"CXCR4 involvement in neurodegenerative diseases" (2018) Translational Psychiatry
CXCR4 involvement in neurodegenerative diseases
(2018) Translational Psychiatry, 8 (1), art. no. 73, .
Bonham, L.W.a , Karch, C.M.b , Fan, C.C.c , Tan, C.d , Geier, E.G.a , Wang, Y.e , Wen, N.b , Broce, I.J.d , Li, Y.d , Barkovich, M.J.d , Ferrari, R.f , Hardy, J.f , Momeni, P.g , Höglinger, G.h i , Müller, U.j , Hess, C.P.d , Sugrue, L.P.d , Dillon, W.P.d , Schellenberg, G.D.k , Miller, B.L.a , Andreassen, O.A.e , Dale, A.M.c l , Barkovich, A.J.d , Yokoyama, J.S.a , Desikan, R.S.a , Hernandez, D.G.m , Nalls, M.A.m , Rohrer, J.D.m , Ramasamy, A.m , Kwok, J.B.J.m , Dobson-Stone, C.m , Schofield, P.R.m , Halliday, G.M.m , Hodges, J.R.m , Piguet, O.m , Bartley, L.m , Thompson, E.m , Haan, E.m , Hernández, I.m , Ruiz, A.m , Boada, M.m , Borroni, B.m , Padovani, A.m , Cruchaga, C.m , Cairns, N.J.m , Benussi, L.m , Binetti, G.m , Ghidoni, R.m , Forloni, G.m , Albani, D.m , Galimberti, D.m , Fenoglio, C.m , Serpente, M.m , Scarpini, E.m , Clarimón, J.m , Lleó, A.m , Blesa, R.m , Waldö, M.L.m , Nilsson, K.m , Nilsson, C.m , MacKenzie, I.R.A.m , Hsiung, G.-Y.R.m , Mann, D.M.A.m , Grafman, J.m , Morris, C.M.m , Attems, J.m , Griffiths, T.D.m , McKeith, I.G.m , Thomas, A.J.m , Pietrini, P.m , Huey, E.D.m , Wassermann, E.M.m , Baborie, A.m , Jaros, E.m , Tierney, M.C.m , Pastor, P.m , Razquin, C.m , Ortega-Cubero, S.m , Alonso, E.m , Perneczky, R.m , Diehl-Schmid, J.m , Alexopoulos, P.m , Kurz, A.m , Rainero, I.m , Rubino, E.m , Pinessi, L.m , Rogaeva, E.m , George-Hyslop, P.S.m , Rossi, G.m , Tagliavini, F.m , Giaccone, G.m , Rowe, J.B.m , Schlachetzki, J.C.M.m , Uphill, J.m , Collinge, J.m , Mead, S.m , Danek, A.m , Van Deerlin, V.M.m , Grossman, M.m , Trojanowski, J.Q.m , Van Der Zee, J.m , Cruts, M.m , Van Broeckhoven, C.m , Cappa, S.F.m , Leber, I.m , Hannequin, D.m , Golfier, V.m , Vercelletto, M.m , Brice, A.m , Nacmias, B.m , Sorbi, S.m , Bagnoli, S.m , Piaceri, I.m , Nielsen, J.E.m , Hjermind, L.E.m , Riemenschneider, M.m , Mayhaus, M.m , Ibach, B.m , Gasparoni, G.m , Pichler, S.m , Gu, W.m , Rossor, M.N.m , Fox, N.C.m , Warren, J.D.m , Spillantini, M.G.m , Morris, H.R.m , Rizzu, P.m , Heutink, P.m , Snowden, J.S.m , Rollinson, S.m , Richardson, A.m , Gerhard, A.m , Bruni, A.C.m , Maletta, R.m , Frangipane, F.m , Cupidi, C.m , Bernardi, L.m , Anfossi, M.m , Gallo, M.m , Conidi, M.E.m , Smirne, N.m , Rademakers, R.m , Baker, M.m , Dickson, D.W.m , Graff-Radford, N.R.m , Petersen, R.C.m , Knopman, D.m , Josephs, K.A.m , Boeve, B.F.m , Parisi, J.E.m , Seeley, W.W.m , Karydas, A.M.m , Rosen, H.m , Van Swieten, J.C.m , Dopper, E.G.P.m , Seelaar, H.m , Pijnenburg, Y.A.L.m , Scheltens, P.m , Logroscino, G.m , Capozzo, R.m , Novelli, V.m , Puca, A.A.m , Franceschi, M.m , Postiglione, A.m , Milan, G.m , Sorrentino, P.m , Kristiansen, M.m , Chiang, H.-H.m , Graff, C.m , Pasquier, F.m , Rollin, A.m , Deramecourt, V.m , Lebouvier, T.m , Kapogiannis, D.m , Ferrucci, L.m , Pickering-Brown, S.m , Singleton, A.B.m , International FTD-Genomics Consortium (IFGC), International Parkinson’s Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer’s Project (IGAP)m
a Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
b Department of Psychiatry, Washington University, St. Louis, MO, United States
c Department of Cognitive Sciences, University of California CA, San Diego, CA, United States
d Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA, United States
e NORMENT, Institute of Clinical Medicine, University of Oslo, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
f Department of Molecular Neuroscience, Institute of Neurology, UCL, London, United Kingdom
g Department of Internal Medicine, Laboratory of Neurogenetics, Texas Tech University Health Science Center, Lubbock, TX, United States
h Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
i Department of Neurology, Technical University of Munich, Munich Cluster for Systems Neurology SyNergy, Munich, Germany
j Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany
k Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
l Department of Neurosciences and Radiology, University of California, San Diego, CA, United States
Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases. © 2017 The Author(s).
