Associations of brain morphology with cortical proteins of cognitive resilience.

In a recent proteome-wide study, we identified several candidate proteins for drug discovery whose cortical abundance was associated with cognitive resilience to late-life brain pathologies. This study examines the extent to which these proteins are associated with the brain structures of cognitive resilience in decedents from the Religious Orders Study and Memory and Aging Project. Six proteins were associated with brain morphometric characteristics related to higher resilience (i.e., larger anterior and medial temporal lobe volumes), and five were associated with morphometric characteristics related to lower resilience (i.e., enlarged ventricles). Two synaptic proteins, RPH3A and CPLX1, remained inversely associated with the lower resilience signature, after further controlling for 10 neuropathologic indices. These findings suggest preserved brain structure in periventricular regions as a potential mechanism by which RPH3A and CPLX1 are associated with cognitive resilience. Further work is needed to elucidate other mechanisms by which targeting these proteins can circumvent the effects of pathology on individuals at risk for cognitive decline.

Volumetric brain correlates of gait associated with cognitive decline in community-dwelling older adults.

Objective: To determine the extent to which the regional brain volumes associated with slow gait speed can inform subsequent cognitive decline in older adults from the Rush Memory and Aging Project. Approach: We utilized deformation-based morphometry (DBM) in a whole-brain exploratory approach to identify the regional brain volumes associated with gait speed assessed over a short distance during an in-home assessment. We created deformation scores to summarize the gait-associated regions and entered the scores into a series of longitudinal mixed effects models to determine the extent to which deformation predicted change in cognition over time, controlling for associations between gait and cognition. Results: In 438 older adults (81 ± 7; 76% female), DBM revealed that slower gait speed was associated with smaller volumes across frontal white matter, temporal grey matter, and subcortical areas and larger volumes in the ventricles during the same testing cycle. When a subset was followed over multiple (5 ± 2) years, slower gait speed was also associated with annual declines in global cognition, executive functioning, and memory abilities. Several of the gait-related brain structures were associated with these declines in cognition; however, larger ventricles and smaller medial temporal lobe volumes proved most robust and attenuated the association between slow gait and cognitive decline. Conclusion: Regional brain volumes in the ventricles and temporal lobe associated with both slow gait speed and faster cognitive decline have potential to improve risk stratification for cognitive decline in older adults.

Late-life depressive symptoms and white matter structural integrity within older Black adults.

Introduction: Older Black adults experience a high burden of depressive symptoms and cerebrovascular disease but the specific neurobiological substrates underlying the association between late-life depressive symptoms and brain integrity are understudied, particularly in within-group designs. Methods: Using the Center for Epidemiologic Studies Depression Scale and diffusion-tensor imaging, within-Black variation in the association between late-life depressive symptoms and white matter structural integrity was examined in 297 older Black participants without dementia that were enrolled across three epidemiological studies of aging and dementia. Linear regression models were used to test associations with DTI metrics (fractional anisotropy, trace of the diffusion tensor) as the outcomes and depressive symptoms as the predictor, while adjusting for age, sex, education, scanner, serotonin-reuptake inhibitor use, total volume of white-matter hyperintensities normalized by intracranial volume, and presence of white-matter hyperintensities at the voxel level. Results: Higher level of self-reported late-life depressive symptoms was associated with greater diffusion-tensor trace (reduced white matter integrity) in connections between commissural pathways and contralateral prefrontal regions (superior and middle frontal/dorsolateral prefrontal cortex), association pathways connecting dorsolateral prefrontal cortex with insular, striatal and thalamic regions, and association pathways connecting the parietal, temporal and occipital lobes and the thalamus. Discussion: This study demonstrated a discernable pattern of compromised white matter structural integrity underlying late-life depressive symptoms within older Black adults.

Dividing attention during the Timed Up and Go enhances associations of several subtask performances with MCI and cognition.

