Faculty Bibliography

IMPORTANCE/UNASSIGNED:The emergency department (ED) is a critical point of contact within the health care system and an opportunity to initiate nonpharmacologic migraine treatment. OBJECTIVE/UNASSIGNED:To examine whether progressive muscle relaxation (PMR) smartphone-based migraine self-management improved patient-reported outcomes for migraine compared with enhanced usual care. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A randomized clinical trial of the smartphone application RELAXaHEAD with and without PMR. Patients aged 18 to 65 years visiting New York University Langone Health EDs for headache who met migraine criteria and self reported 4 or more migraine days per month were recruited from June 2019 to October 2021 with follow-up at 3 months. Data were analyzed from June 2022 to June 2025. INTERVENTION/UNASSIGNED:Participants in the intervention group were asked to listen to the app-based PMR for 60 days. Participants in the control group were asked to use the app as a symptom diary. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcome was change in migraine-related disability (MIDAS). Secondary outcomes were change in migraine-specific quality of life (MSQv2) and monthly headache days (MHDs). Adherence (number of days of diary use, PMR use and total minutes of PMR use over 90-day period) was measured using back-end analytics. RESULTS/UNASSIGNED:Of the 94 patients (median [IQR] age, 33 [26-45] years; 57 [82.6%] female) randomized (48 control patients and 46 PMR patients), 69 of 94 (73%) had 1 or more follow-up MIDAS scores and constituted the modified intent-to-treat population (35 control patients and 34 PMR patients). The mean (SD) change in MIDAS scores from baseline to 3 months (last observation carried forward [LOCF] used if missing 3-month follow-up data) differed between groups (PMR, 25.09 [29.64] vs control, 6.86 [59.61]; P = .01). PMR had nearly double the number of respondents improving by 5 or more MIDAS points (28 of 34 [82.4%] vs 16 of 35 [45.7%] respondents; P = .002). There was no difference in MSQv2 domains from baseline to LOCF between PMR and control (mean [SD] role function preventive domain for PMR, 16.9 [24.5] vs control, 11.3 [25.9]); emotional function domain (mean [SD] for PMR, 26.5 [26.9] vs control, 19.8 [38.5]); and role function restrictive domain (mean [SD] for PMR, 18.1 [22.7] vs control, 18.7 [26.8]). Mean (SD) change in MHDs (baseline to 3 months) did not differ between groups (PMR, 2.9 [8.0]; 23 days vs control, -1.6 [6.5]; 25 days). CONCLUSION AND RELEVANCE/UNASSIGNED:A PMR-based self-management program offered to patients with migraine after ED discharge yielded clinically significant reductions in migraine-related disability. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04281030.

IMPORTANCE/UNASSIGNED:Fluorescence-guided surgery aims to improve intraoperative identification of vital structures. Rizedisben is a myelin-binding fluorophore that fluoresces in the blue light (370-425 nm) spectrum to improve intraoperative nerve identification. OBJECTIVE/UNASSIGNED:To determine the optimal safe and clinically effective dose of rizedisben for sustained intraoperative fluorescence of nerve structures. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A single-arm, open-label, phase 1 study was conducted in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALP) at an urban academic cancer center in New York City between January 2023 and October 2024. Using a dose escalation design, increasing doses of rizedisben were administered after safety was assessed at each level until a clinically effective dose was determined. The obturator nerve served as the reference nerve for measuring fluorescence intensity. Eligible patients were 18 years old and older, diagnosed with prostate cancer, and scheduled for RALP. Patients were recruited in preoperative clinic visits once deemed eligible for the study. Those with prior pelvic surgery or radiation, known central or peripheral nervous system disease, current use of neurotoxic medications, recent exposure to phototoxic drugs, or serious kidney or liver dysfunction were excluded. INTERVENTIONS/UNASSIGNED:Rizedisben was intravenously administered intraoperatively 30 minutes prior to visualization of the obturator nerve. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Safety was assessed through 45 postoperative days. Fluorescence was measured via subjective intraoperative scoring and by post hoc objective image analysis. Clinically effective dose was defined as achieving sustained fluorescence of the obturator nerve in 3 or more of 5 patients in 2 consecutive cohorts, provided fewer than 20% of patients experienced grade 2 or greater toxicity. Sustained fluorescence was defined as moderate or better fluorescence for 90 minutes or longer. At the clinically effective dose, fluorescence assessments of the neurovascular bundles were included. RESULTS/UNASSIGNED:Thirty-eight patients (median [IQR] age, 61.5 [57.8-66.3] years) enrolled in and completed the trial. Dosing was escalated from 0.25 to 3.0 mg/kg. There was 1 grade 2 adverse event (rash) possibly attributable to rizedisben. Sustained fluorescence of the obturator nerve was achieved in all patients at 3.0 mg/kg. Prostate neurovascular bundles demonstrated evidence of fluorescence in 8 of 9 (89%) patients at 3.0 mg/kg. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this phase 1 trial of rizedisben, the 3.0-mg/kg dose was shown to be generally well tolerated and clinically effective. At this dose, there was excellent sustained fluorescence of the obturator nerves, and the neurovascular bundles were visualized in 8 of 9 patients. Based on these data, we are designing phase 2 studies with rizedisben for additional indications. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04983862.

