Faculty Bibliography

INTRODUCTION/BACKGROUND:Progression Independent of Relapse Activity (PIRA) is a critical measure of disability progression in multiple sclerosis (MS) independent of relapses but lacks a standardized definition. Current reliance on the Expanded Disability Status Scale (EDSS) limits sensitivity to non-motor domains, necessitating a stratified framework to enhance detection and guide management. OBJECTIVES/OBJECTIVE:To develop a novel seven-level stratified PIRA definition and assess its validity, enhanced sensitivity, clinical relevance, and feasibility through expert consensus, and propose a simplified framework based on feedback. METHODS:A two-stage study: (1) A four-expert panel developed a seven-level PIRA framework (PIRA 1: EDSS-based; PIRA 2: EDSS-plus measures; PIRA 3: stress tests; PIRA 4: patient-reported outcomes [PROs]; PIRA 5: conventional MRI; PIRA 6: advanced MRI; PIRA 7: biomarkers) via literature synthesis. (2) A survey of 90 MS experts (26 responded, 28.9%) from nine countries evaluated each level's validity, sensitivity (vs. EDSS), relevance, and feasibility (1-5 scale), with open-ended comments on barriers and suggestions. High agreement was defined as a score ≥ 4. Qualitative feedback on barriers and improvement suggestions was thematically analyzed. RESULTS:Strong support (24/26; 92.3%) endorsed a stratified PIRA definition. Respondents included primarily clinician-researchers (22/26; 84.6%), with 11/26 (42.3%) reporting more than 20 years of MS experience. High agreement for validity ranged from 15/26 (57.7%) for PIRA 1-23/26 (88.5%) for PIRA 6. Agreement regarding enhanced sensitivity was highest for PIRA 2 (25/26; 96.2%), followed by PIRA 6 (22/26; 84.6%) and PIRA 5 (19/26; 73.1%). Clinical relevance was rated highly for PIRA 1, PIRA 2, and PIRA 6 (each 25/26; 96.2%). Feasibility was highest for PIRA 1 (24/26; 92.3%) and declined for higher levels, particularly PIRA 7. Barriers included inter-rater variability (PIRA 1, 30.8%), subjectivity (PIRA 4, 23.1%), and cost/expertise (PIRA 6-7, 26.9% each). Suggestions included digital tools (PIRA 2-3), AI for MRI (PIRA 5-6), biomarker validation (PIRA 7), and combining PIRA 5-6. PIRA 1-2 were preferred for clinical practice, PIRA 5-7 for research. A three-tier framework was proposed: Probable PIRA (clinical), Definite PIRA (clinical + MRI), and Definite PIRA Plus (clinical + MRI + biomarkers). CONCLUSIONS:The proposed seven-level PIRA framework demonstrates strong expert support for its conceptual validity and clinical relevance but highlights feasibility challenges for advanced assessments. A simplified three-tier model may provide a practical structure for standardized evaluation of relapse-independent progression in MS. Further empirical validation in diverse clinical cohorts is required.

Alzheimer's disease (AD) remains a major global health challenge, with prevalence projected to increase dramatically in the coming decades and no effective treatments available. Current therapies offer only symptomatic relief, reinforcing the need for disease-modifying strategies targeting underlying pathogenic mechanisms. Advances in understanding amyloid-β (Aβ) and tau pathology have propelled the development of targeted interventions, particularly monoclonal antibodies (mAbs) and small-molecule therapeutics. Recent anti-Aβ antibodies, such as aducanumab, lecanemab, and donanemab, have demonstrated significant biological activity and reductions in amyloid burden, leading to regulatory approvals that represent important proof-of-concept milestones. However, these therapies face ongoing controversies related to modest clinical efficacy, accessibility, cost, and safety concerns. In parallel, small-molecule development has expanded beyond failed secretase inhibitors toward more refined mechanisms, including tau aggregation inhibition, kinase modulation, mitochondrial stabilization, and anti-inflammatory pathways. These compounds offer advantages in oral administration, blood-brain barrier penetration, and multi-target engagement. Together, mAbs and small molecules represent complementary therapeutic strategies addressing different aspects of AD pathophysiology. Their integration with emerging biomarkers, genetic profiling, and early diagnostic frameworks is driving a transition toward personalized and stage-specific treatment approaches. This review synthesizes current mechanistic insights, clinical evidence, and translational challenges of both modalities, highlighting how their convergence may shape the next-generation of AD therapeutics.

