Faculty Bibliography

Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical-pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease-modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. HIGHLIGHTS: We celebrate 40 years of NIA-funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease-modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.

OBJECTIVE:To estimate the risk of epilepsy associated with stroke in a community-based cohort, with consideration of stroke type, number, and severity. METHODS:Data from 15,100 Atherosclerosis Risk in Communities (ARIC) Study participants without stroke at baseline (1987-1989) were analyzed through 12/31/2022. Adjudicated stroke events were modeled as time-varying exposures. Epilepsy was defined using International Classification of Diseases Ninth/Tenth Revisions codes. Adjusted Fine and Gray proportional hazards models were used to estimate the risk of epilepsy associated with stroke. RESULTS:At baseline, the mean age of participants was 54 years, 55% were female, and 26% were of Black race. Over a median of 27 years, 1553 incident all-cause strokes occurred. The risk of epilepsy was higher among individuals with versus without incident stroke (HR = 1.75, 95% CI = 1.50-2.04). There was evidence for interaction by age (p-interaction = 0.03) whereby the risk of epilepsy associated with stroke was higher among individuals with younger versus older baseline age. Compared to no stroke, the point estimate for the risk of epilepsy associated with subarachnoid hemorrhage (HR = 2.94, 95% CI = 1.67-5.17) was higher than that for the risk of epilepsy associated with ischemic stroke (HR = 1.65, 95% CI = 1.40-1.94) and hemorrhagic stroke (HR = 1.47, 95% CI = 0.95, 2.27). The risk of epilepsy was similar by the number of incident strokes but was greater with increasing ischemic stroke severity. INTERPRETATION/CONCLUSIONS:The risk of epilepsy was increased after an incident stroke. This work identifies high-risk subgroups, including younger individuals, individuals with subarachnoid hemorrhage, and individuals with more severe ischemic strokes, who may benefit from closer clinical monitoring for seizures/epilepsy after a stroke.

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.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Impaired consciousness in epilepsy negatively affects quality of life. Previous work has focused on temporal lobe seizures, where cortical slow waves are associated with depressed subcortical arousal and impaired consciousness. However, it is unknown whether frontal lobe seizures also show cortical slow waves or a different activity pattern with impaired consciousness. METHODS:Intracranial EEG (icEEG) recordings from patients at 3 centers were retrospectively assessed to identify seizures originating in the frontal lobe. Seizures were classified as focal preserved consciousness (FPC), focal impaired consciousness (FIC), or focal to bilateral tonic-clonic (FBTC) based on video review. Changes in icEEG power from preictal baseline were calculated in different cortical regions and across frequency ranges in these 3 seizure categories. RESULTS:< 0.001, 95% CI 330.1-781.9 and 375.3-818.2, respectively). DISCUSSION/CONCLUSIONS:The widespread power increases across frequencies in frontal lobe FIC seizures contrast with those in focal temporal lobe epilepsy, where impaired consciousness is associated with cortical slow waves. These findings suggest that different focal seizure types produce impaired consciousness by affecting widespread cortical regions but through different physiologic mechanisms. Insights gained by studying the physiology of impaired consciousness may be the first step toward developing novel treatments to prevent this significant negative consequence of epilepsy and improve quality of life.

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.

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.

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.

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.

Syntax, the abstract structure of language, is a hallmark of human cognition. Despite its importance, its neural underpinnings remain obscured by inherent limitations of non-invasive brain measures and a near total focus on comprehension paradigms. Here, we address these limitations with high-resolution neurosurgical recordings (electrocorticography) and a controlled sentence production experiment. We uncover three syntactic networks that are broadly distributed across traditional language regions, but with focal concentrations in middle and inferior frontal gyri. In contrast to previous findings from comprehension studies, these networks process syntax mostly to the exclusion of words and meaning, supporting a cognitive architecture with a distinct syntactic system. Most strikingly, our data reveal an unexpected property of syntax: it is encoded independent of neural activity levels. We propose that this "low-activity coding" scheme represents a novel mechanism for encoding information, reserved for higher-order cognition more broadly.

Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen 6 genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.