Annual Neurology Research Retreat
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: Stroke
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(link is external), 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.
Part I: Child Neurology: Growing
Sylvie Goldman, PhD
“Research in Autism in Child Neurology: Understanding Motor Manifestations through Kinematics and Neuro-Modulation”
Although not listed among the core diagnostic criteria of autism spectrum disorder (ASD), motor abnormalities are highly prevalent (>85%) in children with ASD. Research by my team and others suggests that these motor signs may be among the earliest and strongest predictors of later ASD diagnosis in high-risk siblings (children with an older sibling with ASD). Motor behaviors are culture-free, observable early in development, and quantifiable using novel, child-friendly, wearable technology. Moreover, these behaviors provide insight into the brain mechanisms underlying ASD and the developmental trajectory.
In collaboration with a physical therapist and mechanical engineer, we have been developing precise quantifiable measures of two specific motor behaviors, stereotypies and gait. Due to common disrupting behaviors presented by children with ASD, it is often challenging to obtain accurate measures of their motor performance. Thus, building on our previous findings, which showed how features of hand stereotypies can help differentiate Rett Syndrome from ASD, we are working to refine the ASD phenotype for further genotype/phenotype research.
Most recently, we have put together a "Big Idea" research group, comprised of faculty from child neurology, movement disorders, epilepsy, electrical bioengineering, and neurosurgery, to develop translational hypotheses aimed at assessing neuro-modulation and deep brain stimulation as treatments for the life-threatening, self-injurious behaviors in young adults with ASD.
Jennifer Gelinas, MD, PhD
"Development of Interictal Neural Networks: Implications for Epilepsy and Cognition"
Interictal epileptiform discharges (IEDs) are a prominent feature in the neural activity of patients with epilepsy. IEDs are commonly used as indicators of spreading epileptogenesis. They are implicated in the development of cognitive impairment and can induce cortical oscillations in anatomically remote brain regions. How IEDs interact with brain rhythms across distributed neural networks and throughout brain development remains poorly elucidated. We study the effects of IEDs on large-scale cortical networks, from the neonatal period to adulthood. Using intracranial EEG data from patients with epilepsy, we found that IEDs couple with sleep spindles across diverse brain regions, extending the anatomical influence of IEDs beyond the local network. We also perform in vivo neurophysiological recordings from mouse pups (aged postnatal day 5 to 14) exhibiting mutations associated with pediatric epileptic encephalopathies, including KCNT1 and dynamin 1. Our high spatiotemporal resolution neural interface devices allow us to map the epileptic network in these animals. We have identified focal IEDs and distinct electrographic seizure patterns that resemble those observed in children with these genetic abnormalities. Overall, we aim to better understand how the aberrant neurophysiologic activity associated with epilepsy perturbs normal development of cortical networks and leads to deficits in cognition.
Jacqueline Montes, PT, EdD, NCS
"Estimating Muscle Oxygen Consumption During Exercise Using Near Infrared Spectroscopy (NIRS) in Ambulatory Patients with Spinal Muscular Atrophy"
Spinal Muscular Atrophy (SMA) is a progressive, recessive neuromuscular disease characterized by weakness and muscle atrophy due to spinal cord motor neuron loss. Individuals with milder SMA phenotypes can walk independently but their residual weakness causes gait impairments, reduced endurance, and fatigue. Ambulatory patients with SMA have a marked reduction in oxidative capacity and a blunted conditioning response to exercise. In contrast, other neuromuscular conditions derive significant benefit from exercise programs of aerobic conditioning. There has been laboratory evidence to suggest that the molecular mechanisms underlying mitochondrial biogenesis may be vulnerable to SMN deficiency.
This project incorporates near-infrared spectroscopy to estimate muscle oxygen consumption during a ramped cardiopulmonary exercise tolerance test in SMA patients, as well as age matched disease and healthy controls. Other clinical measures of function and strength, as well as Dual Energy X-ray Absorptiometry, to measure lean body mass are also included. A reduction in muscle oxygen consumption disproportionate to lean mass would further support evidence of mitochondrial depletion in SMA. Targeted therapeutic treatments, in combination with exercise, may be needed to address the apparent disturbance in mitochondrial biogenesis and permit optimal aerobic conditioning effects.
The More You Know
James Noble, MD, MS
"Old SCHOOL (Seniors Can Have Optimal Aging and Ongoing Longevity) Hip Hop”
Alzheimer’s disease and related dementias are common among elderly individuals, become more prevalent with age, are medically refractory, reduce life expectancy, and diminish quality of life for patients and their caregivers. Cultural barriers to AD diagnosis exist and are potentially modifiable. Interventions that target younger generations may shift cultural perceptions and improve acceptance of AD and reduce barriers to early diagnosis. Emerging evidence suggests that early cognitive impairment may have modifiable or preventable components and a combination of medical and lifestyle interventions may delay or reduce cognitive decline, particularly when delivered early in the course of disease. Health literacy, including perceptions of cognitive aging and awareness of possible modifiable determinants, could be unrealized barriers to diminishing the health disparity of AD. Youth education programs focused on AD could increase community AD awareness, improve AD literacy of parents and grandparents of AD-literate children, shift cultural perceptions of AD to improve its acceptance, and reduce barriers to early diagnosis. Such an approach could uniquely engage minority populations who are least engaged and at greatest risk for AD.