Document Type: Article
"Resting state signal latency predicts laterality in pediatric medically refractory temporal lobe epilepsy" (2018) Child's Nervous System
Resting state signal latency predicts laterality in pediatric medically refractory temporal lobe epilepsy
(2018) Child’s Nervous System, 34 (5), pp. 901-910.
Shah, M.N.a , Mitra, A.c , Goyal, M.S.c , Snyder, A.Z.c d , Zhang, J.a , Shimony, J.S.c , Limbrick, D.D.b , Raichle, M.E.c d e f , Smyth, M.D.b
a Departments of Pediatric Surgery and Neurosurgery, McGovern Medical School at UTHealth, 6431 Fannin St, MSB 5.144, Houston, TX, United States
b Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
f Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
Purpose: Temporal lobe epilepsy (TLE) affects resting state brain networks in adults. This study aims to correlate resting state functional MRI (rsMRI) signal latency in pediatric TLE patients with their laterality. Methods: From 2006 to 2016, 26 surgical TLE patients (12 left, 14 right) with a mean age of 10.7 years (range 0.9–18) were prospectively studied. Preoperative rsMRI was obtained in patients with concordant lateralizing structural MRI, EEG, and PET studies. Standard preprocessing techniques and seed-based rsMRI analyses were performed. Additionally, the latency in rsMRI signal between each 6 mm voxel sampled was examined, compared to the global mean signal, and projected onto standard atlas space for individuals and the cohort. Results: All but one of the 26 patients improved seizure frequency postoperatively with a mean follow-up of 2.9 years (range 0–7.7), with 21 patients seizure-free. When grouped for epileptogenic laterality, the latency map qualitatively demonstrated that the right TLE patients had a relatively early signal pattern, whereas the left TLE patients had a relatively late signal pattern compared to the global mean signal in the right temporal lobe. Quantitatively, the two groups had significantly different signal latency clusters in the bilateral temporal lobes (p < 0.001). Conclusion: There are functional MR signal latency changes in medical refractory pediatric TLE patients. Qualitatively, signal latency in the right temporal lobe precedes the mean signal in right TLE patients and is delayed in left TLE patients. With larger confirmatory studies, preoperative rsMRI latency analysis may offer an inexpensive, noninvasive adjunct modality to lateralize pediatric TLE. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
Default mode network; Functional magnetic resonance imaging; Pediatric epilepsy; Resting state; Temporal lobe epilepsy
Document Type: Article
"Blood-brain barrier disruption and perivascular beta-amyloid accumulation in the brain of aged rats with spontaneous hypertension: Evaluation with dynamic contrast-enhanced magnetic resonance imaging" (2018) Korean Journal of Radiology
Blood-brain barrier disruption and perivascular beta-amyloid accumulation in the brain of aged rats with spontaneous hypertension: Evaluation with dynamic contrast-enhanced magnetic resonance imaging
(2018) Korean Journal of Radiology, 19 (3), pp. 498-507.