We tested the hypothesis that dividing attention would strengthen the ability to detect mild cognitive impairment (MCI) and specific cognitive abilities from Timed Up and Go (TUG) performance in the community setting. While wearing a belt-worn sensor, 757 dementia-free older adults completed TUG during two conditions, with and without a concurrent verbal serial subtraction task. We segmented TUG into its four subtasks (i.e., walking, turning, and two postural transitions), and extracted 18 measures that were summarized into nine validated sensor metrics. Participants also underwent a detailed cognitive assessment during the same visit. We then employed a series of regression models to determine the combinations of subtask sensor metrics most strongly associated with MCI and specific cognitive abilities for each condition. We also compared subtask performances with and without dividing attention to determine whether the costs of divided attention were associated with cognition. While slower TUG walking and turning were associated with higher odds of MCI under normal conditions, these and other subtask associations became more strongly linked to MCI when TUG was performed under divided attention. Walking and turns were also most strongly associated with executive function and attention, particularly under divided attention. These differential associations with cognition were mirrored by performance costs. However, since several TUG subtasks were more strongly associated with MCI and cognitive abilities when performed under divided attention, future work is needed to determine how instrumented dual-task TUG testing can more accurately estimate risk for late-life cognitive impairment in older adults.

Associations of deformation-based brain morphometry with cognitive level and decline within older Blacks without dementia.

Blacks are at higher risk of developing cognitive impairment with age than non-Hispanic Whites, yet most brain morphometry and cognition research is performed with White samples or with mixed samples that control for race or compare across racial groups. A deeper understanding of the within-group variability in associations between brain structure and cognitive decline in Blacks is critically important for designing appropriate outcomes for clinical trials, predicting adverse outcomes, and developing interventions to preserve cognitive function, but no studies have examined these associations longitudinally within Blacks. We performed deformation-based morphometry in 376 older Black participants without dementia and examined associations of deformation-based morphometry with cognitive level and decline for global cognition and five cognitive domains. After correcting for widespread age-associated effects, there remained regions with less tissue and more cerebrospinal fluid associated with level and rate of decline in global cognition, memory, and perceptual speed. Further study is needed to examine the moderators of these associations, identify adverse outcomes predicted by brain morphometry, and deepen knowledge of underlying biological mechanisms.

Association of White Matter Hyperintensities With Pathology and Progression of Parkinsonism in Aging.

Importance: Progressive parkinsonism is common in older adults without a diagnosis of Parkinson disease and is associated with adverse health outcomes, but its pathologic basis is controversial. Objective: To examine if the burden of cerebral white matter hyperintensity (WMH), a common manifestation of cerebrovascular disease pathologies, is associated with the rate of progressive parkinsonism. Design, Setting, and Participants: This community-based cohort study included participants recruited in 3 ongoing cohorts that began enrollment in 1994, 1997, and 2004. Prior to death, participants were observed for a mean of 7.5 years, with annual clinical assessments. From 4427 participants enrolled in the 3 cohorts, 2134 died. Postmortem autopsy was performed in 1725 decedents, and 598 also had ex vivo brain magnetic resonance imaging. Participants were excluded if they were missing any of the 9 postmortem pathology indices (n = 22) or repeated parkinsonism assessment (n = 41) or had received a clinical diagnosis of Parkinson disease at any point before or during the study (n = 19). Data were analyzed from April 2020 to August 2021. Exposures: WMH burden was assessed using a modified Fazekas rating scale. Main Outcomes and Measures: Parkinsonism was assessed annually using 26 items of a modified motor portion of the Unified Parkinson's Disease Rating Scale. A summary score was developed from the item scores, with higher scores indicating more severe parkinsonism. Results: Of 516 included decedents, 364 (70.5%) were female, and the mean (SD) age at death was 90.2 (6.4) years. Higher WMH was associated with faster progressive parkinsonism (estimate, 0.024; SE, 0.008; P = .002). The attenuation of this association was greater when controlling for indices of cerebrovascular disease pathologies than when controlling for neurodegenerative pathologies (cerebrovascular disease: estimate, 0.019; SE, 0.008; P = .02; neurodegenerative: estimate, 0.022; SE, 0.008; P = .003), but both remained significant. Conclusions and Relevance: In this cohort study, higher levels of both WMH and indices of cerebrovascular disease pathologies in aging brains were associated with more rapid progressive parkinsonism. Further studies are needed to determine if in vivo brain imaging of older adults for evidence of WMH and aggressive medical treatment of vascular risk factors and diseases can reduce the occurrence or severity of late-life parkinsonism.

Physical activity, brain tissue microstructure, and cognition in older adults.

