“Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders” (2021) Journal of Neurodevelopmental Disorders
Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders
(2021) Journal of Neurodevelopmental Disorders, 13 (1), art. no. 10, .
Rahn, R.M.a b c , Weichselbaum, C.T.a b d , Gutmann, D.H.d e , Dougherty, J.D.a b d , Maloney, S.E.b d
a Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States
b Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States
c Department of Radiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States
d Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States
e Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States
Abstract
Background: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. Methods: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1+/R681X mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21–30) and one early adulthood time point. Results: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1+/R681X mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. Conclusions: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics. © 2021, The Author(s).
Author Keywords
Gait; mice; neurodevelopmental disorders; Neurofibromatosis Type 1; precision medicine; Williams Syndrome
Document Type: Article
Publication Stage: Final
Source: Scopus
“Applying the RE-AIM framework to evaluate the implementation of the Supporting and Enhancing NICU Sensory Experiences (SENSE) program” (2021) BMC Pediatrics
Applying the RE-AIM framework to evaluate the implementation of the Supporting and Enhancing NICU Sensory Experiences (SENSE) program
(2021) BMC Pediatrics, 21 (1), art. no. 137, .
Pineda, R.a b c , Roussin, J.d e , Kwon, J.d , Heiny, E.d f , Colditz, G.g , Smith, J.h
a Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, United States
b Department of Pediatrics, Keck School of Medicine, Los Angeles, CA, United States
c Gehr Family Center for Health Systems Science and Innovation, University of Southern California, Los Angeles, CA, United States
d Program in Occupational Therapy, Washington University, St. Louis, MO, United States
e Department of Radiation Oncology, Washington University, St. Louis, MO, United States
f Department of Therapy Services, St. Louis Children’s Hospital, St. Louis, MO, United States
g Department of Surgery, Washington University, St. Louis, MO, United States
h Department of Quality, Safety, and Practice Excellence, St. Louis Children’s Hospital, St. Louis, MO, United States
Abstract
Background: To maximize the benefit of parent-directed, positive sensory exposures in the NICU, a structured sensory-based program titled the Supporting and Enhancing NICU Sensory Experiences (SENSE) program was developed that includes specific doses and targeted timing of evidence-based sensory exposures. Methods: The Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework was used to systematically evaluate the SENSE program as an implementation strategy. One-hundred preterm infants ≤32 weeks gestation were studied (61 receiving the SENSE program and 39 standard-of-care). Parent education time and infant sensory exposures were tracked, and parents completed a questionnaire that probed their perceptions about the SENSE program. Results: One-hundered thirty-one families were recruited, and 100 (76%) enrolled. The SENSE program was initiated at an average postmenstrual age of 29.8 (±2.4) weeks; 4.9 (±5.6) days after birth. The average number of education sessions with families was 4.8 (±3.7) amounting to 72.3 (±37.4) total minutes over hospitalization. The total time of logged tactile and auditory exposures among SENSE recipients over the length of hospitalization was a median (IQ range) of 9325 (5295-15,694) minutes over an average of 10.1 (±7.6) weeks of hospitalization. There were differences in the proportion of tactile and auditory exposure targets received by the infant among those receiving the SENSE program compared to standard-of-care (91% compared to 48%; p < 0.0001). Ninety-five percent of infants tolerated the SENSE program as defined, with 5% of infants requiring intermittent adaptations or the interventions being stopped for a period that typically lasted 1–2 weeks. Earlier parent education was related to more parent participation in SENSE program interventions (p = 0.04). Eighty-five percent of participants receiving the SENSE program had most of the sensory interventions completed by parents, as opposed to the medical or sensory support team. Seventy-two percent of infants had at least 100% of the auditory and tactile doses conducted over the length of stay. Parents reported acceptability. Conclusion: The SENSE program had good reach, was effective and acceptable with minimal cost, was adopted, and had good fidelity. Insights from implementation of the SENSE program (within a research study) informed future strategies to aid maintenance during dissemination. © 2021, The Author(s).
Author Keywords
Adoptability; Effectiveness; Environment; Fidelity; Maintenance; Outcomes; Parent; Preterm; Reach; Therapy
Funding details
National Institutes of HealthNIH
National Institute of Child Health and Human DevelopmentNICHDP30 HD062171
Gordon and Betty Moore FoundationGBMF
National Center for Advancing Translational SciencesNCATS
Institute of Clinical and Translational SciencesICTSUL1TR002345
Instituto de Salud Carlos IIIISCIIIRO1 HD 057098
Document Type: Article
Publication Stage: Final
Source: Scopus
“Age bias in the criteria for antisocial personality disorder” (2021) Journal of Psychiatric Research
Age bias in the criteria for antisocial personality disorder
(2021) Journal of Psychiatric Research, 137, pp. 444-451.
