Faculty Bibliography

Understanding normal spinal arterial and venous anatomy, and spinal vascular disease, is impossible without flow-based methods. Development of practical spinal angiography led to site-specific categorization of spinal vascular conditions, defined by the 'seat of disease' in relation to the cord and its covers. This enabled identification of targets for highly successful surgical and endovascular treatments, and guided interpretation of later cross-sectional imaging.Spinal dural and epidural arteriovenous fistulas represent the most common types of spinal shunts. Although etiology is debated, anatomy provides excellent pathophysiologic correlation. A spectrum of fistulas, from foramen magnum to the sacrum, is now well-characterized.Most recently, use of cone beam CT angiography has yielded new insights into normal and pathologic anatomy, including venous outflow. It provides unrivaled visualization of the fistula and its relationship with spinal cord vessels, and is the first practical method to study normal and pathologic spinal veins in vivo-with multiple implications for both safety and efficacy of treatments. We advocate consistent use of cone beam CT imaging in modern spinal fistula evaluation.The role of open surgery is likely to remain undiminished, with increasing availability and use of hybrid operating rooms for practical intraoperative angiography enhancing safety and efficacy of complex surgery.

APOE^ε4 is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOE^ε4 is known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOE^ε3/ε3 and n = 5 APOE^ε4/ε4), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOE^ε3/ε3 and n = 10 APOE^ε4/ε4). Our dataset includes 1130 and 1330 proteins enriched in IP_PHF1 samples from APOE^ε3/ε3 and APOE^ε4/ε4 groups (fold change ≥ 1.50, IP_PHF1 vs IP_{IgG ctrl}). We identified 80 and 68 proteins as probable pTau interactors in APOE^ε3/ε3 and APOE^ε4/ε4 groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOE^ε3/ε3 vs APOE^ε4/ε4 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOE^ε4/ε4 vs APOE^ε3/ε3 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE^ε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE^ε4/ε4 cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOE^ε4 carriers, paving the way to the identification of new therapeutic targets.

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.

BACKGROUND:(p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS:A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS:We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

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 PURPOSE/OBJECTIVE:Several recent works using resting-state fMRI suggest possible alterations of resting-state functional connectivity after mild traumatic brain injury. However, the literature is plagued by various analysis approaches and small study cohorts, resulting in an inconsistent array of reported findings. In this study, we aimed to investigate differences in whole-brain resting-state functional connectivity between adult patients with mild traumatic brain injury within 1 month of injury and healthy control subjects using several comprehensive resting-state functional connectivity measurement methods and analyses. MATERIALS AND METHODS/METHODS:A total of 123 subjects (72 patients with mild traumatic brain injury and 51 healthy controls) were included. A standard fMRI preprocessing pipeline was used. ROI/seed-based analyses were conducted using 4 standard brain parcellation methods, and the independent component analysis method was applied to measure resting-state functional connectivity. The fractional amplitude of low-frequency fluctuations was also measured. Group comparisons were performed on all measurements with appropriate whole-brain multilevel statistical analysis and correction. RESULTS:There were no significant differences in age, sex, education, and hand preference between groups as well as no significant correlation between all measurements and these potential confounders. We found that each resting-state functional connectivity measurement revealed various regions or connections that were different between groups. However, after we corrected for multiple comparisons, the results showed no statistically significant differences between groups in terms of resting-state functional connectivity across methods and analyses. CONCLUSIONS:Although previous studies point to multiple regions and networks as possible mild traumatic brain injury biomarkers, this study shows that the effect of mild injury on brain resting-state functional connectivity has not survived after rigorous statistical correction. A further study using subject-level connectivity analyses may be necessary due to both subtle and variable effects of mild traumatic brain injury on brain functional connectivity across individuals.

BACKGROUND:Hypertension is a stroke risk factor with known disparities in prevalence and management between Black and White patients. We sought to identify if racial differences in presenting blood pressure (BP) during acute ischemic stroke exist. METHODS AND RESULTS/RESULTS:<0.01) were also higher in Black patients. CONCLUSIONS:This population-based study suggests differences in presenting BP between Black and White patients during acute ischemic stroke. Further study is needed to determine whether these differences influence clinical decision-making, outcome, or clinical trial eligibility.

BACKGROUND:This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma. METHODS:This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at three dose levels (DLs; -1, 1, and 2). Actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator.1. RESULTS:Twelve patients received D1D2 ONC201 (DL-1, n=3; DL1, n=3; DL2, n=6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250mg, n=3; D1-625mg, n=3; D1D2-250mg, n=2; D1D2-625mg, n=2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly. CONCLUSIONS:ONC201 given D1D2 was well-tolerated at all DLs and associated with greater AUC0-48.