Faculty Bibliography

The Stroke Treatment Academic Industry Roundtable convened a workshop regarding artificial intelligence (AI) and innovative clinical trial designs during the Stroke Treatment Academic Industry Roundtable XIII meeting on March 28, 2025. This forum brought together stroke physicians and researchers, and industry representatives to discuss the current use and future opportunities for AI and novel trial designs in acute stroke trials. AI already plays a substantial role in the treatment of acute stroke with regards to imaging but is poised to have a much larger impact in clinical care and research trials over the coming years. The quality and understanding of the data are used to train the AI, the human element needed to ensure training is successful, and the clinician and trialist at the bedside, the humans "in the loop," will be necessary to maximize AI's effectiveness in clinical practice and trials. Platform trials address multiple scientific questions in an area of medicine simultaneously within the same trial structure by sharing controls across multiple interventions. While platform trials increase efficiency and potentially decrease the time needed to answer important clinical scientific questions, they also can introduce complexity to standard workflows. Future acute ischemic stroke clinical trials should incorporate elements of pragmatic and patient-centered trial design when possible. Pragmatic trials aim to assess the effectiveness of treatments when they are implemented into routine clinical care rather than under idealized conditions. AI models and platform, pragmatic, and patient-centered trial designs are new tools to answer important clinical questions, but understanding how they work, their best uses, and their limitations is critical for accelerating successful new treatments for stroke.

IMPORTANCE/UNASSIGNED:Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD). OBJECTIVE/UNASSIGNED:To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024. INTERVENTION/UNASSIGNED:Either 4 g/d of valacyclovir (n = 60) or matching placebo (n = 60). MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in 18F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome. RESULTS/UNASSIGNED:Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83]; P = .01). The LSM change in the ADCS-ADL Scale score at 78 weeks was -13.78 (95% CI, -17.00 to -10.56) in the valacyclovir group vs -10.16 (95% CI, -13.37 to -6.96) in the placebo group (between-group difference, -3.62 [95% CI, -8.16 to 0.93]). At 78 weeks, the LSM change in the 18F-florbetapir amyloid PET SUVR was 0.03 (95% CI, -0.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, -0.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, -0.08 to 0.12]). The LSM change in the 18F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, -0.06 to 0.19) in the valacyclovir group vs -0.04 (95% CI, -0.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, -0.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03282916.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

OBJECTIVE:Sudden unexpected death in epilepsy (SUDEP) often follows generalized tonic-clonic seizures during sleep, likely resulting from impaired brainstem cardiorespiratory function. We used ictal electrocardiogram (ECG)-based cross-frequency phase-amplitude coupling (PAC) to detect cardiorespiratory disruptions, comparing SUDEP to non-SUDEP cohorts. Leveraging respiratory modulation of ECG signals can provide a robust indirect proxy of respiratory monitoring despite high-amplitude noise. METHODS:We analyzed ictal ECG and electroencephalographic recordings in 21 SUDEP cases and 21 non-SUDEP epilepsy controls. Ictal ECG segments from 76 seizures (38 SUDEP, 38 non-SUDEP) were processed using continuous wavelet transformation to compute PAC between respiratory (.1-.55 Hz, 6-33 breaths per minute) and cardiac (.7-3.7 Hz, 42-222 beats per minute) frequencies. Relative PAC coupling strength was evaluated for respiratory frequencies > .25 Hz (15 breaths per minute) and cardiac frequencies > 1.7 Hz (102 beats per minute). Furthermore, a 3 × 3 grid of PAC ranges was derived for each 20-s window, yielding 18 features (mean and SD) as inputs to a logistic regression model. RESULTS:Elevated ictal PAC at higher respiratory (>.25 Hz, p < .0001) and cardiac (>1.7 Hz, p < .0142) frequencies in SUDEP patients suggests ictal respiration modulates ictal tachycardia, leading to cardiorespiratory dysfunction, probably brainstem-mediated. The logistic model accurately distinguished 38 seizures in SUDEP cases from 38 seizures in non-SUDEP cases (receiver operating characteristic area under the curve = 91%). Seizures in SUDEP patients had higher propensity scores (p < .001) both per seizure and per patient. All six test seizures (three SUDEP, three non-SUDEP) were correctly classified using the optimal threshold. SIGNIFICANCE/CONCLUSIONS:Ictal ECG-based PAC analysis is a potential noninvasive biomarker for SUDEP risk, capturing cardiorespiratory dysregulation during seizures. Its integration into wearable ECG devices could enable real-time risk assessment, informing clinical interventions such as rescue medications, antiseizure medication adjustments, or surgical evaluations.

