Faculty Bibliography

BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection, more commonly known as long COVID, has emerged as a major health problem. The pathogenesis of long COVID is unknown, but among the leading hypotheses is viral persistence. We aimed to investigate whether the use of the SARS-CoV-2 antiviral nirmatrelvir-ritonavir improved long COVID symptoms. METHODS:We conducted a double-blind, placebo-controlled, randomised trial involving adults who had developed persistent symptoms (≥12 weeks) associated with three major symptom phenotypes (cognitive, autonomic, or exercise) after acute SARS-CoV-2 infection at 69 US sites. Participants were eligible if they were 18 years or older and had a previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization. Eligible participants were also required to have either at least two moderate symptoms from the same phenotype or one severe phenotype-associated symptom, as identified with the Cluster Targeted COVID-19 Symptom Questions. Participants were randomly allocated in a double-blind manner in a 1:1:1 ratio using permuted blocks of size 30 to receive either 15 days of active intervention followed by 10 days of placebo (300 mg nirmatrelvir-100 mg ritonavir twice daily, then 100 mg ritonavir-placebo); 25 days of active intervention (300 mg nirmatrelvir-100 mg ritonavir twice daily); or 25 days of placebo-ritonavir (100 mg ritonavir-placebo). A clinically significant change in patient-reported outcomes at day 90 comprised the primary endpoint: Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, Orthostatic Hypotension Questionnaire question 1, and a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise short form. Secondary outcomes were phenotype-specific performance measures. The study was registered at ClinicalTrials.gov (NCT05595369) and is complete. FINDINGS/RESULTS:Between July 27, 2023, and Sept 6, 2024, 1207 individuals were screened. Of these, 964 were randomly allocated and 959 participants, excluding four participants who were later found ineligible and one who did not initiate treatment, were enrolled in the three phenotypes: 332 to cognitive, 334 to autonomic, and 332 to exercise. In the 959 participants in the mITT population, 643 (67%) self-reported as female, 314 (33%) were male, and two participants had a sex of unknown or undifferentiated; 750 (78%) were White; and 108 (11%) were Hispanic, Latino, or Spanish. The median age was 49 years (IQR 38-59). No statistically significant benefits were observed for any phenotype for primary endpoints. For the cognitive phenotype, adjusted differences compared to placebo were 3·2% (95% CI -10·4 to 16·8, p=0·65) for the 25-day regimen and -2·2% (-15·5 to 11·1, p=0·74) for the 15-day regimen. For the autonomic phenotype, adjusted differences were -6·4% (-18·5 to 5·7, p=0·30) for the 25-day regimen compared to placebo and -0·1% (-12·5 to 12·3, p=0·99) for the 15-day regimen compared to placebo. For exercise, adjusted differences were -7·8% (-19·5 to 3·8, p=0·19) for the 25-day regimen compared to placebo and 0·9% (-11·4 to 13·2, p=0·88) for the 15-day regimen compared to placebo. There were no differences in secondary endpoints, and no safety signals were observed; there were no deaths, and 52 serious adverse events occurred in 42 (4%) of 963 participants over the course of the study. INTERPRETATION/CONCLUSIONS:Nirmatrelvir-ritonavir for 15 days or 25 days showed no evidence of benefit in long COVID in any of the three phenotypes studied. These findings suggest additional approaches to measuring the symptom burden and treating Long COVID are needed. FUNDING/BACKGROUND:National Institutes of Health.

This practice guideline provides updated evidence-based recommendations regarding the use of pharmacologic migraine prevention in adults. A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies published through June 6, 2024, and is available in a companion publication. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Recommendations are provided on how to decide when it is appropriate to start a pharmacologic migraine preventive medication and how to decide which migraine preventive medication to start. Recommendations address decision making on appropriate choices of migraine preventive medications in specific situations and populations, including patients with fibromyalgia, obesity, or hypertension; considerations for older adults; treatment during pregnancy and lactation; sex-related factors in choosing medications; and treatment for patients with medication overuse. Recommendations on assessment of treatment efficacy, adverse effects, and discontinuing migraine preventive medications are provided.

