In VIVRE (NCT04448431), vortioxetine was associated with significantly higher rates of symptomatic and functional remission, better daily and social functioning, and greater treatment satisfaction than desvenlafaxine in patients with major depressive disorder (MDD) and partial response to selective serotonin reuptake inhibitor (SSRI) therapy. This analysis further explored the relative improvement in patient functioning with vortioxetine versus desvenlafaxine.

VIVRE was a randomized, double-blind study of vortioxetine (10 or 20 mg/day) versus desvenlafaxine (50 mg/day) in adults with MDD and partial response to initial SSRI monotherapy. Mean percentage changes from baseline to week 8 in Functioning Assessment Short Test (FAST) total and domain scores were analyzed by treatment group in the overall population and in working patients.

In the overall population, the mean reduction in FAST total score from baseline after 8 weeks of treatment was 37.2% in vortioxetine-treated patients versus 31.8% in desvenlafaxine-treated patients (P = 0.04). Significantly greater improvements versus desvenlafaxine were seen in vortioxetine-treated patients for FAST autonomy, cognitive functioning, and interpersonal-relationships scores (all P < 0.05). In working patients, the mean reduction in FAST total score from baseline at week 8 was 38.7% versus 32.1% in the vortioxetine and desvenlafaxine groups, respectively (P = 0.04). Significant correlations were seen between absolute changes in patient functioning, and those in depression severity and health-related quality of life.

Vortioxetine was significantly better than desvenlafaxine in improving overall functioning as well as daily, social, and cognitive functioning in patients with MDD with inadequate response to prior SSRI therapy.

Symptoms and cognition are both utilized as indicators of recovery following pediatric concussion, yet their interrelationship is not well understood. This study aimed to investigate: 1) the association of post-concussion symptom burden and cognitive outcomes (processing speed and executive functioning [EF]) at 4 and 12 weeks after pediatric concussion, and 2) the moderating effect of sex on this association.

This prospective, multicenter cohort study included participants aged 5.00–17.99 years with acute concussion presenting to four Emergency Departments of the Pediatric Emergency Research Canada network. Five processing speed and EF tasks and the Post-Concussion Symptom Inventory (PCSI; symptom burden, defined as the difference between post-injury and retrospective [pre-injury] scores) were administered at 4 and 12 weeks post-concussion. Generalized least squares models were conducted with task performances as dependent variables and PCSI and PCSI*sex interaction as the main predictors, with important pre-injury demographic and injury characteristics as covariates.

311 children (65.0% males; median age = 11.92 [IQR = 9.14–14.21 years]) were included in the analysis. After adjusting for covariates, higher symptom burden was associated with lower Backward Digit Span (χ2 = 9.85, p = .043) and Verbal Fluency scores (χ2 = 10.48, p = .033) across time points; these associations were not moderated by sex, ps ≥ .20. Symptom burden was not associated with performance on the Coding, Continuous Performance Test, and Color-Word Interference scores, ps ≥ .17.

Higher symptom burden is associated with lower working memory and cognitive flexibility following pediatric concussion, yet these associations were not moderated by sex. Findings may inform concussion management by emphasizing the importance of multifaceted assessments of EF.

As the older adult population increases in the coming decades, the number of persons that develop dementia of the Alzheimer’s type (DAT) will increase accordingly. Though curative treatment for Alzheimer’s disease remains elusive, early detection of cognitive decline allows for initiation of pharmacological treatment to slow disease progression and non-pharmacological approaches to support quality of life and well-being of affected individuals and their care partners. Streamlined approaches that bridge the gap between brief screenings and comprehensive neuropsychological evaluation are needed. The NIH Toolbox Cognition Battery (NIHTB-CB) is a brief, easily administered, computerized cognitive battery that assesses various aspects of both fluid and crystallized cognitive abilities. ARMADA (Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging) is a multi-site study that aims to validate the NIHTB across the spectrum from normal aging to DAT. The current study utilized longitudinal data from ARMADA to determine whether performance on the NIHTB-CB detects cognitive decline in persons with normal cognition (NC), mild cognitive impairment (MCI), and mild DAT over the span of two years. We predicted that scores would decline for the MCI and DAT groups, but not for the NC group.

Participants were 191 participants drawn from the larger ARMADA cohort aged 65-84 (nNC = 118, nMCI = 47, nDAT = 26) that completed the NIHTB-CB at baseline and 12 months. The clinical groups were significantly older than the NC group at baseline (MNC = 72.72, MMCI = 76.63, MDAT = 75.42; p < .001) and the NC and MCI groups had significantly more years of education than the DAT group (MNC = 17.03, MMCI = 16.83, MDAT = 15.54; p = .008).

Mixed model ANOVAs determined differences in uncorrected NIHTB-CB scores between clinical groups at baseline and 12 months, controlling for age and education. There were significant interactions between time and clinical group for Flanker (p < .001), Pattern Comparison (p < .001), and Picture Vocabulary (p = .001), such that the DAT group demonstrated a more negative slope of change than the NC and MCI groups. For Oral Reading, the MCI group demonstrated a more negative slope of change than the NC and DAT groups (p = .01).

Differential score trajectories were found for the Flanker task, with a more negative pattern of change in scores in the DAT group compared to the NC and MCI groups. Contrary to expectation, scores decreased for the two crystallized subtests across groups, which may reflect regression to the mean given high baseline scores, especially for Picture Vocabulary; however, these results were also moderated by group with less decline in scores in the NC group, which may indicate involvement of non-crystallized abilities in executing a single word comprehension task. Group differences were subtle, which may in part reflect the relatively short period of follow up. The Flanker task appears to be most sensitive to decline in mild DAT compared to MCI and NC. Results provide preliminary support for the utility of NIHTB-CB in detecting cognitive decline along the cognitive aging to DAT spectrum.