Wang, Y.a c , Zhang, R.a , Tao, C.b , Xu, Z.a , Chen, W.a , Wang, C.a , Song, L.a , Zheng, J.d , Gao, F.a
a Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
b Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
c Department of Radiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Objective: Whether blood-brain barrier (BBB) disruption induced by chronic spontaneous hypertension is associated with beta-amyloid (Aβ) accumulation in the brain remains poorly understood. The purpose of this study was to investigate the relationship between BBB disruption and Aβ influx and accumulation in the brain of aged rats with chronic spontaneous hypertension. Materials and Methods: Five aged spontaneously hypertensive rats (SHRs) and five age-matched normotensive Wistar-Kyoto (WKY) rats were studied. The volume transfer constant (Ktrans) obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to evaluate BBB permeability in the hippocampus and cortex in vivo. The BBB tight junctions, immunoglobulin G (IgG), Aβ, and amyloid precursor protein (APP) in the hippocampus and cortex were examined with immunohistochemistry. Results: As compared with WKY rats, the Ktrans values in the hippocampus and cortex of the SHRs increased remarkably (0.316 ± 0.027 min-1 vs. 0.084 ± 0.017 min-1, p < 0.001 for hippocampus; 0.302 ± 0.072 min-1 vs. 0.052 ± 0.047 min-1, p < 0.001 for cortex). Dramatic occludin and zonula occludens-1 losses were detected in the hippocampus and cortex of SHRs, and obvious IgG exudation was found there. Dramatic Aβ accumulation was found and limited to the area surrounding the BBB, without extension to other parenchyma regions in the hippocampus and cortex of aged SHRs. Alternatively, differences in APP expression in the hippocampus and cortex were not significant. Conclusion: Blood-brain barrier disruption is associated with Aβ influx and accumulation in the brain of aged rats with chronic spontaneous hypertension. DCE-MRI can be used as an effective method to investigated BBB damage. © 2018 The Korean Society of Radiology.
Alzheimer’s disease; Tight junction protein; Transfer constant; Transmembrane glycoprotein
Document Type: Article
"MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A" (2018) Science
MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A
(2018) Science, 360 (6386), pp. 336-341.
Rocha, A.G.a , Franco, A.a , Krezel, A.M.b , Rumsey, J.M.a , Alberti, J.M.a , Knight, W.C.a , Biris, N.c , Zacharioudakis, E.c , Janetka, J.W.b , Baloh, R.H.d , Kitsis, R.N.e , Mochly-Rosen, D.f , Townsend, R.R.a , Gavathiotis, E.c , Dorn, G.W.a
a Department of Internal Medicine, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Biochemistry and Molecular Biophysics, Washington University, School of Medicine, St. Louis, MO, United States
c Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, United States
d Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
e Departments of Medicine and Cell Biology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, United States
f Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA, United States
Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in Mfn2 cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A).We showed that MFN2 activity can be determined by Met376 and His380 interactions with Asp725 and Leu727 and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser378. Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg94→Gln94 and MFN2 Thr105→Met105, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr105→Met105 mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking. © 2017 The Authors, some rights reserved.
Document Type: Article
"Intrinsic mechanisms of neuronal axon regeneration" (2018) Nature Reviews Neuroscience
Intrinsic mechanisms of neuronal axon regeneration
(2018) Nature Reviews Neuroscience, pp. 1-15. Article in Press.
Mahar, M., Cavalli, V.
Department of Neuroscience, Hope Center for Neurological Disorders and Center of Regenerative Medicine, Washington University School of Medicine, St Louis, MO, United States
Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury. © 2018 Macmillan Publishers Ltd., part of Springer Nature
Document Type: Article in Press
"Spatial eye–hand coordination during bimanual reaching is not systematically coded in either LIP or PRR" (2018) Proceedings of the National Academy of Sciences of the United States of America
Spatial eye–hand coordination during bimanual reaching is not systematically coded in either LIP or PRR
(2018) Proceedings of the National Academy of Sciences of the United States of America, 115 (16), pp. E3817-E3826.
Mooshagian, E., Snyder, L.H.
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
We often orient to where we are about to reach. Spatial and temporal correlations in eye and arm movements may depend on the posterior parietal cortex (PPC). Spatial representations of saccade and reach goals preferentially activate cells in the lateral intraparietal area (LIP) and the parietal reach region (PRR), respectively. With unimanual reaches, eye and arm movement patterns are highly stereotyped. This makes it difficult to study the neural circuits involved in coordination. Here, we employ bimanual reaching to two different targets. Animals naturally make a saccade first to one target and then the other, resulting in different patterns of limb–gaze coordination on different trials. Remarkably, neither LIP nor PRR cells code which target the eyes will move to first. These results suggest that the parietal cortex plays at best only a permissive role in some aspects of eye–hand coordination and makes the role of LIP in saccade generation unclear. © 2018 National Academy of Sciences. All Rights Reserved.
