Faculty Bibliography

Sentence production is the uniquely human ability to transform complex thoughts into strings of words. Despite the importance of this process, language production research has primarily focused on single words. It remains an untested assumption that insights from this literature generalize to more naturalistic utterances like sentences. Here, we investigate this using high-resolution neurosurgical recordings (ECoG) and an overt production experiment where patients produce six words in isolation (picture naming) and in sentences (scene description). We trained machine learning models to identify the unique brain activity pattern for each word during picture naming, and used these patterns to decode which words patients were processing while they produced sentences. Our findings reveal that words share cortical representations across tasks. In sensorimotor cortex, words were consistently activated in the order in which they were said in the sentence. However, in inferior and middle frontal gyri (IFG and MFG), the order in which words were processed depended on the syntactic structure of the sentence. This dynamic interplay between sentence structure and word processing reveals that sentence production is not simply a sequence of single word production tasks, and highlights a regional division of labor within the language network. Finally, we argue that the dynamics of word processing in prefrontal cortex may impose a subtle pressure on language evolution, explaining why nearly all the world's languages position subjects before objects.

BACKGROUND/UNASSIGNED:Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that occurs in children and adults. CASE/UNASSIGNED:We report a case of a 10-year-old female with AQP4+ NMOSD who presented with paraparesis from longitudinally extensive transverse myelitis (LETM) from C2 to the conus medullaris. The patient showed gradual improvement in strength and sensation with solumedrol and plasma exchange therapy. Given her severe presentation, eculizumab therapy was also initiated acutely. She had near complete recovery, although she developed a myelitis relapse during transition to rituximab treatment. CONCLUSION/UNASSIGNED:This case demonstrates the role of eculizumab as a safe and effective treatment option in treating an acute attack of pediatric AQP4+ NMOSD. More data are needed to understand the risk of relapse if transitioning off of these highly effective medications.

Racial/ethnic differences are associated with the symptoms and conditions of post-acute sequelae SARS-CoV-2 infection (PASC) in adults. These differences may exist among children and warrant further exploration. We conducted a retrospective cohort study with difference-in-differences analyzes to assess these differences in children and adolescents under the age of 21. The study utilized data from the RECOVER Initiative in the United States, which aims to learn about the long-term effects of COVID-19. The cohort included 225,723 patients with SARS-CoV-2 infection or COVID-19 diagnosis between March 2020 and October 2022. The study compared minority racial/ethnic groups to Non-Hispanic White (NHW) individuals, stratified by severity during the acute phase of COVID-19. Within the severe group, Asian American/Pacific Islanders (AAPI) had a higher prevalence of fever/chills and respiratory signs and symptoms, Hispanic patients showed greater hair loss prevalence in severe COVID-19 cases, while Non-Hispanic Black (NHB) patients had fewer skin symptoms in comparison to NHW patients. Within the non-severe group, AAPI patients had increased POTS/dysautonomia and respiratory symptoms, and NHB patients showed more cognitive symptoms than NHW patients. In conclusion, racial/ethnic differences related to COVID-19 exist among PASC symptoms and conditions in pediatrics, and these differences are associated with the severity of illness during acute COVID-19.

OBJECTIVE/UNASSIGNED:The long-recognized association of brain injury with increased risk of dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure to repetitive head impacts (RHI). We aim to contextualize CTE within a historical perspective and among emerging data which highlights the scientific and conceptual evolution of CTE-related research in parallel with the broader field of neurodegenerative disease and dementia. METHODS/UNASSIGNED:We provide a narrative state-of-the-science update on CTE neuropathology, clinical manifestations, biomarkers, different types and patterns of head impact exposure relevant for CTE, and the complicated influence of neurodegenerative co-pathology on symptoms. CONCLUSIONS/UNASSIGNED:Now almost 20 years since the initial case report of CTE in a former American football player, the field of CTE continues evolving with increasing clarity but also several ongoing controversies. Our understanding of CTE neuropathology outpaces that of disease-specific clinical correlates or the development of in-vivo biomarkers. Diagnostic criteria for symptoms attributable to CTE are still being validated, but leveraging increasingly available biomarkers for other conditions like Alzheimer's disease may be helpful for informing the CTE differential diagnosis. As diagnostic refinement efforts advance, clinicians should provide care and/or referrals to providers best suited to treat an individual patient's clinical symptoms, many of which have evidence-based behavioral treatment options that are etiologically agnostic. Several ongoing research initiatives and the gradual accrual of gold standard clinico-pathological data will pay dividends for advancing the many existing gaps in the field of CTE.

