4th Annual Neurology Research Retreat

June 7, 2019

Part I
Cognition & Plasticity
Session Moderator: Martin Picard, PhD
Jason Carmel, MD, PhD
“Sensory targets for movement recovery”

Movement relies on efferent commands from brain and afferent feedback. Poor movement after CNS injury is strongly associated with corticospinal tract injury, and less attention is paid to sensory tract dysfunction. In pediatric hemiplegia, sensory system injury is more strongly associated with hand dysfunction than motor system injury, largely due to developmental preservation of a bilateral corticospinal tract. This suggests that therapy might be directed towards sensory, rather than motor, pathways to restore skilled movement.

William Charles Kreisl, MD
“Discerning the relationship between inflammation and Alzheimer’s disease”

Whether neuroinflammation plays a causal role in Alzheimer’s disease (AD) or is just a non-specific response to neurodegeneration is unclear. We sought to determine if upstream amyloid accumulation and downstream cognitive impairment have independent relationships with microglial activation. We demonstrated that amyloid positivity and cognitive impairment are independently associated with increased PET binding of TSPO, a microglial biomarker. These results suggest that neuroinflammation co-occurs with amyloid plaque deposition in the absence of cognitive impairment and with cognitive impairment in the absence of amyloidosis. Our results argue that microglial activation could be both a specific response to amyloid plaque deposition in early stages and a non-specific response to neurodegeneration in later stages of AD.

Sabrina Simoes, PhD
“Alzheimer’s vulnerable brain region relies on a neuronal-enriched retromer”

Anatomical studies have identified the trans-entorhinal cortex (TEC) as a subregion of the brain selectively vulnerable to Alzheimer’s disease (AD). Molecular studies have implicated defects in endosomal trafficking as pathogenic drivers of the disease. Whether and how endosomal trafficking links to anatomical vulnerability remains unknown. Here, in addressing these questions, we focus on retromer, a protein complex central to endosomal trafficking and linked to AD. VPS26 is the only protein of retromer’s trimeric core with two paralogs, VPS26a and VPS26b. First, we begin by establishing that, more than any other cells, neurons are enriched with a functionally distinct VPS26b-retromer that is dedicated to endosomal recycling. Second, using neuroimaging we find that the TEC is differentially affected by VPS26b depletion, a finding further validated by electrophysiology and cognitive testing. Finally, we demonstrate that the AD-target TEC is highly enriched in VPS26b and markers of the recycling endosome. Together with recently established network properties of the TEC, our results suggest a unified mechanism for disease vulnerability.

Part II
Neurodegeneration & Neuroinfections
Session Moderator: Tyler Cutforth, PhD
Badri Vardarajan, PhD, MS
“Large scale sequencing efforts in Alzheimer’s disease: findings and future work”

The Alzheimer's Disease Sequencing Project was presidential initiative launched with aims to identify a) new genes involved in Alzheimer’s Disease (AD), b) gene alleles contributing to increased risk for or protection against the disease, c) modifying genetic factors that protect or delay onset of disease and d) potential avenues for therapeutic approaches and prevention of the disease. In this talk, I will summarized the findings from the large genome-wide association and sequencing studies in Alzheimer’s Disease. I also described ongoing complementary approaches including multi-omics integration of genomics, transcriptomics, metabolomics and proteomics to identify the missing heritability of LOAD.

Kiran Thakur, MD
“Tackling CNS infectious and inflammatory conditions: Identifying the best approach to turn the mysterious into the treatable”

Neurological infections and neuroimmunological conditions pose significant diagnostic and management challenges in the inpatient hospital setting, wherein over 50% of cases remain with an unknown etiology at hospital discharge. Through retrospective ICD-based data and electronic medical record review, our work evaluates patients with neuroinfectious and neuroimmunological conditions, identifying sociodemographic risk factors including older age, active substance abuse, and living in nursing home or public housing prior to discharge to be associated with poor outcome. We are also working with the NYC Health Department to evaluate delays in diagnosis and management of patients with definitive community acquired bacterial meningitis. Our findings suggest that a significant number of patients are misdiagnosed, with delayed time to lumbar puncture and treatment initiation.  We also describe work as part of a multicenter cohort of patients with acute flaccid myelitis (AFM), and describe a significant number of patients (over 50%) misdiagnosed. We describe novel approaches to diagnosis of CNS infections and neuroinflammatory conditions, including multiplex polymerase chain reaction (PCR), next generation sequencing (NGS) and early brain biopsy which utilize a hypothesis free approach to test for possible CNS pathogens and immune mediated conditions. We will be working to define immune signatures in patients with CNS autoimmune conditions and infections, and identify the prevalence of post CNS infectious autoantibodies. 