Arm movement; Monkey; Motor planning; Posterior parietal cortex; Saccade
Document Type: Article
"Smokers' unprompted comments on cigarette additives during conversations about the genetic basis for nicotine addiction: A focus group study" (2018) BMC Public Health
Smokers’ unprompted comments on cigarette additives during conversations about the genetic basis for nicotine addiction: A focus group study
(2018) BMC Public Health, 18 (1), art. no. 495, .
Philpott, S.E., Gehlert, S., Waters, E.A.
Division of Public Health Sciences, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
Background: Research designed to elicit smokers’ cognitive and affective reactions to information about chemicals that tobacco companies add to cigarettes (“additives”) found that knowledge is limited. However, little is known about smokers’ unprompted thoughts and feelings about additives. Such information could be used to shape future communication efforts. We explored the content and possible functions of spontaneous statements about cigarette additives made by smokers during a study examining reactions to learning about the genetic link to nicotine addiction. Methods: Adult smokers (N = 84) were recruited from a medium-sized Midwestern city. Focus groups (N = 13) were conducted between April-September 2012. Data were analyzed by 2 coders using thematic analysis. Results: Comments about cigarette additives arose without prompting by the focus group moderator. Three main themes were identified: (1) discussing additives helped participants navigate the conceptual link between smoking and genetics, (2) additives were discussed as an alternative mechanism for addiction to cigarettes, and (3) additives provided an alternative mechanism by which cigarette smoking exacerbates physical harm. Notably, discussion of additives contained a pervasive tone of mistrust illustrated by words like “they” and “them,” by statements of uncertainty such as “you don’t know what they’re putting into cigarettes,” and by negative affective verbalizations such as “nasty” and “disgusting”. Conclusions: Participants had distinct beliefs about cigarette additives, each of which seemed to serve a purpose. Although mistrust may complicate communication about the health risks of tobacco use, health communication experts could use smokers’ existing beliefs and feelings to better design more effective anti-smoking messages. © 2018 The Author(s).
Document Type: Article
"Effects of environmental support on overt and covert visuospatial rehearsal" (2018) Memory
Effects of environmental support on overt and covert visuospatial rehearsal
(2018) Memory, pp. 1-11. Article in Press.
Lilienthal, L.a , Myerson, J.b , Abrams, R.A.b , Hale, S.b
a Department of Psychology, Penn State Altoona, Altoona, USA
b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, USA
People can rehearse to-be-remembered locations either overtly, using eye movements, or covertly, using only shifts of spatial attention. The present study examined whether the effectiveness of these two strategies depends on environmental support for rehearsal. In Experiment 1, when environmental support (i.e., the array of possible locations) was present and participants could engage in overt rehearsal during retention intervals, longer intervals resulted in larger spans, whereas in Experiment 2, when support was present but participants could only engage in covert rehearsal, longer intervals resulted in smaller spans. When environmental support was absent, however, longer retention intervals resulted in smaller memory spans regardless of which rehearsal strategies were available. In Experiment 3, analyses of participants’ eye movements revealed that the presence of support increased participants’ fixations of to-be-remembered target locations more than fixations of non-targets, and that this was associated with better memory performance. Further, although the total time fixating targets increased, individual target fixations were actually briefer. Taken together, the present findings suggest that in the presence of environmental support, overt rehearsal is more effective than covert rehearsal at maintaining to-be-remembered locations in working memory, and that having more time for overt rehearsal can actually increase visuospatial memory spans. © 2018 Informa UK Limited, trading as Taylor & Francis Group
covert rehearsal; environmental support; overt rehearsal; Visuospatial working memory
Document Type: Article in Press
"BRAF-targeted therapy in the treatment of BRAF-mutant high-grade gliomas in adults" (2018) JNCCN Journal of the National Comprehensive Cancer Network
BRAF-targeted therapy in the treatment of BRAF-mutant high-grade gliomas in adults
(2018) JNCCN Journal of the National Comprehensive Cancer Network, 16 (4), pp. 451-454.