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.

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described inflammatory disorder of the central nervous system. Unlike other demyelinating disorders of the central nervous system, the impact of pregnancy and the postpartum period on MOGAD disease activity remains uncertain. A better understanding of pregnancy-related relapse risk in MOGAD is essential to inform management. METHODS:We conducted a retrospective chart review of all patients followed in two large referral centers in the Northeastern United States with a confirmed diagnosis of MOGAD and at least one post-MOGAD onset pregnancy carried to the third trimester. Demographic, neurological, obstetric, and treatment-related data were extracted from electronic medical records, centered around the 12-month pre-pregnancy, pregnancy, and 12-month post-pregnancy periods, for each of which the annualized relapse rates (ARRs) were calculated. RESULTS:We identified 15 women diagnosed with MOGAD who had 22 post-MOGAD onset pregnancies. No relapses were observed during any of the 22 pregnancies, but 2 relapses were observed in the postpartum period in a single patient with a steroid-dependent relapsing course. The mean ARR was 0.26 ± 0.86 during the 12-month pre-pregnancy period, 0 during pregnancy, and 0.09 ± 0.42 in the 12-month postpartum period. Twelve of 22 pregnancies (55 %) were exposed to disease-modifying therapy (DMT) at conception, and 59 % were continued on DMT into the postpartum period. Obstetric complications were recorded in 5 of 22 pregnancies (22 %). CONCLUSIONS:The two main findings of our retrospective study are: 1) the relapse risk is very low during pregnancy in women with MOGAD, and 2) postpartum relapse risk does not appear to be elevated in patients with a low pre-pregnancy relapse rate. Approximately half of the women in our series were receiving disease-modifying therapies during the postpartum period, which may have decreased relapse rates. Larger prospective studies are needed to validate our observations.

Flickering light is a new promising, fully non-invasive brain stimulation technique that utilizes intermittent sensory stimulation to induce brainwave synchronization (entrainment). While the effects of 40 Hz externally induced neural entrainment have been extensively described, little is known about 60 Hz entrainment in humans. This study presents preliminary observations on the neural and somatic response to flickering 60 Hz light in healthy volunteers over a 3-week period. Fourteen volunteers were randomized to receive either 60 Hz flickering white light or constant light as sham (30-min sessions, 3 weeks, 5 days/week on weekdays). Neural entrainment was assessed with EEG on days 1, 5 and 19. Salivary cortisol and C-reactive protein (CRP) levels, measured with ELISA, assessed the somatic response to stimulation. Side effects and well-being were monitored via questionnaires. EEG recordings showed neural entrainment and synchrony in response to 60 Hz flickering light across multiple cortical regions, including occipital, central, temporal, and frontal areas. The entrainment power and synchronization between different cortical regions declined significantly by day 19 compared to day 1, indicating possible neural habituation. Cortisol and CRP salivary levels were unchanged, and minor side effects were reported with equal frequency in the active and sham groups. Our findings show that 60 Hz flickering light can induce significant neural entrainment and synchrony in healthy adults and is well tolerated. The decline in entrainment strength and neural synchrony observed with repeated 60 Hz stimulations suggests plastic changes in the cortex. To the best of our knowledge, this is the first study to characterize neural and somatic responses to repeated 60 Hz flickering visual stimuli. Given the well-known connection between 60 Hz brain oscillations and cognition, neuroplasticity, and their role in neuropsychiatric disorders, additional research in both preclinical and clinical settings is warranted.