US forces used Agent Orange (AO) during the Vietnam War and continued to store/test it at other locations after the war. AO is a powerful herbicide including dioxin, a highly toxic ingredient classified as a human carcinogen. The National Academies of Sciences, Engineering, and Medicine periodically review the literature on the health effects of AO exposure (AOE) and concluded in 2018 that there is sufficient evidence linking AO with a wide range of adverse health outcomes, including neurologic disorders (e.g., Parkinson’s disease). The VA has a list of medical disorders considered presumptive conditions related to AOE. More recently, AOE has been linked to a nearly double risk compared to those without AOE for receiving a dementia diagnosis. To our knowledge, no one has investigated the association of AOE to mild cognitive impairment (MCI), a condition thought to precede dementia.

We examined men in three waves of the Vietnam Era Twin Study of Aging (VETSA). In wave 3, participants self-reported yes/no to the question of whether they ever had prolonged or serious AOE. MCI was diagnosed by the Jak-Bondi approach. Impairment was defined as 2+ tests within a cognitive domain that were more than 1.5 standard deviations below normative means after adjusting for premorbid cognitive ability. In mixed effects models, we tested the effect of AOE on MCI status. Models were adjusted for age, ethnicity, and non-independence within twin pairs.

In wave 3, 12.6% (230) of 1167 participants reported AOE. Those with AOE data had mean ages of 51.1 (wave 1), 56.0 (wave 2), and 61.4 (wave 3). Those with data on both AOE and MCI numbered 861 (wave 1), 900 (wave 2), 1121 (wave 3), and 766 had AOE and MCI at all waves. AOE was significantly related to wave 2 MCI (p < .001), but not to waves 1 and 3 MCI. AOE was significantly associated with the number of time points at which someone met criteria for MCI (p = .011). Analyses were conducted on six cognitive domains used to diagnose MCI, using available participants per wave. At all 3 waves, AOE was significantly associated with lower scores in processing speed (p = .003, p = .004, p = .005, respectively), working memory (p < .001, p = .002, p = .008) and nearly significant at all waves for executive dysfunction (p < .001, p < .001, p = .050). There were two other significant associations [wave 2 memory (p = .038), wave 3 fluency (p = .024)]. The semantic fluency cognitive domain was unrelated to AOE in all waves.

AOE was consistently associated with lower processing speed, working memory, and executive dysfunction in males ages 51-61. It was also associated with the number of time points at which one met criteria for MCI in that age range, and with MCI in the mid-fifties. Findings support the idea of a risk for greater cognitive decline in those exposed to AO earlier in their lives, and with a risk for developing MCI.

Ecological momentary assessment (EMA) allows for tracking participant responses across multiple timepoints within the context of typical daily experiences. This study used EMA delivered via smartwatches to investigate dynamic associations between older adults’ fluctuations in cognitive performance as measured by an n-back test and self-reports of current internal (i.e., mental sharpness, fatigue, stress) and external (i.e., environmental distractions, time of day) contextual states over seven days. We hypothesized that 1) cognitive test fluctuations throughout the week would be meaningful beyond average cognitive test scores and 2) cognitive test scores would fluctuate in response to internal and external contexts.

Participants were 28 community-dwelling older adults recruited for a larger clinical trial assessing the influence of lifestyle factors and compensatory strategy use on cognitive health. During week one of the trial, participants received a smartwatch which sent prompts four times a day for seven consecutive days. The prompts included a 45-second one-back shape test, along with Likert-style questions about their current experience. Questions assessing participants’ internal contexts asked about participants’ experience “right now” of mental sharpness, physical fatigue, and stress. External context was assessed via the EMA prompt, “Right now my environment is distracting,” and time of day of the response.

Data was screened such that all data points outside the 7-day prompt window were removed, one participant who did not respond to any prompts was removed, and participants who responded to less than 60% of the shape test prompts were removed (n = 10). The sample used for this preliminary analysis included 17 participants (Age, M = 71.94 years; Education, M = 14 years; 88% Female; 88% White) with an average compliance of 75% (Range = 17 - 26 shape test responses) and an average shape test accuracy of > 92%. Hypothesis 1 was supported by the large fluctuations of the average cognitive test scores across timepoints (M = 24.35, Min = 16, Max = 27, SD = 2.54) and by repeated-measures ANOVA of average cognitive test scores by day (F(1,7) = 5.24, p < 0.01). Hypothesis 2: Cross-correlation lags 0 to 4 were assessed. For internal contexts, cross-correlation showed a medium correlation between mental sharpness and cognition for lags 0 (r = 0.46) and 1 (r = 0.4); a small to medium correlation between physical fatigue and cognition for lags 0 (r = -0.51) and 1 (r = -0.31); and no correlation between stress and cognition (r < 0.2). For external contexts, cross-correlation revealed no correlation between environmental distraction and cognition (r < 0.3), and repeated measures ANOVA revealed no effect of time of day on cognition scores (p > 0.05).

Older adults’ cognitive performance on an n-back shape test varied over time with internal contextual states. Cognitive performance was positively associated with feelings of mental sharpness and negatively associated with physical fatigue. Current external environmental distractions and time of day were less influential on cognitive performance. As more data is collected, influences of individual fluctuations in cognitive performance will be investigated.

