Faculty Bibliography

PURPOSE/OBJECTIVE:We previously reported that single doses of the norepinephrine transporter inhibitor, atomoxetine, increased standing blood pressure (BP) and ameliorated symptoms in patients with neurogenic orthostatic hypotension (nOH). We aimed to evaluate the effect of atomoxetine over four weeks in patients with nOH. METHODS:A randomized, double-blind, placebo-controlled crossover clinical trial between July 2016 and May 2021 was carried out with an initial open-label, single-dose phase (10 or 18 mg atomoxetine), followed by a 1-week wash-out, and a subsequent double-blind 4-week treatment sequence (period 1: atomoxetine followed by placebo) or vice versa (period 2). The trial included a 2-week wash-out period. The primary endpoint was symptoms of nOH as measured by the orthostatic hypotension questionnaire (OHQ) assessed at 2 weeks. RESULTS:A total of 68 patients were screened, 40 were randomized, and 37 completed the study. We found no differences in the OHQ composite score between atomoxetine and placebo at 2 weeks (-0.3 ± 1.7 versus -0.4 ± 1.5; P = 0.806) and 4 weeks (-0.6 ± 2.4 versus -0.5 ± 1.6; P = 0.251). There were no differences either in the OHSA scores at 2 weeks (3 ± 1.9 versus 4 ± 2.1; P = 0.062) and at 4 weeks (3 ± 2.2 versus 3 ± 2.0; P = 1.000) or in the OH daily activity scores (OHDAS) at 2 weeks (4 ± 3.0 versus 5 ± 3.1, P = 0.102) and 4 weeks (4 ± 3.0 versus 4 ± 2.7, P = 0.095). Atomoxetine was well-tolerated. CONCLUSIONS:While previous evidence suggested that acute doses of atomoxetine might be efficacious in treating nOH; results of this clinical trial indicated that it was not superior to placebo to ameliorate symptoms of nOH. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov; NCT02316821.

PURPOSE/OBJECTIVE:Defects in the gene encoding selenocysteine insertion sequence binding protein 2, SECISBP2, result in global impaired selenoprotein synthesis manifesting a complex syndrome with characteristic serum thyroid function tests due to impaired thyroid hormone metabolism. Knowledge about this multisystemic defect remains limited. METHODS:Genetic and laboratory investigations were performed in affected members from 6 families presenting with short stature and failure to thrive. RESULTS:Four probands presented a complex neurodevelopmental profile, including absent speech, autistic features, and seizures. Pediatric neurological evaluation prompted genetic investigations leading to the identification of SECISBP2 variants before knowing the characteristic thyroid tests in 2 cases. Thyroid hormone treatment improved motor development, whereas speech and intellectual impairments persisted. This defect poses great diagnostic and treatment challenges for clinicians, as illustrated by a case that escaped detection for 20 years because SECISBP2 was not included in the neurodevelopmental genetic panel, and his complex thyroid status prompted antithyroid treatment instead. CONCLUSION/CONCLUSIONS:This syndrome uncovers the role of selenoproteins in humans. The severe neurodevelopmental disabilities manifested in 4 patients with SECISBP2 deficiency highlight an additional phenotype in this multisystem disorder. Early diagnosis and treatment are required, and long-term evaluation will determine the full spectrum of manifestations and the impact of therapy.