OBJECTIVE: To test whether postmortem MRI captures brain tissue characteristics that mediate the association between physical activity and cognition in older adults. METHODS: Participants (N = 318) were older adults from the Rush Memory and Aging Project who wore a device to quantify physical activity and also underwent detailed cognitive and motor testing. Following death, cerebral hemispheres underwent MRI to quantify the transverse relaxation rate R2, a metric related to tissue microstructure. For analyses, we reduced the dimensionality of the R2 maps from approximately 500,000 voxels to 30 components using spatial independent component analysis (ICA). Via path analysis, we examined whether these R2 components attenuated the association between physical activity and cognition, controlling for motor abilities and indices of common brain pathologies. RESULTS: Two of the 30 R2 components were associated with both total daily physical activity and global cognition assessed proximate to death. We visualized these components by highlighting the clusters of voxels whose R2 values contributed most strongly to each. One of these spatial signatures spanned periventricular white matter and hippocampus, while the other encompassed white matter of the occipital lobe. These two R2 components partially mediated the association between physical activity and cognition, accounting for 12.7% of the relationship (p = .01). This mediation remained evident after controlling for motor abilities and neurodegenerative and vascular brain pathologies. CONCLUSION: The association between physically activity and cognition in older adults is partially accounted for by MRI-based signatures of brain tissue microstructure. Further studies are needed to elucidate the molecular mechanisms underlying this pathway.

Evidence for a Specific Association Between Sustained Attention and Gait Speed in Middle-to-Older-Aged Adults.

Although cognitive decline has previously been associated with mobility limitations and frailty, the relationship between sustained attention and gait speed is incompletely characterized. To better quantify the specificity of the sustained attention and gait speed association, we examined the extent to which this relationship is unique rather than accounted for by executive functioning and physical health characteristics. 58 middle-to-older-aged community-dwelling adults without overt evidence of cognitive impairment (45-90 years old; 21 females) participated in the study. Each participant completed a 4-meter gait speed assessment and validated neuropsychological tests to examine various domains of executive functioning including working memory (i.e., Digit Span), inhibitory control (i.e., D-KEFS Color-Word Interference), and task switching (i.e., D-KEFS Number/Letter Switching). Multiple physical and vascular risk factors were also evaluated. Sustained attention was assessed using the gradual onset continuous performance task (gradCPT), a well-validated go/no-go sustained attention task. A series of linear regression models were used to examine how different aspects of cognition, including sustained attention and traditional measures of executive functioning, related to gait speed while controlling for a variety of physical and vascular risk factors. Among all predictors, gradCPT accuracy explained the most variance in gait speed (R 2 = 0.19, p < 0.001) and was the only significant predictor (ß = 0.35, p = 0.01) when accounting for executive functioning and other physical and vascular risk factors. The present results indicate that sustained attention may be uniquely sensitive and mechanistically linked to mobility limitations in middle-to-older adults.

Bootstrap approach for meta-synthesis of MRI findings from multiple scanners.

BACKGROUND: Neuroimaging data from large epidemiologic cohort studies often come from multiple scanners. The variations of MRI measurements due to differences in magnetic field strength, image acquisition protocols, and scanner vendors can influence the interpretation of aggregated data. The purpose of the present study was to compare methods that meta-analyze findings from a small number of different MRI scanners. METHODS: We proposed a bootstrap resampling method using individual participant data and compared it with two common random effects meta-analysis methods, DerSimonian-Laird and Hartung-Knapp, and a conventional pooling method that combines MRI data from different scanners. We first performed simulations to compare the power and coverage probabilities of the four methods in the absence and presence of scanner effects on measurements. We then examined the association of age with white matter hyperintensity (WMH) volumes from 787 participants. RESULTS: In simulations, the bootstrap approach performed better than the other three methods in terms of coverage probability and power when scanner differences were present. However, the bootstrap approach was consistent with pooling, the optimal approach, when scanner differences were absent. In the association of age with WMH volume, we observed that age was significantly associated with WMH volumes using the bootstrap approach, pooling, and the DerSimonian-Laird method, but not using the Hartung-Knapp method (p < 0.0001 for the bootstrap approach, DerSimonian-Laird, and pooling but p = 0.1439 for the Hartung-Knapp approach). CONCLUSION: The bootstrap approach using individual participant data is suitable for integrating outcomes from multiple MRI scanners regardless of absence or presence of scanner effects on measurements.