Holzer, K.J.a b , Vaughn, M.G.b c , Fearn, N.E.b , Loux, T.M.d , Mancini, M.A.b
a Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b School of Social Work, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO 63103, United States
c Graduate School of Social Welfare, Yonsei University, Seoul, South Korea
d Department of Epidemiology and Biostatistics, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO 63104, United States
Abstract
The prevalence of antisocial personality disorder (ASPD) decreases with age. As such, research regarding ASPD typically focuses on children and younger adults. The apparent age-specific prevalence of ASPD may be due, in part, to diagnostic criteria informed by research excluding older adults. The present study sought to better understand the manifestation of ASPD in older adults and investigate potential age bias in the diagnostic criteria. Item response theory methods were used to the diagnostic criteria for ASPD with data from the National Epidemiologic Survey on Alcohol and Related Conditions Wave III. The measurement of three ASPD criteria showed uniform differential item functioning (DIF), suggesting that older adults were less likely to endorse the item than younger adults despite having the same level of underlying personality disorder. The items with DIF are related to the following criteria for ASPD: Failure to conform to social norms with respect to lawful behaviors as indicated by repeatedly performing acts that are grounds for arrest (3 items with DIF); irritability and aggressiveness, as indicated by repeated physical fights or assaults (1 item with DIF); and consistent irresponsibility, as indicated by repeated failure to sustain consistent work behavior or honor financial obligations (1 item with DIF). Results of the present study can be used to inform the development of criteria that better capture the age-specific experience of this disorder. Improved criteria will result in increased diagnostic accuracy, systematic estimation of the prevalence, improved assessments, and more effective treatment options for this complex population. © 2021 Elsevier Ltd
Author Keywords
Age bias; Antisocial personality disorder; Item response theory; Older adult; Prevalence
Document Type: Article
Publication Stage: Final
Source: Scopus
“Krabbe disease: New hope for an old disease” (2021) Neuroscience Letters
Krabbe disease: New hope for an old disease
(2021) Neuroscience Letters, 752, art. no. 135841, .
Bradbury, A.M.a , Bongarzone, E.R.b , Sands, M.S.c d
a Department of Pediatrics, Nationwide Children’s Hospital, Ohio State University, 700 Children’s Drive, Columbus, OH 43205, United States
b Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States
c Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and adult-onset forms of Krabbe disease have been described, with infantile being the most common. Children with an infantile-onset generally appear normal at birth but begin to miss developmental milestones by six months of age and die by two to four years of age. Krabbe disease is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and sphingolipids, which are abundant in myelin membranes. The absence of GALC leads to the toxic accumulation of galactosylsphingosine (psychosine), a lysoderivative of galactosylceramides, in oligodendrocytes and Schwann cells resulting in demyelination of the central and peripheral nervous systems, respectively. Treatment strategies such as enzyme replacement, substrate reduction, enzyme chaperones, and gene therapy have shown promise in LSDs. Unfortunately, Krabbe disease has been relatively refractory to most single-therapy interventions. Although hematopoietic stem cell transplantation can alter the course of Krabbe disease and is the current standard-of-care, it simply slows the progression, even when initiated in pre-symptomatic children. However, the recent success of combinatorial therapeutic approaches in small animal models of Krabbe disease and the identification of new pathogenic mechanisms provide hope for the development of effective treatments for this devastating disease. This review provides a brief history of Krabbe disease and the evolution of single and combination therapeutic approaches and discusses new pathogenic mechanisms and how they might impact the development of more effective treatment strategies. © 2021 The Author(s)
Author Keywords
Gene therapy; Globoid cell leukodystrophy; Krabbe disease; Lysosomal storage disease
Funding details
R01NS100779
Document Type: Article
Publication Stage: Final
Source: Scopus
“Immediate Postoperative Electroencephalography Monitoring in Pediatric Moyamoya Disease and Syndrome” (2021) Pediatric Neurology
Immediate Postoperative Electroencephalography Monitoring in Pediatric Moyamoya Disease and Syndrome
(2021) Pediatric Neurology, 118, pp. 40-45.
Huguenard, A.L.a , Guerriero, R.M.b , Tomko, S.R.b , Limbrick, D.D.a , Zipfel, G.J.a , Guilliams, K.P.b , Strahle, J.M.a
a Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
b Division of Pediatric and Developmental Neurology, Department of Neurology, St. Louis Children’s Hospital, St. Louis, MO, United States
Abstract
Background: Moyamoya disease and syndrome are progressive steno-occlusive cerebrovascular diseases that manifest clinically with ischemic episodes. There is evidence for the use of electroencephalography (EEG) in preoperative and long-term postoperative evaluation of these patients, as well as in the intraoperative period to monitor for changes correlated with perioperative ischemic events. However, the utility of EEG in the immediate postprocedure time period has not previously been described. Methods: We review six patients who underwent pial synangiosis from 2017 to 2019. EEGs from the preoperative, intraoperative, and immediate postoperative period were evaluated, as well as clinical examination changes and subsequent interventions. Results: Six patients with postoperative EEG monitoring following pial synangiosis were included. EEG data was collected preoperatively, intraoperatively, and continuously postoperatively. Preoperatively, five of six patients had normal background activity on EEG, whereas one of six had hemispheric asymmetry. Three patients had new or worsening hemispheric intracerebral asymmetry on EEG during the immediate postsurgical period. Two of these had no clinical manifestations of ischemia, and one had transient left facial weakness. All three underwent blood pressure augmentation with improvement in the asymmetry on EEG and clinical improvement in the symptomatic patient. Conclusions: Although widely accepted as a useful tool during the preoperative and intraoperative periods of evaluation and management of moyamoya disease and syndrome, we propose that the use of continuous EEG in the immediate postoperative period may have potential as a useful adjunct by both detecting early clinical and subclinical intracranial ischemia. © 2021 Elsevier Inc.