PURPOSE/OBJECTIVE:Examine sex-specific differences in Intracranial Aneurysms (IA) rupture at presentation and to retrospectively benchmark sex-stratified versus pooled classification models for their ability to discriminate rupture status, using a cross-sectional cohort. METHODS:We retrospectively analyzed 203 patients (46 males, 157 females) with 303 IAs from a single-center, IRB-approved registry. Of these, 76 IAs were ruptured and 227 unruptured at presentation. Clinical data and lesion characteristics were summarized into patient-level variables and used to develop sex-specific logistic regression models. Adjusted Odds ratios (ORs) were produced for clinical covariates. Cross-application assessed generalizability across sexes. RESULTS:Among females, 58.7% of ruptures were < 5 mm, with a median ruptured size of 4.2 mm at Anterior Communicating Artery (ACOM). Rupture likelihood in females peaked between ages 40 and 59 (aORs = 2.8 and 1.7), coinciding with perimenopause. In males, ACOM was the most frequent rupture site; although males had higher mean hemoglobin levels (14.1 vs. 12.5 g/dL, p < 0.0001), hemoglobin contributed less to rupture compared to sex-specific models incorporating age, location, and metabolic factors (hemoglobin concentration, blood glucose). Metabolic factors contributed significantly to the female-specific model, achieving strong discrimination (AUC-ROC: 0.80), while the male-specific model underperformed (AUC-ROC: 0.50), due to limited rupture events (n = 19). Cross-application of features between sexes drastically reduced performance, providing the first computational evidence that male and female rupture mechanisms represent distinct biological feature spaces requiring separate modeling architectures CONCLUSION: Women in this cohort more often presented with rupture IAs at smaller sizes and at midlife ages than men. These sex-specific patterns, though strictly cross-sectional and associative rather than predictive, highlight potential biological and clinical contributors to rupture presentation and may partly explain misclassification by pooled risk models. Future longitudinal, multicenter studies with balanced cohorts are required to validate these findings and to develop robust rupture-risk prediction tools that incorporate sex as a biological variable.

BACKGROUND:Familial dysautonomia (FD) is a hereditary neurodevelopmental disorder caused by aberrant splicing of the ELP1 gene, leading to a tissue-specific reduction in ELP1 protein expression. Preclinical models indicate that increasing ELP1 levels can mitigate disease manifestations. A blood-based ELP-1 protein assay may provide a reliable way to monitor gene target engagement. DESIGN AND METHODS/METHODS:Using a newly developed radioimmunoassay, we quantified ELP1 protein levels in peripheral blood samples collected from 59 homozygous FD patients carrying the IVS20 + 6T>C mutation and 66 heterozygous carriers. To assess the reproducibility of the measurement, replicate samples were collected in 43 participants. Longitudinal variability was evaluated in 22 participants who underwent repeat sampling 1 year later. RESULTS: = 0.827, p < 0.001). An ELP1 threshold of 492 pg/mL yielded a sensitivity of 80.2% (CI of 70.6 to 87.2%) and a specificity of 98.2% (95% CI of 90%-99%) with a positive likelihood ratio of 46.5, indicating that individuals with FD were over 46 times more likely to have ELP1 levels below this threshold compared to non-affected carriers. CONCLUSION/CONCLUSIONS:Blood ELP1 levels are robust and reproducible, with concentrations below 492 pg/mL strongly indicative of disease. Moreover, given their longitudinal stability, ELP1 can serve as a marker of target engagement to evaluate the efficacy of gene-targeted therapies aimed at correcting ELP1 gene splicing and protein production.

Recent research demonstrates that large language models can predict neural activity recorded via electrocorticography during natural language processing. To predict word-by-word neural activity, most prior work evaluates encoding models within individual electrodes and participants, limiting generalizability. Here we analyze electrocorticography data from eight participants listening to the same 30-min podcast. Using a shared response model, we estimate a common information space across participants. This shared space substantially enhances large language model-based encoding performance and enables denoising of individual brain responses by projecting back into participant-specific electrode spaces-yielding a 37% average improvement in encoding accuracy (from r = 0.188 to r = 0.257). The greatest gains occur in brain areas specialized for language comprehension, particularly the superior temporal gyrus and inferior frontal gyrus. Our findings highlight that estimating a shared space allows us to construct encoding models that better generalize across individuals.

