Faculty Bibliography

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.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Temporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of gray and white matter structures. Evidence supports a progressive condition, although the temporal evolution of TLE is poorly defined. In this ENIGMA-Epilepsy study, we aim to investigate structural alterations in gray and white matter across the adult lifespan in patients with TLE by charting both gray and white matter changes and explore the covariance of age-related alterations in both compartments. METHODS:scores of all patients. Covariance analyses examined the coupled correlations of gray and white matter lifespan curves for each region. RESULTS: DISCUSSION/CONCLUSIONS:This study highlights that patients with TLE exhibit more pronounced and widespread gray and white matter atrophy across the lifespan. The cross-sectional nature of our study limits definitive conclusions on whether the atrophy shown is progressive but emphasizes the importance of prompt diagnosis and intervention in patients. Collectively, our results motivate future longitudinal studies to clarify consequences of drug-resistant epilepsy.

PURPOSE OF REVIEW/OBJECTIVE:To outline a practical and comprehensive approach to evaluating transient neurologic dysfunction (TND) in adults. RECENT FINDINGS/RESULTS:TNDs are a common reason for neurologic consultation. Diagnosis relies largely on history, as neurologic examination is usually normal in the post-ictal stage. The differential of TNDs is extensive, and testing should be targeted to the more likely etiologies and ones that may portend permanent loss of neurologic function. In addition to the more common causes - transient ischemic attack (TIA), seizures, migraine auras, drug-induced adverse events, hypoglycemia, blood pressure fluctuations, hyperventilation, panic attacks, and paroxysmal vestibular disorders, there are some distinctive TND presentations and special circumstances that may point to the less common etiologies. The article outlines the key features of the common presentations and presents a comprehensive differential diagnosis that includes many rare causes of TNDs in adults and adolescents. The proposed approach relies on carefully elucidating the nature, timeline, and circumstances of the symptoms, gathering examination clues, and seeking to determine whether the event is likely due to neuro-vascular, non-vascular neurologic (paroxysmal or chronic), non-neurologic, or rare neurologic etiologies. Specific diagnoses are listed for each of these categories.

Sound structures such as phonemes and words have highly variable durations. Therefore, there is a fundamental difference between integrating across absolute time (for example, 100 ms) versus sound structure (for example, phonemes). Auditory and cognitive models have traditionally cast neural integration in terms of time and structure, respectively, but the extent to which cortical computations reflect time or structure remains unknown. Here, to answer this question, we rescaled the duration of all speech structures using time stretching and compression and measured integration windows in the human auditory cortex using a new experimental and computational method applied to spatiotemporally precise intracranial recordings. We observed slightly longer integration windows for stretched speech, but this lengthening was very small (~5%) relative to the change in structure durations, even in non-primary regions strongly implicated in speech-specific processing. These findings demonstrate that time-yoked computations dominate throughout the human auditory cortex, placing important constraints on neurocomputational models of structure processing.

INTRODUCTION/BACKGROUND:Poststroke depression affects approximately 30% of stroke survivors and is linked to worse functional outcomes, cognitive decline, reduced quality of life and increased mortality. While early treatment of poststroke mental health conditions is critical, current pharmacological options offer limited efficacy. Music listening interventions are a promising, low-risk, accessible and affordable alternative that may enhance recovery through engagement of reward-related brain circuits. However, most music listening studies have focused on the acute stage of stroke, lack objective measures of music engagement and rarely assess underlying neural mechanisms. To address these gaps, we propose a feasibility study of a remotely delivered music-listening intervention for individuals with chronic stroke, incorporating objective tracking of music exposure and multimodal assessments of mental health, cognitive, neural and physiological changes. METHODS AND ANALYSIS/METHODS:We will conduct a parallel group randomised controlled feasibility trial enrolling 60 patients with chronic stroke from a well-characterised stroke registry in New York City. Participants will be randomised to either an intentional music listening (IML) group or an active control group that listens to audiobooks. The study includes a 4-week preintervention period during which no treatment is administered; this phase is designed to assess the stability of outcome measures. Following this, participants will engage in 1-hour daily listening sessions over a 4-week intervention period. All listening activity (ie, track identity, duration and engagement) will be continuously tracked using custom open-source software, providing a measure of treatment dose. Behavioural outcomes related to mental health will be assessed at baseline, preintervention, postintervention and 3-month follow-up. Multimodal biomarkers (functional and structural MRI, electrodermal activity and heart rate) will be collected preintervention and postintervention. The primary objective is to establish feasibility, defined by rates of retention and adherence, treatment fidelity, feasibility, acceptability and participant burden. Secondary outcomes include recruitment and randomisation rates. This trial will provide essential data to inform the design of future large-scale clinical studies of IML for poststroke mental health recovery. ETHICS AND DISSEMINATION/BACKGROUND:The study was approved by New York University's Institutional Review Board (FY2024-8826). All human participants will provide written informed consent prior to participation and will be adequately compensated for their time. Results will be reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT07127159.