This practice guideline provides updated evidence-based recommendations regarding the use of pharmacologic migraine prevention in adults. A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies published through June 6, 2024, and is available in a companion publication. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Recommendations are provided on how to decide when it is appropriate to start a pharmacologic migraine preventive medication and how to decide which migraine preventive medication to start. Recommendations address decision making on appropriate choices of migraine preventive medications in specific situations and populations, including patients with fibromyalgia, obesity, or hypertension; considerations for older adults; treatment during pregnancy and lactation; sex-related factors in choosing medications; and treatment for patients with medication overuse. Recommendations on assessment of treatment efficacy, adverse effects, and discontinuing migraine preventive medications are provided.

IMPORTANCE:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact exposure. CTE can only be diagnosed post mortem, and the antemortem neuropsychological profile is poorly understood, hindering accurate diagnosis before death. OBJECTIVE:To characterize antemortem neuropsychological test performance of former National Football League (NFL) players with autopsy-confirmed CTE. DESIGN, SETTING, AND PARTICIPANTS:This retrospective case series included former NFL players who completed an antemortem neuropsychological evaluation and had autopsy-confirmed CTE. Data were collected between January 1, 2017, and April 30, 2025. Statistical analysis was performed from September 2025 to June 2026. EXPOSURE:CTE neuropathology, defined by the National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus panel. MAIN OUTCOMES AND MEASURES:Neuropsychological test performance, neuropathologic diagnoses, and semiquantitative phosphorylated tau (p-tau) pathology across 11 brain regions were examined. Raw scores were converted to z scores using age, sex, and/or education level-based normative data. Test results with z scores of -1.5 or less were categorized as impaired; domains with 2 or more impaired test results were considered impaired. RESULTS:The primary analytic sample included 33 men (mean [SD] age at death, 65.4 [13.3] years; mean [SD] time between testing and death, 2.4 [1.6] years), 25 with high- and 8 with low-stage CTE. Learning and memory was most impaired (17 of 27 [63.0%]), followed by executive function (15 of 29 [51.7%]) and language (12 of 29 [41.4%]). High-stage CTE participants generally had worse scores than low-stage CTE participants. Greater global p-tau burden was associated with worse learning and memory performance (B = -0.40; 95% CI, -0.70 to -0.09; P = .01). Findings were similar after excluding 9 participants with co-occurring Alzheimer disease or frontotemporal lobar degeneration tau. CONCLUSIONS AND RELEVANCE:In this retrospective case series of NFL players with autopsy-confirmed CTE, memory, executive function, and language impairments were common, and p-tau burden was associated with worse memory performance. Findings provide insight into the expected CTE neuropsychological profile and may help advance diagnosis before death.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Patients with epilepsy (PWE), especially temporal lobe epilepsy (TLE), experience impaired memory for personally experienced events. However, current assessments of episodic memory are limited in their ecological validity with a potential to miss detection of subtle cognitive decline. We conducted an exploratory study to determine whether a naturalistic film-viewing task with open-ended spoken recall could detect memory differences between TLE patients and healthy controls (HCs). METHODS:TLE patients (ages 18-60, fluent in English, not legally blind) were recruited from a Level 4 Epilepsy Center (2018-2024). TLE diagnosis was based on seizure semiology, MRI Brain, and EEG. TLE patients scored 22/30 on the Montreal Cognitive Assessment (MOCA); HCs scored 26/30. Subjects watched 6 short films and then freely recalled film details. Spoken responses were recorded, transcribed, segmented, and scored for film- and event-level recall. Recall order was assessed using the Damerau-Levenshtein distance. Semantic and causal centrality were quantified using sentence embeddings and rater-identified causal links, respectively. Beta regression with cluster-robust standard errors assessed group and centrality effects on recall probability. Beta regression evaluated the influence of age, MOCA, and testing platform on sequence recall error. RESULTS:We recruited 51 subjects (27 TLEs; 24 HCs, 70.1% F, mean 29.9 ±8.3 years). TLE patients and HCs showed similar recall of films (HC 89% ±11% vs TLE 88% ±18%, p = 0.54), coarse-grained events (HC 50% ±16% vs TLE 44% ±18%, p = 0.19) and fine-grained events (HC 25%±10% vs. TLE 22%±12%, p=0.17). Both groups recalled high causal centrality events better. However, TLE patients showed significantly greater fine-grained event sequence deviations at recall than HCs (HC 15% ±13% vs TLE 23% ±18%, p = 0.02, Hedges' g = 0.85, Cliff's δ = 0.51), with RTLE demonstrating more sequence deviations than HCs (15%±13 vs. 29%±21% p = 0.021) Age, education, MOCA, and performance on standard verbal and visual memory tasks were unrelated to film, event, and sequence recall performance. DISCUSSION/CONCLUSIONS:We demonstrate that a short film task with spontaneous spoken recall can identify group level differences in episodic memory. TLE patients demonstrate impaired sequence memory despite intact film- and event-level recall compared to healthy controls. Sequence memory may represent a subtle manifestation of memory impairment that is not detected by standard cognitive testing.

