Faculty Bibliography

IMPORTANCE/UNASSIGNED:Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. OBJECTIVE/UNASSIGNED:To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. INTERVENTIONS/UNASSIGNED:Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. RESULTS/UNASSIGNED:A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT05965739.

BACKGROUND:In vivo biomarkers that can detect long-term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p-tau217 as a potential biomarker for CTE p-tau pathology, and examined the concordance between plasma p-tau217 and Aβ pathology in an at-risk for CTE sample. METHOD/METHODS:The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F-florbetapir (Aβ+=SUVR≥1.10), and 18F-flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p-tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post-mortem tissue. ANCOVA examined group differences in p-tau217 (football vs controls; TES-CTE no, TES-CTE suggestive, TES-CTE possible/probable). Multivariable regression models tested associations between p-tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4. RESULT/RESULTS:Sample characteristics are in Table 1. p-tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=-0.217, p = 0.005). There were no group differences in Aβ-PET SUVR. No differences were found across TES-CTE certainty levels. In football players, higher p-tau217 was associated with higher Aβ-PET SUVR (B=1.380, 95%CI[0.597-2.155], p = 0.001) but not when Aβ+ (n = 17) participants and those with kidney/liver disease (n = 5) were excluded. Aβ+ participants had the highest p-tau217 (Figure 1). When compared against Aβ-PET, several false Aβ-positives (high p-tau217, Aβ-) were identified, including one extreme outlier (assay related) and a cluster of Aβ- participants with p-tau217 between 0.60-1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p-tau217 outliers had autopsy-confirmed CTE stage III (AD-, Table 2). Of the remaining donors, all were AD- and four had CTE (stages II-IV) with ptau217 between 0.125-0.449. CONCLUSION/CONCLUSIONS:Plasma p-tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at-risk for CTE sample, p-tau217 and Aβ-PET were associated at the group level. At the individual level, false Aβ-positives (and negatives) existed, including Aβ- participants with high p-tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N-terminal binding in p-tau assays.

OBJECTIVE:To assess real-world effectiveness of switching disease-modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. METHODS:Of 2615 pediatric-onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. RESULTS:A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety-three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52-1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20-0.57; rate ratio: 0.38, 95% CI = 0.21-0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09-0.37; rate ratio: 0.21, 95% CI = 0.10-0.44) (p < 0.001). Adjusted number needed to treat in person-years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03-8.69) and infusion over injectable 1.43 (95% CI = 1.00-3.88). INTERPRETATION/CONCLUSIONS:Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long-term safety data are required. ANN NEUROL 2025.

OBJECTIVE:People with focal epilepsy experience one or more seizures prior to diagnosis. The Human Epilepsy Project (HEP) was a prospective study enrolling people with newly diagnosed focal epilepsy. It collected information including cognitive testing at the time of enrollment. This was completed utilizing a computerized test battery called the Cogstate Brief Battery (CBB). A prior analysis found that enrollment CBB test scores were below that of age matched controls and that performance on testing was not independently associated with the longer-term development of treatment resistance over the course of the HEP study. The present study assesses the impact of pretreatment seizures on cognition at time of diagnosis, considering time-to-treatment initiation in relation to seizure onset, pre-treatment seizure frequency, and pretreatment seizure classification. METHODS:Participants with newly diagnosed focal epilepsy and no other major medical comorbidities or intellectual disability (estimated IQ > 70) were enrolled between June 29, 2012, and September 1, 2019. A subset of the 448 enrolled participants (N = 183) were over 18 years old, had complete HEP enrollment data that included pre-treatment seizure histories, and complete enrollment CBB testing for analysis in this study. Performance on enrollment CBB testing was modeled using multiple linear regression with pre-treatment seizure characteristics including seizure type and duration between seizure onset and treatment initiation, controlling for other key baseline participant characteristics. RESULTS:There were no independent associations between cognitive measures on the CBB at the time of enrollment and pre-treatment seizures after correcting for potentially confounding variables. Z-scores for the attention composite on CBB (an average of Identification and Detection tests) were not associated with a global pre-treatment seizure score that quantified time with seizures (days) and seizure count by seizure type (motor, non-motor, bilateral tonic clonic) (p = 0.29). Similarly, z-scores for the memory composite (an average of the One Card Learning test and One Back tests) were not associated with the pre-treatment seizure score (p = 0.1). No additional independent associations were found to be significant between z-scores for attention or memory composites and other potential explanatory variables. SIGNIFICANCE/CONCLUSIONS:This study highlights an important finding for people who develop focal epilepsy and otherwise are in good health: pre-treatment time-limited seizures do not have an independent impact on cognition early on, as measured by a brief validated cognitive screening test. This suggests that that cognition at the time of epilepsy diagnosis may be more strongly related to underlying etiology, chronic disease, and comorbidities.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Pediatric multiple sclerosis (MS) affects children and adolescents at an important time for neurologic and cognitive development. Although cognitive impairment has been described, few longitudinal studies of cognitive functioning in pediatric MS with matched controls are available. Here, we report the 2-year follow-up cognitive results of a cohort of participants with MS and healthy controls (HCs) recruited from multiple regions of the United States. METHODS:Three cohorts-participants with pediatric MS, age-matched pediatric HC, and adults with early-onset MS-were recruited across 7 sites through the United States Network of Pediatric MS Centers. Two cognitive batteries, Cogstate Brief Battery (CBB) and Brief International Cognition Assessment for MS (BICAMS), were administered at baseline and follow-up. The primary outcome was the change in CBB composite z-score compared between groups. Change in BICAMS composite z-score was also compared, as were change in z-scores of individual measures. Reliable change indices (RCIs) were calculated to determine meaningful change over time. RESULTS:= 0.022. DISCUSSION/CONCLUSIONS:Most individuals with pediatric MS early in their disease showed stable cognitive function over a 2-year period and had longitudinal changes that were largely similar to pediatric controls. A subset of participants with pediatric MS declined in cognitive processing speed relative to pediatric controls.

BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection (PASC) is characterized by persistent cognitive deficits alongside anxiety and depression symptoms that adversely affect quality of life. Cognitive training (CT) programs and non-invasive neuromodulation, specifically transcranial direct current stimulation (tDCS), have each shown promise for alleviating similar deficits in non-clinical populations. However, their combined efficacy has not yet been evaluated in PASC patients. Therefore, this study aimed to determine whether the combination of CT and tDCS produces benefits for cognitive and mood-related symptoms in individuals with PASC. METHODS:We conducted a double-blind, randomized, sham-controlled clinical trial in adults aged 18-75 with confirmed SARS-CoV-2 infection within the past six months and persisting cognitive complaints. They were randomized to a 4-week in-person intervention of 20 weekday sessions of either active (2 mA anodal-left, cathodal-right prefrontal stimulation) or sham tDCS paired with an app-based CT program. Primary outcomes were six standardized neuropsychological tests assessing verbal memory, working memory, executive functioning, attention, and language, administered at baseline and immediately post-intervention. As secondary outcomes, we assessed changes in depression and anxiety symptoms over the treatment period. RESULTS:Sixty participants (mean age 43.8 ± 13.2 years, 71.7 % women) were randomized to active tDCS + CT or sham tDCS + CT groups, and 52 finished the trial. Compared to sham, tDCS + CT resulted in significantly greater improvement in tests evaluating inhibitory control (effect size [ES] = 0.07, 95 % CI 0 to 0.23, p = 0.046), processing speed (ES = 0.08, 95 % CI 0 to 0.25, p = 0.034), and divided attention (ES = 0.08, 95 % CI 0 to 0.24, p = 0.039), but not in tests evaluating other domains. Both groups improved similarly in depression and anxiety symptoms. Participant's and rater's active guess rates did not differ between groups (ps > 0.20). CONCLUSION/CONCLUSIONS:An intervention with prefrontal targeted tDCS + CT in patients with PASC with cognitive complaints might be effective in improving attention, processing speed and inhibitory control, although further studies are warranted to prospectively confirm these findings. CLINICALTRIALS/RESULTS:GOV: NCT05389592.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Disturbances in brain catecholamine activity may be associated with symptoms after exposure to repetitive head impacts (RHIs) or related chronic traumatic encephalopathy (CTE). In this article, we studied CSF catecholamines in former professional and college American football players and examined the relationship with football proxies of RHI exposure, CTE probability, cognitive performance, neuropsychiatric symptoms, and parkinsonism. METHODS:In this observational cross-sectional study, we examined male former American football players, professional ("PRO") or college ("COL") level, and asymptomatic unexposed male ("UE") individuals from the DIAGNOSE CTE Research Project. Catecholamines-norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), and dopamine (DA) and its precursor, 3,4-dihydroxyphenylalanine (l-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)-were measured in CSF with high-performance liquid chromatography and compared across groups with analysis of covariance. Multivariable linear regression models tested the relationship between CSF catecholamines and proxies of RHI exposure (e.g., total years of playing American football), factor scores for cognition, and neurobehavioral dysregulation (explosivity, emotional dyscontrol, impulsivity, affective lability), as well as depressive/anxiety symptoms, measured with the Beck Depression/Anxiety Inventories. CTE probability and parkinsonism were assessed using the National Institute of Neurological Disorders and Stroke consensus diagnostic criteria for traumatic encephalopathy syndrome (TES), and biomarkers were compared among different diagnostic groups. RESULTS:The cohort consisted of 120 former American football players (85 PRO players, 35 COL players) and 35 UE participants (age 45-75). Former players had significantly lower levels of NE (mean difference = -0.114, 95% CI -0.190 to -0.038), l-DOPA (-0.121, 95% CI -0.109 to -0.027), and DOPAC (-0.116, 95% CI -0.177 to -0.054) than UE participants. For NE and DOPAC, these overall group differences were primarily due to differences between the PRO and UE cohorts. No significant differences were found across TES-CTE probability subgroups or TES-parkinsonism diagnostic groups. Within the COL cohort, tested as post hoc analyses, higher CSF NE and l-DOPA were associated with higher neurobehavioral dysregulation factor scores, BAI total score, and worse executive functioning and processing speed. CSF DHPG and DOPAC were associated with impulsivity only in this subgroup. DISCUSSION/CONCLUSIONS:We observed reduced CSF catecholamine concentrations in former elite American football players, although the relationship with degree of RHI exposure and the clinical impact needs further study.