Accumulating evidence from case-control and population studies suggests attention-deficit/hyperactivity disorder (ADHD) confers a 2- to 5-fold risk of all-cause dementia later in life. Here, we investigate vascular burden as a potential mediator of this relationship, because vascular integrity is well known to be compromised in ADHD (due to chronic obesity, diabetes, and hypertension) and is also a robust risk factor for neurodegeneration (due to reduced cerebral blood flow). We use brain white matter hyperintensities (WMH) as a measure of vascular burden.

Thirty-nine adults aged 48-81 years with clinical ADHD, and 37 matched controls, completed neuropsychological testing and 1.5 T structural neuroimaging. None had stroke. Cognitive tests were demographically-adjusted to Z scores using regression-based norms generated from the control group, and averaged across tests within domains of short- and long-term verbal memory (forward digit span, California Verbal Learning Test, Logical Memory), visual memory (Visual Recognition, Rey Complex Figure), processing speed (coding, trails A, Stroop word-reading and color-naming), language (Boston Naming Test, semantic fluency), visuoconstruction (clock drawing, Rey Complex Figure copy), and executive function (backward digit span, trails B, phonemic fluency, Stroop inhibition, Wisconsin Card Sorting Test). Total WMH volumes (i.e., combined periventricular and deep) within subcortical, temporal, frontal, parietal, and occipital regions were individually divided by regional volumes to produce a proportion of each region representing WMH, then log-transformed to correct for skew. Age-corrected linear regression quantified total effects of ADHD on cognition; when these were significant, mediation models quantified the direct effects of ADHD on WMH volumes and the direct effect of WMH volumes on cognition. Sobel’s test estimated indirect effects of ADHD on cognition via WMH.

Group had a significant total effect on Processing Speed (ß=-1.154, p<.001) and on Executive Functioning (ß=-0.587, p=.004), where ADHD participants had lower composite scores (M=-1.10, SD=1.76 and M=-0.54, SD=1.14 respectively) than controls (M=0.02, SD=0.74; M=0.00, SD=0.49). Only frontal-lobe WMH had direct effects on Processing Speed (ß=-0.315, p=.012) and Executive Functioning (ß=-0.273, p<.001). The direct effect of ADHD on frontal WMH was significant (ß=-0.734, p=.016), and Sobel’s tests supported an indirect effect of ADHD on Executive Functioning (z=2.079, p=.038) but not Processing Speed (z=1.785, p=.074) via WMH. Because the effect of ADHD on WMH was negative (i.e., fewer WMH in ADHD) despite worse cognition than controls, we tested the a posteriori hypothesis that WMH burden may be relatively more deleterious for ADHD than controls. We found considerably stronger negative correlations between total WMH volumes and Processing Speed (r=-.423, p=.009) and Executive Functioning (r=-.528, p<.001) in the ADHD group than in controls (r=-.231, p=.175 and r=-.162, p=.346, respectively), even though total whole-brain proportion of WMH (M=0.15%, SD=0.27; Mann-Whitney l/=430.0, p=.002) and frontal-lobe proportion of WMH volumes (M=0.33%, SD=0.51; Mann-Whitney U=464.0, p=.007) were lower in ADHD than in controls (M=0.29%, SD=0.42 and M=0.66%, SD=0.88, respectively).

WMH burden contributes significantly to the relationship between ADHD and cognition, but ADHD remains an independent contributor to worse processing speed and executive functioning in older adults. Vascular burden may have relatively more deleterious effects on cognition in ADHD, potentially due to decades of accumulated allostatic load, whereas healthy controls can accumulate greater amounts of WMH before cognition is impacted.

To examine patterns of cognitive function among a clinical sample of patients seeking treatment for Post-Acute Sequelae of COVID-19 (PASC).

One hundred nineteen patients each completed a baseline neuropsychological evaluation, including clinical diagnostic interview, cognitive assessments, and a comprehensive battery of self-report questionnaires. Patients had a mean age of 50 years (range:18 to 74, SD=10.1) and a mean of 15.5 years (SD=2.54) of formal education. Patients were primarily female (74%) and of White/Caucasian race (75%). Hierarchical agglomerative clustering was used to partition the data into groups based on cognitive performance. Euclidean distance was used as the similarity measure for the continuous variables and within-cluster variance was minimized using Ward’s method. The optimal number of clusters was determined empirically by fitting models with 1 to 15 clusters, with the best number of clusters selected using the silhouette index. All analyses were conducted using the NbClust package, an R package for determining the relevant number of clusters in a data set.

Clustering yielded two distinct clusters of cognitive performance. Group 1 (n=57) performed worse than Group 2 (n=62) on most cognitive variables (including a brief cognitive screener and tests of attention/working memory, executive function, processing speed, learning and delayed recall). Of note, there were no significant differences between groups on an infection severity scale, hospitalizations/ICU admissions, initial or current COVID-19 symptoms, or prior comorbidities. Groups did not differ in age or gender, but Group 1 had a lower education level than Group 2 (M=14.7, SD=2.45 vs. M=16.2, SD=2.42; p=.001). Group 1 also had significantly more minorities than Group 2 (40% vs. 8%; p<.001). No other demographic differences (income, living arrangement, or marital status) were observed. In comparison to Group 2 patients, Group 1 patients self-reported significantly higher levels of anxiety and depression and functional impairment (Functional Activities Questionnaire: M=11.3, SD=8.33 vs. M=7.65, SD=7.97), perceived stress (Perceived Stress Scale: M=24.7, SD=7.90 vs. M=20.3, SD=7.89), insomnia (Insomnia Severity Index: M=16.0, SD=6.50 vs. M=13.1, SD=6.76), and subjective cognitive functioning (Cognitive Failures Questionnaire: M=58.8, SD=16.9 vs. M=50.3, SD=18.6; p’s<.05).

