Faculty Bibliography

INTRODUCTION/BACKGROUND:Neurologic complications, including seizures, are common in pediatric patients undergoing heart surgery, especially those requiring postoperative extracorporeal membrane oxygenation (ECMO), requiring prompt, vigilant postoperative monitoring. Prolonged EEG monitoring in critically ill children presents a risk of scalp/pressure injuries. The skin's sensitivity to microcirculatory changes can also provide valuable insights into the patient's overall tissue perfusion, making it a critical component in the management of these vulnerable patients. METHODS:We initiated a quality improvement (QI) project to assess and reduce scalp injuries related to prolonged EEG monitoring in critically ill neonates and infants. The project involved reviewing baseline data, which included 2336 inpatient video EEGs performed from January 2022 to December 2024, and implementing interventions to improve skin safety during electrode placement, while incorporating best practices from ACNS and ASET guidelines. RESULTS:Five critically ill infants developed deep tissue injuries (DTIs) related to EEG electrodes, with most injuries occurring over the occipital region. The frequency of scalp injuries decreased from 0.30% in 2022 to 0% in 2024 after implementing the QI protocol, and was observed in conditions with known hypoperfusion. DISCUSSION/CONCLUSIONS:Electrode-related skin injuries are a common complication of prolonged EEG monitoring, particularly in critically ill pediatric patients. Our findings suggest that adherence to expert guidelines and tailored skin care protocols focused on skin preparation, electrode application, and monitoring parameters can reduce the risk of electrode-related skin injuries. Further research is needed to refine safety protocols and address the unique skin care challenges faced by this high-risk population.

BACKGROUND:In vivo biomarkers that can detect long-term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p-tau217 as a potential biomarker for CTE p-tau pathology, and examined the concordance between plasma p-tau217 and Aβ pathology in an at-risk for CTE sample. METHOD/METHODS:The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F-florbetapir (Aβ+=SUVR≥1.10), and 18F-flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p-tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post-mortem tissue. ANCOVA examined group differences in p-tau217 (football vs controls; TES-CTE no, TES-CTE suggestive, TES-CTE possible/probable). Multivariable regression models tested associations between p-tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4. RESULT/RESULTS:Sample characteristics are in Table 1. p-tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=-0.217, p = 0.005). There were no group differences in Aβ-PET SUVR. No differences were found across TES-CTE certainty levels. In football players, higher p-tau217 was associated with higher Aβ-PET SUVR (B=1.380, 95%CI[0.597-2.155], p = 0.001) but not when Aβ+ (n = 17) participants and those with kidney/liver disease (n = 5) were excluded. Aβ+ participants had the highest p-tau217 (Figure 1). When compared against Aβ-PET, several false Aβ-positives (high p-tau217, Aβ-) were identified, including one extreme outlier (assay related) and a cluster of Aβ- participants with p-tau217 between 0.60-1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p-tau217 outliers had autopsy-confirmed CTE stage III (AD-, Table 2). Of the remaining donors, all were AD- and four had CTE (stages II-IV) with ptau217 between 0.125-0.449. CONCLUSION/CONCLUSIONS:Plasma p-tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at-risk for CTE sample, p-tau217 and Aβ-PET were associated at the group level. At the individual level, false Aβ-positives (and negatives) existed, including Aβ- participants with high p-tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N-terminal binding in p-tau assays.

RATIONALE AND OBJECTIVES/OBJECTIVE:To evaluate the performance, stability, and decision-making behavior of large language models (LLMs) for title and abstract screening for radiology systematic reviews, with attention to prompt framing, confidence calibration, and model robustness under disagreement. MATERIALS AND METHODS/METHODS:We compared five LLMs (GPT-4o, GPT-4o mini, Gemini 1.5 Pro, Gemini 2.0 Flash, Llama 3.3 70B) on two imaging-focused systematic reviews (n = 5438 and n = 267 abstracts) using binary and ternary classification tasks, confidence scoring, and reclassification of true and synthetic disagreements. Disagreements were framed as either "LLM vs human" or "human vs human." We also piloted autonomous PubMed retrieval using OpenAI and Gemini Deep Research tools. RESULTS:LLMs achieved high specificity and variable sensitivity across reviews and tasks, with F1 scores ranging from 0.389 to 0.854. Ternary classification showed low abstention rates (<5%) and modest sensitivity gains. Confidence scores were significantly higher for correct predictions. In disagreement tasks, models more often selected the human label when disagreements were framed as "LLM vs human," consistent with authority bias. GPT-4o showed greater resistance to this effect, while others were more prone to defer to perceived human input. In the autonomous search task, OpenAI achieved moderate recall and high precision; Gemini's recall was poor but precision remained high. CONCLUSION/CONCLUSIONS:LLMs hold promise for systematic review screening tasks but require careful prompt design and circumspect human-in-the-loop oversight to ensure robust performance.

