route for complex cognition in older adulthood.

A consistent finding across studies with older adults is that they typically perform worse at spatial memory tasks, particularly those conducted in virtual reality and involving novel environments, compared to young adults. While the underlying reasons for this difference remain unclear, some proposed hypotheses include differences in sensory cue integration and cue conflict resolution. Here, we tested older (n = 29) and young adults (n = 28) in immersive and walkable virtual reality using both correctly rendered and illusory hallways to test how visual cues (i.e., an intersection) and self-motion cues are integrated. In the illusory or false-intersection condition, we hypothesized that participants who walked an uncrossed path would merge two disconnected intersections, creating the illusion of a crossed path. The overall accuracy and pointing patterns were similar between young and older adults in both true- and false-intersection conditions. We did find, however, a significant age by condition interaction effect in egocentric pointing variability where older adults showed lower variability in the illusory condition and higher variability in the control condition. At the same time, older adults also drew worse maps for the control condition compared to young adults. However, the pointing error correlated with the accuracy of maps drawn regardless of age, suggesting that the pointing patterns shown by both age groups related to their underlying representations of the paths. Our findings are inconsistent with a global deficit in allocentric navigation or path integration and instead suggest that more subtle differences in strategy use might manifest with age.

INTRODUCTION: Neuroinflammation and immune dysregulation are increasingly recognized as early drivers of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), often emerging decades before the onset of clinical symptoms. Despite this, there remains a critical need for non-invasive biomarkers that can capture these early processes, particularly in African Americans, a population at elevated risk for AD/ADRD yet underrepresented in neuroimaging research. In this study, we investigated the relationship between systemic plasma inflammatory markers and brain microstructural integrity in cognitively unimpaired older African Americans. METHODS: Forty-one participants (mean age = 68.68 years) underwent MRI scanning and multi-plex plasma-based inflammatory marker quantification. Microstructural changes were quantified using Diffusion Weighted Imaging (DWI) metrics, including mean diffusivity (MD), radial diffusivity (RD), mean kurtosis (MK), and radial kurtosis (RK). Voxel-wise general linear models, and cluster-based models were used to examine associations between plasma-derived inflammatory markers and brain microstructure. RESULTS: Higher TARC levels were associated with widespread increases in MD and RD across both gray and white matter, implicating reduced microstructural integrity and potential myelin disruption. In contrast, kurtosis-based metrics demonstrated more spatially selective and generally weaker associations, with MK and RK showing limited decreases primarily within white matter tracts. Cluster-level analyses confirmed the robustness of diffusivity findings and highlighted consistent effect sizes across multiple regions. DISCUSSION: These findings suggest that elevated TARC is linked to early microstructural alterations detectable with diffusion MRI, with diffusivity metrics demonstrating greater sensitivity to inflammation-related changes than kurtosis measures in this cohort. This work underscores the importance of incorporating inflammatory biomarkers in neuroimaging studies of aging and highlights diffusion MRI as a promising tool for detecting early neurobiological signatures of AD/ADRD risk in African American populations. Keywords: Systemic Inflammation, TARC, Eotaxin-3, Diffusion MRI, African Americans, ADRD, Aging