Findings indicate two predominant subtypes of patients seeking treatment for PASC, with one group presenting as more cognitively impaired and reporting greater levels of anxiety, depression, insomnia, perceived stress, functional limitations, and subjective cognitive impairment. Future directions include follow-up assessments with these patients to determine cognitive trajectories over time and tailoring treatment adjuncts to address mood symptoms, insomnia, functional ability, and lifestyle variables. Understanding mechanisms of differences in cognitive and affective symptoms is needed in future work. Limitations to the study were that patients were referred for evaluation based on the complaint of “brain fog” and the sample was a homogenous, highly educated, younger group of individuals who experienced generally mild COVID-19 course.

To determine the effects of the non-classic psychedelic, ibogaine, on cognitive functioning. Ibogaine is an indole alkaloid derived from the Tabernanthe Iboga plant family, indigenous to Africa, and traditionally used in spiritual and healing ceremonies. Ibogaine has primarily been studied with respect to its clinical efficacy in reducing substance addiction. There are, however, indications that it also may enhance recovery from traumatic experiences. Ibogaine is a Schedule 1 substance in the USA.

Participants were U.S. Special Operations Veterans who had independently and voluntarily referred themselves for an ibogaine retreat at a specialized clinic outside the USA prior to learning about this observational study. After meeting rigorous screening requirements, 30 participants were enrolled, all endorsing histories of combat and repeated blast exposure, as well as traumatic brain injury. Participants were seen in person pre-treatment, post-treatment, and one-month post-treatment for neuropsychological testing, neuroimaging, and collection of clinical outcome measures. All 30 participants were seen pre- and post-treatment, of whom 27 were also able to return one-month post-treatment.

The neuropsychological battery included the the Hopkins Verbal Learning Test (HVLT), the Brief Visuospatial Memory Test - Revised (BVMT-R), the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) Working Memory Index (Digit Span and Arithmetic) and Processing Speed Index (Symbol Search and Coding), and the Delis-Kaplan Executive Function System (D-KEFS) tests of Verbal Fluency (VF), Trail Making (TMT), Color Word (CW), and Tower Test (TT). For repeated measures, alternate forms were used whenever possible.

Repeated-measures ANOVA revealed significant effects of time, with post-treatment improvements across multiple measures including processing speed (WAIS-IV PSI; F(2,25) = 26.957, p < .001), executive functions (CW Conditions 3 and 4: F(1.445,25) = 11.383, p < .001 and F(1.381,25) = 7.687, p = .004, respectively), verbal fluency (VF Condition 3 correct and accuracy: F(2,25) = 6.419, p = .003 and F(2,25) = 153.076, p < .001, respectively), and verbal learning (HVLT Total Recall (alternate forms used at each time point): F(1.563,23) = 6.958, p = .004). Score progression graphs are presented. Performance on all other cognitive measures did not significantly change following treatment.

To our knowledge, this is the first prospective study examining neuropsychological test performance following ibogaine use at post-treatment and one-month post-treatment time points. Our results indicated that several cognitive domains improved either post-treatment or one-month post-ibogaine treatment, suggesting ibogaine’s therapeutic potential for cognition in the context of traumatic brain injury and mood disorders. Potential explanations include neuroplastic changes, reduction of PTSD and mood-related effects on cognitive functioning, and practice effects. While we found no evidence of negative cognitive consequences for up to one-month post-single-ibogaine treatment, further study of this substance is necessary to clarify its clinical utility and safety parameters.

Apathy, or loss of motivation and interest, is a common sequela of moderate to severe traumatic brain injury (msTBI) and has been associated with frontal lesions and with executive dysfunction in a sample an average of one year post injury (Andersson & Bergdalen, 2002). In older adults sustaining msTBI in particular, the appearance of apathy is more likely to be comorbid with depression when compared to injury in younger adults (Kant et al., 1998). However, studies have consistently shown an important dissociation between apathy and depression, despite overlapping symptoms, with apathy in particular associated with frontal lobe damage (Worthington & Wood, 2018). The present study holds two primary goals. First, to examine the relationship between current apathy ratings and cognition after controlling for ratings of depression and perceived changes in apathy, to account for the unique relationship of injury-related apathy on cognition. Second, to examine the potential variable role of APOE4 carrier status on depression and apathy ratings.

110 older adults with a lifetime history of msTBI (M=9.5 years post-injury) were included as part of a cross-sectional study. Apathy was measured using the Frontal Systems and Behaviors Scale (FrSBe) for both current apathy ratings and perceived change in apathy from pre- to post-injury. Depression was measured using the depression subscale of the Brief Symptom Inventory (BSI). Outcome measures included normed scores for learning (HVLT-R total recall), retention (HVLT-R percent retention), processing speed (Trails A), set-shifting and working memory (Trails B, Digit Span Backwards), and phonemic and category fluency (D-KEFS letter and category fluency). The main independent variable of interest was current apathy ratings. Depression and perceived apathy change were included as control variables for all analyses. Vif scores were calculated for all analyses to ensure that variables were not multicollinear. Finally, we ran an ANOVA to examine the relationship between apathy, depression, and APOE4 carrier status.