BACKGROUND:Primary brain calcifications are observed in several inherited diseases due to different pathogenic mechanisms, including the disruption of the neurovascular unit, mitochondrial dysfunction, and impaired nucleic acid metabolism. OBJECTIVE:The aim of the study was to identify a novel genetic cause of brain calcifications in genetically unresolved cases. METHODS:Exome sequencing data from two unrelated Pakistani patients with generalized dystonia and primary brain calcifications were analyzed. The best candidate gene (ie, RRP12) was then investigated in two large cohorts of patients with brain calcifications from France (n = 111) and China (n = 543). RRP12 loss-of-function phenotype was explored through Western blot and immunocytofluorescence studies on patient-derived fibroblasts and in a knockdown zebrafish model. RESULTS:A combined approach of exome sequencing and homozygosity mapping allowed the prioritization of a rare homozygous variant in RRP12 (c.1558C>T, p.R520C) in two apparently unrelated Pakistani patients from consanguineous families, presenting with infantile-onset generalized dystonia, spasticity, and widespread brain calcifications. Screening of two large cohorts of patients with unresolved brain calcifications revealed two affected French siblings and one unrelated Chinese individual, each carrying rare, biallelic, missense variants in the RRP12 gene (c.1429G>A, p.E477K and c.2634T>G, p.F878L, respectively). Molecular studies revealed a significant reduction in RRP12 protein and abnormal nucleolar morphology in patient'derived fibroblasts. Consistent with its essential role in RNA metabolism, rrp12 knockdown in zebrafish caused severe developmental delay, crimping, and early lethality. CONCLUSIONS:RRP12 is a novel candidate gene for autosomal recessive brain calcifications, possibly associated with a wide clinical spectrum ranging from early-onset severe forms to adult-onset paucisymptomatic presentations. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

OBJECTIVE:To examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms. METHODS:We conducted a US-based observational case-control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome-wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non-motor symptoms according to genetic exposure. RESULTS:By the age of 80 years, the cumulative incidence of PD was 30% for dual carriers, 24% for LRRK2 p.G2019S carriers, 4% for GBA1 p.N409S carriers, and 2% for noncarriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. GBA1 p.N409S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 p.G2019S with the lowest. APOE E4 dosage was associated with greater odds of reporting hallucinations and cognitive impairment in addition to carrier status. INTERPRETATION/CONCLUSIONS:Our findings support the use of genetic screening to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetics.

BACKGROUND:. However, the microstructural alterations driving these differences are unclear. Here, we assess associations of MK and KFA with neurite orientation dispersion and density imaging (NODDI) and magnetization transfer imaging (MTI) metrics, which provide a more specific characterization of tissue microstructure. METHOD/METHODS:(75 SCD) ages 55-88 were included in the analysis. Participants were defined as SCD if they endorsed problems with their memory and in the control group otherwise. Diffusion images were processed to obtain MK, Radial Kurtosis (RK), Axial Kurtosis (AK) and KFA from DKI and Neurite Density (ND) and Orientation Dispersion (OD), a marker of neurite organization, from NODDI. MTI was used to calculate the Magnetization Transfer Ratio (MTR), a marker of myelin and potentially amyloid aggregation. Mean metric values were calculated for bilateral amygdala (Figure 1). Between-group comparisons were conducted using Wilcoxon rank-sum tests, corrected for multiple testing. Associations between DKI, NODDI, and MTR metrics were examined using linear models corrected for age and sex. RESULT/RESULTS:SCD had lower KFA, higher MK, and higher RK in the right amygdala (Table 1). KFA had a weak negative correlation with ND, while MK and RK had strong positive correlations (Figure 2A-C). Only MK had a weak positive correlation with OD (Figure 2D-F). Neither KFA, MK, nor RK correlated with MTR (Figure 2G-I). CONCLUSION/CONCLUSIONS:DKI metrics are more sensitive to amygdala changes in SCD than NODDI metrics or MTR. Lower KFA, higher MK, and higher RK were associated with higher ND but not MTR, suggestive of dendritic or glial branching. Higher MK was additionally associated with higher OD, potentially indicating reduced neurite organization. Further analyses on the impact of these amygdala changes on SCD related neuropsychiatric symptoms are needed. References 1. Flaherty R, Sui YV, Li M, et al. Alzheimers Dement. 2024;20(S9):e093982. 2. Shafto MA, Tyler LK, Dixon M, et al. BMC Neurol. 2014;14(1):1-25.