Author Keywords
Complications; Electroencephalography; Monitoring; Moyamoya disease; Pial synangiosis; Postoperative
Document Type: Article
Publication Stage: Final
Source: Scopus
“Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning” (2021) The Journal of Pharmacology and Experimental Therapeutics
Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning
(2021) The Journal of Pharmacology and Experimental Therapeutics, 377 (1), pp. 181-188.
Izumi, Y.a , Mennerick, S.J.a , Doherty, J.J.a , Zorumski, C.F.b
a Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri (Y.I., S.J.M., C.F.Z.); and Sage Therapeutics, Cambridge, Massachusetts (J.J.D.)
b Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri (Y.I., S.J.M., C.F.Z.); and Sage Therapeutics, Cambridge, Massachusetts (J.J.D.) zorumskc@wustl.edu
Abstract
Ethanol is a noncompetitive inhibitor of N-methyl-d-aspartate receptors (NMDARs) and acutely disrupts hippocampal synaptic plasticity and learning. In the present study, we examined the effects of oxysterol positive allosteric modulators (PAMs) of NMDARs on ethanol-mediated inhibition of NMDARs, block of long-term potentiation (LTP) and long-term depression (LTD) in rat hippocampal slices, and defects in one-trial learning in vivo. We found that 24S-hydroxycholesterol and a synthetic oxysterol analog, SGE-301, overcame effects of ethanol on NMDAR-mediated synaptic responses in the CA1 region but did not alter acute effects of ethanol on LTD; the synthetic oxysterol, however, overcame acute inhibition of LTP. In addition, both oxysterols overcame persistent effects of ethanol on LTP in vitro, and the synthetic analog reversed defects in one-trial inhibitory avoidance learning in vivo. These results indicate that effects of ethanol on both LTP and LTD arise by complex mechanisms beyond NMDAR antagonism and that oxysterol NMDAR PAMS may represent a novel approach for preventing and reversing acute ethanol-mediated changes in cognition. SIGNIFICANCE STATEMENT: Ethanol acutely inhibits hippocampal NMDARs, LTP, and learning. This study found that certain oxysterols that are NMDAR-positive allosteric modulators can overcome the acute effects of ethanol on NMDARs, LTP, and learning. Oxysterols differ in their effects from agents that inhibit integrated cellular stress responses. Copyright © 2021 by The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
“Impact of Type 1 Diabetes in the Developing Brain in Children: A Longitudinal Study” (2021) Diabetes Care
Impact of Type 1 Diabetes in the Developing Brain in Children: A Longitudinal Study
(2021) Diabetes Care, 44 (4), pp. 983-992.
Mauras, N.a , Buckingham, B.b , White, N.H.c , Tsalikian, E.d , Weinzimer, S.A.e , Jo, B.f , Cato, A.g , Fox, L.A.a , Aye, T.b , Arbelaez, A.M.c , Hershey, T.h , Tansey, M.d , Tamborlane, W.e , Foland-Ross, L.C.f , Shen, H.f , Englert, K.a , Mazaika, P.f , Marzelli, M.f , Reiss, A.L.i , Diabetes Research in Children Network (DirecNet)j
a Division of Endocrinology, Diabetes & Metabolism, Department of Pediatrics, Nemours Children’s Health System, FL, Jacksonville, United States
b Division of Endocrinology and Diabetes, Department of Pediatrics, Stanford University, Stanford, CA
c Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO
d Division of Endocrinology and Diabetes, Stead Family Department of Pediatrics, University of Iowa, IA, Iowa City, United States
e Department of Pediatrics, Yale University, CT, New Haven, United States
f Center for Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA
g Division of Neurology, Nemours Children’s Health System, FL, Jacksonville, United States
h Departments of Radiology and Psychiatry, Washington University in St. Louis, St. Louis, MO
Abstract
OBJECTIVE: To assess whether previously observed brain and cognitive differences between children with type 1 diabetes and control subjects without diabetes persist, worsen, or improve as children grow into puberty and whether differences are associated with hyperglycemia. RESEARCH DESIGN AND METHODS: One hundred forty-four children with type 1 diabetes and 72 age-matched control subjects without diabetes (mean ± SD age at baseline 7.0 ± 1.7 years, 46% female) had unsedated MRI and cognitive testing up to four times over 6.4 ± 0.4 (range 5.3-7.8) years; HbA1c and continuous glucose monitoring were done quarterly. FreeSurfer-derived brain volumes and cognitive metrics assessed longitudinally were compared between groups using mixed-effects models at 6, 8, 10, and 12 years. Correlations with glycemia were performed. RESULTS: Total brain, gray, and white matter volumes and full-scale and verbal intelligence quotients (IQs) were lower in the diabetes group at 6, 8, 10, and 12 years, with estimated group differences in full-scale IQ of -4.15, -3.81, -3.46, and -3.11, respectively (P < 0.05), and total brain volume differences of -15,410, -21,159, -25,548, and -28,577 mm3 at 6, 8, 10, and 12 years, respectively (P < 0.05). Differences at baseline persisted or increased over time, and brain volumes and cognitive scores negatively correlated with a life-long HbA1c index and higher sensor glucose in diabetes. CONCLUSIONS: Detectable changes in brain volumes and cognitive scores persist over time in children with early-onset type 1 diabetes followed longitudinally; these differences are associated with metrics of hyperglycemia. Whether these changes can be reversed with scrupulous diabetes control requires further study. These longitudinal data support the hypothesis that the brain is a target of diabetes complications in young children. © 2021 by the American Diabetes Association.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Histological assessment of a chronically implanted cylindrically-shaped, polymer-based neural probe in the monkey” (2021) Journal of Neural Engineering
Histological assessment of a chronically implanted cylindrically-shaped, polymer-based neural probe in the monkey
(2021) Journal of Neural Engineering, 18 (2), art. no. 024001, .