When controlling for depression and perceived changes in apathy, current apathy ratings were associated with poorer performance on learning (p=.04, n2=.04), processing speed (p=.001, n2=.10), set-shifting (p=.02, n2=.05), attention (p=.04, n2=.04), phonemic fluency (p=.001, n2=.09), category fluency (p=.001, n2=.10). Current apathy ratings were not associated with retention or working memory. Apathy was significantly associated with depression (p <.001), but was not associated with APOE4 carrier status or the interaction between depression and carrier status.

Despite overlap between depressive symptoms and apathy questionnaires (i.e., loss of interest/pleasure), by controlling for depressive symptoms and perceived changes following injury, we demonstrate the significant independent association of apathy and cognition in an older sample with chronic msTBI. Further, although previous work has shown strong associations between depression and APOE4 carrier status in chronic msTBI samples (Vervoordt et al., 2021), there was no significant relation with apathy directly in our sample, providing further evidence that these are neurobiologically distinct syndromes.

1) Evaluate the association of self- and study-partner report of subjective cognitive decline (SCD) to objective cognitive performance across ethnoracial groups. 2) Evaluate the concordance of self- and study partner report of SCD across ethnoracial groups.

Participants were 5241 non-Hispanic White (NHW), 267 non-Hispanic Black (NHB), 225 Hispanic, and 228 Asian participants screened for the A4 study (N=5961). Participants completed the Preclinical Alzheimer Cognitive Composite (PACC), and self- and study partner-report of SCD using the Cognitive Function Index (CFI). Analysis of variance was used to assess difference in key variables by ethnoracial group. Regression analyses were conducted to evaluate the association of SCD and objective performance by ethnoracial group, and the association between self-and study partner report of SCD by ethnoracial group.

Asian participants reported the highest mean CFI relative to all other groups, while NHW reported the lowest (F(3,5957)=41.93, p <.001). Asian and NHW participants had higher PACC scores relative to NHB and Hispanic participants (F(3,5957)=41.93, p <.001). Regression analyses revealed higher CFI was associated with lower PACC score across groups, and this association was strongest in the Asian sample relative to other groups (F(10, 5897)=40.49, p<.001,R2=.06). Evaluation of study partner characteristics suggested NBH participants had the highest proportion on non-spousal study partners relative to other groups. Regression analyses revealed no differences in the association of self- and study partner report of SCD across ethnoracial groups (F(10, 5859)=132.9, p<.001, R2=0.18).

Results suggest that that SCD is associated with objective cognitive performance across racial groups, although the strength of this association appears to vary in this sample. There is also consistent concordance between self- and study partner report of SCD across groups, despite differences in study partner relationships. SCD may be considered a valid predictor of subtle cognitive change across groups in the A4 sample. Limitations include small group sizes relative to the large NHW sample. Future work with larger, more representative samples are needed to further validate these findings.

Determine how characteristics of deployment mild traumatic brain injury (TBI) and blast exposure influence the relationship between the functional brain connectome with cognitive outcomes and symptom severity.

N = 181 Iraq and Afghanistan combat veterans completed structured clinical interviews, cognitive testing, self-report questionnaires, and magnetoencephalography (MEG). MEG data were acquired in the resting-state with eyes open. MEG data were beamformed to identify brain regions active at rest. Functional brain connectomes representing the unique network present for a given individual were created using active brain regions identified for each participant. Network metrics describing these connectomes were calculated at the participant level. Cognitive tests included the WAIS-IV, Trail Making Test Parts A&B, and the Controlled Oral Word Association test. Due to differences in normative data across tests, raw scores were used in analyses. Symptom measures included the PTSD Checklist - 5 (PCL-5), Patient Health Questionnaire (PHQ-9), Neurobehavioral Symptoms Inventory (NSI), Quality of Life After Brain Injury (QOLIBRI), Pittsburgh Sleep Quality Index (PsQi), the Distress Tolerance Scale (DTS), and the PROMIS Pain Interference Scale (PROMIS-PI).

Hierarchical linear regression analyses revealed that several network metrics were significantly related to both cognitive outcomes and symptom severity after adjusting for demographic covariates and clinical characteristics.

The relationship between Global Efficiency (GE) and cognitive outcomes was moderated by deployment TBI on the WAIS-IV Full Scale Index (FSI), Perceptual Reasoning Index (PRI), and General Ability Index (GAI). In all cases, when deployment TBI was absent, greater GE was associated with poorer cognitive scores. The relationship between GE and symptom severity was moderated by the severity of blast exposure. Greater GE was associated with lower symptom severity at lower blast severities for the PHQ-9 and QOLIBRI A (thinking) and E (negative emotions). Moderation effects were also observed for the PSQI. In the absence of deployment TBI, greater GE was associated with better sleep quality; however, in the presence of deployment TBI, greater GE was associated with poorer sleep quality. Other connectome-outcome relationships were not consistently moderated by Deployment TBI or blast history

Results demonstrated relationships between several aspects the functional connectome of the brain with both cognitive outcomes and symptom severity beyond effects of common demographic and clinical variables. Moderation analyses revealed that the relationship between GE of the connectome and outcomes is frequently disrupted by deployment TBI and blast. GE is a measure of the ease of information transfer through the network. These results identified consistent relationships between GE and outcomes in the absence of deployment TBI or blast, but these relationships disappear when deployment TBI or blast are present. Participants in this study were on average 11 years post-TBI or blast exposure, suggesting these are chronic rather than acute effects. GE was significantly correlated with most symptom severity measures as well as the WAIS-IV PRI, GAI, VCI, and FSI. Future efforts to normalize the relationship between GE and outcomes following TBI may improve rehabilitation outcomes and directly affect areas of concern commonly reported by service members following TBI or blast exposure.