Association between metabolic syndrome and resting-state functional brain connectivity.

The objective of this study is to examine whether metabolic syndrome (MetS), the clustering of 3 or more cardiovascular risk factors, disrupts the resting-state functional connectivity (FC) of the large-scale cortical brain networks. Resting-state functional magnetic resonance imaging data were collected from seventy-eight middle-aged and older adults living with and without MetS (27 MetS; 51 non-MetS). FC maps were derived from the time series of intrinsic activity in the large-scale brain networks by correlating the spatially averaged time series with all brain voxels using a whole-brain seed-based FC approach. Participants with MetS showed hyperconnectivity across the core brain regions with evidence of loss of modularity when compared with non-MetS individuals. Furthermore, patterns of higher between-network MetS-related effects were observed across most of the seed regions in both right and left hemispheres. These findings indicate that MetS is associated with altered intrinsic communication across core neural networks and disrupted between-network connections across the brain due to the co-occurring vascular risk factors in MetS.

Development of brain atlases for early-to-middle adolescent collision-sport athletes.

Human brains develop across the life span and largely vary in morphology. Adolescent collision-sport athletes undergo repetitive head impacts over years of practices and competitions, and therefore may exhibit a neuroanatomical trajectory different from healthy adolescents in general. However, an unbiased brain atlas targeting these individuals does not exist. Although standardized brain atlases facilitate spatial normalization and voxel-wise analysis at the group level, when the underlying neuroanatomy does not represent the study population, greater biases and errors can be introduced during spatial normalization, confounding subsequent voxel-wise analysis and statistical findings. In this work, targeting early-to-middle adolescent (EMA, ages 13-19) collision-sport athletes, we developed population-specific brain atlases that include templates (T1-weighted and diffusion tensor magnetic resonance imaging) and semantic labels (cortical and white matter parcellations). Compared to standardized adult or age-appropriate templates, our templates better characterized the neuroanatomy of the EMA collision-sport athletes, reduced biases introduced during spatial normalization, and exhibited higher sensitivity in diffusion tensor imaging analysis. In summary, these results suggest the population-specific brain atlases are more appropriate towards reproducible and meaningful statistical results, which better clarify mechanisms of traumatic brain injury and monitor brain health for EMA collision-sport athletes.

Every hit matters: White matter diffusivity changes in high school football athletes are correlated with repetitive head acceleration event exposure.

Recent evidence of short-term alterations in brain physiology associated with repeated exposure to moderate intensity subconcussive head acceleration events (HAEs), prompts the question whether these alterations represent an underlying neural injury. A retrospective analysis combining counts of experienced HAEs and longitudinal diffusion-weighted imaging explored whether greater exposure to incident mechanical forces was associated with traditional diffusion-based measures of neural injury-reduced fractional anisotropy (FA) and increased mean diffusivity (MD). Brains of high school athletes (N = 61) participating in American football exhibited greater spatial extents (or volumes) experiencing substantial changes (increases and decreases) in both FA and MD than brains of peers who do not participate in collision-based sports (N = 15). Further, the spatial extents of the football athlete brain exhibiting traditional diffusion-based markers of neural injury were found to be significantly correlated with the cumulative exposure to HAEs having peak translational acceleration exceeding 20 g. This finding demonstrates that subconcussive HAEs induce low-level neurotrauma, with prolonged exposure producing greater accumulation of neural damage. The duration and extent of recovery associated with periods in which athletes do not experience subconcussive HAEs now represents a priority for future study, such that appropriate participation and training schedules may be developed to minimize the risk of long-term neurological dysfunction.

Motor-Cognitive Neural Network Communication Underlies Walking Speed in Community-Dwelling Older Adults.

