Exercise: Just What the Doctor Ordered, But Why? Elucidating Mechanisms for Women's Increased High-Density Lipoprotein Benefit From Exercise and for the Health ABC Study.

High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: ß = 0.09, p = .013; exercise on HDL in women: ß = 0.07, p = .015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer's disease risk, findings have implications for sex differences in AD risk factors.

Effects of Perceived Discrimination on Behavioral Health Outcomes in People Aging With Traumatic Brain Injury.

OBJECTIVE: To evaluate major and everyday experiences of discrimination (MED and EED, respectively) in relation to behavioral health outcomes in people with traumatic brain injury (PwTBI). SETTING: Outpatient research laboratory. PARTICIPANTS: Adults, 50 years or older, with a chronic (1+ year) history of moderate or severe TBI ( N = 118). DESIGN: Cross-sectional observational study. MAIN MEASURES: MED and EED (primary measures of interest) and behavioral health outcomes: global cognition, psychological symptoms, neurobehavioral symptoms, societal participation, and health-related quality of life (HRQoL). In participants with available geodata ( N = 28), neighborhood socioeconomic deprivation (ND) was examined as a potential contributor to MED, EED, and measured outcomes. RESULTS: EED and MED were significantly associated with psychological symptoms, neurobehavioral symptoms, and HRQoL after correction for multiple comparisons. Counter to expectations, EED were related to higher societal participation. MED and EED were unrelated to cognition. When MED and EED were entered together in hierarchical regressions, only EED made significant contributions beyond demographic and injury-related covariates to each outcome. Sensitivity analyses revealed that most of these relationships were not solely accounted for by disability-related discrimination. ND showed negligible associations with discrimination but moderate effect sizes for cognition and participation. Race was not significantly related to discrimination and was not a significant predictor in regression models but was strongly associated with ND. CONCLUSION: The current data provide preliminary support for perceived discrimination as an important factor in neurobehavioral and psychosocial health, but not cognitive performance, after TBI. These relationships appear to be driven by daily experiences of discriminatory treatment versus single major instances of injustice. Measured outcomes may also reflect socioeconomic challenges and structural discrimination faced by diverse PwTBI, although more work in this area is urgently needed. Multiple sources of marginalization and disenfranchisement and their functional effects should be considered in TBI rehabilitation and outcome monitoring.

The neuroinflammatory marker sTNFR2 relates to worse cognition and tau in women across the Alzheimer's disease spectrum.

Introduction: Despite women showing greater Alzheimer's disease (AD) prevalence, tau burden, and immune/neuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact remain unknown. We examined sex differences in how cerebrospinal fluid (CSF) neuroinflammation relates to cognition across the aging-mild cognitive impairment (MCI)-AD continuum and the mediating role of phosphorylated tau (p-tau) versus other AD biomarkers. Methods: Participants included 284 individuals from the Alzheimer's Disease Neuroimaging Initiative study. CSF neuroinflammatory markers included interleukin-6, tumor necrosis factor α, soluble tumor necrosis factor receptor 2 (sTNFR2), and chitinase-3-like protein 1. AD biomarkers were CSF p-tau181 and amyloid beta1-42 levels and magnetic resonance imaging measures of hippocampal and white matter hyperintensity volumes. Results: We found a sex-by-sTNFR2 interaction on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Higher levels of sTNFR2 related to poorer cognition in women only. Among biomarkers, only p-tau181 eliminated the female-specific relationships between neuroinflammation and cognition. Discussion: Women may be more susceptible than men to the adverse effects of sTNFR2 on cognition with a potential etiological link with tau to these effects.

Cognitive Reserve in Individuals Aging With Traumatic Brain Injury: Independent and Interactive Effects on Cognitive Functioning.

