Faculty Bibliography

Gliomas are a major cause of cancer-related deaths in adolescents and young adults (AYAs; ages 15-39 years). Different molecular alterations drive gliomas in children and adults, leading to distinct biology and clinical consequences, but the implications of pediatric- versus adult-type alterations in AYAs are unknown. Our population-based analysis of 1,456 clinically and molecularly characterized gliomas in patients aged 0-39 years addresses this gap. Pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. AYA low-grade gliomas with specific RAS-MAPK alterations exhibited senescence, tended to arise in different locations and were associated with superior outcomes compared to gliomas in children, suggesting different cellular origins. Hemispheric IDH-mutant, BRAF p.V600E and FGFR-altered gliomas were associated with the risk of malignant transformation, having worse outcomes with increased age. These insights into gliomagenesis may provide a rationale for earlier intervention for certain tumors to disrupt the typical behavior, leading to improved outcomes.

This study explores the use of virtual reality (VR) as an innovative tool to enhance awareness, understanding of accessibility for persons with vision loss (VL), and acceptance. Through a VR-based workshop developed in collaboration with New York City's Department Of Transportation, participants experienced immersive simulations of VL and related immersive mobility challenges. The methodology included the development of a VR environment, simulations of vision loss, testing with the DOT team during the workshop, and an assessment of changes in participants' knowledge, confidence in addressing accessibility challenges, and overall perception through pre- and post-intervention questionnaires. Participants included urban planners, designers, and architects. Results showed a significant increase in awareness of VL-related challenges that affect design guidelines, as well as improved confidence in addressing such challenges. Participants also expressed strong support for VR as a pedagogical tool, noting its potential for reshaping professional practices, improving capacity building, and enhancing inclusive design. The study demonstrates the effectiveness of VR as an experiential learning platform, fostering empathy and a long-term commitment to integrating VL considerations into urban design. These findings highlight the transformative potential of VR in advancing equity and accessibility in urban environments.

Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility of neurologically vulnerable individuals to SARS-CoV-2 infection. Human Chromosome-21 (HSA21) triplication in DS causes global transcriptional deregulation, affecting multiple genes that may directly (e.g., TMPRSS2) or indirectly influence the SARS-CoV-2 entry into central nervous system (CNS) cells. The anti-viral immune response may also be altered in cells with trisomy-21 (T21) due to triplication of genes encoding for several interferon receptor subunits and interferon-stimulated genes (ISGs). Here, we demonstrate that human cells derived from fetal cortical specimens and maintained in primary cultures are susceptible to infection with a molecular clone of vesicular stomatitis virus engineered to express the Spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and to authentic SARS-CoV-2. The level of SARS-CoV-2 infectivity in cultures originated from different cortical specimens varied, seemingly depending on ploidy and chromosomal sex of the cells. We confirmed the presence of ACE2 and TMPRSS2 in cultures and found that XY T21 group had the highest TMPRSS2 mRNA levels, which was associated with increased infectivity in XY-compared to XX T21 cultures. The XX T21 cultures exhibited elevated expression of several ISGs (MX1, STAT1, and STAT2) which was associated with lower infectivity. The comparisons of postmortem aged brain specimens revealed reduced ACE2, TMPRSS2, but elevated STAT2 protein levels in individuals with DS and Alzheimer's disease (DS-AD) compared to control and Alzheimer's disease (AD) group. Collectively, these results suggest multifactorial regulation of SARS-CoV-2 infectivity in cortical cells that involves ploidy, chromosomal sex, and the expression of genes implicated in regulation of virus entry and anti-viral response as contributing factors.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Dural arteriovenous fistula (dAVF) surgery is a microsurgical procedure that requires confirmation of obliteration using formal cerebral angiography, but the lack of intraoperative angiogram or need for postoperative angiogram in some settings necessitates a search for alternative, less invasive methods to verify surgical success. This study evaluates the use of indocyanine green videoangiography FLOW 800 hemodynamic intraoperatively during cranial and spinal dAVF obliteration to confirm obliteration and predict surgical success. METHODS:A retrospective analysis was conducted using indocyanine green videoangiography FLOW 800 to intraoperatively measure 4 hemodynamic parameters-Delay Time, Speed, Time to Peak, and Rise Time-across venous drainage regions of interest pre/post-dAVF obliteration. Univariate and multivariate statistical analyses to evaluate and visualize presurgical vs postsurgical state hemodynamic changes included nonparametric statistical tests, logistic regression, and Bayesian analysis. RESULTS:A total of 14 venous drainage regions of interest from 8 patients who had successful spinal or cranial dAVF obliteration confirmed with intraoperative digital subtraction angiography were extracted. Significant hemodynamic changes were observed after dAVF obliteration, with median Speed decreasing from 13.5 to 5.5 s-1 (P = .029) and Delay Time increasing from 2.07 to 7.86 s (P = .020). Bayesian logistic regression identified Delay Time as the strongest predictor of postsurgical state, with a 50% increase associated with 2.16 times higher odds of achieving obliteration (odds ratio = 4.59, 95% highest density interval: 1.07-19.95). Speed exhibited a trend toward a negative association with postsurgical state (odds ratio = 0.62, 95% highest density interval: 0.26-1.42). Receiver operating characteristic-area under the curve analysis using logistic regression demonstrated a score of 0.760, highlighting Delay Time and Speed as key features distinguishing preobliteration and postobliteration states. CONCLUSION/CONCLUSIONS:Our findings demonstrate that intraoperative FLOW 800 analysis reliably quantifies and visualizes immediate hemodynamic changes consistent with dAVF obliteration. Speed and Delay Time emerged as key indicators of surgical success, highlighting the potential of FLOW 800 as a noninvasive adjunct to traditional imaging techniques for confirming dAVF obliteration intraoperatively.