While walking was once thought to be a highly automated process, it requires higher-level cognition with older age. Like other cognitive tasks, it also becomes further challenged with increased cognitive load (e.g., the addition of an unrelated dual task) and often results in poorer performance (e.g., slower speed). It is not well known, however, how intrinsic neural network communication relates to walking speed, nor to this "cost" to gait performance; i.e., "dual-task cost (DTC)." The current study investigates the relationship between network connectivity, using resting-state functional MRI (rs-fMRI), and individual differences in older adult walking speed. Fifty participants (35 females; 84 ± 4.5 years) from the MOBILIZE Boston Study cohort underwent an MRI protocol and completed a gait assessment during two conditions: walking quietly at a preferred pace and while concurrently performing a serial subtraction task. Within and between neural network connectivity measures were calculated from rs-fMRI and were correlated with walking speeds and the DTC (i.e., the percent change in speed between conditions). Among the rs-fMRI correlates, faster walking was associated with increased connectivity between motor and cognitive networks and decreased connectivity between limbic and cognitive networks. Smaller DTC was associated with increased connectivity within the motor network and increased connectivity between the ventral attention and executive networks. These findings support the importance of both motor network integrity as well as inter-network connectivity amongst higher-level cognitive networks in older adults' ability to maintain mobility, particularly under dual-task (DT) conditions.

Dependence on subconcussive impacts of brain metabolism in collision sport athletes: an MR spectroscopic study.

Long term neurological impairments due to repetitive head trauma are a growing concern for collision sport athletes. American Football has the highest rate of reported concussions among male high school athletes, a position held by soccer for female high school athletes. Recent research has shown that subconcussive events experienced by collision sport athletes can be a further significant source of accrued damage. Collision sport athletes experience hundreds of subconcussive events in a single season, and these largely go uninvestigated as they produce no overt clinical symptoms. Continued participation by these seemingly uninjured athletes is hypothesized to increase susceptibility to diagnoseable brain injury. This study paired magnetic resonance spectroscopy with head impact monitoring to quantify the relationship between metabolic changes and head acceleration event characteristics in high school-aged male football and female soccer collision sport athletes. During the period of exposure to subconcussive events, asymptomatic male (football) collision sport athletes exhibited statistically significant changes in concentrations of glutamate+glutamine (Glx) and total choline containing compounds (tCho) in dorsolateral prefrontal cortex, and female (soccer) collision sport athletes exhibited changes in glutamate+glutamine (Glx) in primary motor cortex. Neurometabolic alterations observed in football athletes during the second half of the season were found to be significantly associated with the average acceleration per head acceleration events, being best predicted by the accumulation of events exceeding 50 g. These marked deviations in neurometabolism, in the absence of overt symptoms, raise concern about the neural health of adolescent collision-sport athletes and suggest limiting exposure to head acceleration events may help to ameliorate the risk of subsequent cognitive impairment.

Compromised prefrontal structure and function are associated with slower walking in older adults.

Our previous work demonstrates that reduced activation of the executive network is associated with slow walking speed in a cohort of older adults from the MOBILIZE Boston Study. However, the influence of underlying white matter integrity on the activation of this network and walking speed is unknown. Thus, we used diffusion-weighted imaging and fMRI during an n-back task to assess associations between executive network structure, function, and walking speed. Whole-brain tract-based spatial statistics (TBSS) were used to identify regions of white matter microstructural integrity that were associated with walking speed. The integrity of these regions was then entered into multiple regression models to predict task performance and executive network activation during the n-back task. Among the significant associations of FA with walking speed, we observed the anterior thalamic radiation and superior longitudinal fasciculus were further associated with both n-back response speed and executive network activation. These findings suggest that subtle damage to frontal white matter may contribute to altered executive network activation and slower walking in older adults.

Executive Network Activation is Linked to Walking Speed in Older Adults: Functional MRI and TCD Ultrasound Evidence From the MOBILIZE Boston Study.

BACKGROUND: Changes in cerebral blood flow velocity (CBF) in response to a cognitive task (task-related ΔCBF) have been shown by Transcranial Doppler ultrasonography (TCD) to be reduced in slow walkers. However, it is unknown whether reduced task-related ΔCBF is associated with reduced neural activity in specific brain regions, as measured by blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI). METHODS: We assessed the regional changes in neural activity associated with reduced middle cerebral artery (MCA) task-related ΔCBF to an executive task and slow walking speed in 67 community-dwelling older adults from the MOBILIZE Boston Study. Participants underwent walking assessments and TCD ultrasonography measures of MCA ΔCBF during the n-back task of executive function. A subset of participants (n = 27) completed the same task during fMRI. Individual BOLD activation maps for the n-back task were correlated with TCD measures and network-level averages were associated with TCD and preferred walking speed. RESULTS: Participants with diminished task-related ΔCBF walked more slowly (ß = .39, p = .001). fMRI revealed significant associations between task-related ΔCBF and regional BOLD activation in several brain regions/networks supplied by the MCA. Of these regions and networks, those within the executive network were most strongly associated with walking speed (ß = .36, p = .01). CONCLUSIONS: Task-related ΔCBF during an executive function task is related to activation in several neural networks and impairment in the ability to recruit the executive network in particular is associated with slow walking speed in older adults.