Parsonage-Turner syndrome (PTS) is a spontaneous neuropathy characterized by severe upper extremity pain and muscle denervation and is considered to be a rare disease that is under-recognized. Quantitative MRI (qMRI) characterizes muscle denervation but has not been previously assessed in a longitudinal PTS cohort. The aims of this study are to prospectively and longitudinally characterize qMRI changes in PTS patients at baseline (< 6 months' symptom onset) and at follow-up timepoints (3, 6, and 12 months), to measure associations against electromyography (EMG) and muscle strength, and to predict muscle strength at follow-up. A total of 49 subjects (age = 47.2 ± 14.0 years, 31 M/18 F) underwent 3-Tesla qMRI with T2-mapping, diffusion-based muscle fiber diameter, volumetry, and fat fraction (FF) mapping. Image segmentation of involved muscles was performed by two raters. Linear regression between qMRI metrics and days from symptom onset (DSO) was performed. Pearson's correlation quantified correlations between qMRI metrics, and Kendall's tau assessed correlations between qMRI and EMG and muscle strength. For predictive modeling of muscle strength, a generalized linear model was used, and the coefficient of determination (r²) was compared for combinations of baseline inputs. Regression detected a mean T2 increase of 0.66 ms/week and a mean muscle fiber diameter decrease of 0.96 μm/week within DSO of 100. Muscle fiber diameter correlated with muscle volume (r = 0.850). T2 correlated with EMG (|τ| = 0.34-0.78) and muscle strength (|τ| = 0.40-0.83) in most muscles that could be analyzed. Muscle fiber diameter was correlated to EMG (|τ| = 0.43-0.72) and muscle strength in some muscles (|τ| = 0.39-0.56). The addition of baseline T2 values improved the prediction of muscle strength at 3-month (from r² = 0.57 to 0.67, with -0.057 to -0.068 muscle grade per ms T2), at 6-month (r² = 0.40-0.59, -0.057 to -0.071 grade per ms), and at 12-month follow-up (r² = 0.40-0.62, -0.053 to -0.080 grade per ms). Muscle qMRI measurements in PTS depict muscle denervation and provide complementary characterization of muscle quality for diagnosis and follow-up assessment.

INTRODUCTION/BACKGROUND:Neighborhood deprivation is associated with shorter survival, cognitive impairment, and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown. METHODS:= 161) with complete baseline data across measures of global cognition, executive function, and language, we examined the association of ADI with longitudinal change. RESULTS:Compared to adults living in the least deprived neighborhoods, those living in the most deprived neighborhoods showed shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk. DISCUSSION/CONCLUSIONS:Living in more deprived neighborhoods was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis. CLINICAL TRIAL REGISTRATION INFORMATION/BACKGROUND:N/A.

BACKGROUND:Deep medullary veins (DMVs) play important roles within the cerebrovascular network related to brain drainage and clearance. Although they have been previously correlated with brain volume, it is unknown whether their count is specifically correlated with subcortical or cortical volume changes. PURPOSE/OBJECTIVE:This study aims to better understand the relationship between DMVs, subcortical (lateral ventricle to intracranial volume ratio (ICV)) and cortical atrophy (cortical thickness) to identify whether DMVs can be a predictor of volume changes in these regions. METHODS:We performed a retrospective analysis of 332 cognitively healthy subjects previously followed between 2010 and 2019. Imaging and patient charts were analyzed for baseline demographic and clinical characteristics. Patients underwent a standardized cognitive interview and received a magnetic resonance imaging scan to assess DMVs, cortical thickness, lateral ventricle and global gray matter (GM) volumes, white matter lesions (WMLs) and microbleeds. RESULTS:Among 332 patients (62% female, median age 70), lateral ventricle/ICV was significantly related to DMV count (p<0.001). Similarly, sex stratified analyses confirmed that a larger lateral ventricle/ICV ratio, but not cortical thickness or global GM volumes, was associated with fewer DMVs. In the entire group, subcortical atrophy remained a significant predictor of DMVs even after accounting for baseline characteristics, WMLs, microbleeds and total gray matter volume. CONCLUSIONS:In a large cohort of cognitively unaffected people, subcortical, but not cortical, atrophy was significantly correlated with venous health as measured by DMVs. Reduced DMVs are a strong predictor of ventricular enlargement.