Pediatric traumatic brain injury (TBI) is the leading cause of disability in children under the age of 15, often resulting in executive function deficits and poor behavioral outcomes. Damage to white matter tracts may be a driving force behind these difficulties. We examined if whether 1) greater TBI severity was associated with worse neurobehavioral outcome, 2) greater TBI severity was associated with tract-based white matter microstructure, and 3) worse neurobehavioral outcome was associated with white matter microstructure.

Twelve children with complicated-mild TBI (cmTBI; Mage=12.59, nmale=9), 17 with moderate-to-severe TBI (msTBI; Mage =11.50, nmale=11), and 21 with orthopedic injury (OI; Mage =11.60, nmale=16), 3.94 years post injury on average, were recruited from a large midwestern children’s hospital with a Level 1 Trauma Center. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL) while children completed 64-direction diffusion tensor imaging in a Siemens 3T scanner. White matter microstructure was quantified with FMRIB’s Diffusion Toolbox (FSLv6.0.4). Tract-Based Spatial Statistics computed fractional anisotropy (FA) and mean diffusivity (MD) for the cingulum bundle (CB), inferior fronto-occipital fasciculus (IFOF), superior longitudinal fasciculus (SLF), and uncinate fasciculus (UF), bilaterally.

Group differences were assessed using one-way ANOVA. Children with msTBI were rated as having worse Sluggish Cognitive Tempo on the CBCL than children with cmTBI and OI (p=.02, eta2=.143); no other parent-rated differences reached significance. Group differences were found in left SLF FA (p=.031; msTBI<cmTBI=OI) and approached significance in left UF FA (p=.062, eta2=.114; msTBI<OI). Group differences were also found in right IFOF MD (p=.048; msTBI>OI) and left SLF MD (p=.013; msTBI>cmTBI=OI). Bivariate correlations assessed cross-domain associations. Higher left IFOF FA was associated with better BRIEF Metacognitive Skills (r=-.301, p=.030) and CBCL School Competence (r=.280; p=.049). Higher left SLF FA was associated with better BRIEF Behavioral Regulation and Metacognitive Skills (r=-.331, p=.017 and r=-.291, p=.036, respectively), and CBCL School Competence and Attention Problems (r=.398, p=.004 and r=-.435, p=.001, respectively). Similarly, higher right UF FA was broadly associated with better neurobehavioral outcomes, including Behavioral Regulation and Metacognitive Skills (r=-.324, p=.019 and r=-.359, p=.009, respectively), and School Competence, Attention Problems, and Sluggish Cognitive Tempo (r=.328, p=.020, r=-.398, p=.003, and r=-.356, p=.010, respectively). Higher right CB MD was associated with worse Behavioral Regulation (r=.327, p=.018) and more Attention Problems (r=.278, p=.046); higher left and right SLF MD was associated with Sluggish Cognitive Tempo (r=.363, p=.008, r=.408, p=.003, respectively).

Children with TBI, particularly msTBI, were rated as having cognitive slowing; while other anticipated group differences in neurobehavioral outcomes were not found, this appears driven by milder difficulties in cmTBI and OI groups. In fact, across CBCL and BRIEF subscales, children with msTBI were rated as approaching or exceeding a full standard deviation deficit based on normative data. TBI severity was also associated with white matter microstructure and cross-domain associations linked microstructure with observable neurobehavioral morbidities, suggesting a possible mechanism post-injury. Future longitudinal studies would be useful to examine the temporal evolution of deficits.

Health disparities among African Americans (AAs) in the United States are evident, especially among older adults and people living with HIV (PLWH). These health disparities include worse cognitive functioning among AAs than White counterparts. Though disparities in health literacy among AAs impact health outcomes across clinical populations, less is known on the mechanistic role health literacy may play in explaining racial differences in cognitive functioning among older PLWH. The current study investigated the association between health literacy and global cognitive functioning among middle-aged and older AA and White adults with and without HIV in the Deep South.

Two hundred and seventy-three people (170 PLWH: 146 AA, 24 White; 103 HIV-negative: 67 AA, 36 White) were enrolled in an observational study and completed measures of sociodemographic characteristics, as well as the reading subtest of the Wide Range Achievement Test-3rd Edition to assess verbal IQ. A composite score of socioeconomic status (SES) was created using total years of education and annual household income. Neurocognitive functioning was assessed using a comprehensive cognitive battery (i.e., verbal, attention/working memory, executive function, learning, recall, speed of processing, and motor), from which a sample-based global Z-score composite was created. Health literacy was measured using a sample-based composite Z-score derived from the Rapid Estimate of Adult Literacy in Medicine, Test of Functional Health Literacy in Adults Reading Comprehension, Newest Vital Sign, and Expanded Numeracy Scale. First, multivariable linear regression analyses were performed within both PLWH and HIV-negative samples examining the association between race, SES, verbal IQ, and health literacy with cognitive functioning. These results informed two bootstrap confidence interval mediation analyses to determine whether health literacy mediated the association between race and global cognitive functioning.