“Old SCHOOL (Seniors Can Have Optimal aging and Ongoing Longevity) Hip Hop” is a validated model using a brief, multimedia, culturally tailored intervention designed to teach minority children key AD signs and symptoms, and actions taken when AD is recognized, which is early clinical evaluation by a physician. Twenty schools (with 3000 total students) will be randomly assigned to either the OSHH intervention arm or attentional control. This program will test the hypotheses that the program will lead to significant improvement of dementia knowledge in parents, and that gains are influenced by child knowledge, the degree of child-parent communication about the topic, and socioeconomic status. The program is additionally designed to create a novel, brief “dementia action test” to fulfill a critical missing tool for efficiently assessing AD recognition and behavioral response.
The Peripheral Nervous System: Front and Center
Hasan Orhan Akman, PhD
"Can Inhibition of Glycogen Synthesis be a Treatment for Glycogen Storage Diseases?"
Adult Polyglucosan Body Disease (APBD) is a late-onset disease caused by the intracellular accumulation of polyglucosan bodies, formed due to glycogen branching enzyme (GBE) deficiency. To find a treatment for APBD, we screened 1700 FDA-approved compounds in fibroblasts derived from an APBD modeling Gbe1-knock-in mice. Capitalizing on fluorescent periodic-acid Schiff reagent which interacts with polyglucosans in the cell, this screen discovered that the flavoring agent Guaiacol can lower polyglucosans, a result also confirmed in APBD patient fibroblasts. Biochemical assays using purified muscle glycogen synthase (GYS1) proved that guaiacol decreases basal and glucose-6-phosphate stimulated GYS1 activity. In cell lysates, Guaiacol also increased inactivating GYS1 phosphorylation and phosphorylation of the master activator of catabolism, the AMP-dependent protein kinase. Guaiacol treatment in the APBD mouse model rescued grip strength and a shorter lifespan. These treatments had no adverse effects except making the mice slightly hyperglycemic, possibly due to the reduced liver glycogen levels. Also, guaiacol corrected penile prolapse in aged Gbe1-knockin mice. Interestingly, despite its curative effect, Guaiacol reduced polyglucosan in the liver and heart only which apparently are not pertinent to neurological damage in APBD. Our results form the basis to use Guaiacol as a treatment and prepare for the clinical trials in APBD.
Joriene de Nooij, PhD
“Sensory Control of Movement”
Proprioceptive sensory feedback is an integral element of motor control. By providing the CNS with a representation of limb and body position, muscle feedback is critical in the planning and adjustment of motor output. Consequently, the absence of this somatic sense, as in large caliber sensory neuropathy (Friedreich’s Ataxia, CIPN, MS, DM), severely impacts overall quality of life. Effective treatment options are limited, due in part to our poor understanding of the molecular basis of the development and maintenance of proprioceptive sensory neurons, and a lack of adequate model systems to evaluate neuroprotective molecules.
We previously identified two molecular markers that uniquely distinguish MS and GTO afferent proprioceptors from other classes of spinal sensory neurons (de Nooij et al, 2013). This enabled us to develop new intersectional genetic approaches to label and purify these neurons for transcriptome analysis. Bulk and single cell RNAseq analysis reveals that proprioceptors undergo extensive molecular changes during their development, and that their subtype maturation may in part depend on extrinsic target-derived signals – a new concept in the field. In addition, our studies begin to identity the molecules that distinguish between MS and GTO afferent subclasses, thus providing genetic access to study their circuitry and role in motor control under normal and pathological conditions. Complementing our in vivo mouse models, we developed new in vitro approaches to differentiate human proprioceptors from embryonic and pluripotent stem cells to model large caliber sensory neuropathy, and to advance new therapeutic strategies using high-throughput drug screening approaches.
Jinsy Andrews, MD, MSc
"Skeletal Muscle Activators as a Potential Treatment for Amyotrophic Lateral Sclerosis (ALS)"
Reldesemtiv, is a selective small molecule fast skeletal muscle troponin activator (FSTA) that sensitizes the sarcomere to calcium by increasing the affinity of troponin for calcium. Reldesemtiv has been shown to increase the force generated by the tibialis anterior muscle versus placebo in response to nerve stimulation in a dose-, plasma concentration-, and frequency-dependent manner in healthy volunteers and has potential in the treatment of amyotrophic lateral sclerosis (ALS). In phase 1 studies in healthy volunteers, reldesemtiv showed a greater pharmacodynamic effect at lower plasma concentrations and a more favorable tolerability profile relative to tirasemtiv, a FSTA of an unrelated chemical structural class. This is a potential novel approach to treating ALS. An international phase 2 clinical trial is underway in patients with ALS.
Seize the Brain
Melodie Winawer, MD, MS
Somatic variants cause epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants underlie a wider range of focal epilepsy, including non-lesional focal epilepsy (NLFE). Through genetic analysis of resected brain, we assessed somatic variation in focal epilepsy with and without MCD.