Gerbella, M.a , Borra, E.a , Pothof, F.b , Lanzilotto, M.c , Livi, A.e , Fogassi, L.a , Paul, O.b d , Orban, G.A.a , Ruther, P.b d , Bonini, L.a
a Dipartimento di Medicina e Chirurgia, Universit Degli Studi di Parma, IT, Parma, Italy
b Department of Microsystems Engineering (IMTEK), University of Freiburg, Freiburg, DE, Germany
c Department of Psychology, University of Turin, IT, Turin, Italy
d BrainLinks-BrainTools, University of Freiburg, Freiburg, DE, Germany
e Department of Neuroscience, Washington University, St. Louis, MO 63110, United States
Abstract
Objective. Previous studies demonstrated the possibility to fabricate stereo-electroencephalography probes with high channel count and great design freedom, which incorporate macro-electrodes as well as micro-electrodes offering potential benefits for the pre-surgical evaluation of drug resistant epileptic patients. These new polyimide probes allowed to record local field potentials, multi- and single-unit activity (SUA) in the macaque monkey as early as 1 h after implantation, and yielded stable SUA for up to 26 d after implantation. The findings opened new perspectives for investigating mechanisms underlying focal epilepsy and its treatment, but before moving to possible human application, safety data are needed. In the present study we evaluate the tissue response of this new neural interface by assessing post-mortem the reaction of brain tissue along and around the probe implantation site. Approach. Three probes were implanted, independently, in the brain of one monkey (Macaca mulatta) at different times. We used specific immunostaining methods for visualizing neuronal cells and astrocytes, for measuring the extent of damage caused by the probe and for relating it with the implantation time. Main results. The size of the region where neurons cannot be detected did not exceed the size of the probe, indicating that a complete loss of neuronal cells is only present where the probe was physically positioned in the brain. Furthermore, around the probe shank, we observed a slightly reduced number of neurons within a radius of 50 µm and a modest increase in the number of astrocytes within 100 µm. Significance. In the light of previous electrophysiological findings, the present data suggest the potential usefulness and safety of this probe for human applications. © 2021 The Author(s). Published by IOP Publishing Ltd.
Author Keywords
chronic probes; focal epilepsy; histocompatibility; SEEG; stereoelectroencephalography
Document Type: Article
Publication Stage: Final
Source: Scopus
“Cingulo-opercular control network and disused motor circuits joined in standby mode” (2021) Proceedings of the National Academy of Sciences of the United States of America
Cingulo-opercular control network and disused motor circuits joined in standby mode
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (13), art. no. e2019128118, .
Newbold, D.J.a , Gordon, E.M.b , Laumann, T.O.c , Seider, N.A.a , Montez, D.F.a c , Gross, S.J.a , Zheng, A.a , Nielsen, A.N.a d , Hoyt, C.R.e , Hampton, J.M.c , Ortega, M.a , Adeyemo, B.a , Miller, D.B.a , Van, A.N.a f , Marek, S.a , Schlaggar, B.L.g h i , Carter, A.R.a e , Kay, B.P.a , Greene, D.J.b c , Raichle, M.E.a b , Petersen, S.E.a b f j k , Snyder, A.Z.a b , Dosenbach, N.U.F.a b e f l
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
d Institute for Innovations in Developmental Sciences, Northwestern University, Chicago, IL 60611, United States
e Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
g Kennedy Krieger Institute, Baltimore, MD 21205, United States
h Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
i Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
j Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
k Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63110, United States
l Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions. © 2021 National Academy of Sciences. All rights reserved.
Author Keywords
Disuse; FMRI; Network neuroscience; Plasticity; Spontaneous activity
Funding details
14-011
1IK2CX001680
National Institutes of HealthNIHMH096773, MH1000872, MH104592, MH112473, MH122066, MH124567, NS080675, NS088590, NS090978, NS098577, NS110332, TR000448
James S. McDonnell FoundationJSMF
Child Neurology FoundationCNF
McDonnell Center for Systems Neuroscience
Hope Center for Neurological Disorders
Jacobs Foundation2016121703
Document Type: Article
Publication Stage: Final
Source: Scopus
“Screening for Hearing Loss in Older Adults: Insufficient Evidence Does Not Mean Insufficient Benefit” (2021) JAMA – Journal of the American Medical Association
Screening for Hearing Loss in Older Adults: Insufficient Evidence Does Not Mean Insufficient Benefit
(2021) JAMA – Journal of the American Medical Association, 325 (12), pp. 1162-1163.