In both PLWH and HIV-negative individuals, linear regressions showed that Whites had better global cognitive functioning, health literacy, and verbal IQ than AAs. Linear regressions showed that health literacy had an independent association with cognitive function when accounting for verbal IQ and SES. Mediations showed that health literacy significantly mediated the association between race and global cognitive functioning in both samples, independent of verbal IQ (PLWH: b = .07, 95% CI [0.0096, 0.2149]; HIV-negative: b = .15, 95% CI [0.0518, 0.2877]), indicating that Whites were expected to obtain higher global cognitive Z-scores than AAs in both PLWH and HIV-negative samples, through the mediating effect of better health literacy.

Health literacy significantly mediated the association between race and global cognitive functioning among middle-aged and older adults with and without HIV, underscoring the importance of health literacy in explaining racial disparities in cognitive outcomes among AAs in the Deep South. Findings have implications for guiding clinicians and healthcare providers in developing interventions that promote health literacy in these underserved populations, which may have downstream impacts on cognitive functioning. Future work is needed to examine mechanisms whereby health literacy impacts neurocognition among AA PLWH.

To present the Mobile Toolbox (MTB), comprised of an expandable library of cognitive and other tests, including adapted versions of NIH Toolbox® measures. The MTB provides a complete research platform for app creation, study management, data collection, and data management. We will describe the MTB project and MTB research platform and demonstrate examples of assessments.

MTB is the product of an NIH-funded, multi-institutional effort involving Northwestern University, Sage Bionetworks, Penn State, University of California San Francisco, University of California San Diego, Emory University, and Washington University. The MTB assessment library is a dynamic repository built upon Sage Bionetworks mobile health platform. All MTB measures are created or adapted for a mobile interface using iOS and Android smartphones. Guided by the principles of open science, many components are open source to allow researchers and developers to integrate externally developed tests, including supplemental scales (e.g., passively collected contextual factors) assessing variables such as mood and fatigue that might influence cognitive test performance.

The current MTB library includes eight core cognitive tests based on well-established neuropsychological measures: two language tasks (Spelling and Word Meaning), two executive functioning tasks (Arrow Matching and Shape-Color Sorting), an associative memory task (Faces and Names), an episodic memory task (Arranging Pictures), a working memory task (Sequences) and a processing speed task (Numbers and Symbols). Additional cognitive assessments from other popular test libraries including the International Cognitive Ability Resource (ICAR), Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) and Test My Brain are currently being implemented, as are non-cognitive measures from the NIH Toolbox Emotion Battery and the Patient-Reported Outcomes Measurement Information System (PROMIS). The MTB library includes measures suitable for use in research studies incorporating point-in-time and burst designs as well as ecological momentary assessment (EMA).

The MTB was created to address many of the scientific, practical, and technical challenges to cognitive assessment by capitalizing on advances in technology measurement and cognitive research. Initial psychometric evaluation of measures has been performed, and additional clinical validation is underway in studies with persons at risk for cognitive impairment or Alzheimer’s disease (AD), diagnosed with mild cognitive impairment (MCI) or AD, Parkinson’s disease, and HIV-associated Neurocognitive Disorders. Calculation of norms and reliable change indicators is in progress. The MTB is currently available to beta testers with public release planned for Summer, 2023. Clinical researchers will be able to use the MTB system to design smartphone-based test batteries, deploy and manage mobile data collection in their research studies, and aggregate and analyze results in the context of large-scale norming data.

There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer’s disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults. We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of <129 across subgroups.

A hierarchical cluster analysis was conducted using 11 baseline neuropsychological test scores from 365 CU participants in the UCSD Shiley-Marcos Alzheimer’s Disease Research Center (age M=71.93 years, SD=7.51; 55.9% women; 15.6% Hispanic/Latino/a/x/e). A discriminate function analysis was then conducted to test whether the individual neuropsychological scores predicted cluster-group membership. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score <129, by cluster group.

Cluster analysis identified 5 groups: All-Average (n=139), Low-Visuospatial (n=46), Low-Executive (n=51), Low-Memory/Language (n=83), and Low-All Domains (n=46). The discriminant function analysis using the neuropsychological measures to predict group membership into these 5 clusters correctly classified 85.2% of the participants. Subgroups had unique demographic and clinical characteristics. Relative to the All-Average group, the Low-Visuospatial (hazard ratio [HR] 2.39, 95% CI [1.03, 5.56], p=.044), Low-Memory/Language (HR 4.37, 95% CI [2.24, 8.51], p<.001), and Low-All Domains (HR 7.21, 95% CI [3.59, 14.48], p<.001) groups had greater risk of progression to MCI/dementia. The Low-Executive group was also twice as likely to progress to MCI/dementia compared to the AllAverage group, but did not statistically differ (HR 2.03, 95% CI [0.88,4.70], p=.096). A similar pattern of results was found for progression to DRS score <129, with the Low-Executive (HR 2.82, 95% CI [1.26, 6.29], p=.012), Low-Memory/Language (HR 3.70, 95% CI [1.80, 7.56], p<.001) and Low-All Domains (HR 5.79, 95% CI [2.74, 12.27], p<.001) groups at greater risk of progression to a DRS score <129 than the All-Average group. The Low-Visuospatial group was also twice as likely to progress to DRS <129 compared to the All-Average group, but did not statistically differ (HR 2.02, 95% CI [0.80, 5.06], p=.135).