We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD.
We observed somatic variants in five cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in brain, not leukocytes, in 3/18 individuals (17%) with NLFE, with variant allele frequencies (VAFs) in brain DNA of 2-14%. Pathology revealed focal cortical dysplasia type Ia (FCD1a) in 2/3. In MCD, brain nonsynonymous variants in SCL35A2 were detected from two individuals with intractable epilepsy, developmental delay, and MRI suggesting FCD, with VAFs of 19-53%. However, FCD1a was not found on MCD pathology.
Somatic variants in SLC35A2 explain a significant fraction of NLFE, largely unexplained previously, as well as focal MCD, previously linked to somatic mutation only in PI3K-AKT-mTOR pathway genes. This suggests and important role for glycosylation defects in intractable epilepsies
Part II: Neuroinflammation: Brains on Fire
Wassim Elyaman, PhD
"Influence of MS Genetic Risks on Adaptive Immunity"
Multiple sclerosis (MS) is a T cell-mediated CNS autoimmunity. It is suggested that MS is caused by the interaction of genetic and environmental factors. While genome-wide association studies (GWAS) have identified over 110 MS susceptibility loci, the molecular events leading to the onset of MS remain largely unknown and are untargeted therapeutically. Here, we have characterized the rs6908428 single nucleotide polymorphism (SNP) that is robustly associated with MS susceptibility (p=1.8 x 10-20), and located near the transcription start site (TSS) of the Abelson helper Integration site 1 (AHI1). We characterized the chromatin state of T cells in the MS-associated AHI1 linkage disequilibrium (LD) block. The expression and the role of the AHI1 variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of AHI1 was explored using T cells from Ahi1 knockout mice. We found that Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, p = 1.65 × 10-13), overlaps with strong enhancer regions that are present in human naive and memory CD4+ T cells. Relative to the rs4896153A protective allele, the rs4896153T susceptibility allele is associated with decreased AHI1 mRNA expression, specifically in naive CD4+ T cells (p = 1.73 × 10-74, n = 213), and we replicate this effect in an independent set of subjects (p = 2.5 × 10-9, n = 32). Functional studies then showed that the rs4896153T risk variant and the subsequent decreased AHI1 expression were associated with reduced CD4+ T cell proliferation and a specific differentiation into interferon gamma (IFNγ)-positive T cells when compared with the protective rs4896153A allele. This T cell phenotype was also observed in murine CD4+ T cells with genetic deletion of Ahi1. Our findings suggest that the effect of the AHI1 genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ+ T cells that have previously been implicated in MS and its mouse models.
Dritan Agalliu, PhD
"Elucidating the Mechanisms of CNS Entry and the Role of Th17 Cells in Post-Infectious Autoimmune Basal Ganglia Encephalitis"
Group A Streptococcus (GAS) infections in children cause autoimmune basal ganglia encephalitis (BGE) that manifests with either motor [Sydenham’s chorea] or psychiatric [Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)] symptoms. Autoantibodies that recognize neuronal targets are found in sera from SC/PANDAS children. These autoantibodies elicit behavioral abnormalities when infused into rodent brains or administered intravenously (i.v.) to rodents. We have shown that an intranasal (i.n.) route of GAS infection leads to production of Th17 cells in nasal-associated lymphoid tissue. Th17 cells migrate from the nose into the brain and their presence correlates with BBB breakdown, extravasation and brain deposition of antibodies, microglia activation and synaptic dysfunction. Here, we examine the mechanisms by which GAS-specific Th17 cells enter the CNS in mice and determine the role that Th17 cells and autoantibodies play in BBB damage, neuroinflammation and circuit dysfunction.
We find that two chemokines are expressed in the olfactory epithelium and bulb when Th17 cells enter the CNS. We are currently testing the role that these chemokines play in this process using genetic studies in mice. We find that genetic ablation of two chemokine receptors that bind to chemokines upregulated in the CNS leads to a significant reduction in T cell entry into the CNS. Using mice that lack Th17 cells and undergo GAS infections, we find that, although the number of T cells is reduced, Th1 cells enter the CNS and produce neurovascular and synaptic damage. In conclusion, Th17 and Th1 cells are both important for disease pathogenesis in post-infectious BGEs.
Amelia Boehme, PhD, MSPH
Infection, particularly severe infection, has been identified as a potential risk factor or trigger for stroke. Our recent analyses of administrative datasets has identified sepsis as a risk factor for stroke. However, while there is a low absolute risk of stroke post sepsis, those who are at risk remain at risk up to a year after their sepsis event. We found that younger people have a higher risk of stroke after surviving their sepsis event. Additionally, racial disparities in sepsis and stroke have been identified, with Black patients twice as likely to develop sepsis or stroke as white patients. Prior research has found that even while adjusting for poverty or medically underserved areas, Black patients remain at higher risk of both sepsis and stroke, indicating a link between racial and geographic disparities with sepsis and stroke. Additional novel risk factors such as inflammation and more common infections, including influenza like illness (ILI), or environmental exposures, such as air pollution, are known to be risk factors for stroke. Moreover, ambient air pollution increases the risk of ILI, suggesting the potential for air pollution triggering an ILI event, which then subsequently triggers a stroke event. Racial disparities are highly prevalent in not only the levels of air pollution, but also in the health effects of air pollution, as well as having a major role in the risk of ILI, stroke. Racial and ethnic minorities are at higher risk to be exposed to high levels of air pollution, and are at higher risk for infections, and stroke. We are investigating these relationships in a number of administrative datasets to determine the direct and indirect effects of each of these exposures on the risk of stroke.