Johanns, T.M.a , Ansstas, G.b , Dahiya, S.c
a Division of Medical Oncology, Department of Medicine, Washington University, School of Medicine, Alvin J. Siteman Cancer Center, Barnes Jewish Hospital, Washington University, School of Medicine, United States
b Division of Medical Oncology, Department of Medicine, Washington University, School of Medicine, Alvin J. Siteman Cancer Center, Center for Human Immunology and Immunotherapy, Barnes Jewish Hospital, Washington University, School of Medicine, United States
c Division of Neuropathology, Department of Pathology and Immunology, Washington University, School of Medicine, Alvin J. Siteman Cancer Center, Barnes Jewish Hospital, Washington University, School of Medicine, United States
Document Type: Note
"High-Intensity Variable Stepping Training in Patients with Motor Incomplete Spinal Cord Injury: A Case Series" (2018) Journal of Neurologic Physical Therapy
High-Intensity Variable Stepping Training in Patients with Motor Incomplete Spinal Cord Injury: A Case Series
(2018) Journal of Neurologic Physical Therapy, 42 (2), pp. 94-101.
Holleran, C.L.a , Hennessey, P.W.b , Leddy, A.L.b , Mahtani, G.B.b , Brazg, G.b , Schmit, B.D.c , Hornby, T.G.b d e
a Program in Physical Therapy, School of Medicine, Washington University, St Louis, MO, United States
b Rehabilitation Institute of Chicago, 355 West 16th St, Indianapolis, IN, United States
c Department of Biomedical Engineering, Marquette University, Milwaukee, WI, United States
d Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg, School of Medicine, Chicago, IL, United States
e Department of Physical Medicine and Rehabilitation, Indiana University, School of Medicine, Indianapolis, IN, United States
Background and Purpose: Previous data suggest that large amounts of high-intensity stepping training in variable contexts (tasks and environments) may improve locomotor function, aerobic capacity, and treadmill gait kinematics in individuals poststroke. Whether similar training strategies are tolerated and efficacious for patients with other acute-onset neurological diagnoses, such as motor incomplete spinal cord injury (iSCI), is unknown. Individuals with iSCI potentially have greater bilateral impairments. This case series evaluated the feasibility and preliminary short- A nd long-term efficacy of high-intensity variable stepping practice in ambulatory participants for more than 1 year post-iSCI. Case Series Description: Four participants with iSCI (neurological levels C5-T3) completed up to 40 one-hour sessions over 3 to 4 months. Stepping training in variable contexts was performed at up to 85% maximum predicted heart rate, with feasibility measures of patient tolerance, total steps/session, and intensity of training. Clinical measures of locomotor function, balance, peak metabolic capacity, and gait kinematics during graded treadmill assessments were performed at baseline and posttraining, with more than 1-year follow-up. Outcomes: Participants completed 24 to 40 sessions over 8 to 15 weeks, averaging 2222 ± 653 steps per session, with primary adverse events of fatigue and muscle soreness. Modest improvements in locomotor capacity where observed at posttraining, with variable changes in lower extremity kinematics during treadmill walking. Discussion: High-intensity, variable stepping training was feasible and tolerated by participants with iSCI although only modest gains in gait function or quality were observed. The utility of this intervention in patients with more profound impairments may be limited. Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A200). © 2018 Academy of Neurologic Physical Therapy, APTA.
locomotion; physical therapy; walking recovery
Document Type: Article
"Cognitive Training for Older Adults: What Works?" (2018) Journal of the American Geriatrics Society
Cognitive Training for Older Adults: What Works?
(2018) Journal of the American Geriatrics Society, 66 (4), pp. 645-647.
Lenze, E.J.a , Bowie, C.R.b
a Department of Psychiatry, Washington University, St Louis, MO, United States
b Department of Psychology, Queen’s University, Kingston, ON, Canada
Document Type: Editorial
"Synapse maintenance and restoration in the retina by NGL2" (2018) eLife
Synapse maintenance and restoration in the retina by NGL2
(2018) eLife, 7, art. no. e30388, .
Soto, F.a , Zhao, L.a , Kerschensteiner, D.a b c d
a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, United States
b Department of Neuroscience, Washington University School of Medicine, Saint Louis, United States
c Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, United States
Synaptic cell adhesion molecules (CAMs) promote synapse formation in the developing nervous system. To what extent they maintain and can restore connections in the mature nervous system is unknown. Furthermore, how synaptic CAMs affect the growth of synapse-bearing neurites is unclear. Here, we use adeno-associated viruses (AAVs) to delete, re-, and overexpress the synaptic CAM NGL2 in individual retinal horizontal cells. When we removed NGL2 from horizontal cells, their axons overgrew and formed fewer synapses, irrespective of whether Ngl2 was deleted during development or in mature circuits. When we re-expressed NGL2 in knockout mice, horizontal cell axon territories and synapse numbers were restored, even if AAVs were injected after phenotypes had developed. Finally, overexpression of NGL2 in wild-type horizontal cells elevated synapse numbers above normal levels. Thus, NGL2 promotes the formation, maintenance, and restoration of synapses in the developing and mature retina, and restricts axon growth throughout life. © Soto et al.
