Frontiers in Aging Neuroscience

Connectivity of somatosensory cortex (S1) and cerebellum with the motor cortex (M1) is critical for balance control. While both S1-M1 and cerebellar-M1 connections are affected with aging, the implications of altered connectivity for balance control are not known. We investigated the relationship between S1-M1 and cerebellar-M1 connectivity and standing balance in middle-aged and older adults. Our secondary objective was to investigate how cognition affected the relationship between connectivity and balance. Our results show that greater S1-M1 and cerebellar-M1 connectivity was related to greater postural sway during standing. This may be indicative of an increase in functional recruitment of additional brain networks to maintain upright balance despite differences in network connectivity. Also, cognition moderated the relationship between S1-M1 connectivity and balance, such that those with lower cognition had a stronger relationship between connectivity and balance performance. It may be that individuals with poor cognition need increased recruitment of brain regions (compensation for cognitive declines) and in turn, higher wiring costs, which would be associated with increased functional connectivity.

Aging is frequently perceived negatively due to its association with the decline of various brain and bodily functions. While it is evident that motor abilities deteriorate with age, it is incorrect to assume that all aspects of movement execution are equally affected. The cerebellum, a brain region that is closely involved in motor control among other functions, undergoes clear structural changes with aging. While several studies suggest that cerebellar degeneration causes age-related motor control deficits, other studies suggest that the cerebellum might act as a motor reserve and compensate for its structural degeneration, leaving cerebellar motor function intact despite cerebellar degeneration. The present study aims at thoroughly investigating the impact of age on cerebellar function across an array of tasks and domains. We investigated cerebellar motor and cognitive functions across the lifespan by examining 50 young adults (20-35 years), 80 older adults (55-70 years), and 30 older-old adults (>80 years). Participants completed a test battery comprising seven motor control tasks and one cognitive task, each designed to probe cerebellar function through different paradigms. This multi-task approach allowed for a comprehensive evaluation of performance patterns, providing a balanced perspective on cerebellar function across the different age groups. In addition, we analyzed outcomes from the same tasks that, while related to movement, were not specifically linked to cerebellar function. Structural magnetic resonance imaging was also conducted to assess whether cerebellar atrophy was present in the older and older-old groups compared to the young. Our results revealed that, despite age-related cerebellar degeneration, cerebellar functions in older adults remained intact compared to young adults, even in adults above 80 years old. In contrast, the sensorimotor measures that were not directly linked to cerebellar function exhibited a clear pattern of decline in older adults, and were further deteriorated in the older-old adults compared to the older adults. These findings indicate that cerebellar motor control functions remain largely preserved with age, providing compelling evidence that the cerebellum possesses a remarkable degree of functional resilience and redundancy. This suggests that cerebellar circuits may be uniquely equipped to preserve function despite structural degeneration.

Aging leads to alterations in the sensorimotor system and balance control but it is not well understood how changes in sensorimotor function affect how people respond to postural disturbances. Elucidating the relationships between balance control and sensorimotor function is crucial for developing effective rehabilitations. Here, we compared the kinematic responses to platform translations and rotations during standing in 10 young and 30 older adults and explored relationships between sensorimotor function and balance responses. We found that older adults were less able to withstand perturbations without stepping, not because their non-stepping strategies were less effective but because they chose to step at smaller deviations of the extrapolated center of mass. Older adults performed worse than young adults on measures of sensory and motor function but lower stepping thresholds were associated with susceptibility to unreliable visual information and not with reduced sensory acuity or reduced strength. Poor sensory reweighting may contribute to and combine with age-related cognitive rigidity, leading to a higher priority on safer strategies. Older adults may resort to stepping, even if a step is not necessary, rather than rely on potentially inaccurate sensory signals to inform a corrective response. Our results provide initial evidence that sensory reweighting could be a potential target for fall prevention methods. NEW & NOTEWORTHYThe relationship between age-related changes in sensorimotor function and postural control is poorly understood. Here, we did a comprehensive assessment of sensorimotor function and reactive standing balance. We found that healthy older adults chose safer strategies, i.e. they step at smaller disturbances, than young adults. Although we found many differences in sensorimotor function, only a reduced ability to suppress conflicting sensory information was related to the use of a safer strategy.