OBJECTIVE: To examine the influence of 2 temporal factors-age and injury chronicity-on the relationship between cognitive reserve (CR) and cognitive functioning in older adults with chronic traumatic brain injury (TBI). SETTING: Outpatient research laboratory. PARTICIPANTS: Adults, 50 years or older, with a 1- to 45-year history of moderate or severe TBI (N = 108). DESIGN: Cross-sectional observational study. MAIN MEASURES: CR was estimated using demographically corrected performance on a word-reading test (an approximation of premorbid IQ). Injury chronicity was operationalized as number of years since the date of injury. Composite cognitive scores were computed from performances on neuropsychological tests of processing speed, executive functioning, and memory. RESULTS: CR was positively and significantly related to all cognitive performances independent of age, injury chronicity, and injury severity. Greater injury chronicity significantly attenuated the effect of CR on processing speed such that individuals more distal from their injury date evidenced a weaker positive relationship between CR and performance. CONCLUSION: Temporal factors may modify associations between CR and cognition. Findings suggest that the protective effects of CR are temporally delimited, potentially contending with declines in brain reserve. The prognostic value of traditional outcome determinants should be considered in the context of injury chronicity.

Perceived discrimination and blood pressure in individuals aging with traumatic brain injury.

Purpose/Objective: Older adults with a history of traumatic brain injury (TBI) remain an understudied population, resulting in a paucity of geriatric-specific guidelines. Given an increased vascular risk among older adults with TBI, we aimed to examine distal predictors of vascular health in this population. Specifically, we sought to compare levels of perceived discrimination in Black and White older adults with a history of complicated mild, moderate, or severe TBI, and to examine the relationship between levels of discrimination and pulse pressure, a measure of vascular health. Research Method/Design: Self-report measures of everyday discrimination (ED) and major experiences of discrimination (MED) were completed by 106 individuals aging with TBI (27 identified as Black, 79 identified as White). Resting blood pressure was collected during the assessment. Results: MED, but not ED, was significantly higher among Black individuals versus White individuals aging with TBI. Greater MED was significantly associated with higher pulse pressure independent of race and antihypertensive medication status. There was a marginally significant race by MED interaction, where the association between MED and pulse pressure was observed in Black individuals but not White individuals. Injury severity was not associated with pulse pressure, nor were there significant severity by discrimination interactions on pulse pressure. Conclusions/Implications: Discrimination, which may arise from multiple sources of bias (e.g., related to race, disability), is associated with vascular burden. These findings suggest that patients' experiences of discrimination should be addressed as a factor that contributes to health and well-being in brain injury rehabilitation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Elevated Inflammatory Markers and Arterial Stiffening Exacerbate Tau but Not Amyloid Pathology in Older Adults with Mild Cognitive Impairment.

BACKGROUND: Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer's disease (AD), although their interactive effects have yet to be fully examined. OBJECTIVE: The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI). METHODS: This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1-42 (Aß42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified. RESULTS: Multiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aß42 (B = -1.01, p = 0.02); greater inflammation was associated with higher levels of Aß42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s < 0.05). CONCLUSION: PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults.

Race and ethnicity considerations in traumatic brain injury research: Incidence, reporting, and outcome.

PRIMARY OBJECTIVE: This study has three goals: to determine whether there is a higher rate of traumatic brain injury (TBI) for people of color (POC), whether TBI studies report racial/ethnic demographics, and whether there is a discrepancy in discharge destinations between Whites and POC. We examined whether 1) a higher percentage of POC would sustain head injuries than expected, 2) the majority of TBI studies examined (>50%) would not include racial/ethnic demographics, and 3) Whites would be discharged to further treatment over POC. RESEARCH DESIGN: Retrospective study and literature review. METHODS AND PROCEDURES: Data from the Pennsylvania Trauma System Foundation was used to determine the number of POC with TBI using X2 analysis, as well as where patients with TBI were being discharged using a configural frequency analysis. PubMed was used for the literature search to examine the frequency of reporting race/ethnicity in TBI literature. MAIN OUTCOMES AND RESULTS: Results demonstrated that Blacks sustain more TBIs than would be expected (p < .05), the majority of scientific studies (78%) do not report racial/ethnic demographic information, and Whites are discharged to further care more often than POC. CONCLUSIONS: These findings highlight differences in incidence and treatment of TBI between White individuals and POC, raising important considerations for providers and researchers.

Traumatic brain injury and frontal lobe plasticity.