OBJECTIVES/OBJECTIVE:Distinguishing Idiopathic Generalized Epilepsy (IGE) from focal epilepsy (FE) can be challenging when IGE cases present with asymmetric clinical or electroencephalographic (i.e., atypical) features. We aimed to identify factors that lead to discordance in IGE diagnoses among epileptologists. METHODS:41 patients with IGE and 6 patients with FE or mixed focal and generalized epilepsy followed at the NYU Comprehensive Epilepsy Center for ≥5 years were identified. IGE cases included typical (n = 18) and atypical (n = 23) presentations. Anonymized summaries of patients at initial presentation and 5-year follow-up were presented in random order to epileptologists who categorized them as generalized epilepsy (GE), FE, or other. Factors leading to discordance were identified. RESULTS:Inter-rater agreement was moderate for atypical IGE cases at initial presentation (AC1 = 0.54, 95% CI 0.31-0.77, p < 0.01) and 5-year follow-up (AC1 = 0.48, 95% CI 0.25-0.72, p < 0.01). For atypical cases, asymmetric epileptiform activity was most commonly associated with increased discordance. DISCUSSION/CONCLUSIONS:Epileptologists may underdiagnose IGE when patients have asymmetric EEG or clinical features. Review of one time point (i.e., vignettes) may mask the diversity of features that may support a localized epilepsy when serial reviews reveal a generalized epilepsy.

BACKGROUND AND PURPOSE/OBJECTIVE:Although visibility of Deep Medullary Veins (DMVs) has been suggested as an imaging biomarker for cerebral small vessel disease (CSVD) and brain atrophy, qualitative visual assessment of DMVs may lack reliability. In this study, we used a rigorous, automated approach to segment DMVs on SWI and to estimate a vein voxel fraction (VVF). We hypothesized that VVF would be associated with vascular risk factors, imaging markers of CSVD, and brain volumes. MATERIAL AND METHODS/METHODS:A retrospective analysis of data from participants enrolled in studies of brain aging and prediction of Alzheimer's disease. All underwent 3T MRI (T1WI, FLAIR, SWI, and arterial spin labeling), clinical evaluations, and laboratory tests to assess vascular risks. A SWI image processing pipeline included denoising, bias field correction, adaptive histogram equalization, and multi-scale Jerman filtering that yielded vesselness maps. The vein voxel fraction (VVF) was calculated as a ratio of DMVs voxels in a periventricular region to the volume of the periventricular region. White matter hyperintensities, microbleeds, brain volumes, and CBF were also assessed. RESULTS:This study included 131 cognitively healthy participants, 71 (65, 76) years (median, Q1, Q3), (51%) female, and a subgroup of subjects with cognitive impairment (n=30, 69 (59, 76) years, 43% female). In the unimpaired group, the VVF positively correlated with systolic blood pressure and body mass index. It showed an inverse association with lateral ventricle volume (all at p < 0.05). It was related to white matter hyperintensities volume only in unadjusted analysis. CONCLUSION/CONCLUSIONS:Vein voxel fraction was associated with increased weight and high blood pressure. Possibly, these observations reflect venous stasis. These factors should be accounted for while evaluating brain venous system with SWI. In addition, subcortical atrophy was related to less visible DMVs.