Document Type: Article
Access Type: Open Access
"Preserved neural event segmentation in healthy older adults" (2018) Psychology and Aging
Preserved neural event segmentation in healthy older adults
(2018) Psychology and Aging, 33 (2), pp. 232-245.
Kurby, C.A.a , Zacks, J.M.b
a Department of Psychology, Grand Valley State University, United States
b Department of Psychological and Brain Sciences, Washington University, St. Louis, United States
An important feature of action understanding is that comprehenders segment the perceptual stream into events. Event segmentation dynamically engages a network of brain regions that likely play a role in how events are encoded. Here, in a sample of older adults, we assessed the relationship between changes in brain dynamics during movie watching and event understanding performance. Forty healthy older adults and a comparison sample of 12 younger adults passively viewed short movies of everyday activities while their brain activity was measured with fMRI. Afterward, they segmented the movies into events and performed memory tasks for movie content. The older adults engaged a similar event segmentation network during movie watching as the younger adults. Individual differences analyses revealed that although behavioral measures of event segmentation predicted memory, activity in the segmentation network did not. Intersubject correlation analyses revealed that normative brain dynamics during viewing in the right posterior temporal sulcus and left dorsolateral prefrontal cortex predicted better segmentation performance. These data suggest that these regions play an important role in event understanding, and also that the event segmentation network is preserved in healthy aging. © 2018 American Psychological Association.
Cognitive aging; Event memory; Event segmentation; FMRI; Neural synchrony
Document Type: Article
"Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities" (2018) Molecular Genetics and Genomic Medicine
Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities
(2018) Molecular Genetics and Genomic Medicine, 6 (2), pp. 294-300.
Brereton, E.a , Fassi, E.b , Araujo, G.C.c , Dodd, J.c , Telegrafi, A.d , Pathak, S.J.e , Shinawi, M.a b
a Washington University School of Medicine, St. Louis, MO, United States
b Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychology, St Louis Children’s Hospital, St. Louis, MO, United States
d GeneDx, Gaithersburg, MD, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Background: Dynamin 1 is a protein involved in the synaptic vesicle cycle, which facilitates the exocytosis of neurotransmitters necessary for normal signaling and development in the central nervous system. Pathogenic variants in DNM1 have been implicated in global developmental delay (DD), severe intellectual disability (ID), and notably, epileptic encephalopathy. All previously reported DNM1 pathogenic variants causing this severe phenotype occur in the GTPase and Middle domains of the dynamin 1 protein. Methods: We used whole-exome sequencing to characterize the molecular basis of DD and autistic symptoms in two identical siblings. Results: The twin siblings exhibit mild to moderate ID and autistic symptoms but no epileptic encephalopathy. Exome sequencing revealed a genetic variant, c.1603A>G (p.Lys535Glu), in the PH domain of dynamin 1. Previous in vitro studies showed that mutations at Lys535 inhibit endocytosis and impair PH loop binding to PIP2. Conclusions: Our data suggest a previously undescribed milder phenotype associated with a missense genetic variant in the PH domain of dynamin 1. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
developmental delay; domain; dynamin 1; epileptic encephalopathy; intellectual disability; synaptic vesicle
Document Type: Article
Access Type: Open Access
"Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length" (2018) Journal of Molecular Biology
Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length
(2018) Journal of Molecular Biology, . Article in Press.
Newcombe, E.A.a , Ruff, K.M.b , Sethi, A.a , Ormsby, A.R.a , Ramdzan, Y.M.a , Fox, A.c , Purcell, A.W.d , Gooley, P.R.a , Pappu, R.V.b , Hatters, D.M.a
a Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of MelbourneVIC, Australia
b Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St Louis, MO, United States
c School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia
d Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington’s disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild-type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen–deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ regions and the tail encompassing the C-terminal proline-rich region. The surface area of the globular domain increases monotonically with polyQ length. This stimulates sharp increases in gain-of-function interactions in cells for expanded polyQ, and one of these interactions is with the stress-granule protein Fus. Our results highlight plausible connections between Httex1 structure and routes to neurotoxicity. © 2018 The Authors
Huntington’s disease; hydrogen–deuterium exchange; molecular simulations; NMR spectroscopy
Document Type: Article in Press
Access Type: Open Access
"Neurofibromatosis type 1" (2018) Handbook of Clinical Neurology
Neurofibromatosis type 1
(2018) Handbook of Clinical Neurology, 148, pp. 799-811.