Over 1.4 million people in the United States experience traumatic brain injury (TBI) each year and approximately 52,000 people die annually due to complications related to TBI. Traditionally, TBI has been viewed as a static injury with significant consequences for frontal lobe functioning that plateaus after some window of recovery, remaining relatively stable thereafter. However, over the past decade there has been growing consensus that the consequences of TBI are dynamic, with unique characteristics expressed at the individual level and over the life span. This chapter first discusses the pathophysiology of TBI in order to understand its dynamic process and then describes the behavioral changes that are the result of injury with focus on frontal lobe functions. It integrates a historical perspective on structural and functional brain-imaging approaches used to understand how TBI impacts the frontal lobes, as well as more recent approaches to examine large-scale network changes after TBI. The factors most useful for outcome prediction are surveyed, along with how the theoretical frameworks used to predict recovery have developed over time. In this chapter, the authors argue for the need to understand outcome after TBI as a dynamic process with individual trajectories, taking a network theory perspective to understand the consequences of disrupting frontal systems in TBI. Within this framework, understanding frontal lobe dysfunction within a larger coordinated neural network to study TBI may provide a novel perspective in outcome prediction and in developing individualized treatments.

Enhanced default mode connectivity predicts metacognitive accuracy in traumatic brain injury.

OBJECTIVE: To examine the role that intrinsic functional networks, specifically the default mode network, have on metacognitive accuracy for individuals with moderate to severe traumatic brain injury (TBI). METHOD: A sample of 44 individuals (TBI, n = 21; healthy controls [HCs], n = 23) were included in the study. All participants underwent an MRI scan and completed neuropsychological testing. Metacognitive accuracy was defined as participants' ability to correctly judge their item-by-item performance on an abstract reasoning task. Metacognitive values were calculated using the signal detection theory approach of area under the receiver operating characteristic curve. Large-scale subnetworks were created using Power's 264 Functional Atlas. The graph theory metric of network strength was calculated for six subsystem networks to measure functional connectivity. RESULTS: There were significant interactions between head injury status (TBI or HC) and internetwork connectivity between the anterior default mode network (DMN) and salience network on metacognitive accuracy (R2 = 0.13, p = .047) and between the posterior DMN and salience network on metacognitive accuracy (R2 = 0.15, p = .038). There was an interpretable interaction between head injury status and internetwork connectivity between the attention network and salience network on metacognitive accuracy (R2 = 0.13, p = .067). In all interactions, higher connectivity predicted better metacognitive accuracy in the TBI group, but this relationship was reversed for the HC group. CONCLUSION: Enhanced connectivity to both anterior and posterior regions within the DMN facilitates metacognitive accuracy postinjury. These findings are integrated into a larger literature examining network plasticity in TBI. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Correction: The evolution of cost-efficiency in neural networks during recovery from traumatic brain injury.

[This corrects the article DOI: 10.1371/journal.pone.0170541.].

Diminished neural network dynamics after moderate and severe traumatic brain injury.

Over the past decade there has been increasing enthusiasm in the cognitive neurosciences around using network science to understand the system-level changes associated with brain disorders. A growing literature has used whole-brain fMRI analysis to examine changes in the brain's subnetworks following traumatic brain injury (TBI). Much of network modeling in this literature has focused on static network mapping, which provides a window into gross inter-nodal relationships, but is insensitive to more subtle fluctuations in network dynamics, which may be an important predictor of neural network plasticity. In this study, we examine the dynamic connectivity with focus on state-level connectivity (state) and evaluate the reliability of dynamic network states over the course of two runs of intermittent task and resting data. The goal was to examine the dynamic properties of neural networks engaged periodically with task stimulation in order to determine: 1) the reliability of inter-nodal and network-level characteristics over time and 2) the transitions between distinct network states after traumatic brain injury. To do so, we enrolled 23 individuals with moderate and severe TBI at least 1-year post injury and 19 age- and education-matched healthy adults using functional MRI methods, dynamic connectivity modeling, and graph theory. The results reveal several distinct network "states" that were reliably evident when comparing runs; the overall frequency of dynamic network states are highly reproducible (r-values>0.8) for both samples. Analysis of movement between states resulted in fewer state transitions in the TBI sample and, in a few cases, brain injury resulted in the appearance of states not exhibited by the healthy control (HC) sample. Overall, the findings presented here demonstrate the reliability of observable dynamic mental states during periods of on-task performance and support emerging evidence that brain injury may result in diminished network dynamics.