BackgroundCurrent clinical trials are investigating gamma frequency sensory stimulation as a potential therapeutic strategy for Alzheimers disease, yet we lack a comprehensive picture of the effects of this stimulation on multiple aspects of brain function. While most prior research has focused on gamma frequency sensory stimulation, we previously showed that exposing mice to visual flickering stimulation increased MAPK and NF{kappa}B signaling in the visual cortex in a manner dependent on duration and frequency of sensory stimulation exposure. Because these pathways control multiple neuronal and glial functions and are differentially activated based on the duration and frequency of flicker stimulation, we aimed to define the transcriptional effects of different frequencies and durations of flicker stimulation on multiple brain functions. MethodsWe exposed 5xFAD mice to different frequencies of audio/visual flicker stimulation (constant light, 10Hz, 20Hz, 40Hz) for durations of 0.5hr, 1hr, or 4hr, then used bulk RNAseq to profile transcriptional changes within the visual cortex and hippocampus tissues. Using weighted gene co-expression network analysis, we identified modules of co-expressed genes controlled by frequency and/or duration of stimulation. ResultsWithin the visual cortex, we found that all stimulation frequencies caused fast activation of a module of immune genes within 1hr and slower suppression of synaptic genes after 4hrs of stimulation. Interestingly, all frequencies of stimulation led to slow suppression of astrocyte specific gene sets, while activation of neuronal gene sets was frequency and duration specific. In contrast, in the hippocampus, immune and synaptic modules were suppressed based on the frequency of stimulation. Specifically,10Hz activated a module of genes associated with mitochondrial function, metabolism, and synaptic translation while 10Hz rapidly suppressed a module of genes linked to neurotransmitter activity. ConclusionCollectively, our data indicate that the frequency and duration of flicker stimulation controls immune, neuronal, and metabolic genes in multiple regions of the brain affected by Alzheimers disease. Flicker stimulation may thus represent a potential therapeutic strategy that can be tuned based on the brain region and the specific cellular process to be modulated.

Age-related reductions in cognitive flexibility may limit modulation of control processes during systematic increases to cognitive-motor demands, exacerbating dual-task costs. In this study, behavioral and neurophysiologic changes to proactive and reactive control during progressive cognitive-motor demands were compared across older and younger adults to explore the basis for age-differences in cognitive-motor interference (CMI). 19 younger (19 - 29 years old, mean age = 22.84 +/- 2.75 years, 6 male, 13 female) and 18 older (60 - 77 years old, mean age = 67.89 +/- 4.60 years, 9 male, 9 female) healthy adults completed cued task-switching while alternating between sitting and walking on a treadmill. Gait kinematics, task performance measures, and brain activity were recorded using electroencephalography (EEG) based Mobile Brain/Body Imaging (MoBI). Response accuracy on easier trial types improved in younger, but not older adults when they walked while performing the cognitive task. As difficulty increased, walking provoked accuracy costs in older, but not younger adults. Both groups registered faster responses and reduced gait variability during dual-task walking. Older adults exhibited lower amplitude modulations of proactive and reactive neural activity as cognitive-motor demands systematically increased, which may reflect reduced flexibility for progressive preparatory and reactive adjustments over behavioral control.

Cognitive function can decline irreversibly with age, potentially progressing to dementia. Intervention during the preclinical stage is considered effective, but evaluation often requires large-scale equipment and tests. A decline in inhibitory function precedes and is involved in a general decline in higher-order brain functions, making its assessment a key target for early detection. We focused on error-related negativity (ERN) to capture the neural network of inhibitory function. While larger ERN amplitudes indicate higher error detection ability and correlate with inhibitory function, the causal relationship, mutual influences, and age-related effects in older adults remain unclear. This study measured brain activity during an inhibitory task in young and older adults to examine the neural networks related to error detection and inhibitory function. We used LORETA iCoh Full Vector Field analysis to verify directional connectivity. In the elderly group, during error responses, we observed significantly stronger beta-band directionality from the ventral anterior cingulate cortex (ACC) to the left frontal pole. Between the ventral and dorsal ACC, we also found significantly stronger directionality in the theta, alpha, and beta bands. During correct responses, they showed significantly stronger alpha and beta-band directionality from the left dorsolateral prefrontal cortex (DLPFC) to the right frontal pole. Compared to the elderly, the young group exhibited significantly stronger mutual directionality between the ventral and dorsal prefrontal cortices in the alpha and beta bands. They also showed widespread, significantly strong directionality among the ACC, bilateral DLPFC, and frontal poles. These results suggest that error detection ability is important for the normal functioning of inhibitory control in older adults. Furthermore, an age-related decline in metacognitive abilities may be associated with impaired inhibitory function. The insights from this study can contribute to developing risk prediction models for cognitive decline and establishing effective preventive strategies.