The introduction of immune checkpoint inhibitors (ICIs) has dramatically changed the landscape of treatment for a variety of cancers. However, there is increasing recognition of neurotoxicity related to ICI use. In this review, we will discuss the peripheral nervous system neurologic immune related adverse events (PNS-nirAEs) of anti-CTLA4, anti-PD1, and anti-PDL1 ICIs, including nerve, neuromuscular junction, muscle, and overlap syndromes. We will discuss the relevant epidemiology, pathophysiology, clinical syndromes, diagnostic approaches, treatment, and prognosis of PNS-nirAEs. We will discuss the safety and efficacy of ICIs when utilized in patients with pre-existing neurologic autoimmune disorders (NAIDs). Lastly, we will discuss relevant treatment options and when to consider rechallenging with ICI after an initial de novo PNS-nirAE or exacerbation of a pre-existing NAID.

INTRODUCTION/BACKGROUND:Down syndrome (DS) is caused by a complete or partial trisomy of chromosome 21, resulting in variable intellectual disabilities and a high risk for early-onset Alzheimer's disease (DS-AD). Dysregulation of the mammalian target of rapamycin (mTOR) and insulin (INS) signaling pathways has been reported in DS. We hypothesized that upstream alterations in these two pathways contribute to hippocampal dysfunction in DS-AD. METHODS:We used spatial transcriptomics and localized proteomic techniques to examine mTOR/INS signaling pathways in subregions of the hippocampus in post mortem tissue from individuals with DS-AD and age-matched neurotypical controls. RESULTS:mTOR pathways were significantly altered in specific hippocampal subfields in DS-AD, and INS pathways were significantly altered in dentate granule neurons. DISCUSSION/CONCLUSIONS:These preliminary spatial transcriptomics and localized proteomics findings demonstrate an interplay between select hippocampal mTOR/INS pathways and cellular populations, suggesting potential novel drug targets and early biomarkers for DS.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Former American football players exposed to repetitive head impacts (RHI) are at a risk of chronic traumatic encephalopathy (CTE), but chronic pain, polypharmacy, and extensive orthopedic surgeries may also contribute to cognitive and behavioral symptoms. This study evaluated associations between chronic pain, centrally acting medications (CAMs), and orthopedic surgeries with cognitive and behavioral symptoms among former American football players. METHODS:The sample included former professional (PRO) and collegiate (COL) football players and unexposed, asymptomatic men (UE) from DIAGNOSE CTE. Number of CAMs, orthopedic surgeries, and average pain scores were compared between the groups. Among former football players, logistic regression tested associations between CAMs, average pain score, and orthopedic surgeries with diagnoses of cognitive impairment and neurobehavioral dysregulation (NBD) using traumatic encephalopathy syndrome (TES) research criteria. Linear regression tested associations between CAMs, average pain score, and orthopedic surgeries with the Montreal Cognitive Assessment (MoCA) and behavioral and mood symptom scales. Covariates included age, education, race, and total years of football. RESULTS:The study included 236 men (120 PRO, 60 COL, 56 UE). The mean ages were 59.1 (PRO), 53.5 (COL) and 59.6 (UE) years. PRO and COL used more CAMs (mean PRO = 0.76, COL = 1.14, UE = 0.14), had higher average pain scores (PRO = 4.22, COL = 3.21, UE = 1.05), and more orthopedic surgeries than the UE (mean PRO = 2.76, COL = 1.22, UE = 0.34). CAMs and average pain scores were associated with increased odds of consensus diagnosed NBD (CAMs OR = 2.15, 95% CI 1.53 to 3.26; average pain score OR = 1.55, 95% CI 1.32 to 1.85). CAMs and average pain scores were associated with increased measures of impulsivity, depression, anxiety, behavioral regulation, and aggression. CAMs and average pain scores were not associated with consensus diagnosed cognitive impairment, but CAMs were negatively associated with MoCA score (estimate = -0.47, 95% CI -0.81 to -0.13). There was no association between number of orthopedic surgeries and cognition or NBD. DISCUSSION/CONCLUSIONS:CAMs and chronic pain are associated with NBD and CAMs are associated with reduced MoCA scores in former American football players.