Faculty Bibliography

Models of reading emphasize that visual (orthographic) processing provides input to phonological as well as lexical-semantic processing. Neurobiological models of reading have mapped these processes to distributed regions across occipital-temporal, temporal-parietal, and frontal cortices. However, the role of the precentral gyrus in these models is ambiguous. Articulatory phonemic representations in the precentral gyrus are obviously involved in reading aloud, but it is unclear if the precentral gyrus is recruited during reading silently in a time window consistent with participation in phonological processing contributions. Here, we recorded intracranial electrophysiology during a speeded semantic decision task from 24 patients to map the spatio-temporal flow of information across the cortex during silent reading. Patients selected animate nouns from a stream of nonanimate words, letter strings, and false-font stimuli. We characterized the distribution and timing of evoked high-gamma power (70-170 Hz) as well as phase-locking between electrodes. The precentral gyrus showed a proportion of electrodes responsive to linguistic stimuli (27%) that was at least as high as those of surrounding peri-sylvian regions. These precentral gyrus electrodes had significantly greater high-gamma power for words compared to both false-font and letter-string stimuli. In a patient with word-selective effects in the fusiform, superior temporal, and precentral gyri, there was significant phase-locking between the fusiform and precentral gyri starting at ∼180 msec and between the precentral and superior temporal gyri starting at ∼220 msec. Finally, our large patient cohort allowed exploratory analyses of the spatio-temporal reading network underlying silent reading. The distribution, timing, and connectivity results place the precentral gyrus as an important hub in the silent reading network.

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [¹⁸F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [¹⁸F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [¹⁸F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

Introduction: Patients with MS and related conditions may be at higher risk for COVID-19 complications due to disease or medication- related factors. Elucidating those factors is imperative for appropriate counseling of patients.
Objective(s): To determine outcomes of COVID-19 in patients with MS and related conditions, and to determine predictors of these outcomes.
Aim(s): To assess impact of COVID-19 in MS patients.
Method(s): This was a multicenter, observational cohort study of patients with MS or related CNS autoimmune disorders who developed confirmed or highly suspected COVID-19 infection from 2/1/2020 to 12/31/2020. Patients from 5 MS centers in New York City and tri-state area were identified by the treating neurologist. The primary outcome measure was hospitalization status due to COVID-19. Data relating to COVID-19 symptoms, diagnostic testing including SARS-CoV-2 nasopharyngeal swab results (NAAT or antigen testing) and SARS-CoV-2 serologic status as well as data regarding potential risk factors and comorbidities was obtained.
Result(s): Of 474 patients in the study, 63.3% had confirmed COVID-19 infection and 93.9% were diagnosed with an MS phenotype. Mean age was 45+/-13 (mean+/-SD) years, 72% were female, and 86% were treated with a DMT at the time of infection. 58 patients (12.2%) were hospitalized. 24 patients (5.1%) were critically ill (requiring ICU care or outcome of death), of which 15 patients (3.2%) died. Higher neurological disability and older age independently predicted hospitalization. There was no association between specific DMTs or DMT classes and COVID-19 severity. 85% (102/120) of patients with known antibody results who were not treated with anti-CD20 therapies were seropositive while only 39.5% (17/43) of patients being treated with anti-CD20 demonstrated seropositivity (p<0.0001). Only 25% (2/8) of patients with PCR-confirmed COVID-19 being treated with anti-CD20 therapies demonstrated seropositivity. Conclusions and relevance: In this multicenter study, neurological disability and older age were independent predictors of hospitalization due to COVID-19. These findings will improve counseling of patients regarding risk from COVID-19. Additionally, the results demonstrate that anti-CD20 therapies significantly blunt humoral responses post-infection, a finding that carries potential implications with regards to natural or vaccine- mediated immunity