IMPORTANCE/UNASSIGNED:Seizure-induced brain injury is central to the treatment urgency of new-onset refractory status epilepticus (NORSE). Identifying biomarkers that reflect ongoing neuronal damage could inform therapeutic timing and improve outcomes. OBJECTIVE/UNASSIGNED:To quantify acute brain injury in patients with cryptogenic NORSE (cNORSE), etiology-defined status epilepticus (eSE), and chronic epilepsy. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was an international cross-sectional study conducted between 2013 and 2025. Patients were enrolled at 36 hospitals in the US, 2 in Canada, and 1 in Italy, France, and Belgium. Patients with cNORSE and eSE for which biological samples were obtained during ongoing seizure activity were enrolled in the study. Comparison groups without status epilepticus comprised individuals with chronic epilepsy and healthy participants. None were excluded. EXPOSURES/UNASSIGNED:Neurofilament light chain (NfL) and S100-beta (S100B) protein concentrations in serum and cerebrospinal fluid (CSF). MAIN OUTCOMES AND MEASURES/UNASSIGNED:Degree of neuronal and glial damage, indexed by NfL and S100B levels, and their association with short-term functional outcomes. RESULTS/UNASSIGNED:A total of 78 patients with cNORSE (mean [95% CI] age, 37 [30-41] years; 44 female [56%]) and 2 independent cohorts of 211 patients (mean [95% CI] age, 69 [66-71] years; 128 female [61%]) and 73 patients (mean [95% CI] age, 56 [45-65] years; 39 male [53%]) with eSE were included. NfL concentrations were markedly elevated in cNORSE-approximately 10-fold higher in CSF and 4-fold higher in serum-compared with the eSE cohorts (CSF: median [IQR], 6408 [1503-22 963] pg/mL compared with 694 [219-2389] pg/mL; serum: median [IQR], 231 [99-855] pg/mL compared with 55 [20-135] pg/mL; P <.001). Serum NfL levels were nearly 20-fold higher in cNORSE than in the cohort with epilepsy and in healthy controls (median [IQR], 11 [7-19 ] and 7 [5-14 ] pg/mL, respectively). Serum and CSF NfL levels were strongly correlated (Spearman ρ = 0.75; P < .001) and rose sharply between week 1 (median [IQR], 101 [51-137] pg/mL), week 2 (median [IQR], 197 [117-324] pg/mL), and week 3 (median [IQR], 598 [163-1000] pg/mL) after onset (P < .001). In contrast, S100B concentrations did not differ between groups and showed no consistent temporal pattern. NfL discriminated cNORSE from eSE (area under the receiver operating characteristic curve [AUROC], 0.79; 95% CI, 0.68-0.90) and from cohorts without status epilepticus (AUROC, 0.99; 95% CI, 0.78-1.00). Higher serum NfL was independently associated with poor functional outcome at discharge (Glasgow Outcome Scale extended score, 1-4; odds ratio, 1.01; 95% CI, 1.00-1.03; P = .03). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Results of this cross-sectional study suggest that acute neuroaxonal injury, as reflected by elevated NfL levels, was substantially greater in cNORSE than in the cohorts with eSE and in controls without status epilepticus. The rapid early rise in NfL highlights a narrow therapeutic window, emphasizing the need for prompt, effective, and potentially neuroprotective interventions in cNORSE.

Human pluripotent stem cells (hPSCs) are a valuable tool for disease modeling. Further stem cells can be reprogrammed from adult somatic cells, called induced pluripotent stem cells (iPSC). iPSC technology allows for the evaluation of specific study participants and populations and ventures into personalized medicine. Blood is routinely taken and cryopreserved for research purposes. These samples are processed either as buffy coats, a blood sample containing white blood cells and platelets, or as peripheral blood mononuclear cells (PBMCs), which represent a more purified population of white blood cells without eosinophils, basophils, platelets, or red blood cells. Both are a readily available and relatively non-invasive source for reprogrammable somatic cells. Several reports detail reprogramming from PBMCs, whereas only one describes this process from frozen buffy coats. Recent experience revealed PBMC reprogramming protocols available in the literature and from manufacturers to be unsuccessful when applied to frozen buffy coat samples, necessitating the adaptations and troubleshooting strategies described here. For many researchers, who employ iPSC technologies, it is imperative to have thorough protocols with a high success rate, especially in cases, where patient samples may contain only few cells, are obtained in wide time intervals, are from limited participant pool, or are otherwise highly valuable. Here, checkpoints and troubleshooting strategies are identified to increase the chance of reprogramming human frozen buffy coats or purified PBMCs. Ultimately, this protocol will allow researchers to identify predictors of reprogramming success and strategize alternative approaches to improve the chances of successful iPSC derivation.