Marta Olah, MSc
Poster Platform: "A Single Cell-Based Atlas of Human Microglial States Reveals Associations with Neurological Disorders and Histopathological Features of the Aging Brain"
Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.
Jose Gutierrez, MD, MPH
Poster Platform: "Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and Dementia"
There is ample evidence that relates vascular disease to Alzheimer disease, and the vascular contributions to cognitive decline and dementia are a national research priority. The field has long focused on atherosclerosis and stenosis as the sole contributors to cerebrovascular health, however. We believe that brain arterial dilatation may also be deleterious to brain health. Consequently, in our research proposal we propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates brain arterial dilatation as a distinct pathological phenotype. In Aim 1, we will define genetic loci that relate to brain arterial dilatation in >5,000 participants of four well-characterized, population-based studies with longitudinal follow-up who also have neuroimaging and cognitive assessments. In Aim 2, we will establish the hemodynamic consequences of brain arterial dilatation by relating it to cerebral blood flow velocities and autoregulation. In Aim 3, we will first confirm the relationship between brain arterial dilatation with cognitive performance and risk of dementia. We will then perform a modification analysis using genetic loci related to brain arterial dilatation and measures of autoregulation as presumed effect modifiers. At the conclusion of these studies, we will definitively establish a role for brain arterial dilatation in cognition and dementia.
Adam M. Brickman, PhD
"White Matter Hyperintensities and Alzheimer’s Disease: In Media Res"
Recently-published diagnosed criteria for Alzheimer’s disease (AD) require biomarker evidence of amyloid and tau pathology without consideration of clinical symptomatology. These criteria have been criticized for many reasons, one of which the lack of consideration of other pathological factors that may contribute to disease pathogenesis and clinical presentation. Small vessel cerebrovascular disease, best visualized as white matter hyperintensities (WMH) on MRI scans, commonly co-occurs with AD pathology and has been hypothesized to be a core feature of the disease. Over the past several years, we have been studying the role of WMH in AD. Our work has shown that individuals with prevalent AD and who are at risk for AD have elevated WMH volumes, particularly in posterior brain regions. Longitudinal analyses showed that increasing posterior WMH volumes predict clinical conversion from non-dementia status to AD dementia and recent work in individuals with autosomal dominant, fully-penetrant genetic mutations for AD have elevated WMH volumes in posterior brain regions up to 20 years prior to the estimated time of symptom onset. These WMH increases interact with amyloid pathology, such that those with biomarker evidence of amyloid are much more likely to manifest symptoms if they also have elevated WMH. Our work over the past several years establishes WMH as a core feature of AD. We are currently engaged in a number of projects that seek to understand whether WMH plays an additive role in the expression of AD or whether it is more causally or mechanistically related to AD per se. Our initial findings suggest that WMH potentiate tau-related neurodegenerative changes independently of amyloid. We have used a murine transient hypoperfusion model of WMH, which, on initial analysis, parallels our human observations: hypoperfusion induces tau hyperphosphorylation in APP and wild type mice. In fact, APP mice do not appear to manifest tau pathology without hypoperfusion perturbation. Our work will continue to establish the role of small vessel cerebrovascular disease in AD using translational neuroscientific approaches.
Badri Vardarajan, PhD, MS
ADSP-FUS (PI- Pericak-Vance [Miami], Vardarajan and Mayeux)
The Alzheimer’s Disease Sequencing Project (ADSP) is a national sequencing initiative focused on identifying genetic risk and protective variants for late onset Alzheimer disease (LOAD) in an effort to identify new pathways for prevention and new targets for drug development. The ADSP’s discovery phase included whole exome sequencing (WES) of 10,914 unrelated cases (N=5,778) and controls (N=5,136) (10,571 were Non-Hispanic White (NHW) and only 343 were Hispanic (HI)), and whole genome sequencing (WGS) of 1,019 familial samples (NHW (N=551) and HI (N=468)). The ADSP Replication Working Group met and a ‘Follow-Up Study’ (FUS) Phase was outlined and focused on confirming candidate variants from the discovery phase, and identification of novel variants through combined analysis of diverse datasets. The working group recommended that the highest priority for inclusion in the FUS WGS phase be given to new cohorts with unrelated LOAD cases that‘encompass the richest possible ethnic diversity’. To fulfill the goals of this RFA, we have identified several existing cohorts of African-American (AA) and pan-HI ancestry that specifically addresses this FUS Phase mandate. The cohorts include 2,322 AA LOAD cases and 1,843 AA controls and 2,928 HI LOAD cases and 2,875 HI controls from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, the Northern Manhattan Study (NOMAS), the Research in African-American Alzheimer’s Disease Initiative (REAAADI), the Mexican Health and Aging Study (MHAS), the Puerto Rican 1066 Study, the Puerto Rican Alzheimer’s Disease Initiative (PRADI), and the Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) study. We will also incorporate existing WGS from the Multi-Ethnic Study of Atherosclerosis (MESA) (~171 AA cases and ~171 AA controls; ~155 HI cases and ~155 HI controls). In total we have 10,430 samples identified for the FUS. Combining these cohorts with existing sequencing from the Washington Heights-Hamilton Heights-Inwood Community Aging Project (WHICAP), the Alzheimer’s Disease Genetics Consortium (ADGC) and the ADSP will provide large ethnically diverse datasets for both validation and generalization of ADSP discovery phase findings and discovery of novel risk and protective variants/genes for LOAD. Additionally, these datasets will become an invaluable resource for the AD research community at-large.