BACKGROUND AND OBJECTIVES/UNASSIGNED:Previous research has demonstrated that simulation-based medical education (SBME) can improve neurology trainees' confidence, knowledge, and competence. However, a general needs assessment and review of current SBME used within neurology are needed to guide SBME curriculum development. The objective of this study was to describe the current use of SBME in resident education and to assess perceived barriers to expanding SBME interventions. METHODS/UNASSIGNED:We surveyed adult neurology residency program directors (PDs) listed in the Accreditation Council for Graduate Medical Education directory using a Qualtrics-based survey platform. Survey questions addressed current utilization of SBME and barriers to SBME growth. RESULTS/UNASSIGNED:Seventy-five PDs of 171 contactable PDs responded to our survey (response rate 44%). Of the respondents, 84% (64/75) report using SBME in their adult neurology residencies. Of those using SBME, 87% (55/64) programs create their own cases. Most programs use simulation to teach neurocritical care topics (63%) and vascular neurology (78%); few use simulation to teach outpatient topics and teleneurology. Among programs that use SBME, there was variability in the frequency of the SBME interventions and in the target trainee cohort. Among responding programs, most expressed interest in expanding SBME in their curriculum (69%, 52/64), but frequently cited lack of faculty protected time (55%), funding (35%), and resident availability (32%) as barriers to doing so. DISCUSSION/UNASSIGNED:Most responding programs use SBME. However, the frequency and target learner for SBME interventions varied between programs. Many programs wish to expand SBME at their institutions but are constrained by limited protected time and institutional financial support. We discuss potential solutions to the perceived barriers to SBME, including intra-institutional collaboration to advance SBME use and case diversity for learners and help innovate neurology medical education.

BACKGROUND:The Center for Medicare and Medicaid Services requires Organ Procurement Organizations (OPOs) to verify and document that any potential organ donor has been pronounced dead per applicable legal requirements of local, state, and federal laws. However, OPO practices regarding death by neurologic criteria (DNC) verification are not standardized, and little is known about their DNC verification processes. This study aimed to explore OPO practices regarding DNC verification in the United States. METHODS:An electronic survey was sent to all 57 OPOs in the United States from June to September 2023 to assess verification of policies and practices versus guidelines, concerns about policies and practices, processes to address concerns about DNC determination, and communication practices. RESULTS:Representatives from 12 OPOs across six US regions completed the entire survey; 8 of 12 reported serving > 50 referral hospitals. Most respondents (11 of 12) reported comparing their referral hospital's DNC policies with the 2010 American Academy of Neurology Practice Parameter and/or other (4 of 12) guidelines. Additionally, most (10 of 12) reported independently reviewing and verifying each DNC determination. Nearly half (5 of 12) reported concerns about guideline-discordant hospital policies, and only 3 of 12 thought all referral hospitals followed the 2010 American Academy of Neurology Practice Parameter in practice. Moreover, 9 of 12 reported concerns about clinician knowledge surrounding DNC determination, and most (10 of 12) reported having received referrals for patients whose DNC declaration was ultimately reversed. All reported experiences in which their OPO requested additional assessments (11 of 12 clinical evaluation, 10 of 12 ancillary testing, 9 of 12 apnea testing) because of concerns about DNC determination validity. CONCLUSIONS:Accurate DNC determination is important to maintain public trust. Nearly all OPO respondents reported a process to verify hospital DNC policies and practices with medical society guidelines. Many reported concerns about clinician knowledge surrounding DNC determination and guideline-discordant policies and practices. Educational and regulatory advocacy efforts are needed to facilitate systematic implementation of guideline-concordant practices across the country.