Yueh, B.a , Piccirillo, J.F.b
a Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, Minneapolis, United States
b Department of Otolaryngology-Head and Neck Surgery, Washington University, School of Medicine in St Louis, 660 S Euclid Ave, Campus Box 8115, St Louis, MO 63110, United States
Document Type: Editorial
Publication Stage: Final
Source: Scopus
“The Impact of Late-Life Disability Spectrum on Depressive Symptoms: A Fixed-Effects Analysis of Panel Data” (2021) The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences
The Impact of Late-Life Disability Spectrum on Depressive Symptoms: A Fixed-Effects Analysis of Panel Data
(2021) The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 76 (4), pp. 810-819.
Xiang, X.a , Yang, Y.b , Cheng, J.a , An, R.c
a School of Social Work, University of Michigan, Ann Arbor, United States
b Social and Behavioral Science, School of Public Health, University of MemphisTN
c Brown School, Washington University in St. Louis
Abstract
OBJECTIVES: This study examines the impact of a previously validated disability spectrum that accounts for compensatory strategies on depressive symptoms in older adults. METHODS: This study was a secondary data analysis of 2011 through 2018 surveys from the National Health and Aging Trends Study (N = 7,609). The disability spectrum was categorized using a 5-level hierarchical scheme: fully able, successful accommodation, reduced activity, difficulty, and assistance for 12 mobility, self-care, and household activities. The individual fixed-effects panel model was used to examine the impact of this disability spectrum on depressive symptoms. RESULTS: Depressive symptoms rose progressively with each successive category on the disability spectrum in descriptive analyses. In fixed-effects models, moving from “fully able” to “successful accommodation” was not associated with significant changes in depressive symptoms; this result held for all self-care and mobility activities. Moving from “fully able” to “reduced activity” was associated with a significant increase in depressive symptoms for 3 household activities (doing laundry, making hot meals, and shopping for groceries) but not for paying bills/banking or keeping track of medications. Going up 2 or more stages above “fully able” on the disability spectrum was associated with a significant increase in depressive symptoms across all 12 activities. DISCUSSION: While limitations in a range of daily activities have harmful effects on mental health, using compensatory strategies that do not erode one’s perception of autonomy can help older adults cope with the psychological detriments of late-life disability. © The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
Depression; Late-life disability; Mental health
Document Type: Article
Publication Stage: Final
Source: Scopus
“Mesenchymal stem cells successfully deliver oncolytic virotherapy to diffuse intrinsic pontine glioma” (2021) Clinical Cancer Research
Mesenchymal stem cells successfully deliver oncolytic virotherapy to diffuse intrinsic pontine glioma
(2021) Clinical Cancer Research, 27 (6), pp. 1766-1777. Cited 1 time.
Chastkofsky, M.I.a , Pituch, K.C.a , Katagi, H.a , Zannikou, M.a , Ilut, L.a , Xiao, T.a , Han, Y.a , Sonabend, A.M.a , Curiel, D.T.b , Bonner, E.R.c d , Nazarian, J.c e , Horbinski, C.M.a f , James, C.D.a , Saratsis, A.M.a g h , Hashizume, R.a h , Lesniak, M.S.a , Balyasnikova, I.V.a
a Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
b Department of Radiation Oncology, University of Washington, St. Louis, MO, United States
c Center for Genomics and Precision Medicine, Children’s National Medical Center, Washington, D.C., United States
d Institute for Biomedical Sciences, George Washington University, School of Medicine and Health Sciences, Washington, D.C., United States
e Department of Integrative Systems Biology, George Washington University, School of Medicine and Health Sciences, Washington, D.C., United States
f Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
g Division of Neurosurgery, Department of Pediatric Surgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
h Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
Abstract
Purpose: Diffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiotherapy is the standard-of-care treatment for DIPG, but offers only transient relief of symptoms for patients with DIPG without providing significant survival benefit. Oncolytic virotherapy is an anticancer treatment that has been investigated for treating various types of brain tumors. Experimental Design: Here, we have explored the use of mesenchymal stem cells (MSC) for oncolytic virus (OV) delivery and evaluated treatment efficacy using preclinical models of DIPG. The survivin promoter drives the conditional replication of OV used in our studies. The efficiency of OV entry into the cells is mediated by fiber modification with seven lysine residues (CRAd.S.pK7). Patients’ samples and cell lines were analyzed for the expression of viral entry proteins and survivin. The ability of MSCs to deliver OV to DIPG was studied in the context of a low dose of irradiation. Results: Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins and survivin that enable efficient OV entry and replication in DIPG cells. MSCs loaded with OV disseminate within a tumor and release OV throughout the DIPG brainstem xenografts in mice. Administration of OV-loaded MSCs with radiotherapy to mice bearing brainstem DIPG xenografts results in more prolonged survival relative to that conferred by either therapy alone (P < 0.01). Conclusions: Our study supports OV, CRAd.S.pK7, encapsulated within MSCs as a therapeutic strategy that merits further investigation and potential translation for DIPG treatment. © 2020 American Association for Cancer Research.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Atoh7-independent specification of retinal ganglion cell identity” (2021) Science Advances
Atoh7-independent specification of retinal ganglion cell identity
(2021) Science Advances, 7 (11), .