PR AD Initiative (PRADI) (PI- Pericak-Vance/Beecham [Miami], CU Site-PI, Vardarajan)
With over 5 million individuals, the Puerto Rican (PR) population makes up over 1.5% of the US population, and is the 2nd largest Hispanic/Latino population in the continental US. The prevalence of AD in the Caribbean Hispanic population of the island of PR is estimated in 65,000. Yet genetic studies have been limited to a few rare families with PSEN mutations. The PR population is highly admixed, with average ancestry values of 64% European, 21% African, and 15% Native American, but individual ancestries are highly variable. The unique genetic make-up of the PR AD population will be critical in new discovery, as well as in replication of findings from the ADSP Caribbean Hispanic data and the Alzheimer’s Disease Genetics Consortium (ADGC) AA data. Our hypothesis is that AD risk in the PR population is due both to race/ethnic-specific genetic factors, as well as genetic risk factors across multiple populations. Thus, discovery of genetic contributions to AD risk and protective variants in PR HI would have a substantial influence on our understanding of AD, and our goal of identifying new treatment targets. Through this proposal in response to PAR-15-356 we will address this important issue by conducting genomic studies of AD in PR. Specifically we propose a family-based study in PR that parallels the family-based efforts in the ADSP Discovery phase and that will enhance and extend both current ADSP and ADGC efforts to a broader AD community.
Christiane Reitz, MD, PhD
"Genetics of Early-Onset Alzheimer’s Disease and Alzheimer’s Disease in African Americans"
Mutations in APP, PSEN1 and PSEN2 explain less than 10% of early-onset Alzheimer’s Disease (EOAD) cases and few studies have been performed using subjects and families with EOAD without clear Mendelian inheritance patterns. The few studies that have assessed this EOAD subtype have suggested that the genetic architectures overlap with the late-onset form, but only partially. Thus, studying EOAD in subjects without APP, PSEN1 and PSEN2 mutations (i.e. unexplained EOAD) is a critical gap that provides a unique opportunity for discovery of novel targets and pathways. To begin addressing this issue, in collaboration with Dr. Gary Beecham from the University of Miami, we are assembling the Resource for Early-onset Alzheimer’s Disease Research (READR), an initiative that ascertains and whole-genome sequences multiplex families with unexplained EOAD from various ethnic groups.
A second focus of research that I am pursuing is the identification of genetic risk factors underlying Alzheimer’s Disease in African Americans. African Americans have a higher prevalence of dementia than non-Hispanic Whites but are significantly underrepresented in research studies. Through the REAAADI initiative, a project performed in collaboration with the Universities of Miami and North Carolina A&T, we are collecting multiplex African American families with Alzheimer’s disease, who are then thoroughly phenotyped and whole-genome sequenced for variant discovery.
Shaking it Up
Un Kang, MD
The focus of my research is understanding basal ganglia plasticity in Parkinson’s disease (PD), to explore neurorestorative therapy. We focus on a component of L-DOPA’s anti-parkinsonian response, known as the long-duration response (LDR), that occurs in the scales of days to weeks. We are testing the hypothesis that gradual motor impairment during LDR decay is task specific and results from aberrant long-term potentiation (LTP) in specific ensembles of indirect pathway medium spiny neurons, which are normally suppressed but become pathologically active during task exposure if dopamine (DA) is depleted. Another aspect of motor fluctuation is excessive abnormal involuntary movements that develop over several years of treatment. We utilize chemogenetic and optogenetic modulation of the striatal cholinergic neurons and circuitry involving substantia nigra pars reticulata to study their functional effects. We also employ transcriptomic analysis to find potential mechanisms of altered activity and therapeutic targets. Understanding the changes in specific cell types and connectivity between the basal ganglia structures will help us to design new approaches that overcome the limitation of current pharmacological therapy that targets the whole brain, and the current deep brain stimulation (DBS) that targets anatomical structures and passing fibers without discriminating circuit and cell type specificity.