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.

We introduce an intracranial EEG (iEEG) dataset collected as part of an adversarial collaboration between proponents of two theories of consciousness: Global Neuronal Workspace Theory and Integrated Information Theory. The data were recorded from 38 patients undergoing intracranial monitoring of epileptic seizures across three research centers using the same experimental protocol. Participants were presented with suprathreshold visual stimuli belonging to four different categories (faces, objects, letters, false fonts) in three orientations (front, left, right view), and for three durations (0.5, 1.0, 1.5 s). Participants engaged in a non-speeded Go/No-Go target detection task to identify infrequent targets with some stimuli becoming task-relevant and others task-irrelevant. Participants also engaged in a motor localizer task. The data were checked for its quality and converted to Brain Imaging Data Structure (BIDS). The de-identified dataset contains demographics, clinical information, electrode reconstruction, behavioral performance, and eye-tracking data. We also provide code to preprocess and analyze the data. This dataset holds promise for reuse in consciousness science and vision neuroscience to answer questions related to stimulus processing, target detection, and task-relevance, among many others.

Optic disc swelling, frequently associated with vitamin A toxicity, is infrequently linked to vitamin A deficiency. This report describes a 6-year-old male with autism spectrum disorder (ASD) and avoidant restrictive food intake disorder who presented with xerophthalmia, optic disc swelling, vision changes, and deficiencies in vitamins A, B₁, and iron. The patient's behavioral dysregulation posed important challenges for the evaluation, diagnosis, and treatment of his hypovitaminoses. This case underscores the importance of considering multiple nutritional deficiencies as the etiology of optic disc swelling in pediatric populations with autism spectrum disorder and avoidant restrictive food intake disorder, diagnoses that have increased in frequency. Early recognition and intervention can prevent further complications such as visual loss and improve outcomes.

In treating malignant cerebral edema after a large middle cerebral artery stroke, clinicians need quantitative tools for real-time risk assessment. Existing predictive models typically estimate risk at one, early time point, failing to account for dynamic variables. To address this, we developed Hybrid Ensemble Learning Models for Edema Trajectory (HELMET) to predict midline shift severity, an established indicator of malignant edema, over 8-h and 24-h windows. The HELMET models were trained on retrospective data from 623 patients and validated on 63 patients from a different hospital system, achieving mean areas under the receiver operating characteristic curve of 96.6% and 92.5%, respectively. By integrating transformer-based large language models with supervised ensemble learning, HELMET demonstrates the value of combining clinician expertise with multimodal health records in assessing patient risk. Our approach provides a framework for accurate, real-time estimation of dynamic clinical targets using human-curated and algorithm-derived inputs.

Immune-mediated protection generated to COVID-19 mRNA vaccines is associated with anti-Spike (S) protein neutralizing antibodies. However, humoral immunity is compromised in B cell depleting (BCD) therapies, used to treat autoimmune diseases such as Multiple Sclerosis (MS). To study the effect of BCD on the durability and protective efficacy of vaccine-induced immunity, we evaluated S-reactive antibodies and T cell responses 1-70 weeks post-vaccination in MS cohorts treated with BCD compared to non-BCD therapies from four centers. BCD-treated participants had significantly reduced antibody levels and enhanced frequencies of S-reactive CD4⁺ and CD8⁺ memory T cells to COVID-19 vaccination compared to the non-BCD group, with some variations among different BCD formulations. T cell memory responses persisted up to 14 months post-vaccination in both BCD and non-BCD cohorts, who experienced similar clinical protection from COVID-19. Together, our results establish a critical role for T cell-mediated immunity in anti-viral protection independent of humoral immunity.

Alexia without agraphia is a neurological syndrome characterised by an acquired inability to read with a preserved ability to write. It is caused by the combined effect of two lesions: in the splenium of the corpus callosum and in the occipital lobe of the dominant hemisphere. Splenial lesions disconnect the language areas in the temporal and parietal lobes of the dominant hemisphere from the visual areas in the occipital cortex of the contralateral side, while lesions in the dominant occipital lobe cause homonymous hemianopia. We describe two patients with lesions affecting the splenium and dominant occipital lobe, with different causes. Together, these cases highlight the importance of performing a thorough language evaluation in patients presenting with homonymous visual field deficits, as otherwise, clinicians may overlook impairments in writing (agraphia) or reading (alexia).