Prefrontal gray matter volume predicts metacognitive accuracy following traumatic brain injury.

OBJECTIVE: To examine metacognitive ability (MC) following moderate to severe traumatic brain injury (TBI) using an empirical assessment approach and to determine the relationship between alterations in gray matter volume (GMV) and MC. METHOD: A sample of 62 individuals (TBI n = 34; healthy control [HC] n = 28) were included in the study. Neuroimaging and neuropsychological data were collected for all participants during the same visit. MC was quantified using an approach borrowed from signal detection theory (Type II area under the receiver operating characteristic curve calculation) to evaluate judgments during a modified version of the 3rd edition of the Wechsler Adult Intelligence Scale's Matrix Reasoning subtest where half of the items were presented randomly and half were presented in the order of increasing difficulty. Retrospective confidence judgments were collected on an item-by-item basis. Brain volumetric analyses were conducted using FreeSurfer software. RESULTS: Analyses of the modified Matrix Reasoning task data demonstrated that HCs significantly outperformed TBIs (ordered: d = .63; random: d = .58). There was a significant difference between groups for MC for the randomly presented stimuli (d = .54) but not the ordered stimuli. There was an association between GMV and MC in the TBI group between the right orbital region and MC (R2 = .11). In the HC group, there were associations between the left posterior (R2 = .17), left orbital (R2 = .29), and left dorsolateral (R2 = .21) regions and MC. CONCLUSIONS: These results are consistent with those of previous research on MC in the cognitive neurosciences, but this study demonstrates that injury may moderate the regional contributions to MC. (PsycINFO Database Record

Diminished neural network dynamics in amnestic mild cognitive impairment.

Mild cognitive impairment (MCI) is widely regarded as an intermediate stage between typical aging and dementia, with nearly 50% of patients with amnestic MCI (aMCI) converting to Alzheimer's dementia (AD) within 30 months of follow-up (Fischer et al., 2007). The growing literature using resting-state functional magnetic resonance imaging reveals both increased and decreased connectivity in individuals with MCI and connectivity loss between the anterior and posterior components of the default mode network (DMN) throughout the course of the disease progression (Hillary et al., 2015; Sheline & Raichle, 2013; Tijms et al., 2013). In this paper, we use dynamic connectivity modeling and graph theory to identify unique brain "states," or temporal patterns of connectivity across distributed networks, to distinguish individuals with aMCI from healthy older adults (HOAs). We enrolled 44 individuals diagnosed with aMCI and 33 HOAs of comparable age and education. Our results indicated that individuals with aMCI spent significantly more time in one state in particular, whereas neural network analysis in the HOA sample revealed approximately equivalent representation across four distinct states. Among individuals with aMCI, spending a higher proportion of time in the dominant state relative to a state where participants exhibited high cost (a measure combining connectivity and distance), predicted better language performance and less perseveration. This is the first report to examine neural network dynamics in individuals with aMCI.

Psychometrics of the AAN Caregiver Driving Safety Questionnaire and contributors to caregiver concern about driving safety in older adults.

ABSTRACTBackground:The American Academy of Neurology (AAN) updated their practice parameters in the evaluation of driving risk in dementia and developed a Caregiver Driving Safety Questionnaire, detailed in their original manuscript (Iverson Gronseth, Reger, Classen, Dubinsky, & Rizzo, 2010). They described four factors associated with decreased driving ability in dementia patients: history of crashes or citations, informant-reported concerns, reduced mileage, and aggressive driving. METHOD: An informant-reported AAN Caregiver Driving Safety Questionnaire was designed with these elements, and the current study was the first to explore the factor structure of this questionnaire. Additionally, we examined associations between these factors and cognitive and behavioral measures in patients with mild cognitive impairment or early Alzheimer's disease and their informants. RESULTS: Exploratory factor analysis revealed a four-component structure, consistent with the theory behind the AAN scale composition. These four factor scores also were significantly associated with performance on cognitive screening instruments and informant reported behavioral dysfunction. Regressions revealed that behavioral dysfunction predicted caregiver concerns about driving safety beyond objective patient cognitive dysfunction. CONCLUSIONS: In this first known quantitative exploration of the scale, our results support continued use of this scale in office driving safety assessments. Additionally, patient behavioral changes predicted caregiver concerns about driving safety over and above cognitive status, which suggests that caregivers may benefit from psychoeducation about cognitive factors that may negatively impact driving safety.