Mariko Taga, PhD
“Dissecting BIN1 in AD: reduced protein-level expression of exon 7 in human astrocytes is associated with increased Tau pathology”

BIN1, an Alzheimer’s disease (AD) susceptibility gene, has 10 isoforms that are expressed in various CNS cell types. The BIN1-related molecular events that lead to AD and the cell type(s) in which these events occur remain unclear. Here, we mapped the distribution of BIN1 isoforms and defined the cell type(s) in which BIN1 exerts its AD-related effects.

We found that exon 7, contained in isoforms 1, 2 and 3, is expressed in both neurons and astrocytes. SRM measures of exon 7 peptides have a negative association with tau tangles. Further, we found a significant decrease in the number of astrocytes expressing BIN1 exon 7 in AD subjects. The total number of astrocytes was not reduced in AD, and we found no difference in the expression of neuronal BIN1 exon 7 in AD.

Our study has refined the cell type specific expression patterns of different BIN1 isoforms. Further, we find that altered splicing of exon 7 in astrocytes is associated with Tau pathology and AD. These effects are independent of the AD genetic risk attributed to BIN1 SNP, rs6733839. Our studies also prioritize astrocytes as the potential target cell type of BIN1 in AD.

Part III
Neuromuscular Diseases
Session Moderator: George Mentis, PhD
Livio Pellizzoni, PhD
“RNA-mediated mechanisms of spinal muscular atrophy”

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by ubiquitous deficiency in SMN, a protein with essential functions in RNA regulation. How dysfunction of a ubiquitously expressed protein that carries out biological processes required by all cells leads to selective degeneration of motor neurons is a major conundrum in SMA. Our studies reveal that this selectivity results from the convergence of distinct insults driven by dysregulation of specific RNA processing events in vulnerable SMA neurons. Furthermore, dissection of this pathogenic cascade is yielding new entry points for the development of neuroprotective approaches for SMA.

Francesco Lotti, PhD
“Mechanisms of axon degeneration and neuroprotection in chemotherapy-induced peripheral neuropathy”

Peripheral neuropathy is the principal dose-limiting adverse reaction of the major frontline chemotherapeutic agents such as vincristine. Neuropathy can be so disabling that many patients will drop out of potentially curative therapy. The hallmark of vincristine peripheral neuropathy is axonopathy. Based on this premise, we developed a comprehensive drug discovery pipeline to identify neuroprotective agents against vincristine-induced axon degeneration. Among the hits identified, molsidomine prevents vincristine-induced axon loss in both motor and sensory neurons, and it does so without compromising vincristine anti-cancer potency. This study opens the way to further investigations of molsidomine as a therapeutic agent to prevent vincristine-induced peripheral neuropathy.

Emily Lowry, PhD
“Targeting MAP4 kinase networks to prevent motor neuron degeneration in ALS”

While the clinical manifestations of different neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS) vary widely, many of these disorders share a common feature at the cellular level: the accumulation of misfolded proteins. If left unchecked, misfolded proteins can trigger cell death through a series of pathways linked to endoplasmic reticulum (ER) stress.

We developed an in vitro model of ER stress in human stem cell-derived motor neurons, the neuronal subtype that is selectively vulnerable to degeneration in ALS. By screening for compounds that could prevent ER stress-mediated neurodegeneration, we identified a series of kinase inhibitors that shared the same targets. Genetic ablation of these targets in motor neurons confirmed their role in cell death. We then developed a safe and brain-penetrant compound that could better inhibit these targets, and found that it promotes functional improvements in the phenotypes of ALS model mice.

Part IV
Bioinformatics & Modeling Disease
Session Moderator: Estela Area Gomez, PhD
Hemali Phatnani, PhD
“An integrative multi-omics approach to reveal disease mechanisms in ALS-FTD”

At the New York Genome Center (NYGC), I direct the Center for Genomics of Neurodegenerative Disease (CGND), which has three main goals: 1) To serve as the hub of collaborative interactions between clinicians, computational biologists, and basic scientists; 2) To establish a research program aimed at understanding intercellular interactions in neurodegenerative disease; and 3) To build and disseminate tools and resources for the neurodegenerative disease research community. I will continue these activities as a member of the faculty in the Department of Neurology at Columbia University Irving Medical Center. In my talk, I will briefly outline each of these goals in the context of my work on the clinical spectrum of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD), but our approach can be applied to any neurodegenerative disease. My research program focuses on using novel tools and technologies in conjunction with cellular and animal models and patient-derived tissue samples to understand how disease-causing mutations perturb the intricate interplay between glial and neuronal cells in ALS. To understand the role of intercellular interactions in disease, we are applying Spatial Transcriptomics to deconvolve both spatial and cell-type specific gene expression changes across entire brain or spinal cord regions from rodent and human post-mortem tissue. We are pioneering novel computational and analytical tools specifically tailored to overcoming the unique analytical challenges associated with such complex data sets. We have also developed image acquisition and analytical tools to study finer details in the CNS. Finally, we are using CRISPR technology in combination with ribosome profiling to manipulate patient-derived cells to specifically interrogate disease-associated mechanisms in various cell types implicated in disease.