More than one million people in the United States and over 38 million people worldwide are living with human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) greatly improves the health of people living with HIV (PLWH); however, the increased life longevity of PLWH has revealed consequences of HIV-associated comorbidities. HIV can enter the brain and cause inflammation even in individuals with well-controlled HIV infection. The quality of life for PLWH can be compromised by cognitive deficits and memory loss, termed HIV-associated neurological disorders (HAND). HIV-associated dementia is a related but distinct diagnosis. Common causes of dementia in PLWH are similar to the general population and can affect cognition. There is an urgent need to identify treatments for the aging PWLH population. We previously developed AI-based biomedical literature mining systems to uncover a potential novel connection between HAND the renin-angiotensin system (RAAS), which is a pharmacological target for hypertension. RAAS-targeting anti-hypertensives are gaining attention for their protective benefits in several neurocognitive disorders. To our knowledge, the effect of RAAS-targeting drugs on the cognition of PLWH development of dementia has not previously been analyzed. We hypothesized that exposure to angiotensin-converting enzyme inhibitors (ACEi) that cross the blood brain barrier (BBB) reduces the risk/occurrence of dementia in PLWH. We report a retrospective cohort study of electronic health records (EHRs) to examine the proposed hypothesis using data from the United States Department of Veterans Affairs, in which a primary outcome of dementia was measured in controlled cohorts of patients exposed to BBB-penetrant ACEi versus those unexposed to BBB-penetrant ACEi. The results reveal a statistically significant reduction in dementia diagnosis for PLWH exposed to BBB-penetrant ACEi. These results suggest there is a potential protective effect of BBB ACE inhibitor exposure against dementia in PLWH that warrants further investigation.

BackgroundCognitive slowing accompanies normal aging, yet understanding of the mechanisms of slowing is limited at the network and neuronal level. Relating the pathophysiological factors responsible for cognitive slowing, and interpreting its relationship to working memory, requires multiscale computer modeling. ObjectiveThe aim of this research is to explore multiple mechanisms of cognitive slowing using computational modeling of the cortex to link neuronal activity with cognitive content. MethodWe developed multiscale computer models of a simple cognitive task - Condition 1 of the Stroop recognition task - using the Nengo system, a cognitive simulation environment with a semantic pointer architecture developed to model cognitive tasks using spiking neural networks. We explored how changes associated with aging such as increased input noise, axonal loss, neuronal loss, and feedback would affect the function of the models. ResultsAxonal loss and increased input noise produced profound slowing. High levels of neuronal loss severely impaired memory and paradoxically decreased slowing via the ability to respond more quickly by "releasing" a prior memory. Increased feedback improved memory at the cost of increased slowing. ConclusionOur simulations suggest that significant slowing could be caused by white matter loss (axonal loss) or input signal degradation (which could be caused by visual or other afferent system worsening). As neuronal loss markedly decreased the duration of working memory, we propose that physiological feedback is increased to preserve working memory at the cost of further cognitive slowing.

Several age-related oral health problems have been associated with neurodegenerative diseases such as Alzheimers Disease (AD), yet how oromotor dysfunction in healthy aging differ from those found in pathological aging is still unknown. This is partly because changes in the cortical and biomechanical ("neuromechanical") control of oromotor behavior in healthy aging are poorly understood. To this end, we investigated the natural feeding behavior of young and aged rhesus macaques (Macaca mulatta) to understand the age-related differences in tongue and jaw kinematics. We tracked tongue and jaw movements in 3D using high-resolution biplanar videoradiography and X-ray Reconstruction of Moving Morphology (XROMM). Older subjects exhibited a reduced stereotypy in tongue movements during chews and a greater lag in tongue movements relative to jaw movements compared to younger subjects. Overall, our findings reveal age-related changes in tongue and jaw kinematics, which may indicate impaired tongue-jaw coordination. Our results have important implications for the discovery of potential neuromechanical biomarkers for early diagnosis of AD.