The evolution of cost-efficiency in neural networks during recovery from traumatic brain injury.

A somewhat perplexing finding in the systems neuroscience has been the observation that physical injury to neural systems may result in enhanced functional connectivity (i.e., hyperconnectivity) relative to the typical network response. The consequences of local or global enhancement of functional connectivity remain uncertain and this is particularly true for the overall metabolic cost of the network. We examine the hyperconnectivity hypothesis in a sample of 14 individuals with TBI with data collected at approximately 3, 6, and 12 months following moderate and severe TBI. As anticipated, individuals with TBI showed increased network strength and cost early after injury, but by one-year post injury hyperconnectivity was more circumscribed to frontal DMN and temporal-parietal attentional control regions. Cost in these subregions was a significant predictor of cognitive performance. Cost-efficiency analysis in the Power 264 data parcellation suggested that at 6 months post injury the network requires higher cost connections to achieve high efficiency as compared to the network 12 months post injury. These results demonstrate that networks self-organize to re-establish connectivity while balancing cost-efficiency trade-offs.

Data quality assurance and control in cognitive research: Lessons learned from the PREDICT-HD study.

We discuss the strategies employed in data quality control and quality assurance for the cognitive core of Neurobiological Predictors of Huntington's Disease (PREDICT-HD), a long-term observational study of over 1,000 participants with prodromal Huntington disease. In particular, we provide details regarding the training and continual evaluation of cognitive examiners, methods for error corrections, and strategies to minimize errors in the data. We present five important lessons learned to help other researchers avoid certain assumptions that could potentially lead to inaccuracies in their cognitive data.

An Evolutionary Computation Approach to Examine Functional Brain Plasticity.

One common research goal in systems neurosciences is to understand how the functional relationship between a pair of regions of interest (ROIs) evolves over time. Examining neural connectivity in this way is well-suited for the study of developmental processes, learning, and even in recovery or treatment designs in response to injury. For most fMRI based studies, the strength of the functional relationship between two ROIs is defined as the correlation between the average signal representing each region. The drawback to this approach is that much information is lost due to averaging heterogeneous voxels, and therefore, the functional relationship between a ROI-pair that evolve at a spatial scale much finer than the ROIs remain undetected. To address this shortcoming, we introduce a novel evolutionary computation (EC) based voxel-level procedure to examine functional plasticity between an investigator defined ROI-pair by simultaneously using subject-specific BOLD-fMRI data collected from two sessions seperated by finite duration of time. This data-driven procedure detects a sub-region composed of spatially connected voxels from each ROI (a so-called sub-regional-pair) such that the pair shows a significant gain/loss of functional relationship strength across the two time points. The procedure is recursive and iteratively finds all statistically significant sub-regional-pairs within the ROIs. Using this approach, we examine functional plasticity between the default mode network (DMN) and the executive control network (ECN) during recovery from traumatic brain injury (TBI); the study includes 14 TBI and 12 healthy control subjects. We demonstrate that the EC based procedure is able to detect functional plasticity where a traditional averaging based approach fails. The subject-specific plasticity estimates obtained using the EC-procedure are highly consistent across multiple runs. Group-level analyses using these plasticity estimates showed an increase in the strength of functional relationship between DMN and ECN for TBI subjects, which is consistent with prior findings in the TBI-literature. The EC-approach also allowed us to separate sub-regional-pairs contributing to positive and negative plasticity; the detected sub-regional-pairs significantly overlap across runs thus highlighting the reliability of the EC-approach. These sub-regional-pairs may be useful in performing nuanced analyses of brain-behavior relationships during recovery from TBI.