BACKGROUND:Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Generalised-particularly nocturnal-convulsive seizures, longstanding epilepsy, and solitary living have been identified retrospectively as risk factors. No definitive electroclinical biomarkers have been prospectively ascertained. This study aimed to identify SUDEP risk markers using multimodality data with long-term follow-up. METHODS:This prospective, multicentre, observational cohort study, conducted at nine centres (eight in the USA and one in the UK), recruited children and adults with epilepsy who were undergoing prolonged video-electroencephalographic (EEG) monitoring. Inclusion criteria were diagnosis of epilepsy by an epilepsy specialist, with or without drug resistance; age older than 2 months; admission to the epilepsy monitoring unit of a participating centre, with video-EEG monitoring; and completion of at least one 6-month follow-up. Demographic, electroclinical, and cardiorespiratory data were collected at baseline. Participants were followed up long term through routine clinic visits, review of electronic health records, and telephone interviews to collect information about seizure frequency, medication status, and mortality. The primary endpoint was time to SUDEP. Cox proportional hazards models were used to assess significant risk factors. FINDINGS/RESULTS:Between Sept 17, 2011, and Dec, 30, 2021, 2632 children and adults with epilepsy were enrolled in this study; 164 were lost to follow-up. 38 (1·54%) of 2468 participants died from SUDEP (12 definite, 18 probable, and eight possible SUDEP cases) and two had near-SUDEP events. Incident SUDEP mortality rate was 4·76 (95% CI 3·37-6·53) cases per 1000 person-years, from a cohort of 7982 person-years. Living alone (hazard ratio 7·62, 95% CI 3·94-14·71), three or more generalised convulsive seizures in the previous year (3·1, 1·64-5·87]), longer ictal central apnoea (1·11, 1·05-1·18), and longer postictal central apnoea (1·32, 1·14-1·54]) were significant predictors of increased SUDEP risk. In a subanalysis excluding possible and near-SUDEP cases, longer ictal central apnoea was not significant. INTERPRETATION/CONCLUSIONS:This study shows an association between premortem peri-ictal apnoea and increased SUDEP risk. Cardiorespiratory monitoring during seizures might benefit assessments of epilepsy mortality risk. Together with solitary living and convulsive seizure frequency, peri-ictal apnoea (>14 s for postictal central apnoea and >17 s for ictal central apnoea) could inform the development of a validatable SUDEP risk index. FUNDING/BACKGROUND:US National Institutes of Health.

This study evaluated the efficacy of the multiple sclerosis disease-modifying therapies, intramuscular interferon beta-1a (Avonex) and subcutaneous peginterferon beta-1a (Plegridy), using data from the United States Network of Pediatric Multiple Sclerosis Centers. In this retrospective analysis, 154 patients with multiple sclerosis were included who were treated with Avonex (n = 130), Plegridy (n = 23), or both treatments (n = 1) before the age of 18 years. After 3 months' sustained use acclimation ("wash-in"), the probability of being relapse-free during the first year was 68.3% for Avonex-treated patients and 69.9% for Plegridy-treated patients; annualized relapse rates were 0.50 and 0.59, respectively. Both disease-modifying therapies demonstrated efficacy similar to that reported in adult populations. Despite the lack of formal approval for pediatric multiple sclerosis, these outcomes indicate that patients may benefit from treatment with Avonex or Plegridy. Understanding efficacy of specific disease-modifying therapies in pediatric multiple sclerosis is essential to making informed treatment decisions.

IMPORTANCE/UNASSIGNED:The Implantable Neurostimulator for the Treatment of Parkinson's Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). OBJECTIVE/UNASSIGNED:To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson's Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. INTERVENTION/UNASSIGNED:Bilateral STN-DBS for moderate to advanced PD. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. RESULTS/UNASSIGNED:A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-III improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.

Brain death, or death by neurologic criteria (BD/DNC), is the permanent loss of brain function, defined by coma with loss of capacity for consciousness and complete brainstem areflexia, including the inability to breathe spontaneously. The 2023 American Academy of Neurology/American Academy of Pediatrics/Child Neurology Society (CNS)/Society for Critical Care Medicine guidelines state that pregnancy is not a contraindication for BD/DNC evaluation. Clinical evaluation of BD/DNC includes an apnea test to demonstrate the absence of spontaneous respiratory effort in response to hypercapnia and acidosis. The safety of apnea testing to the fetus in pregnant patients remains uncertain.We convened a panel of experts in BD/DNC, neurocritical care, maternal-fetal medicine, neonatology, fetal/neonatal/child neurology, and pediatric/fetal anesthesiology to perform a scoping review of apnea testing in pregnant persons. We found no studies directly assessing safety of apnea testing on the fetus. Apnea testing consists of fetal exposure to parental hyperoxia and hypercapnia; therefore, we searched for evidence related to these conditions in pregnancy. Case reports, series, and literature on physiologic changes induced during apnea testing and their potential effects on placental, fetal systemic, and fetal cerebral circulations were identified. In reported cases of BD/DNC in pregnant persons, some authors described explicitly avoiding apnea testing because of safety concerns, but whether apnea testing was performed at all was inconsistently reported. Evidence from studies evaluating hyperoxia and hypercapnia in healthy pregnant persons and in other animal models suggested possible adverse effects caused by reduced uteroplacental blood flow, fetal metabolic acidosis, and hypercapnia-induced cerebral hyperperfusion. Further possible complications of apnea testing, such as hypotension or hypoxemia in pregnant persons, could also contribute to fetal injury. These potential detrimental risks to the fetus raise the question as to whether apnea testing should be deferred if a fetus may be viable. Ancillary tests, such as radionuclide cerebral blood flow imaging or transcranial Doppler ultrasonography, can be used if the remainder of the BD/DNC evaluation and neurologic examination is otherwise consistent with BD/DNC. Further research is essential to assess the physiologic consequences of apnea testing in pregnant persons and potential risks to the fetus.