Background: Although a more aggressive disease course has been reported in African-American (AA) patients with multiple sclerosis (MS) in comparison with Caucasian (CA) patients, differences in disability outcomes might be partly related to socioeconomic factors limiting access to cure or influencing lifestyle choices.
Aim(s): To assess the impact of demographics, socioeconomic status and comorbidities on disability differences between AA and CA MS patients.
Method(s): As part of an ongoing longitudinal study, 120 MS patients (60 AA, 60 CA) and 82 HC (43 AA, 39 CA) were prospectively enrolled. All subjects included in the study self-identified as AA or CA. Data on demographic, socioeconomic and clinical status of all subjects were collected. Differences in disability scales between AA and CA MS patients were assessed via ordinal logistic or multivariable linear regression, as appropriate, entering in the final model demographic features (age, gender), indirect indicators of socioeconomic status (educational level, body mass index) and comorbidities.
Result(s): No difference in disease management (diagnostic delay, number of therapeutic switches, treatment with first or second line disease modifying therapies) was present between the two groups. No differences in strength, sensitivity, balance and verbal fluency were detected between AA and CA MS patients. Differences in Expanded Disability Status Scale, walking endurance and verbal memory disappeared in the models including socioeconomic status and comorbidities. On the contrary, even in complex models accounting for confounders, AA showed higher Multiple Sclerosis Severity Score (3.17 vs 1.96, p=0.017), worse manual dexterity (9-hole peg test 25.34 vs 22.44, p=0.005; grooved pegboard test 12.65 vs 15.02, p=0.001; finger tapping test non dominant hand 48.53 vs 52.94, p=0.009), and worse cognitive performance in the attentional, visuospatial and executive domains (symbol digit modality test 50.82 vs 56.78, p=0.014; multitasking test 3.93 vs 5.13, p=0.002; brief visuospatial memory test 16.43 vs 20.90, p<0.001; Stroop test 37.76 vs 44.29, p=0.020).
Conclusion(s): AA patients with MS present a more severe disability status than CA patients. Observed differences are only partly accounted for by sociodemographic factors

Migraine affects over 40 million Americans and is the world's second most disabling condition. As the majority of medical care for migraine occurs in primary care settings, not in neurology nor headache subspecialty practices, healthcare system interventions should focus on primary care. Though there is grade A evidence for behavioral treatment (e.g., biofeedback, cognitive behavioral therapy (CBT), and relaxation techniques) for migraine, these treatments are underutilized. Behavioral treatments may be a valuable alternative to opioids, which remain widely used for migraine, despite the US opioid epidemic and guidelines that recommend against them. Identifying and removing barriers to the use of headache behavioral therapy could help reduce the disability as well as the personal and social costs of migraine. These techniques will have their greatest impact if offered in primary care settings to the lower socioeconomic status groups at greatest risk for migraine. We review the societal and cultural challenges that impose barriers to optimal use of non-pharmacological treatment services. These barriers include insufficient knowledge of migraine/headache behavioral treatments and insufficient availability of clinicians trained in non-pharmacological treatment delivery; limited access in underserved communities; financial burden; and stigma associated with both headache and mental health diagnoses and treatment. For each barrier, we discuss potential approaches to minimizing its effect and thus enhancing non-pharmacological treatment utilization.Case ExampleA 25-year-old graduate student with a prior history of headaches in college is attending school in the evenings while working a full-time job. Now, his headaches have significant nausea and photophobia. They are twice weekly and are disabling enough that he is unable to complete homework assignments. He does not understand why the headaches occur on Saturdays when he pushes through all week to get through his examinations that take place on Friday evenings. He tried two different migraine preventive medications, but neither led to the 50% reduction in headache days his doctor had hoped for. His doctor had suggested cognitive behavioral therapy (CBT) before initiating the medications, but he had been too busy to attend the appointments, and the challenges in finding an in-network provider proved difficult. Now with the worsening headaches, he opted for the CBT and by the fifth week had already noted improvements in his headache frequency and intensity.