Our results add to a growing literature documenting heterogeneity in the earliest cognitive and pathological presentations associated with Alzheimer’s disease and related disorders. Participants with subtle memory/language, executive, and visuospatial weaknesses all declined at faster rates than the All-Average group, suggesting that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. These results have important implications for early identification of individuals at risk for MCI/dementia. Given that the same classification approach may not be optimal for everyone, determining profiles of subtle cognitive difficulties in CU individuals and implementing neuropsychological test batteries that assess multiple cognitive domains may be a key step towards an individualized approach to early detection and fewer missed opportunities for early intervention.

Sexual dimorphism in human brain structure and behavior is influenced by exposure to sex hormones during critical developmental periods. In children, cancer and cancer treatments may alter hormone activity and brain development, impacting neurocognitive functions.

Five-year survivors of childhood cancer (N=15,560) diagnosed at <21 years from 1970 to 1999, and 3,206 siblings from the Childhood Cancer Survivor Study completed the Neurocognitive Questionnaire (NCQ), a measure of self-reported task efficiency (TE), emotion regulation (ER), Organization, and working memory (WM). We compared rates of cognitive impairment (i.e., NCQ scores >90th percentile) in survivors and same-sex siblings, and sex differences in risk factors for cognitive impairment (i.e., treatment exposures, chronic health conditions (CHCs), cancer diagnosis, age at diagnosis) using modified Poisson regressions.

Survivors were more likely to report cognitive impairment than same-sex siblings (Males: TE OR=2.3, p<.001; ER OR=1.7, p=.008; Organization OR=1.5, p=.04; WM OR=2.3, p<.001. Females: TE OR=2.6, p<.001; ER OR=1.9, p<.001; Organization OR=1.5, p=.02; WM OR=2.6, p<.001). Within survivors, females were more likely than males to report impairment in TE (OR=1.2, p=.001), ER (OR=1.5, p<.001), and WM (OR=1.2, p<.001). There were no sex differences in symptom severity in siblings (all ps>.05). Risk factors for cognitive impairment in survivors included cranial radiation dose (TE <20Gy OR=1.5, p=.008, ≥20Gy OR=2.5, p<.001; ER OR=1.5, p<.001; Organization <20 Gy OR=1.4, p<.001; < WM 20 Gy OR=1.8, p<.001, ≥20Gy OR=2.7, p<.001), presence of moderate to severe CHCs (TE 1 CHC OR=1.9, p<.001, >1 CHC OR=3.6, p<.001; ER 1 CHC OR=1.7, p<.001, >1 CHC OR=2.2, p<.001; Organization 1 CHC OR=1.5, p=.001, >1 CHC OR=2.5, p<.001; WM 1 CHC OR=1.8, p<.001, >1 CHC OR=4.1, p<.001). There were sex differences in cognitive impairment risk factors in survivors. In females, cranial radiation dose (<20 Gy TE OR=1.6, p=.02; ≥20Gy TE OR=1.4, p=.01), leukemia diagnosis (TE OR=1.4, p=.02), or diagnosis age between 3-5 years (WM OR=1.4, p=.02) conferred higher risk for cognitive impairment compared to males with the same history. Females diagnosed with Hodgkin’s lymphoma (Organization OR=0.61, p=.05) or non-Hodgkin’s lymphoma (Organization OR=0.55, p=.03) were at lower risk for cognitive impairment compared to males.

We found sex-specific differences in rates of, and risk factors for, neurocognitive impairment, suggesting a sex vulnerability. Future studies examining interactions between sex hormones and treatment exposures during brain development will enable tailoring treatments follow-up interventions to ensure that quality of life is maximized.

Alzheimer’s disease (AD), a leading cause of dementia worldwide, affected an estimated 47 million people in 2015, placing a burden of over $1 trillion on health systems. Subclinical markers of AD pathology are seen many years before the clinical onset of dementia, suggesting that steps could be taken to prevent progression to disease in healthy individuals. Sleep optimizes cognition by creating a window of opportunity to consolidate memories, prune synaptic networks, and clear waste products. Studies that characterize the relationship between sleep and cognitive function prior to the onset of clinical AD could guide research into effective methods of delaying AD onset or preventing it altogether. The objective of our study is to describe how sleep quality and quantity correlate with performance on cognitive assessments within a healthy, aging population.

Seventeen participants, between 62-82 years of age enrolled in an ongoing clinical trial assessing the effects of melatonin (5mg daily) versus placebo, were included in our study. Participants were observed over a 2-month period, during which no experimental interventions were administered. At study entry, participants underwent a comprehensive neuropsychological evaluation evaluating cognitive domains of attention, memory, speed of information processing, language, executive functioning, and mood. Afterwards, all participants wore a watch that measured actigraphy and light data (Philips Actiwatch Spectrum Pro actigraphy monitor) for 8 weeks to evaluate their sleep habits. Pearson and Spearman partial correlations were used to evaluate relationships between objective sleep parameters and baseline cognitive function test scores.

Aberrations of sleep length, sleep fragmentation, and daytime activity measures significantly correlated with cognitive performance on memory, language, visuospatial skills, and speed of processing tests (p = <0.05). Greater variability of awakenings at nighttime associated with better scores on memory tests but worse scores on language tests. Longer sleep times associated with worse language scores, while greater variability in daily activity correlated with poorer scores on visuospatial skills tests and speed of processing tests.

This study establishes a framework for obtaining longitudinal sleep data in conjunction with serial cognitive function testing, encouraging further exploration into how sleep metrics affect specific domains of cognitive function. Findings suggest that having a less consistent sleep routine correlates with poorer cognitive function across multiple domains. The authors recommend broader analysis of actigraphy and cognitive function testing as objective measures of sleep and cognition in research and clinical practice.