Intrinsic functional connectivity predicts individual differences in distractibility.

Distractor suppression, the ability to filter and ignore task-irrelevant information, is critical for efficient task performance. While successful distractor suppression relies on a balance of activity in neural networks responsible for attention maintenance (dorsal attention network; DAN), reorientation (ventral attention network; VAN), and internal thought (default mode network, DMN), the degree to which intrinsic connectivity within and between these networks contributes to individual differences in distractor suppression ability is not well-characterized. For the purposes of understanding these interactions, the current study collected resting-state fMRI data from 32 Veterans and, several months later (7±5 months apart), performance on the additional singleton paradigm, a measure of distractor suppression. Using multivariate support vector regression models composed of resting state connectivity between regions of the DAN, VAN, and DMN, and a leave-one-subject-out cross-validation procedure, we were able to predict an individual's task performance, yielding a significant correlation between the actual and predicted distractor suppression (r=0.48, p=0.0053). Network-level analyses revealed that greater within-network DMN connectivity was predictive of better distractor suppression, while greater connectivity between the DMN and attention networks was predictive of poorer distractor suppression. The strongest connection hubs were determined to be the right frontal eye field and temporoparietal junction of the DAN and VAN, respectively, and medial (ventromedial prefrontal and posterior cingulate cortices) and bilateral prefrontal regions of the DMN. These results are amongst a small but growing number of studies demonstrating that resting state connectivity is related to stable individual differences in cognitive ability, and suggest that greater integrity and independence of the DMN is related to better attentional ability.

Sub-concussive hit characteristics predict deviant brain metabolism in football athletes.

Magnetic resonance spectroscopy and helmet telemetry were used to monitor the neural metabolic response to repetitive head collisions in 25 high school American football athletes. Specific hit characteristics were determined highly predictive of metabolic alterations, suggesting that sub-concussive blows can produce biochemical changes and potentially lead to neurological problems.

Effects of repetitive sub-concussive brain injury on the functional connectivity of Default Mode Network in high school football athletes.

Sub-concussive head impacts are identified as a source of accrued damage. Football athletes experience hundreds of such blows each season. Resting state functional magnetic resonance imaging was used to prospectively study changes in Default Mode Network connectivity for clinically asymptomatic high school football athletes. Athletes exhibited short-term changes relative to baseline and across sessions.

Alteration of default mode network in high school football athletes due to repetitive subconcussive mild traumatic brain injury: a resting-state functional magnetic resonance imaging study.

Long-term neurological damage as a result of head trauma while playing sports is a major concern for football athletes today. Repetitive concussions have been linked to many neurological disorders. Recently, it has been reported that repetitive subconcussive events can be a significant source of accrued damage. Since football athletes can experience hundreds of subconcussive hits during a single season, it is of utmost importance to understand their effect on brain health in the short and long term. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) was used to study changes in the default mode network (DMN) after repetitive subconcussive mild traumatic brain injury. Twenty-two high school American football athletes, clinically asymptomatic, were scanned using the rs-fMRI for a single season. Baseline scans were acquired before the start of the season, and follow-up scans were obtained during and after the season to track the potential changes in the DMN as a result of experienced trauma. Ten noncollision-sport athletes were scanned over two sessions as controls. Overall, football athletes had significantly different functional connectivity measures than controls for most of the year. The presence of this deviation of football athletes from their healthy peers even before the start of the season suggests a neurological change that has accumulated over the years of playing the sport. Football athletes also demonstrate short-term changes relative to their own baseline at the start of the season. Football athletes exhibited hyperconnectivity in the DMN compared to controls for most of the sessions, which indicates that, despite the absence of symptoms typically associated with concussion, the repetitive trauma accrued produced long-term brain changes compared to their healthy peers.