OBJECTIVE:NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant genetic disorder characterized by the development of schwannomas, meningiomas, and spinal ependymomas. Treatment with bevacizumab, a monoclonal antibody against VEGF, has been shown to result in decreased vestibular schwannoma size and hearing improvement in ~50% of NF2-SWN patients. It is unknown whether the same degree of benefit is seen in younger patients compared with older patients. The objective of this study is to determine the association between age and bevacizumab treatment outcomes in NF2-SWN. STUDY DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Thirty-seven patients with NF2-SWN. INTERVENTIONS/METHODS:Bevacizumab. MAIN OUTCOME MEASURES/METHODS:Change in tumor size of 20% or more. RESULTS:This study includes 37 patients with NF2-SWN who were treated with bevacizumab at our institution between 2014 and 2024. They were divided into 2 groups: 22 adults over the age of 25 (26 to 71 y) and 15 adolescent and young adult (AYA) patients under the age of 25 (12 to 24 y). The median treatment duration was 2.1 years. A significantly higher proportion of AYA schwannomas (37.5%, n=9) exhibited radiographic tumor progression during the treatment period compared with those of the older patient group (11.9%, n=5) (P=0.026), despite similar pre-treatment growth rates. There was no significant difference in the proportion of older and younger patients with hearing decline, improvement, or stability (P>0.05). CONCLUSIONS:AYA patients were significantly more likely to exhibit progression of tumor growth during bevacizumab treatment compared with older patients, though no significant differences were detected in hearing outcomes.

OBJECTIVE:To update the 2016 American Headache Society (AHS) guideline on parenteral pharmacologic therapies for the management of migraine attacks in the emergency department (ED). METHODS:We conducted a systematic review and meta-analysis using the same methodology as the 2016 guideline. The original search strategy was repeated and expanded to include studies of nerve blocks and sphenopalatine ganglion (SPG) blocks. We searched Medline, Embase, Cochrane, clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform through February 10, 2025. Eligible studies were randomized controlled trials (RCTs) involving adults diagnosed with migraine, treated in the ED with intravenous (IV), intramuscular (IM), subcutaneous (SC), or nerve block (including SPG block) interventions. Two reviewers independently screened titles/abstracts and full texts; a third reviewer resolved disagreements. Data were extracted using a standardized form and verified by a second reviewer. Risk of bias was assessed using the American Academy of Neurology (AAN) criteria. Where applicable, meta-analyses were performed. Efficacy was categorized as highly likely, likely, or possibly effective or ineffective. Clinical recommendations were developed using the AAN guideline development process. RESULTS:The search identified 26 new RCTs evaluating 20 injectable treatments. Of these, 12 were rated class I (low risk of bias), 9 class II, and 4 class III. Prochlorperazine IV, dexketoprofen IV, sumatriptan SC, and greater occipital nerve blocks (GONB) were considered highly likely to be effective based on multiple class I studies. Chlorpromazine IV, metoclopramide IV, eptinezumab IV, ketorolac IV, and supraorbital nerve blocks (SONB) were considered likely effective based on one class I or multiple class II studies. Hydromorphone IV, propofol IV, and paracetamol IV were considered likely ineffective based on class I or multiple class II studies. After review of the evidence and a consensus process, recommendations were made for each intervention. CONCLUSIONS:Prochlorperazine IV and GONB must be offered to eligible adults presenting to the ED with a migraine attack for treatment of headache requiring parenteral therapy (level A - must offer) in those without contraindications, while hydromorphone IV must not be offered (level A - must not offer). Treatments that should be offered when appropriate (level B - should offer) include dexketoprofen IV, ketorolac IV, metoclopramide IV, sumatriptan SC, and SONB. Chlorpromazine IV, dexamethasone IV, and valproate IV may be offered (level C - may offer). Paracetamol IV may not be offered (level C - should not offer). Eptinezumab should be offered (level B) only for patients matching the clinical trial population but is rated level U - no recommendation for an ED-specific population. Additional evidence is needed for caffeine, granisetron, ibuprofen, ketamine, lidocaine, normal saline, propofol, and SPG blocks, all currently rated level U - no recommendation.