Reliable structural brain measurements are essential for studying neurodegeneration and for designing adequately powered aging and Alzheimer's disease (AD) research. We evaluated the test-retest reliability of FreeSurfer 7.1 morphometric measures in 100 older adults (mean age 73.5 years) ranging from cognitively unimpaired to dementia. Each participant underwent two T1-weighted 3T MRI scans on the same scanner within a short interval (mean 5.5 weeks), minimizing biological change. Segmentation was performed in both standard cross-sectional and longitudinal FreeSurfer modes, focusing on AD-relevant volumes of entorhinal cortex, hippocampus, lateral ventricles, choroid plexus, and the AD cortical thickness signature. Reliability was quantified using absolute and root-mean-square test-retest differences, standard deviation of differences, and intraclass correlation coefficients. Longitudinal processing improved precision by 15-50% across most measures compared with cross-sectional processing, with the largest gain observed for entorhinal thickness. Larger, anatomically well-defined regions (e.g., hippocampus, AD signature) demonstrated higher reliability than small structures or those with complex geometry (e.g., entorhinal cortex, choroid plexus). Image quality, indexed by the Euler characteristic, was the only factor significantly associated with measurement variability; reliability was unrelated to age, sex, cognitive status, inter-scan interval, or amyloid/tau PET burden. Power analyses indicated that detecting a 1% within-individual change requires sample sizes ranging from 36 (AD signature) to >300 (entorhinal cortex). We observed low reliability of choroid plexus volumetry by FreeSurfer 7. These results provide practical benchmarks for expected FreeSurfer measurement variability in older adults. They highlight the advantages of longitudinal processing and rigorous quality control for research on brain aging and AD.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Traditional medical board examinations present clinical information in static vignettes with multiple-choices (MC), fundamentally different from how physicians gather and integrate data in practice. Recent advances in large language models (LLMs) offer promising approaches to creating more realistic clinical interactive conversations. However, these approaches are limited in neurosurgery, where patient communication capacity varies significantly and diagnosis heavily relies on objective data such as imaging and neurological examinations. We aimed to develop and evaluate a multi-artificial intelligence (AI) agent conversation framework for neurosurgical case assessment that enables realistic clinical interactions through simulated patients and structured access to objective clinical data. METHODS:We developed a framework to convert 608 Self-Assessment in Neurological Surgery first-order diagnosis questions into conversation sessions using 3 specialized AI agents: patient AI for subjective information, system AI for objective data, and clinical AI for diagnostic reasoning. We evaluated generative pretrained transformer 4o's (GPT-4o's) diagnostic accuracy across traditional vignettes, patient-only conversations, and patient + system AI interactions, with human benchmark testing from 10 neurosurgery residents. RESULTS:= .0030) using fewer interactions and reported high educational value of the interactive format. CONCLUSION/CONCLUSIONS:This multi-AI agent framework provides both a more challenging evaluation method for LLMs and an engaging educational tool for neurosurgical training. The significant performance drops in conversational formats suggest that traditional MC testing may overestimate LLMs' clinical reasoning capabilities, while the framework's interactive nature offers promising applications for enhancing medical education.

The effectiveness of COVID-19 vaccination in children and adolescents with prior SARS-CoV-2 infection remains unclear, particularly for Omicron subvariants. We evaluate vaccine effectiveness against reinfection with Omicron BA.1/BA.2, BA.4/BA.5, XBB, and later subvariants among 5- to 17-year-olds using data from the RECOVER initiative, a national electronic health record database covering 37 U.S. children's hospitals and health institutions. We emulate target trials by age group and variant period, comparing previously infected participants between January 2022 and August 2023. During the BA.1/BA.2 period, vaccination reduces the risk of reinfection, with effectiveness rates of 62% in children and 65% in adolescents. During the BA.4/BA.5 period, protection effectiveness in children was 57%, whereas no statistically significant protection is observed in adolescents. During the XBB and later period, no significant protection is observed in either group. In summary, COVID-19 vaccination provides protection against reinfection during the early and mid-Omicron periods in previously infected pediatric populations, but effectiveness declines for later variants.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Implementation of telemedicine expanded options for outpatient neurology care. It remains uncertain which new neurology patients can be appropriately evaluated virtually. We compared subsequent health care utilization after virtual vs in-person new patient neurology visits across 3 academic medical centers. METHODS:We conducted a retrospective multicenter cohort study of adults with a new outpatient neurology visit from September 2020 through December 2021 using the Vizient Clinical Data Base and Clinical Practice Solutions Center databases. Virtual and in-person patients were matched 1:1 using propensity scores incorporating demographics, clinical characteristics, time period, and previous health care utilization. Outcomes were analyzed overall and stratified by neurologic chief complaint category and institution. We compared rates of subsequent neurologic clinic follow-up, emergency department (ED) visits, and hospitalizations after virtual and in-person encounters. Testing and all-cause ED visits/hospitalizations were also assessed. RESULTS:= 0.13, respectively). Analyses by chief complaint found that 90-day follow-up was higher after in-person visits for dementia, whereas 30- and 90-day follow-up was higher after virtual visits for Parkinson disease and multiple sclerosis, and 90-day follow-up was higher after virtual visits for headache. Testing was more frequent after in-person visits for certain chief complaints. DISCUSSION/CONCLUSIONS:In this propensity score-matched multicenter cohort, new neurology patients seen virtually had similar downstream utilization as those seen in-person, including comparable 90-day follow-up and similar neurologic and all-cause ED visits and hospitalizations. Although follow-up varied modestly by chief complaint and testing was more frequent after some in-person visits, no major differences emerged overall.