Aging is associated with declines in sensorimotor and cognitive functions that affect internal motor models, thought to mediate the risk of falls. Motor imagery, an experimental window into internal models, has been studied in aging, but it remains unclear whether age differentially impacts their predictive versus updating components. In this study, younger and older adults completed the Timed Up and Go task along with imagined trials before and after execution, enabling separate assessment of prediction and update accuracy. It was found that older adults exhibited similar or better accuracy during prediction and update, but the accuracy measures were linked with distinct cognitive and sensorimotor factors in the two age groups. These findings suggest that while internal model function is preserved in healthy aging, at least for every-day tasks, it is shaped by different compensatory mechanisms across the lifespan.

Aging is accompanied by various neurophysiological changes that may affect cognitive and motor function. Compared to younger adults, motor performance in older adults engages more brain regions and exhibits elevated neural activity in the motor-related alpha (8-12 Hz) and beta (15-30 Hz) frequency bands of electro-encephalography (EEG) signals. To what extent these functional changes correlate with the quality of motor performance is underexplored. We recorded EEG in 19 young and 19 older adults during unimanual and bimanual visuomotor tasks with different degrees of difficulty. Older participants showed a lower quality of performance than younger adults, especially during asymmetric bimanual tasks. We analyzed source-localized activity in bilateral parietal and (pre-)motor areas to investigate, especially, the hypothesized pivotal role of left premotor cortex (PMCL) activity within the motor network during motor performance. In PMCL, beta activity was indeed significantly affected by age during bimanual performance, while alpha activity was altered in the bilateral (pre-)cuneus. When predicting error of performance via alpha and beta modulations, we found significant associations in bilateral M1 and (pre-)cuneusR during unimanual performance, while in bimanual performance, PMCL and (pre-)cuneusL were also included in the significant association. Our results confirm the importance of PMCL and (pre-)cuneusL for the performance of bimanual tasks, especially when the tasks are challenging. The age-related differences in alpha power in bilateral (pre-)cuneus and their associations with motor performance suggest that altered visuomotor integration has an important contribution to the reduction of the quality of motor performance in older adults.

Recovering balance after perturbations becomes challenging with aging, but an effective balance training could reduce such challenges. In this study, we examined the effect of balance training on feedback control after unpredictable perturbations by investigating balance performance, recovery strategy, and muscle synergies. We assessed the effect of balance training on unipedal perturbed balance in twenty older adults (>65 years) after short-term (one session) and long-term (3-weeks) training. Participants were exposed to random medial and lateral perturbations consisting of 8-degree rotations of a robot-controlled balance platform. We measured full-body 3D kinematics and activation of 9 muscles (8 stance leg muscles, one trunk muscle) during 2.5 s after the onset of perturbation. The perturbation was divided into 3 phases: phase1 from the onset to maximum rotation of the platform, phase 2 from the maximum rotation angle to the 0-degree angle and phase 3 after platform movement. Balance performance improved after long-term training as evidenced by decreased amplitudes of center of mass acceleration and rate of change of body angular momentum. The rate of change of angular momentum did not directly contribute to return of the center of mass within the base of support, but it reoriented the body to an aligned and vertical position. The improved performance coincided with altered activation of synergies depending on the direction and phase of the perturbation. We concluded that balance training improves control of perturbed balance, and reorganizes feedback responses, by changing temporal patterns of muscle activation. These effects were more pronounced after long-term than short-term training.