Cimino, P.J.a , Gutmann, D.H.b
a Department of Pathology, University of Washington, Seattle, WA, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
The neurofibromatoses are a group of three heterogeneous disorders that include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. NF1 is the most common of these three conditions, and represents one of the most frequently diagnosed cancer predisposition disorders involving the nervous system. While NF1 primarily affects the central and peripheral nervous system, multisystem involvement is the rule, with dermatologic, cardiovascular, gastrointestinal, and orthopedic affectation often reported. Importantly, NF1 is a disorder of heterogeneity, such that affected individuals can be variably affected, even within the same family. This heterogeneity also presents significant challenges to the actualization of effective treatments. However, recent studies aimed at understanding the role of the NF1 protein (neurofibromin) as a tumor suppressor have revealed that this profound level of clinical heterogeneity may reflect tissue and region-specific effects, sexually dimorphic influences, and the contribution of germline genetics and genomics. With the availability of accurate preclinical Nf1 small-animal models, human induced pluripotent stem cells, and an efficient clinical trials consortium, we are now uniquely positioned to identify and efficiently evaluate promising therapies for NF1-related medical problems. © 2018 Elsevier B.V.
astrocytoma; attention deficit; glioma; inherited cancer syndrome; malignant peripheral nerve sheath tumor; neurodevelopmental disorder; neurofibroma; NF1
Document Type: Book Chapter
"Testing Encourages Transfer Between Factual and Application Questions in an Online Learning Environment" (2018) Journal of Applied Research in Memory and Cognition
Testing Encourages Transfer Between Factual and Application Questions in an Online Learning Environment
(2018) Journal of Applied Research in Memory and Cognition, . Article in Press.
Thomas, R.C.a , Weywadt, C.R.b , Anderson, J.L.b c , Martinez-Papponi, B.b , McDaniel, M.A.d
a Hendrix College, United States
b University of New Mexico, United States
c Harvard University, United States
d Washington University in St Louis, United States
Quizzing improves retention compared to additional study opportunities, a phenomenon known as test-enhanced learning. Two experiments investigated whether the type of question at quiz improves retention for factual and applied course material on exams in an online college course. Students were given quizzes with either factual questions or questions designed to encourage application of a particular concept. As expected, quizzing with feedback improved exam performance compared to material that had not been quizzed. Further, the benefits of quizzing transferred to different question types. Performance on application exam questions improved if students were quizzed with factual questions. Likewise, performance on factual exam questions improved if students were quizzed with application questions. These results replicate the finding that quizzing benefits retention in an online learning environment and, more importantly, that the benefits of quizzing transfer to exam questions that differ in type from the quiz question. © 2018 Society for Applied Research in Memory and Cognition
Memory; Retrieval; Test-enhanced learning; Testing effect; Transfer
Document Type: Article in Press
"Prescription opioid use before and after kidney transplant: Implications for posttransplant outcomes" (2018) American Journal of Transplantation
Prescription opioid use before and after kidney transplant: Implications for posttransplant outcomes
(2018) American Journal of Transplantation, . Article in Press.