Session I: Neuroimmunity
Moderated by Dr. Hynek Wichterle
Phil De Jager, MD, PhD
“Dissecting the Cell Population Structure of the Aging Brain at the Single Cell Level”
The Center for Translational & Computational Neuroimmunology has several different data and experimental resources that are available to the community to drive collaborations. Working with colleagues at RUSH University who have developed and maintained superb cohort studies of aging subjects, we have generated multiple layers of “omic” data from frozen brain on up to 1000 brains. Data generation has focused on the dorsolateral prefrontal cortex with RNA sequencing, H3K9Acetylation with sequencing, DNA methylation (Illumina 450), miRNA (Nanostring) data available currently. In 2018, new data will come online: RNAseq from posterior cingulate and head of the caudate, ATACseq from dorsolateral prefrontal cortex neuronal nuclei, shotgun proteomics with up to 800 proteins, and RNAseq profiles from peripheral monocytes. I shared some of the sources of variation that we have mapped in these data, including effects of diurnal and seasonal rhythms, genetic variation, and alternative splicing. In the context of genetic variation, we have shown that some variants affect the epigenome, and their effect is propagated into the transcriptome. We have also established a pipeline for extracting live microglia from human autopsy material, which has been used to generate RNAseq and proteomic data from these cells. In addition, we have now generated single microglia RNAseq profiles using the 10x platforms in 11 individuals - gray and white matter. Further, we are optimizing, with colleagues at the Broad Institute, a protocol for Drop-seq on single nuclei. This protocol is working and is now being applied in 100 subjects to generate single nucleus profiles of the frontal cortex and deep frontal white matter.
Wendy Vargas, MD
“Is the Symbol Digit Modalities Test a Sensitive Predictor of Academic Outcomes in Pediatric MS”
Cognitive impairment occurs in 30 to 50% of children and adolescents with multiple sclerosis (MS). The consequences of cognitive disability in adults with MS are well documented, however, little is known regarding the functional impact of cognitive impairment in children with MS. To our knowledge, no study has examined the concordance of performance on standard neuropsychological (NP) measures and academic achievement in children with MS.
We evaluated whether the Symbol Digit Modalities Test (SDMT) and other NP tests are related to academic achievement in a pilot sample of children and adolescents with MS. Our soon-to-be-published results suggest that SDMT, though a widely used screening measure for detection of cognitive impairment in pediatric MS, is not an effective screening measure for academic achievement in this pilot sample. Future longitudinal work in larger samples is needed to determine whether standard neuropsychological tests adequately capture/predict decrements in academic achievement in children with multiple sclerosis.
Tyler Cutforth, PhD
“Mechanisms of Immune Cell Entry into the CNS During Autoimmune Encephalitis”
Streptococcus pyogenes infections are associated with two autoimmune diseases of the nervous system: the movement disorder Sydenham’s chorea and the neuropsychiatric syndrome PANDAS. This bacterium is known to induce autoreactive, mimetic antibodies against several targets in the CNS and other tissues. Delivery of antibodies into the mouse brain induces behavioral and motor deficits similar to those in PANDAS patients. We have shown that intranasal S. pyogenes infections lead to an antigen-specific Th17 cell response in the nasal-associated lymphoid tissue (NALT), a functional analog of human tonsils/adenoids. Repeated infections drive those cells towards an IL-17+ IFN-g+ phenotype that has been implicated in BBB breakdown. Moreover, repeated infections promote entry of S. pyogenes-specific T cells into the olfactory bulb and other CNS regions. We also find microglial activation and barrier breakdown in close proximity to CNS-infiltrating T cells, as measured by leakage of both serum IgG and the tracer biocytin-TMR, as well as disruption of endothelial tight junctions. Recently, we have characterized the immune response from both PANDAS patients and S. pyogenes-infected mice towards brain endothelial cell antigens and the D1R and D2R dopamine receptors. Our findings provide novel insight into how recurrent Streptococcus infections impair brain function and suggest a general mechanism by which infectious agents that induce Th17 immunity exacerbate other CNS autoimmune diseases to provoke long-term neurovascular damage.
Amelia Boehme, PhD, MSPH
“Systemic Inflammatory Response Syndrome and Stroke”
Systemic Inflammatory Response Syndrome (SIRS) has been recognized as a risk factor for poor outcomes in patients with non-neurological critical illness, and subarachnoid hemorrhage. SIRS, and its components, has been identified as a devastating complication related to cardiovascular disease outcomes, particularly stroke outcomes, with stroke patients with SIRS having worse functional outcomes and poor discharge dispositions. The prevalence of SIRS in ischemic and hemorrhagic stroke patients is similar (20-40%), but has been shown to be lower than the prevalence of SIRS in subarachnoid hemorrhage patients (54-86%). Building on her prior work in small single-center studies, Dr. Amelia Boehme is investigating the relationship between SIRS and infections in ischemic and hemorrhagic stroke patients, and the relationship among SIRS, infections and outcomes in ischemic and hemorrhagic stroke patients using data from multi-center studies.