Motor lateralization refers to differences in the neural organization of cerebral hemispheres, resulting in different control specializations between the dominant and the non-dominant motor systems. Multiple studies proposed that the dominant hemisphere is specialized for open-loop optimization-like processes. Recently, comparing arm kinematics between upward and downward movements, we found that the dominant arm outperformed the non-dominant one regarding gravity-related motor optimization in healthy young participants. The literature about aging effects on motor control presents several neurophysiological and behavioral evidences for an age-related reduction of motor lateralization. Here, we compare the lateralization of a well-known gravity-related optimal motor control process between young and older adults. Forty-one healthy young (mean age = 24.3 {+/-} 3 years) and forty-two healthy older adults (mean age = 72.0 {+/-} 6 years) performed single degree-of-freedom vertical arm movements between two targets (upward and downward). Participants alternatively reached with their dominant and non-dominant arms. We recorded arm kinematics and electromyographic activities of the prime movers (Anterior and Posterior Deltoids) and we analyzed parameters thought to represent the hallmark of the gravity-related optimization process (i.e directional asymmetries and negative epochs on the phasic EMG activity). We found strong age x arm interaction effects on all parameters; i.e., relative durations to peak acceleration and peak velocity and the negativity of antigravity muscles phasic signals. Although all three parameters showed a lateralization effect where the dominant arm was superior to the non-dominant arm in young adults (as in Poirier et al. 2022), we found no such effect in older adults. With both arms, the results of older adults lied between those of the dominant and non-dominant arm of young adults. These results add to those of recent literature showing that feedforward motor control remains functional in older adults. More, the results obtained with the non-dominant arm may support a previously hypothesized increased reliance on predictive mechanisms in older adults.

We lack a clear understanding of how cortical contributions to balance are altered in aging and Parkinsons disease (PD), which limits development of rehabilitation strategies. Processes like balance control are typically mediated through brainstem circuits, with higher-order circuits becoming engaged as needed. Using reactive balance recovery, we investigated how hierarchical neural mechanisms shape balance- correcting muscle activity across task difficulty in older adults (OAs) with and without PD. We hypothesize that feedback loops involving brainstem and cortical circuits contribute to balance control, and cortical engagement increases with challenge, aging, and PD. We decomposed perturbation-evoked agonist and antagonist muscle activity into hierarchical components based on latency using neuromechanical models consisting of two feedback loops with different delays to reflect different neural conduction and processing times. Agonist muscle activity was decomposed into two components that both increased with balance challenge in both groups. The first component occurred [~]120ms and the second occurred [~]210ms, consistent with the latencies of brainstem and transcortical circuits, respectively. Exploratory comparisons to young adults revealed larger transcortical components in OA and PD groups at lower balance challenge levels, consistent with increased cortical involvement with aging. Antagonist muscle activity included destabilizing and stabilizing components, with the destabilizing component correlating to balance ability in OAs but not in PD. These findings demonstrate that neuromechanical models can identify changes in the hierarchical control of balance without direct brain measurements. Identifying cortical contributions during balance control may complement clinical measures of balance ability to inform balance rehabilitation and assistive devices. NEW & NOTEWORTHYA neuromechanical model can decompose perturbation evoked muscle activity into components attributed to brainstem and higher-order sensorimotor feedback based on latency. In older adults with and without PD contributions from higher-order neural circuits increase with balance challenge and are related to clinical measures of balance ability. Interpreting the neural substrates of motor output for balance may reveal individual differences in the hierarchical control of balance, that could inform rehabilitation.

Safe gait requires visually cued (VC) step adjustments for negotiating targets and obstacles. Effective step adjustments rely on good visuospatial processing. The posterior parietal cortex (PPC) is implicated in visuospatial processing, yet empirical evidence is limited for the PPCs role during gait in humans. Increased cortical control of gait is associated with higher gait variability, a marker of gait performance and fall risk among older adults. However, the cortical underpinnings of gait variability in visually complex environments are not well established. The primary aim of this preliminary study was to assess PPC activity during VC gait and VC gait with perturbations (VCP). A secondary aim was to determine how PPC activity relates to gait variability during VC and VCP gait. Twenty-one healthy young adults completed three treadmill gait conditions at preferred speed: non-cued (NC) gait, VC gait, where stepping targets were presented in a regular pattern, and VCP gait, where stepping target positions were pseudorandomly shifted. Functional near-infrared spectroscopy quantified relative changes in deoxygenated and oxygenated hemoglobin ({Delta}HbO2) concentrations in the PPC. Inertial measurement units quantified gait variability. Moderate effects were observed for more positive {Delta}HbO2 from NC to both VC and VCP gait, likely reflecting the increased visuospatial processing demands. Stride time variability was positively correlated with PPC {Delta}HbO2 during VC gait, suggesting a potential role for the PPC in modulating temporal components of VC gait. Extending these findings to older adults will help to elucidate the PPCs role in gait adaptability and fall risk with aging.