Lentine, K.L.a , Lam, N.N.b , Naik, A.S.c , Axelrod, D.A.d , Zhang, Z.a , Dharnidharka, V.R.e , Hess, G.P.f , Segev, D.L.g , Ouseph, R.a , Randall, H.a , Alhamad, T.e , Devraj, R.h , Gadi, R.a , Kasiske, B.L.i , Brennan, D.C.g , Schnitzler, M.A.a
a Center for Abdominal Transplantation Saint Louis University School of Medicine St. Louis, MO USA
b Division of Nephrology University of Alberta Edmonton, AB Canada
c Division of Nephrology Department of Medicine University of Michigan Ann Arbor, MI USA
d Division of Transplantation Department of Surgery Lahey Clinic Burlington, MA USA
e Transplant Nephrology Washington University School of Medicine St. Louis MO USA
f Symphony Health Conshohocken, PA USA
g Center for Transplantation Johns Hopkins School of Medicine Baltimore, MD USA
h School of Pharmacy Southern Illinois University Edwardsville, IL USA
i Department of Medicine Hennepin County Medical Center Minneapolis, MN USA
Evolving literature suggests that the epidemic of prescription opioid use affects the transplant population. We examined a novel database wherein national U.S. transplant registry records were linked to a large pharmaceutical claims warehouse (2007-2015) to characterize prescription opioid use before and after kidney transplant, and associations (adjusted hazard ratio, 95% LCLaHR95% UCL) with death and graft loss. Among 75 430 eligible patients, 43.1% filled opioids in the year before transplant. Use was more common among recipients who were women, white, unemployed, publicly insured, and with longer pretransplant dialysis. Of those with the highest level of pretransplant opioid use, 60% continued high-level use posttransplant. Pretransplant opioid use had graded associations with one-year posttransplant outcomes; the highest-level use predicted 46% increased risk of death (aHR 1.281.461.66) and 28% increased risk of all-cause graft failure (aHR 1.171.281.41). Effects of high-level opioid use in the first year after transplant were stronger, predicting twice the risk of death (aHR 1.932.242.60) and 68% higher all-cause graft failure risk (aHR 1.501.681.89) over the subsequent year; increased risk persisted over five years. While associations may, in part, reflect underlying conditions or behaviors, opioid use history is relevant in assessing and providing care to transplant candidates and recipients. © 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.
Clinical research/practice; Epidemiology; Kidney transplantation/nephrology; Scientific Registry for Transplant Recipients (SRTR)
Document Type: Article in Press
"Understanding activity participation among individuals with Wolfram syndrome" (2018) British Journal of Occupational Therapy
Understanding activity participation among individuals with Wolfram syndrome
(2018) British Journal of Occupational Therapy, . Article in Press.
Bumpus, E.a , Hershey, T.b , Doty, T.c , Ranck, S.d , Gronski, M.e , Urano, F.f , Foster, E.R.g
a Washington University School of Medicine, St. Louis, Occupational Therapy Doctoral Student, Program in Occupational Therapy, USA
b Washington University School of Medicine, St. Louis, Associate Professor, Departments of Neurology, Psychiatry, and Radiology, USA
c Washington University School of Medicine, St. Louis, Professional Rater III, Program in Occupational Therapy and Department of Psychiatry, USA
d Washington University School of Medicine, St. Louis, Professional Rater III, Department of Psychiatry, USA
e Director, Department of Occupational Therapy, Methodist University, Fayetteville, USA
f Washington University School of Medicine, St. Louis, Professor, Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, and Department of Pathology and Immunology, USA
g Washington University School of Medicine, St. Louis, Assistant Professor, Program in Occupational Therapy and Departments of Neurology and Psychiatry, USA
Introduction: Wolfram syndrome is a rare genetic disease associated with a variety of progressive metabolic and neurologic impairments. Previous research has focused on Wolfram syndrome-related impairments and biomarkers for disease progression; however, information about how Wolfram syndrome impacts participation in daily activities is lacking. Method: Wolfram syndrome (n = 45; 20 children, 25 adults) participants completed an online questionnaire about activity participation. Thirty-six non-Wolfram syndrome comparison participants (11 children; 25 adults) completed a portion of the questionnaire. Symptom data from a subset of Wolfram syndrome participants (n = 20) were also examined in relation to participation data. Results: Wolfram syndrome children and adults had lower participation than non-Wolfram syndrome children and adults in almost all activity domains, and social and exercise-related activities were the most problematic. In the subset of Wolfram syndrome adults with symptom data, poorer vision, balance, gait, hearing, and overall symptom severity were related to lower participation. Conclusion: Wolfram syndrome appears to negatively impact participation in a variety of activities, and this effect may increase as people age and/or Wolfram syndrome progresses. The most functionally pertinent Wolfram syndrome symptoms are those associated with neurodegeneration, especially vision loss and walking and balance problems. This study revealed symptoms and activity domains that are most relevant for people with Wolfram syndrome and, thus, can inform current practice and treatment development research. © 2018, The Author(s) 2018.
function; neurodegeneration; occupational therapy; participation; Wolfram syndrome
Document Type: Article in Press
"Use of eeg for determining propofol requirement during neuroanesthesia" (1990) Journal of Neurosurgical Anesthesiology
Use of eeg for determining propofol requirement during neuroanesthesia
(1990) Journal of Neurosurgical Anesthesiology, 2 (3), p. 233.
Department of Anesthesiology, Washington University, St. Louis, MO, United States
Document Type: Article