Background and aims: Intracranial arterial calcification (IAC) has been identified as an independent risk factor for ischemic stroke. The predictive value of calcification severity for the underlying pathophysiological mechanism of an ischemic stroke remains undetermined. We aimed to assess the degree of intracranial artery calcification in patients with ischemic stroke and evaluate its correlation with intracranial artery atherosclerotic disease as the underlying mechanism.
Method(s): Two hundred and eleven patients with strokes attributed to large vessel atherosclerotic disease from the NYU Ischemic Stroke Database, determined by two independent vascular neurologists, were enrolled. Patients with tandem lesions or competing pathophysiologic mechanisms were excluded. Head CT scans for each patient were reviewed. The degree of calcification of each vertebral and basilar artery was determined by two physicians using the Woodcock Score (interrater reliability score of kappa = 0.88).
Result(s): The highest prevalence of calcification was seen in the left vertebral artery (47%), and less commonly in the basilar artery (15%). There was a trend towards higher prevalence of moderate-severe IAC in patients with stroke due to intracranial atherosclerosis than patients with stroke due to extracranial atherosclerosis (40% vs. 28%, P = 0.073). The most common risk factors were hypertension (42 vs. 26%, p = 0.890), dyslipidemia (25 vs. 19%, p = 0.496), and type 2 diabetes (21 vs. 13%, p = 0.415), in patients with stroke due to intracranial atherosclerosis vs extracranial atherosclerosis, respectively.
Conclusion(s): There may be a positive correlation between the severity of vertebrobasilar atherosclerotic disease as determined by the Woodcock score and the likelihood that the underlying pathophysiological mechanism of an ischemic stroke is intracranial atherosclerotic disease.
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Objective: To compare humoral and T-cell responses to COVID- 19 vaccines in 400 MS patients who were on Ocrelizumab ('OCR') v. other disease-modifying therapies ('non-OCR') at the time of vaccination. Introduction: Peripheral B-cell depletion with anti-CD20 therapies attenuates humoral responses to vaccines. Whether immune responses to COVID-19 vaccines differ between B-cell depleted and non-B cell depleted MS patients is not known.
Method(s): Consecutive MS patients from NYU MS Care Center were invited to participate if they completed COVID-19 vaccination >=6 weeks previously. Immune testing included anti-spike RBD antibody (Elecsys Anti-SARS-CoV-2) (Roche Diagnostics); multiplex bead-based immunoassays of antibody-responses to SARS-COV-2 spike proteins; T-cell responses to SARS-CoV-2 Spike protein using IFNgamma enzyme-linked immune-absorbent spot (Invitrogen) and TruCulture (Myriad RBM) assays; high dimensional immunophenotyping; and live virus immunofluorescencebased microneutralization assay.
Result(s): As of 7/15/2021, 105 MS subjects were enrolled (mean age: 40.5 years; 76% female; 41% non-white; 38% on OCR; 12% with prior COVID-19 infection). 95% were fully vaccinated with mRNA vaccines (Pfizer/Moderna); 5% - with adenovirus-based vaccine (Johnson&Johnson). Median time from sample collection to last vaccine was 79 days. Positive Elecsys Anti-SARS-CoV-2 Ab titers post-vaccine were detected in 11/37 (30%) in OCR (mean level: 702 U/mL among seropositives) and 54/54 (100%) patients in non-OCR (mean level: 2310 U/mL; p<0.0001). Positive response by multiplex assay (threshold of 'positive' defined as 2 SD below the mean for the non-OCR) were detected in 10/27 (37%) OCR and 29/31 (94%) non-OCR (p<0.00001). T-cell activation based on induced IFNgamma secretion (TruCulture) was detected in 20/25 (80%) OCR and 16/19 (84%) non-OCR patients (p=0.71).
Conclusion(s): Preliminary results suggest robust T-cell immune response to SARS-CoV2 vaccines in approximately 80% of both OCR and non-OCR MS patients. Antibody responses were markedly attenuated in OCR compared to non-OCR group. Updated results will be presented