Brodie-Kommit, J.a , Clark, B.S.b c , Shi, Q.d , Shiau, F.b , Kim, D.W.e , Langel, J.f , Sheely, C.a , Ruzycki, P.A.b , Fries, M.g h , Javed, A.g h , Cayouette, M.g h i j , Schmidt, T.k , Badea, T.l m , Glaser, T.n , Zhao, H.a , Singer, J.d , Blackshaw, S.o p q r , Hattar, S.s
a Department of Biology, Johns Hopkins University, MD, Baltimore, United States
b John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
d Department of Biology, University of Maryland, MD, College Park, United States
e Department of Neuroscience, Johns Hopkins University School of Medicine, MD, Baltimore, United States
f National Institute of Mental Health (NIMH), National Institutes of Health (NIH), MD, Bethesda, United States
g Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Canada
h Molecular Biology Programs, Université de MontréalQC H3C 3J7, Canada
i Department of Anatomy and Cell Biology, McGill University, Montréal, Canada
j Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada
k Department of Neurobiology, Northwestern University, Evanston, United States
l National Eye Institute, National Institutes of Health, MD, Bethesda, United States
m Research and Development Institute, Transylvania University of Brasov, School of MedicineBrasov, Romania
n Department of Cell Biology and Human Anatomy, University of California, Davis School of Medicine, Davis, CA, USA
o Department of Neuroscience, Johns Hopkins University School of Medicine, MD, Baltimore, United States
p Department of Neurology, Johns Hopkins University School of Medicine, MD, Baltimore, United States
q Department of Ophthalmology, Johns Hopkins University School of Medicine, MD, Baltimore, United States
r Kavli Neuroscience Discovery Institute, Johns Hopkins University, MD, Baltimore, United States
s National Institute of Mental Health (NIMH), National Institutes of Health (NIH), MD, Bethesda, United States
Abstract
Retinal ganglion cells (RGCs) relay visual information from the eye to the brain. RGCs are the first cell type generated during retinal neurogenesis. Loss of function of the transcription factor Atoh7, expressed in multipotent early neurogenic retinal progenitors leads to a selective and essentially complete loss of RGCs. Therefore, Atoh7 is considered essential for conferring competence on progenitors to generate RGCs. Despite the importance of Atoh7 in RGC specification, we find that inhibiting apoptosis in Atoh7-deficient mice by loss of function of Bax only modestly reduces RGC numbers. Single-cell RNA sequencing of Atoh7;Bax-deficient retinas shows that RGC differentiation is delayed but that the gene expression profile of RGC precursors is grossly normal. Atoh7;Bax-deficient RGCs eventually mature, fire action potentials, and incorporate into retinal circuitry but exhibit severe axonal guidance defects. This study reveals an essential role for Atoh7 in RGC survival and demonstrates Atoh7-dependent and Atoh7-independent mechanisms for RGC specification. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Document Type: Article
Publication Stage: Final
Source: Scopus
“The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy” (2021) Journal of Neuropathology and Experimental Neurology
The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy
(2021) Journal of Neuropathology and Experimental Neurology, 80 (3), pp. 210-219.
Bieniek, K.F.a , Cairns, N.J.b , Crary, J.F.c , Dickson, D.W.d , Folkerth, R.D.e , Keene, C.D.f , Litvan, I.g , Perl, D.P.h , Stein, T.D.i j k , Vonsattel, J.-P.l , Stewart, W.m , Dams-O’Connor, K.n o , Gordon, W.A.n , Tripodis, Y.k , Alvarez, V.E.i k p , Mez, J.k p , Alosco, M.L.k p , McKee, A.C.i j k p , TBI/CTE Research Groupq
a Department of Pathology, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, Mexico
b Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri
c Departments of Pathology & Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Freidman Brain Institute, Icahn School of Medicine at Mount Sinai SchoolNY
d Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
e New York City Office of Chief Medical Examiner and Department of Forensic Medicine, New York University School of MedicineNY
f Department of Pathology, University of Washington School of Medicine, Seattle, WA, United States
g Department of Neurosciences, University of California San Diego School of Medicine, La JollaCA
h Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
i VA Boston Healthcare System, Boston, MA
j Department of Pathology, Boston University School of Medicine, Boston, Massachusetts; Department of Veteran Affairs Medical Center, Bedford, Massachusetts
k Alzheimer’s Disease Center, CTE Program, Boston University School of Medicine, Boston, Massachusetts; Department of Veteran Affairs Medical Center, Bedford, Massachusetts
l Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical CenterNY
m Department of Neuropathology, University of Glasgow Institute of Neuroscience and Psychology and Queen Elizabeth University Hospital, Glasgow, United Kingdom
n Department of Rehabilitation Medicine, Icahn School of Medicine at Mount SinaiNY
o Department of Neurology (KD-O), Icahn School of Medicine at Mount SinaiNY
p Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Department of Veteran Affairs Medical Center, Bedford, Massachusetts
Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as “an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern,” based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as “Low CTE” or “High CTE” for use in future clinical, pathological, and molecular studies. © 2021 American Association of Neuropathologists, Inc.
Author Keywords
Brain trauma; Chronic traumatic encephalopathy; Neurodegenerative disorders; Tauopathy; Traumatic brain injury
Document Type: Article
Publication Stage: Final
Source: Scopus
“Evidence for Early and Regular Physical Therapy and Exercise in Parkinson’s Disease” (2021) Seminars in Neurology
Evidence for Early and Regular Physical Therapy and Exercise in Parkinson’s Disease
(2021) Seminars in Neurology, .