Session II: Metabolism and the Brain
Moderated by Dr. Ai Yamamoto
Catarina Quinzii, MD
“Molecular Mechanisms of CoQ10 Deficiency in Cerebellar Ataxia”
Autosomal recessive cerebellar ataxias are heterogeneous neurodegenerative diseases, characterized by incoordination of movement and unsteadiness, due to cerebellar dysfunction. Muscle deficiency of coenzyme Q10 (CoQ10), a mitochondrial lipid which functions mainly as an electron carrier in the mitochondrial respiratory chain and as antioxidant in cell membranes, has been reported in 13% of patients with autosomal recessive cerebellar ataxia of unknown molecular etiology. Although cerebellum seems to be selectively vulnerable to low levels of CoQ, the mechanisms underlying CoQ10 deficiency in cerebellar ataxia, and the role of CoQ10 deficiency in the pathogenesis or progression of the disease are undefined. However, CoQ10 supplementation seems to improve or slow down the progression of the disease, suggesting a role of CoQ10 deficiency in the pathogenesis of these diseases. We and other groups reported CoQ10 deficiency in muscle and/or fibroblasts of patients carrying mutations in APTX, encoding aprataxin (APTX), cause of ataxia-oculomotor-apraxia 1 (AOA1). In order to understand the link between cerebellar ataxia and CoQ10 deficiency, we studied APTX mutant and depleted cells. We found reduced expression of the genes involved in CoQ10 biosynthesis, associated with low levels of the transcription factors nuclear respiratory factors 1 and 2 (NRF1/2). Overexpression of NRF1/2 in APTX depleted cells and pharmacological up-regulation of NRF1/2 in patients cells rescued the molecular and biochemical phenotypes. Therefore, we conclude that lack of APTX in vitro causes down-regulation of NRF1/2 and their targets genes, including CoQ10 biosynthetic genes. We hypothesize that 1) lack of APTX in vivo causes tissue-specific mitochondrial abnormalities, which can be rescued by NRF1/2; and 2) reduction of NRF1/2 causes down regulation of CoQ10 biosynthesis and CoQ10 deficiency in inherited cerebellar ataxias, independently of the primary molecular etiology.
Martin Picard, PhD
"Mitochondrial Stress Signal Transduction from Organelle to Organism"
The Picard Lab aims to understand how stress is transduced intracellularly to affect mitochondrial disease progression and aging. We focus on three main areas: 1.Characterizing the effects of psychological, neuroendocrine, and metabolic stressors on mitochondrial morphology and function; 2. Identifying structural mechanisms for mito-to-mito communication, including mitochondrial “synapses” and nanotunnels; and 3. Mapping the effects of mitochondrial signaling on gene expression and cell non-autonomous (i.e., organismal) stress regulation.
Carlos Rueda Diez, PhD and Maoxue Tang, PhD
“The Glut1 Deficiency Syndrome”
Maoxue Tang and Carlos Rueda jointly presented their work on Glut1 deficiency syndrome with the title “Reduced glucose transport to the brain impairs angiogenesis and brain development in the mouse model for Glut1 deficiency syndrome”. As Postdoctoral researchers, they are working on a joint project between the laboratories of Dr. Darryl De Vivo (Neurology Department) and Dr. Umrao Monani (Pathology Department) to uncover the mechanisms of Glut1 deficiency syndrome (Glut1 DS) and develop new therapeutic approaches for this neurological disease that was originally described by Dr. De Vivo here at Columbia University Medical Center (De Vivo et al. NEJM 1991).
Glut1 DS is a severely debilitating neurodevelopmental disorder caused by haploinsufficiency of the SLC2A1 gene. In Glut1 DS patients, brain function is disrupted by the reduced levels of the Glucose Transporter Type 1 (Glut1) protein. But, how the insufficient Glut1 protein results in the Glut-1 DS phenotype is still unclear, and the patients still lack an optimal treatment. Their recent finding (Tang et al. Nat Comm 2017) that Brain angiogenesis is reduced due to decreased glucose transport into the brain in Glut1 deficiency has shed some light on this connection and they are now trying to establish the molecular mechanisms that account for this decreased angiogenesis. Glut1 is the main glucose transporter in endothelial cells and glial cells (Astrocytes and oligodendrocytes), providing glucose to the brain across the blood brain barrier. Glut1 deficiency promotes decreased glucose levels in the brain parenchyma leading to decelerated brain growth and altered neuronal function (Seizures, motor symptoms, intellectual disability). The mechanisms connecting decreased brain glucose levels to these symptoms are not clear, and that’s what we are trying to uncover. Maoxue Tang presented the Glut1 deficient mouse model and the results of a successful and recently published gene therapy approach to treat this mouse model with AAV9-Glut1 (Tang et al. Nat Comm 2017). Carlos Rueda presented unpublished data on the mechanisms leading to decreased microvasculature in Glut1 deficiency by impairment of endothelial and glial cell function.