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R² = .77), DS and LOAD (R² = .73), and EOAD and LOAD (R² = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10^-5) for DS, immune system regulation (p = 4.33 × 10^-5) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R² = .59) and LOAD (R² = .33) compared to the correlation between EOAD and LOAD (R² = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein-DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.

OBJECTIVE:The neuropsychological adverse effects of antiseizure medications (ASMs) influence the tolerability, and in turn effectiveness of these medications, which can occur in a dose-dependent fashion. In this study, we examine the neuropsychological effects of perampanel (PER) at 4 mg daily as this dose has not been previously assessed with objective cognitive tests. METHODS:The study was originally designed to assess (1) effects of perampanel at 4 mg using different titration rates, and (2) habituation over time. Due to the COVID-19 pandemic, the study was halted, limiting the sample size needed to analyze titration and habituation effects. Therefore, we compared the neuropsychological effects of perampanel 4 mg daily from non-drug baseline to the end of drug titration and end of drug maintenance in this randomized double-blind study of healthy volunteers. Treatment period was 6 weeks total with 2 weeks of variable titration followed by 4-week maintenance. Composite Z-scores were calculated by combining Z-scores from both cognitive (computerized and non-computerized) and behavioral tests. Secondary analyses were conducted on the independent cognitive and behavioral domain Z-scores, and on the raw scores from 19 items in the full battery. RESULTS:The overall composite Z-scores did not differ across baseline, the end of titration, and the end of maintenance. Similarly, individual cognitive and behavioral domain Z-scores did not differ across the three titration rates. Exploratory analyses of the raw scores were marginally significant on only two of the 19 neuropsychological measures. CONCLUSIONS:Perampanel 4 mg daily was well tolerated with few neuropsychological effects in healthy volunteers.

BACKGROUND:Lipids are of particular interest for the study of neuroinjury and neuroinflammation as structural lipids are major components of myelin, and a variety of lipid species modulate inflammation. In this study, we performed an in-depth lipidomics analysis to identify lipids associated with injury and disease activity. METHODS:Plasma samples were collected from paediatric-onset multiple sclerosis (MS) cases within 4 years of disease onset from 17 sites. The lipidome was measured using untargeted and targeted mass spectrometry. For cross-sectional analyses, the agreement between multiple machine learning models was used to predict neurofilament light chain (NfL) levels. In longitudinal analyses, the association between clinical (relapse count) and imaging (MRI count with ≥1 enhancing or new T2 lesion) outcomes with each metabolite was estimated using adjusted negative binomial regression. RESULTS:At sample collection, 68% of the 435 included individuals were treatment-naive, with a median disease duration of 0.8 years (IQR 0.3-1.7). For longitudinal analyses, 381 and 335 subjects had at least 1 year of clinical and imaging follow-up, respectively. In cross-sectional analyses, NfL chain levels identified structural lipids (phosphatidylcholines and phosphatidylethanolamines) as the highest-performing predictors, including external validation. In contrast, longitudinal analyses found polyunsaturated fatty acids (PUFAs) and their derivatives to be protective from subsequent disease activity (q<0.001, multiple outcomes). CONCLUSION/CONCLUSIONS:There are two categories of lipids associated with MS processes. First, structural lipids strongly associated with NfL levels may result from cell lysis secondary to acute inflammation. In contrast, PUFAs, especially ω-3, had a protective effect on subsequent disease activity.