Soojin Park, MD, FAHA
“Computational approaches to detection of subclinical events in critically ill neurologic patients”

Applying time series analysis and machine learning to physiologic data, I seek to discover informative signals of subclinical states. My goal is to transform these signals into clinical decision supports that can support timely decision making and improve outcome for severely brain injured patients. Projects include heart rate variability as a biomarker to detect neurocardiogenic injury, intracranial pressure morphology to detect ventriculitis, and cardiopulmonary vital signs to predict delayed cerebral ischemia in subarachnoid hemorrhage.  

Vilas Menon, PhD
“Identifying potential cell type-specific dysregulation in Alzheimer’s Disease using single-nucleus RNA-seq”

Alzheimer’s disease (AD) is a progressive disease defined by the accumulation of pathology and manifests symptomatically with behavioral changes and cognitive decline. Although the ultimate cellular outcome is neurodegeneration and neuronal death, many cell types have been implicated in the progression of the disease. Here, we use single-nucleus RNA-sequencing to examine changes in cell type signatures and putative interactions in an unbiased way, at high resolution, in donors with and without AD. We identify multiple non-neuronal cell types with changes in molecular signatures associated with AD, thereby furthering our understanding of the putative role of these subtypes in this disease.

Fabio Iwamoto, MD
“Predictors of response to PD-1 inhibitors in gliomas”

Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders.

Part V
Session Moderator: Jennifer Gelinas, MD, PhD
Jose Gutierrez, MD, MPH
“Beyond atherosclerosis: brain arterial dilatation as a novel imaging biomarker of cerebrovascular disease”

The focus of my research is non-atherosclerotic brain arterial aging and how it relates  to cerebrovascular disease and Alzheimer disease. My objective is to broaden the spectrum of what is traditionally considered large artery disease to include non-atherosclerotic forms of arterial aging as a novel imaging biomarker of cerebrovascular disease. The overall hypothesis is that  brain arterial aging accelerates brain parenchyma degeneration and it may influence the risk of Alzheimer disease via capillary disruption, neuroinflammation and/or amyloid/tau altered metabolism. Also, non-atherosclerotic brain arterial aging increases mechanical sheer forces on penetrating arteries and relates similarly to lacunar infarcts.

Eliza Miller, MD
“Cerebrovascular complications of preeclampsia: the maternal brain at risk”

Preeclampsia, a multisystem disorder occurring in 3-8% of pregnancies, causes hypertension during the second half of pregnancy and widespread endothelial dysfunction. Preeclampsia increases maternal stroke risk up to 6-fold. Most deaths in preeclamptic women are due to intracerebral hemorrhage, usually in the first 2 weeks postpartum. However, we have no tools to predict which women with preeclampsia are at highest risk for postpartum stroke. In collaboration with Columbia’s Division of Maternal-Fetal Medicine, I am investigating mechanisms of postpartum neurovascular dysfunction in women with preeclampsia, aiming to identify biomarkers and develop prediction tools to reduce neurological maternal morbidity and mortality.

Saptarshi Biswas, PhD
“Neuronal activity regulates angiogenesis and barriergenesis in the retina”

We investigated whether retinal glutamatergic synaptic activity modulates angiogenesis and vascular barriergenesis. Glutamatergic wave occurs in the retina from P10-P14 via glutamate released by bipolar cells. At the same time, photoreceptors release glutamate in the absence of light. We show that Vglut1-/- (a transporter essential for glutamate release retina) retina exhibits delayed deep plexus angiogenesis in the retina, due to reduced endothelial cell proliferation. Vglut1-/- retina also exhibits disrupted paracellular barrier integrity, as seen by increased tracer leakage. In contrast, raising wild type (WT) pups in the dark results in hyper-angiogenesis and precocious paracellular barrier maturation.  

Sachin Agarwal, MD, MPH
"Identifying Novel Targets for Reducing Secondary Cardiovascular and Psychological Risk in Cardiac Arrest Patients"

Recent advances in treatment for cardiac arrest (CA) have allowed patients to survive neurologically intact, but 1 in 3 screens positive for PTSD symptomatology at hospital discharge, which may increase the risk for non-adherence to healthy behaviors, secondary cardiovascular events, and mortality. There are currently no clinical practice guidelines for identifying or treating psychological consequences of CA, because there is currently little evidence to guide clinicians.  Here, we have identified novel, modifiable upstream targets for reducing psychological distress related to cardiac anxiety, and improving secondary cardiovascular risk. Further, through my experience in establishing the first-of-kind NeuroCardiac Comprehensive Care Clinic here at Columbia, I will discuss first steps toward standard psychosocial interventions to improve event-free survival in CA.