Ellis, T.D.a , Colón-Semenza, C.b , Deangelis, T.R.b , Thomas, C.A.c d , Hilaire, M.-H.S.c e f , Earhart, G.M.g , Dibble, L.E.h i
a Department of Physical Therapy and Athletic Training, College of Health and Rehabilitation Sciences, Sargent College, Boston University, Boston, MA, United States
b Center for Neurorehabilitation, College of Health and Rehabilitation Sciences, Sargent College, Boston University, Boston, MA, United States
c Parkinson’s Disease and Movement Disorders Center, Boston University Medical Campus, Boston, MA, United States
d American Parkinson Disease Association Information and Referral Center, Boston University Medical Center, Boston, MA, United States
e Department of Neurology, Boston University School of Medicine, Boston, MA, United States
f American Parkinson Disease Association Center for Advanced Research, Boston University Medical Center, Boston, MA, United States
g Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
h Department of Physical Therapy and Athletic Training, The University of Utah, Salt Lake City, UT, United States
i Health-Kinesiology-Recreation, The University of Utah, Salt Lake City, UT, United States
Abstract
Advances in medical management of Parkinson’s disease (PD) have resulted in living longer with disability. Although disability worsens over the course of the disease, there are signs of disability even in the early stages. Several studies reveal an early decline in gait and balance and a high prevalence of nonmotor signs in the prodromal period that contribute to early disability. There is a growing body of evidence revealing the benefits of physical therapy and exercise to mitigate motor and nonmotor signs while improving physical function and reducing disability. The presence of early disability coupled with the benefits of exercise suggests that physical therapy should be initiated earlier in the disease. In this review, we present the evidence revealing early disability in PD and the effectiveness of physical therapy and exercise, followed by a discussion of a secondary prevention model of rehabilitation to reduce early disability and optimize long-term outcomes. © 2021 Georg Thieme Verlag. All rights reserved.
Author Keywords
exercise; Parkinson’s disease; physical activity; physical therapy; rehabilitation
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“miR-181a Mediates Inflammatory Gene Expression After Intracerebral Hemorrhage: An Integrated Analysis of miRNA-seq and mRNA-seq in a Swine ICH Model” (2021) Journal of Molecular Neuroscience
miR-181a Mediates Inflammatory Gene Expression After Intracerebral Hemorrhage: An Integrated Analysis of miRNA-seq and mRNA-seq in a Swine ICH Model
(2021) Journal of Molecular Neuroscience, .
Walsh, K.B.a b , Zimmerman, K.D.c , Zhang, X.d , Demel, S.L.a e , Luo, Y.f , Langefeld, C.D.c , Wohleb, E.g h , Schulert, G.i , Woo, D.a e , Adeoye, O.j
a University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH, United States
b Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, United States
c Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC, United States
d Department of Environmental Health, University of Cincinnati, Cincinnati, OH, United States
e Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, United States
f Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, United States
g Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, United States
h University of Cincinnati Neurobiology Research Center, Cincinnati, OH, United States
i Division of Pediatric Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
j Department of Emergency Medicine, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. Inflammation after ICH contributes to clinical outcomes, but the relevant molecular mechanisms remain poorly understood. In studies of peripheral leukocyte counts and mRNA-sequencing (mRNA-seq), our group previously reported that monocytes and Interleukin-8 (IL-8) were important contributors to post-ICH inflammation. microRNA (miRNA) are powerful regulators of gene expression and promising therapeutic targets. We now report findings from an integrated analysis of miRNA-seq and mRNA-seq in peripheral blood mononuclear cells (PBMCs) from a swine ICH model. In 10 pigs, one PBMC sample was collected immediately prior to ICH induction and a second 6 h later; miRNA-seq and mRNA-seq were completed for each sample. An aggregate score calculation determined which miRNA regulated the differentially expressed mRNA. Networks of molecular interactions were generated for the combined miRNA/target mRNA. A total of 227 miRNA were identified, and 46 were differentially expressed after ICH (FDR < 0.05). The anti-inflammatory miR-181a was decreased post-ICH, and it was the most highly connected miRNA in the miRNA/mRNA bioinformatic network analysis. miR-181a has interconnected pathophysiology with IL-8 and monocytes; in prior studies, we found that IL-8 and monocytes contributed to post-ICH inflammation and ICH clinical outcome, respectively. miR-181a was a significant mediator of post-ICH inflammation and is promising for further study, including as a potential therapeutic target. This investigation also demonstrated feasible methodology for miRNA-seq/mRNA-seq analysis in swine that is innovative, and with unique challenges, compared with transcriptomics research in more established species. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
Author Keywords
Inflammation; Intracerebral hemorrhage; Preclinical models; RNA-seq; Stroke; Transcriptomics
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“The Role of the IL-4 Signaling Pathway in Traumatic Nerve Injuries” (2021) Neurorehabilitation and Neural Repair
The Role of the IL-4 Signaling Pathway in Traumatic Nerve Injuries
(2021) Neurorehabilitation and Neural Repair, .
Daines, J.M., Schellhardt, L., Wood, M.D.