- Karen Marder, MD, MPH
- “New R01s and Update on Multicentric/Multidisciplinary Initiatives: NeuroNext”
- Mitch Elkind, MD, MS, MPhil
- “Trial Innovation Network”
- Amelia Boehme, PhD, MSPH
- Mu Yang, PhD
- “Mouse Behavior Core”
- Neil Shneider, MD, PhD
- “NIH PMI Cohort Program”
Session III: Neural Circuits
Moderated by Dr. Dritan Agalliu
Rui Costa, PhD
"Starting new Actions and Learning from it"
The ability to decide when to perform and action and what action to perform is critical for survival. Many basal ganglia disorders affect movement initiation. We used deep brain imaging and optogenetics in behaving animals to understand how novel self-paced actions are initiated. Using endoscopic imaging and electrophysiology, we uncovered that transient activity in dopaminergic neurons precedes movement initiation. Using optogenetic manipulations of dopaminergic activity, we showed that dopaminergic activity gates movement initiation. Furthermore, using electrophysiology, endoscopic imaging, and fiber photometry we found that basal ganglia direct and indirect pathways are both active before initiation. Finally, we showed that both direct and indirect pathways are necessary for movement initiation, but have complementary roles. These data invite new models of how basal ganglia circuits modulate movement initiation.
George Mentis, PhD
“Reduced Sensory Synaptic Drive Impairs Motor Neuron Function via Kv2.1 Potassium Channels in Spinal Muscular Atrophy”
Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contribution of their synaptic partners to the disease process is largely unknown. We have shown recently (Fletcher et al, 2017, Nature Neurosci) in a mouse model of spinal muscular atrophy (SMA) that a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing which could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Increasing neuronal activity genetically (by selective restoration of SMN in sensory neurons) or pharmacologically (by chronic exposure in vivo) led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.
Sheng Han Kuo, MD
“Cerebellar Synaptic Pathology in Essential Tremor”
Cerebellar synaptic pathology has been identified in essential tremor (ET) patient brains, however, how this synaptic pathology leads to tremor remains unknown. In collaboration with others, my team established a mouse model with cerebellar climbing fiber (CF) synaptic pathology and this mouse model developed ET-like kinetic tremor. By using optogentics and microinfusion, we showed that the synaptic connections between CFs and Purkinje cells (PCs) are important for the generation of tremor. Interestingly, this mouse model generates oscillatory rhythms coherent with tremor, suggesting that the tremor could be originated from the cerebellar cortex and propagate to the downstream brain regions, leading to tremor. By understanding the tremor circuitry in the brain, we will be able develop better treatment for ET.
Session IV: Modeling Disease
Moderated by Dr. Adam Brickman
Neil Shneider, MD, PhD
“hnRNP H Deficiency in C9orf72-related ALS/FTD”
An expanded GGGGCC hexanucleotide in C9ORF72 is the most frequent known cause of ALS and FTD. I described a series of experiments that demonstrate that the splicing factor hnRNP H is the protein that predominantly associates with the GGGGCC repeat RNA, and results in the dysregulation of alternative splicing of hnRNP H-dependent exons. Our data suggests that hnRNP H deficiency may contribute to neurodegeneration in C9orf72-related ALS and FTD, and perhaps related forms of these disorders.
Stephanie Cosentino, PhD
"Toward a Model of Subjective Cognitive Decline"
There is growing interest in subjective cognitive decline (SCD) as a potential marker of pre-clinical AD. SCD, or the perception that one’s cognition has declined despite “normal” performance on standard diagnostic testing, is an important health outcome that is concerning to many older adults, and leads some to seek medical attention. Determining the extent to which SCD may serve as a pre-clinical marker of AD is of great value, as SCD is non-invasive, inexpensive, and easily obtainable. However, SCD is a complex, multi-factorial construct. In order to determine its true utility as a marker of pre-clinical AD, it is critical to comprehensively characterize the factors that influence SCD, and that affect the degree to which SCD reflects “true” or actual cognitive functioning. Indeed, SCD is certain to reflect not only a person’s actual cognitive functioning, but also task-specific factors (i.e., how SCD is measured) and person-specific factors (e.g., how good one is at self-evaluation; how old one feels; what one believes about aging). Our work examines novel task-specific and person-specific factors that are likely to influence SCD and its association with AD risk.
Frank Provenzano, PhD
“Retrospective Functional Brain MRI: Framework, Feasibility and Applications”
Functional imaging is the focus of my research, primarily through the collection, curation and repurposing of previously acquired clinical scans. I have previously written several algorithms used in identifying selectively vulnerable regions within the hippocampal circuit in neurological and psychiatric disorders. By developing ways to obtain and catalogue existing clinical images, I have developed approaches to process and glean research-derived and potentially clinically informative information from those scans. This approach has led to the development of a system capable of ‘sieving’ from an existing clinical image system and functionally processing these scans. Since contrast enhanced MRI permits extraction of functionally important metrics like Cerebral Blood Volume (CBV), efforts have focused on several patient cohorts with hypothesized functional changes whom would have likely received contrast agent per protocol. This application opens up the possibility of large-scale functional MR analysis and machine learning approaches on millions of scans. While new MR research often focuses on novelty of machinery and pulse sequences, there are a plethora of validated approaches that have not previously been tested on MRI dedicated for clinical use. We are excited to test this new method on significantly larger sample sizes to discover new imaging biomarkers.