INTRODUCTION/BACKGROUND:Cannabis use is rising in the United States. Up to 30 % of individuals who use cannabis develop cannabis use disorder (CUD), for which there are no FDA-approved treatments. This randomized controlled trial (RCT) evaluated the feasibility and efficacy of a novel, one-month telehealth intervention of remotely supervised tDCS (RS-tDCS) paired with mindfulness meditation. This home-based telehealth intervention was evaluated in a cohort of women with multiple sclerosis (MS), a vulnerable subpopulation of adults with high rates of CUD. METHODS:The intervention included 20 home-based RS-tDCS sessions targeting the left DLPFC, delivering 2.0mA for 20minutes, paired with guided mindfulness meditation. Sessions were conducted 5 days per week for four weeks. Fifty-two women with MS and CUD (age: 44 ± 10 years) consented to participate; 47 were randomized 2:1 to active or sham tDCS. Feasibility was assessed via retention and adherence, while preliminary efficacy was measured by cannabis use, withdrawal symptoms, and MS-related symptom scales. RESULTS:Of 47 randomized participants (31 active, 16 sham), 39 (83 %) completed the intervention. The active tDCS group showed significant reductions in weekly cannabis use (Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory, DFAQ-CU: 5.3 ± 2.4 vs. 3.9 ± 2.7 days, p = 0.014) and withdrawal symptoms (CWS: p < 0.001). A trend toward reduced MS-related symptoms was observed (SymptoMScreen: p = 0.031). Cognitive performance improvement at the end of the intervention was significant in the active group (p = 0.011 vs. p = 0.172), supporting functional benefits of reduced cannabis use. CONCLUSIONS:This pilot RCT supports the feasibility and preliminary efficacy of telehealth tDCS in a medical subpopulation. Studying women with MS highlights its potential for large-scale RCTs and clinical use.

OBJECTIVE:The application of transcranial direct current stimulation (tDCS) at home for the treatment of depression and other neuropsychiatric disorders presents both significant opportunities and inherent challenges. Ensuring safety and maintaining high-quality stimulation are paramount for the efficacy and safety of at-home tDCS. This study investigates tDCS quality based on its technical parameters as well as safety of at-home and in-clinic tDCS applications comparing the data from two randomized controlled trials in patients with major depressive disorder. METHODS:We analyzed 229 active stimulation sessions from the HomeDC study (at-home tDCS) and 835 sessions from the DepressionDC study (in-clinic tDCS). Notably, five adverse events (skin lesions) were reported exclusively in the at-home cohort, highlighting the critical need for enhanced safety protocols in unsupervised environments. RESULTS:= .097). The at-home tDCS sessions exhibited higher impedance variability (M = 837, SD = 328) compared to in-clinic sessions (M = 579, SD = 309). Furthermore, at-home tDCS sessions resulting in adverse events (AEs) were associated with significantly higher average impedances than sessions without such issues. CONCLUSION/CONCLUSIONS:The study demonstrates that monitoring the technical parameters of at-home tDCS used in this study is essential. However, it may be not sufficient for ensuring safety and promptly detecting or preventing adverse events. Quality control protocols including digital training and monitoring techniques should be systematically developed and tested for a reliable and safe application of at-home tDCS therapies.