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2nd Annual Neurology Research Retreat

June 16, 2017


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.  

Blitz Session:

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.