Smouldering disease in multiple sclerosis (MS) refers to chronic central nervous system processes that occur beyond acute inflammation, driving long-term disability. Although current therapies effectively reduce relapse rates and MRI lesions, many individuals experience progression independent of relapse activity. While clinical progression is uncommon during childhood or adolescence, growing evidence suggests that subclinical progressive disease biology is already active even in this young age group, warranting early intervention to preserve function. Conventional MRI, while critical for diagnosis, lacks sensitivity for subtle damage. Advanced MRI techniques, including detection of chronic active lesions, global and focal brain damage, hold promise for early identification. Fluid biomarkers, such as neurofilament light chain and glial fibrillary acidic protein, provide non-invasive measures of neuroaxonal injury and ongoing chronic inflammation. This review summarises the role of MRI and fluid biomarkers in detecting smouldering disease in paediatric-onset MS and their application in supporting therapeutic decision-making.

Repetitive head impacts are associated with structural brain changes and an increased risk for chronic traumatic encephalopathy, a progressive neurodegenerative disease that can only be diagnosed after death. Chronic traumatic encephalopathy is defined by the abnormal accumulation of phosphorylated tau protein, particularly at the depths of the superior frontal sulci, suggesting that sulcal morphology may serve as a relevant structural biomarker. Contact sport athletes, such as former football players, are at elevated risk due to their prolonged exposure to repetitive head impacts. Cortical atrophy linked to underlying tau accumulation may result in shallower and wider sulci, potentially making sulcal morphology an imaging marker for identifying individuals at risk for this disease. This study investigated sulcal morphological differences in former football players and examined associations with age, football-related exposure, clinical diagnosis of traumatic encephalopathy syndrome, levels of certainty for chronic traumatic encephalopathy pathology, neuropsychological performance, and positron emission tomography imaging using flortaucipir. We analysed structural magnetic resonance imaging data from 169 male former football players (mean age 57.2 (8.2) years, range 45-74) and 54 age-matched, unexposed asymptomatic male controls (mean age 59.4 (8.5) years, range 45-74). Sulcal depth and width were quantified using the CalcSulc, focusing on two regions in each hemisphere commonly affected by chronic traumatic encephalopathy pathology: the superior frontal and occipitotemporal sulci. Generalized least squares models were used to assess group differences and interactions with age and football exposure variables, including age of first exposure, total years played, and cumulative head impact exposure. An analysis of covariance evaluated relationships between sulcal morphology, clinical measures, and flortaucipir uptake, adjusting for age, race, body mass index, education, imaging site, apolipoprotein E4 status, and total intracranial volume. Former football players demonstrated significantly shallower sulcal depth in the left superior frontal sulcus compared to unexposed controls. Earlier age of first exposure and longer football careers were associated with greater widening of the left occipitotemporal sulcus. Higher cumulative head impact exposure was linked to reduced sulcal depth in the left superior frontal region. However, sulcal morphology was not associated with clinical diagnosis, levels of certainty, neuropsychological test performance, or flortaucipir imaging. These findings suggest that sulcal morphology may reflect cumulative exposure to repetitive head impacts, particularly in brain regions vulnerable to chronic traumatic encephalopathy pathology. Future ante- and post-mortem validation studies are needed to determine whether sulcal morphology can serve as a reliable in vivo biomarker of risk.

INTRODUCTION/BACKGROUND:Blood-based biomarkers (BBMs) are promising tools for Alzheimer's disease (AD) diagnosis, but their accuracy may be affected by body mass index (BMI) and blood volume (BV) through dilution. We investigated how BMI and BV influence BBM concentrations and PET prediction. METHODS:, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and BBM-based PET predictions. RESULTS:and NfL, independent of brain amyloid burden. BMI-stratified thresholds improved amyloid PET prediction, with higher BBM thresholds and area under the curve (AUC) values seen in normal weight compared to overweight or obese participants. Drastic BMI/BV declines due to weight loss increased BBM variability and systematic PET misclassification. DISCUSSION/CONCLUSIONS:Adjusting for BMI/BV in BBM-based diagnostics appears to improve accuracy and reliable detection of AD pathology, especially in preclinical stages. HIGHLIGHTS/CONCLUSIONS:Body mass index (BMI) and blood volume (BV) significantly influenced plasma BBM concentrations in cognitively unimpaired (CU) individuals. Blood-based biomarkers (BBMs) associated more strongly with BV than with BMI. Dilution effects were independent of brain amyloid burden. BMI-stratified BBM thresholds improved amyloid positron emission tomography (PET) classification accuracy. Declines in BMI/BV resulted in PET prediction bias and systematic errors.