Alzheimers disease (AD) is correlated with brain atrophy, neuronal loss, neurotransmitter imbalance, and cognitive decline, which also occur in normal aging. Thus, comparing the differences between normal aging and AD is of interest in order to test the accelerated aging hypothesis of AD. An imbalance between excitatory/inhibitory (E/I) neurotransmission, especially in gamma-aminobutyric acid (GABA) inhibition dysfunction, is involved in both AD and normal aging. In the present study, we performed correlation analyses between electroencephalograms (EEGs) and memory in middle-aged ([~]12 months old) wild-type mice (WT) and AD model mice (APP/PS1) after E/I balance adjustment via GABAA agonist muscimol and antagonist bicuculline administration (0.1 mg/kg intraperitoneally). Specifically, EEGs of the hippocampus and prefrontal cortex were recorded during Y-maze performance. Overall, WT and AD mice showed different correlation patterns between EEG activity and behavioral memory performance. Significant correlations were observed in EEG activity across a wider range of frequency bands (2-100 Hz, except 4-8 Hz) in WT mice, but were mainly observed in low frequency bands (delta-theta, 2-8 Hz) in AD mice. In addition, muscimol and bicuculline treatment contributed to better brain function in AD mice; in contrast, bicuculline administration resulted in poorer brain function in WT mice. Thus, our study suggests that AD shows a distinct pattern of disrupted brain function, rather than accelerated aging. Importantly, this work reveals new insights into future AD treatment by influencing low-frequency EEG activity through E/I balance adjustment, thereby aiding cognitive recovery.

Reaching for an object in space forms the basis for many activities of daily living and is important in rehabilitation after stroke and in other neurological and orthopedic conditions. It has been the object of motor control and neuroscience research for over a century, but studies often constrain movement to eliminate the effect of gravity or reduce the degrees of freedom. In some studies, aging has been shown to reduce target accuracy, with a mechanism suggested to be impaired corrective movements. We sought first to explore the changes in control of shoulder and elbow joint movements that occur with aging during performance of reaching movements to different target heights with the normal effects of gravity, unconstrained hand movement, and stable target locations. Three-dimensional kinematic data and electromyography were collected in 14 young (25{+/-}6 years) and 10 older adults (68{+/-}3 years) during second-long reaches to three targets aligned vertically in front of the participants. Older adults took longer to initiate a movement than the young adults and were more variable and inaccurate in their initial and final movements. Target height had greater effect on trajectory curvature variability in older than young adults, with angle variability relative to target position being greater in older adults around the time of peak speed. There were significant age-related differences in use of the multiple degrees of freedom of the upper extremity, with less variability in shoulder abduction in the older group. Muscle activation patterns were similar, except for a higher biceps-triceps co-contraction and tonic levels of some proximal muscle activation. The path length of movements was not affected by age. These results show an age-related deficit in the motor planning and online correction of reaching movements against a predictable force (i.e., gravity). These results will facilitate interpretation of our forthcoming study of transcranial magnetic stimulation effects on the same task in these two populations, and is relevant to any study that seeks to measure the effect of pathological processes on upper extremity motor performance in the elderly.

A major health burden for the elderly, vascular cognitive impairment (VCI) is a disease that combines cognitive (CD) and cardiovascular (CVD) components. The molecular mechanisms underlying this disease are poorly understood, and our work attempts to bridge this knowledge gap by building protein-protein interaction (PPI) networks of CD and CVD. Our earlier research not only showed how well these two primary components work together, but also hinted at the potential role of inflammation in the development of VCI. For this reason, we decided to examine the relationship between inflammation and VCI in further detail.We identified the top three most connected clusters, which could represent significant modules, enriched these clusters with alternative conformations, and used PRISM to predict the interactions between the conformations. We proposed putative VCI-related interactions, such as NFKBIA-RELA and the proteasome complex, as well as their effects. The five interactions that we discovered have a higher predicted binding affinity when one of the conformations is mutated: LTF-SNCA, FGA-LTF, UBE2D1-VCP, ERBB4-INS, and NFE2L2-VCP. Additionally, since VCP has a conformational mutation linked to dementia, we proposed that the cancer-related protein BRCA1 may have implications for VCI. BRCA1s interaction with both wild-type and mutant XRCC4 and LIG4 suggests the significance of the DNA damage response pathway which can be shared between VCI and cancer.Altogether, our results suggest various pathways and interactions that can act as targets for therapeutic interventions or early diagnosis of VCI.

