Faculty Bibliography

OBJECTIVE:The Human Epilepsy Project (HEP) is a large multinational cohort study of people with newly diagnosed and treated focal epilepsy. HEP utilized the Cogstate Brief Battery (CBB) as a self-directed online assessment to examine cognitive outcomes in study participants. The CBB has previously been validated in healthy individuals and people with various brain disorders, but its use in adults participating in HEP has not been assessed. In this study, we describe how the CBB was used in the HEP cohort and assess factors associated with test completion among study participants. METHODS:Enrollment data for HEP included 408 participants with comprehensive enrollment records, of whom 249 completed CBB assessments. HEP enrolled cognitively normal-range participants between the ages of 12 and 60 from June 29, 2012, to November 7, 2017, with newly diagnosed focal epilepsy and within 4 months of initial treatment. Baseline participant characteristics were analyzed, including demographics, pre-treatment seizure histories, MRI abnormalities, and the presence of any learning difficulties while in school, including formal learning disability diagnoses, repeated grades, and remediation. HEP participant characteristics for those who completed CBB testing were compared to those who did not using multiple logistic regression. RESULTS:The analysis of HEP participants who completed CBB testing showed that, after controlling for other factors, male participants were more likely to engage in testing (OR 2.14, 95 % CI 1.29 to 3.5, p < 0.01), Black subjects were less likely (OR 0.45, 95 % CI 0.22 to 0.9, p = 0.02), primary English speakers were more likely (OR 3.1, 95 % CI 1.21 to 7.96, p = 0.02), and those with a history of learning challenges were less likely (OR 0.69, 95 % CI 0.49 to 0.97, p = 0.03). There were no significant associations between completing CBB testing and age, employment (employed or student vs not), education (higher education vs not), diagnostic delay, pre-diagnostic seizure burden, or initial seizure semiology (motor vs non-motor). SIGNIFICANCE/CONCLUSIONS:The findings from this study highlight factors associated with the application of remote and unsupervised assessments of cognition in a prospective cohort of adults with focal epilepsy. These factors can be considered when interpreting performance on the CBB in HEP, as well as assisting the design of future studies that use similar approaches.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Psychosocial adversity and stress, known to predispose adults to neurodegenerative and inflammatory immune disorders, are widespread among children who experience socioeconomic disadvantage, and the associated neurotoxicity and proinflammatory profile may predispose these children to multiple sclerosis (MS). We sought to determine associations of socioeconomic disadvantage and psychosocial adversity with odds of pediatric-onset MS (POMS), age at POMS onset, and POMS disease activity. METHODS:This case-control study used data collected across 17 sites in the United States by the Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis Study. Cases (n = 381) were youth aged 3-21 years diagnosed with POMS or a clinically isolated demyelinating syndrome indicating high risk of MS. Frequency-matched controls (n = 611) aged 3-21 years were recruited from the same institutions. Prenatal and postnatal adversity and postnatal socioeconomic factors were assessed using retrospective questionnaires and zip code data. The primary outcome was MS diagnosis. Secondary outcomes were age at onset, relapse rate, and Expanded Disability Status Scale (EDSS). Predictors were maternal education, maternal prenatal stress events, child separation from caregivers during infancy and childhood, parental death during childhood, and childhood neighborhood disadvantage. RESULTS:= 0.025). There were no associations of the socioeconomic variables with age at onset, relapse rate, or EDSS, or of prenatal or postnatal adverse events with risk of POMS, age at onset, relapse rate, or EDSS. DISCUSSION/CONCLUSIONS:Low socioeconomic status at the neighborhood level may increase the risk of POMS while high parental education may be protective against POMS. Although we did not find associations of other evaluated prenatal or postnatal adversities with POMS, future research should explore such associations further by assessing a broader range of stressful childhood experiences.

OBJECTIVES/OBJECTIVE:When administered in repeated daily doses, transcranial direct current stimulation (tDCS) directed to the prefrontal cortex has cumulative efficacy for the treatment of depression. Depression can be marked by altered processing of emotionally salient information. An acute marker of response to tDCS may be measured as an immediate change in emotional information processing. Using an easily administered web-based task, we tested immediate changes in emotional information processing in acute response to tDCS in participants with and without depression. MATERIALS AND METHODS/METHODS:We enrolled n = 21 women with mild-to-moderate depression and n = 20 controls without depression to complete a web-based visual search task before and after 30 minutes of tDCS directed to the prefrontal cortex. The timed task required participants to identify a target face among arrays showing sad, neutral, or mixed (distractor) expressions. RESULTS:At baseline, as predicted, the participants with depression differed from those without in emotional processing speed (mean z score difference -0.66 ± 0.27, p = 0.022) and accuracy in identifying sad stimuli (error rate: 4.4% vs 1.8%, p = 0.039). In response to tDCS, the participants with depression became significantly faster on the distractor condition (pre- vs post-tDCS z scores: -0.45 ± 0.65 vs -0.85 ± 0.65, p = 0.009), suggesting a specific reduction in bias toward negative emotional information. In response to tDCS, the depressed group also had significant improvements in self-reported mood (increased happy, decreased sad and anxious mood). CONCLUSIONS:Participants with depression vs those without were differentiated by their performance of the visual search task at baseline and in response to tDCS. Given that measurable effects on depression scales may require weeks of tDCS treatments, acute change in emotional information processing can serve as an easily obtainable marker of depression and its response to tDCS. CLINICAL TRIAL REGISTRATION/BACKGROUND:The Clinicaltrials.gov registration number for the study is NCT05188248.

BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection (PASC) symptoms have broad impact, and may affect individuals regardless of COVID-19 severity, socioeconomic status, race, ethnicity, or age. A prominent PASC symptom is cognitive dysfunction, colloquially referred to as "brain fog" and characterized by declines in short-term memory, attention, and concentration. Cognitive dysfunction can severely impair quality of life by impairing daily functional skills and preventing timely return to work. METHODS:RECOVER-NEURO is a prospective, multi-center, multi-arm, phase 2, randomized, active-comparator design investigating 3 interventions: (1) BrainHQ is an interactive, online cognitive training program; (2) PASC-Cognitive Recovery is a cognitive rehabilitation program specifically designed to target frequently reported challenges among individuals with brain fog; (3) transcranial direct current stimulation (tDCS) is a noninvasive form of mild electrical brain stimulation. The interventions will be combined to establish 5 arms: (1) BrainHQ; (2) BrainHQ + PASC-Cognitive Recovery; (3) BrainHQ + tDCS-active; (4) BrainHQ + tDCS-sham; and (5) Active Comparator. The interventions will occur for 10 weeks. Assessments will be completed at baseline and at the end of intervention and will include cognitive testing and patient-reported surveys. All study activities can be delivered in Spanish and English. DISCUSSION/CONCLUSIONS:This study is designed to test whether cognitive dysfunction symptoms can be alleviated by the use of pragmatic and established interventions with different mechanisms of action and with prior evidence of improving cognitive function in patients with neurocognitive disorder. If successful, results will provide beneficial treatments for PASC-related cognitive dysfunction. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.

OBJECTIVE:A previous investigation of people with newly diagnosed focal epilepsy participating in the Human Epilepsy Project 1 (HEP1) revealed an association between learning difficulties and structural brain differences, suggesting an underlying relationship prior to seizure onset. To investigate physicians' practices of documentation learning difficulties during clinical encounters, we conducted a review of initial epileptologist encounter notes from HEP1 participants who self-reported early life learning difficulties separately as part of study enrollment. METHODS:HEP1 enrolled 67 North American participants between June 2012 and November 2017 who self-reported one or more difficulties with learning (i.e., having repeated grade, receiving learning support/remediation, and/or formal diagnosis of a learning disability) prior to epilepsy diagnosis as part of the study enrollment. The epileptologist's initial encounter note was then reviewed in detail for each of these participants. Documentation of learning issues and specific diagnoses of learning disabilities was compared to participant characteristics. Regression analysis was used to test for any independent associations between participant characteristics and physician documentation of learning difficulties. RESULTS:There were significant independent relationships between age, sex, and physician documentation of learning difficulties. On average, participants ages 22 and younger were 12.12 times more likely to have their learning difficulties documented compared to those 23 years and older (95 % CI: 2.226 to 66.02, p = 0.004). Additionally, male participants had 7.2 times greater odds of having their learning difficulty documented compared to female participants (95 % CI: 1.538 to 33.717, p = 0.012). There were no significant independent associations between race, language, employment, or geographical region. SIGNIFICANCE/CONCLUSIONS:These findings highlight disparities in physician documentation for people with newly diagnosed focal epilepsy and a history of learning difficulties. In the HEP1 cohort, physicians were more likely to document learning difficulties in males and in younger individuals. Systematic practice standards are important for reducing healthcare disparities across populations, improving clinical care to individuals, as well as enabling more accurate retrospective study of clinical phenomenon.

BACKGROUND AND OBJECTIVES/UNASSIGNED:Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. METHODS/UNASSIGNED:The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. RESULTS/UNASSIGNED:gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. DISCUSSION/UNASSIGNED:Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

INTRODUCTION/BACKGROUND:Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD/METHODS:We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS:Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION/CONCLUSIONS:Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health. METHODS:ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI. RESULTS:(158%), and FA (287%) than the unexposed men. DISCUSSION/CONCLUSIONS:and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.

Former American football players are at risk for developing traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The objective of this study was to determine whether hyposmia is present in traumatic encephalopathy syndrome. The study included 119 former professional American football players, 60 former college football players, and 58 same age asymptomatic unexposed men from the DIAGNOSE CTE Research Project. All subjects included in the analysis had completed the Brief Smell Identification Test (B-SIT). Traumatic encephalopathy syndrome and the level of CTE certainty were diagnosed using the 2021 NINDS consensus diagnostic criteria. TES is categorized antemortem by provisional levels of increasing CTE certainty: Suggestive, Possible, and Probable. Former players who had traumatic encephalopathy syndrome and Probable CTE had lower B-SIT scores than those with TES and Suggestive CTE. Hyposmia was more likely in the former players with TES who were either CTE Possible or Probable than in those who did not have TES or had TES but were less likely to have CTE, CTE Suggestive. There was no difference in B-SIT scores between all former players versus unexposed men nor overall between the football players with and without TES. We conclude that lower B-SIT scores may be a clinical biomarker for underlying CTE in former American football players.