Objective: To examine antibody and T-cell responses to mRNAplatform COVID-19 vaccines in Ocrelizumab-treated MS patients over a 12-month period. Introduction: B-cell depletion with Ocrelizumab attenuates humoral responses to vaccines. The kinetics of humoral and cellular immune responses to COVID-19 vaccines in B-cell depleted MS patients has not been reported.
Method(s): VIOLA (NCT04843774) is an open-label, observational study enrolling 60 MS patients on Ocrelizumab from NYU and Rocky Mountain at the University of Colorado MS Centers. First vaccine dose occurred >=2 weeks after ocrelizumab infusion; second-dose >=8 weeks before the next infusion. Antibody responses to SARS-COV-2 spike proteins were assessed with Elecsys Anti-SARS-CoV-2 (Roche Diagnostics) and multiplex bead-based immunoassays. T-cell responses to SARS-CoV-2 Spike protein were assessed with IFNgamma ELISpot (Invitrogen) and TruCulture (Myriad RBM) and high-dimensional immunophenotyping. Samples are collected pre-vaccination and at 4, 12, 24, and 48-weeks post-vaccination.
Result(s): As of 7/15/2021, 52 subjects have been enrolled (39.7+/-10.0 years; 73% female; 47% non-white), of whom 47 were fully vaccinated (85% Pfizer, 15% Moderna). Anti-spike RBD antibody (Elecsys Anti-SARS-CoV-2) were available for pre- and post-vaccine timepoints for 15 patients. Pre-vaccine, 1/15 (7%) patients had detectable titers, while at 4-weeks postvaccine, 10/15 (66%) patients had detectible titers (mean for positives: 1189 U/ml; 5 patients had positive titers <25 U/ml). T-cell activation based on induced IFNgamma secretion (TruCulture) at baseline and 4-week post-vaccine timepoints were available for 13 patients, of whom 12 (92%) were increased (mean pre-vaccine: 24 pg/ml; mean post-vaccine: 366 pg/ml, two-tailed t-test, p=0.0032).
Conclusion(s): This prospective study of humoral and cellular immune responses to COVID-19 vaccines in Ocrelizumab-treated patients will generate data to help guide management of MS patients on anti-CD20 therapies. Early results suggest that 4-weeks post-vaccination nearly all Ocrelizumab-treated MS patients develop T-cell immunity and two-thirds showed evidence of humoral response. Additional 4-week and 12-week post-vaccination data will be presented

BACKGROUND AND PURPOSE/OBJECTIVE:A subset of ischaemic stroke patients with atrial fibrillation (AF) have ischaemic stroke despite anticoagulation. We sought to determine the association between prestroke anticoagulant therapy and recurrent ischaemic events and symptomatic intracranial haemorrhage (sICH). METHODS:We included consecutive patients with acute ischaemic stroke and AF from the Initiation of Anticoagulation after Cardioembolic stroke (IAC) study from eight comprehensive stroke centres in the USA. We compared recurrent ischaemic events and delayed sICH risk using adjusted Cox regression analyses between patients who were prescribed anticoagulation (ACp) versus patients who were naïve to anticoagulation therapy prior to the ischaemic stroke (anticoagulation naïve). RESULTS:Among 2084 patients in IAC, 1518 had prior anticoagulation status recorded and were followed for 90 days. In adjusted Cox hazard models, ACp was associated with some evidence of a higher risk higher risk of 90-day recurrent ischaemic events only in the fully adjusted model (adjusted HR 1.50, 95% CI 0.99 to 2.28, p=0.058) but not increased risk of 90-day sICH (adjusted HR 1.08, 95% CI 0.46 to 2.51, p=0.862). In addition, switching anticoagulation class was not associated with reduced risk of recurrent ischaemic events (adjusted HR 0.41, 95% CI 0.12 to 1.33, p=0.136) nor sICH (adjusted HR 1.47, 95% CI 0.29 to 7.50, p=0.641). CONCLUSION/CONCLUSIONS:AF patients with ischaemic stroke despite anticoagulation may have higher recurrent ischaemic event risk compared with anticoagulation-naïve patients. This suggests differing underlying pathomechanisms requiring different stroke prevention measures and identifying these mechanisms may improve secondary prevention strategies.