Faculty Bibliography

Accumulation of phosphorylated tau is a key pathological feature of Alzheimer's disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer's disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer's disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer's disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer's disease.

Objective: Cognitive dysfunction is prevalent amongst individuals who have undergone neurosurgical intervention, significantly impacting daily functioning and quality of life. The aim of this pilot study was to investigate the impact of Cogmed Working Memory Training (CWMT), a five-week, home-based, computerized cognitive rehabilitation intervention, within a neurosurgical population. Method: Thirty adult participants who underwent neurosurgical intervention, regardless of etiology, were included in this study. Participants were administered a neuropsychological battery at three time points post-neurosurgical intervention: (a) at baseline, prior to engaging in CWMT; (b) within two weeks of completing the training; and (c) after three months of completing the training. Results: Following CWMT, participants demonstrated significant improvement on measures of attention, working memory, processing speed, verbal learning, and memory. In addition, participants reported significant improvement in quality of life (i.e., physical, social, emotional, and functional well-being), mood (i.e., anxiety and depression), and neurobehavioral functioning (i.e., apathy). Implications: Results suggest that CWMT may improve aspects of cognitive and functional outcomes for neurosurgical patients.

Attention is thought to be the gateway between information and learning, yet there is much we do not understand about how students pay attention in the classroom. Leveraging ideas from cognitive neuroscience and psychology, we explore a framework for understanding attention in the classroom, organized along two key dimensions: internal/external attention and on-topic/off-topic attention. This framework helps us to build new theories for why active-learning strategies are effective teaching tools and how synchronized brain activity across students in a classroom may support learning. These ideas suggest new ways of thinking about how attention functions in the classroom and how different approaches to the same active-learning strategy may vary in how effectively they direct students' attention. We hypothesize that some teaching approaches are more effective than others because they leverage natural fluctuations in students' attention. We conclude by discussing implications for teaching and opportunities for future research.

BACKGROUND:Telehealth provides health care to a patient from a provider at a distant location. Prior to the COVID-19 pandemic adoption of telehealth modalities was increasing slowly but steadily. During the public health emergency rapid widespread telehealth implementation has been encouraged to promote patient and provider safety and preserve access to health care. EVIDENCE ACQUISITION/METHODS:Evidence was acquired from English language Internet-searches of medical and business literature and following breaking news on the COVID-19 pandemic and responses from health care stakeholders including policy makers, payers, physicians and health care organizations, and patients. We also had extensive discussions with colleagues who are developing telehealth techniques relevant to neuro-ophthalmology. RESULTS:Regulatory, legal, reimbursement and cultural barriers impeded the widespread adoption of telehealth prior to the COVID-19 pandemic. With the increased use of telehealth in response to the public health emergency, we are rapidly accumulating experience and an evidence base identifying opportunities and challenges related to the widespread adoption of tele-neuro-ophthalmology. One of the major challenges is the current inability to adequately perform funduscopy remotely. CONCLUSIONS:Telehealth is an increasingly recognized means of healthcare delivery. Tele-neuro-ophthalmology adoption is necessary for the sake of our patients, the survival of our subspecialty, and the education of our trainees and students. Telehealth does not supplant but supplements and complements in-person neuro-ophthalmologic care. Innovations in digital optical fundus photography, mobile vision testing applications, artificial intelligence and principles of channel management will facilitate further adoption of tele-neuro-ophthalmology and bring the specialty to the leading edge of healthcare delivery.

Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institutes of Health Stroke Scale was 10 (interquartile range [IQR], 4-18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institutes of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4-18] versus 6 [IQR, 3-14]), P=0.03; (odds ratio, 1.69 [95% CI, 1.08-2.65] for higher National Institutes of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2-6] versus 2 [IQR, 1-4], P<0.001) and death (odds ratio, 4.3 [95% CI, 2.22-8.30]) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.

OBJECTIVE:To summarize for the trainee audience the possible mechanisms of headache in patients with COVID-19 as well as to outline the impact of the pandemic on patients with headache disorders and headache medicine in clinical practice. BACKGROUND:COVID-19 is a global pandemic caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2, of which a large subset of patients features neurological symptoms, commonly headache. The virus is highly contagious and is, therefore, changing clinical practice by forcing limitations on in-person visits and procedural treatments, more quickly shifting toward the widespread adaptation of telemedicine services. DESIGN/RESULTS:We review what is currently known about the pathophysiology of COVID-19 and how it relates to possible mechanisms of headache, including indirect, potential direct, and secondary causes. Alternative options for the treatment of patients with headache disorders and the use of telemedicine are also explored. CONCLUSIONS:Limited information exists regarding the mechanisms and timing of headache in patients with COVID-19, though causes relate to plausible direct viral invasion of the nervous system as well as the cytokine release syndrome. Though headache care in the COVID-19 era requires alterations, the improved preventive treatment options now available and evidence for feasibility and safety of telemedicine well positions clinicians to take care of such patients, especially in the COVID-19 epicenter of New York City.