BackgroundCognition may be influenced by health-related factors such as blood pressure (BP). However, variations in BP may differentially affect cognition as a function of race. This study investigates the relationship between normal, high, and variable BP and cognitive decline in older Black and White adults. Methods2284 participants (1139 Blacks, 1145 Whites, MAge=73.4, SD=6.6) from 3 harmonized cohorts of older adults from the Rush Alzheimers Disease Center, were divided into 3 groups (normal, high, variable) based on systolic BP mean and standard deviation. Cognitive scores were computed from multiple assessments in 5 domains (i.e., episodic memory, semantic memory, working memory, processing speed, visuospatial ability). Performance across 19 tests were averaged to create a measure of global cognition. Linear mixed-effects models examined racial differences between BP and cognitive change over an average of 6.7 years. ResultsWhite adults with high or variable BP had faster rates of decline in global cognition compared to Black adults. White adults with high BP declined faster in perceptual speed, semantic memory, and working memory compared to Black adults with high BP, whereas White adults with variable BP had faster rates of decline in all cognitive domains compared to Black adults with variable BP. No racial differences were observed in individuals with normal BP. ConclusionsWhite older adults with elevated or fluctuating BP show faster rates of cognitive decline compared to older Black adults. Findings highlight the complex interplay between BP and cognitive health, emphasizing the need for targeted interventions to address racial disparities in cognitive well-being.

Locomotor perturbations elicit cortical and muscular responses that help minimize motor errors through neural processes involving multiple brain regions. The anterior cingulate cortex monitors motor errors, the supplementary motor areas integrate sensory and executive control, and the posterior parietal cortices process sensorimotor predictions, while muscles show increased activation and co-contraction patterns. With aging, these neural control strategies shift; older adults demonstrate less flexible cortical and muscular responses, using compensatory overactivation and simpler muscle synergies to maintain performance comparable to young adults. We investigated corticomuscular connectivity patterns during perturbed recumbent stepping in seventeen young adults (age 25{+/-}4.9 years) and eleven older adults (age 68{+/-}3.6 years) using high-density EEG (128 electrodes) and EMG from six bilateral muscles. Brief mechanical perturbations (200ms of increased resistance) were applied at left or right leg extension-onset or mid-extension during continuous stepping at 60 steps per minute. We applied independent component analysis, source localization, and direct directed transfer function to quantify bidirectional information flow between cortical clusters and muscles in theta (3-8 Hz), alpha (8-13 Hz), and beta (13-35 Hz) bands. Young adults demonstrated concentrated electrocortical sources in anterior cingulate cortex, bilateral supplementary motor areas, and bilateral posterior parietal cortices, with strong theta-band synchronization following perturbations. In contrast, older adults showed fewer differentiated cortical sources, particularly lacking distinct anterior cingulate activity, and exhibited only minimal synchronization changes. Baseline corticomuscular connectivity was significantly stronger in older adults compared to young adults (p=0.012), suggesting fundamental differences in resting motor control states. During perturbations, young adults employed flexible, task-specific connectivity modulation involving error-processing networks, with the anterior cingulate showing selective bidirectional connectivity changes with specific muscles. Older adults relied on more diffuse (i.e., not focused to specific brain area) connectivity patterns dominated by motor and posterior parietal cortices, with strong connections to multiple upper and lower limb muscles simultaneously. These findings reveal an age-related strategic reorganization from dynamic, error-driven neural control to a more constrained, stability-focused approach that may reflect compensation for sensorimotor changes. The distinct connectivity signatures establish perturbed recumbent stepping as a valuable tool for assessing corticomuscular communication and provide normative benchmarks for developing targeted rehabilitation interventions to restore efficient motor control in aging and neurological populations.