BACKGROUND:The choroid plexus (ChP), a densely vascularized structure, has drawn increasing attention for its involvement in brain homeostasis and waste clearance. While the volumetric changes have been explored in many imaging studies, few studies have investigated the vascular degeneration associated with aging in the ChP. PURPOSE/OBJECTIVE:To investigate the sub-structural characteristics of the ChP, particularly the vascular compartment using high-resolution 7T imaging enhanced with Ferumoxytol, an ultrasmall super-paramagnetic iron oxide, which greatly increase the susceptibility contrast for vessels. STUDY TYPE/METHODS:Prospective. SUBJECTS/METHODS:Forty-nine subjects without neurological disorders (age: 21-80 years; 42 ± 17 years; 20 females). FIELD STRENGTH/SEQUENCE/UNASSIGNED:7-T with 2D and 3D T2* GRE, 3D MPRAGE T1, 2D TSE T2, and 2D FLAIR. ASSESSMENT/RESULTS:ratio) and susceptibility change (Δχ) induced by Ferumoxytol were analyzed on 3D GRE-derived susceptibility-weighted imaging and quantitative susceptibility mapping, respectively. STATISTICAL TESTS/METHODS:Independent t-test, Mann-Whitney U test, and Chi-square test were utilized for group comparisons. The relationship between age and ChP's vascular alterations was examined using Pearson's correlation. Intra-class coefficient was calculated for inter-observer agreement. A P value <0.05 was considered statistically significant. RESULTS:2D GRE images demonstrated superior contrast and accurate delineation of ChP substructures (ICC = 0.86). Older subjects exhibited a significantly smaller vascular density (16.5 ± 4.34%) and lower Δχ (22.10 ± 12.82 ppb) compared to younger subjects (24.85 ± 6.84% and 34.64 ± 12.69 ppb). Vascular density and mean Δχ within the ChP negatively correlated with age (r = -0.48, and r = -0.45). DATA CONCLUSION/CONCLUSIONS:Ferumoxytol-enhanced 7T images can demonstrate ChP alterations in elderly with decreased vascular density and expansion of nonvascular compartment. EVIDENCE LEVEL/METHODS:1 TECHNICAL EFFICACY: Stage 2.

BACKGROUND AND OBJECTIVES/UNASSIGNED:variants. METHODS/UNASSIGNED:variants were included. We used standardized tools to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder, and adaptive behavioral skills of patients. RESULTS/UNASSIGNED:= 0.04). DISCUSSION/UNASSIGNED:variants.

Sudden unexplained death in childhood (SUDC) is death of a child ≥ 12 months old that is unexplained after autopsy and detailed analyses. Among SUDC cases, ~ 30% have febrile seizure (FS) history, versus 2-5% in the general population. SUDC cases share features with sudden unexpected death in epilepsy (SUDEP) and sudden infant death syndrome (SIDS), in which brainstem autonomic dysfunction is implicated. To understand whether brainstem protein changes are associated with FS history in SUDC, we performed label-free quantitative mass spectrometry on microdissected midbrain dorsal raphe, medullary raphe, and the ventrolateral medulla (n = 8 SUDC-noFS, n = 11 SUDC-FS). Differential expression analysis between SUDC-FS and SUDC-noFS at p < 0.05 identified 178 altered proteins in dorsal raphe, 344 in medullary raphe, and 100 in the ventrolateral medulla. These proteins were most significantly associated with increased eukaryotic translation initiation (p = 3.09 × 10^-7, z = 1.00), eukaryotic translation elongation (p = 6.31 × 10^-49, z = 6.01), and coagulation system (p = 1.32 × 10^-5, z = 1.00). The medullary raphe had the strongest enrichment for altered signaling pathways, including with comparisons to three other brain regions previously analyzed (frontal cortex, hippocampal dentate gyrus, cornu ammonus). Immunofluorescent tissue analysis of serotonin receptors identified 2.1-fold increased 5HT2A in the medullary raphe of SUDC-FS (p = 0.025). Weighted gene correlation network analysis (WGCNA) of case history indicated that longer FS history duration significantly correlated with protein levels in the medullary raphe and ventrolateral medulla; the most significant gene ontology biological processes were decreased cellular respiration (p = 9.8 × 10^-5, corr = - 0.80) in medullary raphe and decreased synaptic vesicle cycle (p = 1.60 × 10^-7, corr = - 0.90) in the ventrolateral medulla. Overall, FS in SUDC was associated with more protein differences in the medullary raphe and was related with increased translation-related signaling pathways. Future studies should assess whether these changes result from FS or may in some way predispose to FS or SUDC.

Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with cerebrospinal fluid/positron emission tomography biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/amyloid-β₄₂ ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.