Washington University, St Louis, MO, United States
Abstract
Following traumatic peripheral nerve injury, adequate restoration of function remains an elusive clinical goal. Recent research highlights the complex role that the immune system plays in both nerve injury and regeneration. Pro-regenerative processes in wounded soft tissues appear to be significantly mediated by cytokines of the type 2 immune response, notably interleukin (IL)-4. While IL-4 signaling has been firmly established as a critical element in general tissue regeneration during wound healing, it has also emerged as a critical process in nerve injury and regeneration. In this context of peripheral nerve injury, endogenous IL-4 signaling has recently been confirmed to influence more than leukocytes, but including also neurons, axons, and Schwann cells. Given the role IL-4 plays in nerve injury and regeneration, exogenous IL-4 and/or compounds targeting this signaling pathway have shown encouraging preliminary results to treat nerve injury or other neuropathy in rodent models. In particular, the exogenous stimulation of the IL-4 signaling pathway appears to promote postinjury neuron survival, axonal regeneration, remyelination, and thereby improved functional recovery. These preclinical data strongly suggest that targeting IL-4 signaling pathways is a promising translational therapy to augment treatment approaches of traumatic nerve injury. However, a better understanding of the type 2 immune response and associated signaling networks functioning within the nerve injury microenvironment is still needed to fully develop this promising therapeutic avenue. © The Author(s) 2021.
Author Keywords
anti-inflammatory; inflammation; interleukin; peripheral nerve; regeneration
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
“ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes” (2021) Journal of Inherited Metabolic Disease
ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes
(2021) Journal of Inherited Metabolic Disease, .
Alsharhan, H.a b c , He, M.b , Edmondson, A.C.a , Daniel, E.J.P.b , Chen, J.b , Donald, T.d e , Bakhtiari, S.f g , Amor, D.J.h , Jones, E.A.i j , Vassallo, G.k , Vincent, M.l , Cogné, B.l , Deb, W.l , Werners, A.H.m , Jin, S.C.n , Bilguvar, K.o , Christodoulou, J.p q , Webster, R.I.r , Yearwood, K.R.s , Ng, B.G.t , Freeze, H.H.t , Kruer, M.C.f g , Li, D.a , Raymond, K.M.u , Bhoj, E.J.a , Sobering, A.K.v w
a Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
b Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
c Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
d Pediatrics Ward, Grenada General Hospital, St. George’s, Grenada
e Clinical Teaching Unit, St. George’s University, St. George’s, Grenada
f Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
g Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, AZ, United States
h Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, and Department of Pediatrics, University of Melbourne, Melbourne, Australia
i Manchester Centre for Genomic Medicine, Saint Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
j Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
k Department of Pediatric Neurology, Royal Manchester Children’s Hospital, Manchester University Foundation Trust, Manchester, United Kingdom
l Service de génétique médicale, CHU de Nantes, Nantes, France
m Department of Anatomy, Physiology and Pharmacology, St. George University School of Veterinary Medicine, St. George’s, Grenada
n Department of Genetics and Pediatrics, Washington University, St. Louis, MO, United States
o Department of Genetics, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, United States
p Brain and Mitochondrial Research Group, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, and Department of Pediatrics, University of Melbourne, Melbourne, Australia
q Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia
r Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Sydney, NSW, Australia
s St. George’s University, University Health Services, St. George’s, Grenada
t Human Genetics Program, Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
u Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
v Department of Biochemistry, St. George’s University School of Medicine, St. George’s, Grenada
w Windward Islands Research and Education Foundation, True Blue, St. George’s, Grenada
Abstract
Pathogenic variants in ALG13 (ALG13 UDP-N-acetylglucosaminyltransferase subunit) cause an X-linked congenital disorder of glycosylation (ALG13-CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi-quantitative flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry (ESI-QTOF/MS) N-glycan assay, we report subtle abnormalities in N-glycans that normally account for <0.3% of the total plasma glycans that may increase up to 0.5% in females with the p.(Asn107Ser) variant. Among our 11 unrelated ALG13-CDG individuals, one male had abnormal serum transferrin glycosylation. We describe seven previously unreported subjects including three novel variants in ALG13 and report a milder neurodevelopmental course. We also summarize the molecular, biochemical, and clinical data for the 53 previously reported ALG13-CDG individuals. We provide evidence that ALG13 pathogenic variants may mildly alter N-linked protein glycosylation in both female and male subjects, but the underlying mechanism remains unclear. © 2021 SSIEM.
Author Keywords
carbohydrate deficient transferrin; congenital disorders of glycosylation; epilepsy; exome sequencing; mass spectrometry; N-glycans
Funding details
HICF‐1009‐003
WT098051
UM1HG006504
National Institutes of HealthNIHR01DK99551, T32 GM008638, U54 NS115198
National Human Genome Research InstituteNHGRI
Minnesota Department of HealthMDH
Wellcome TrustWT
National Institute for Health ResearchNIHR
State Government of Victoria
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“The Spinal Muscular Atrophy Health Index: A novel outcome for measuring how a patient feels and functions” (2021) Muscle and Nerve
The Spinal Muscular Atrophy Health Index: A novel outcome for measuring how a patient feels and functions
(2021) Muscle and Nerve, .
Zizzi, C.E.a b , Luebbe, E.a , Mongiovi, P.a , Hunter, M.c , Dilek, N.a , Garland, C.d , Ciafaloni, E.a , Zaidman, C.M.e , Kissel, J.T.f , McDermott, M.P.a b g , Johnson, N.h , Sansone, V.i , Heatwole, C.R.a b
a Department of Neurology, University of Rochester, Rochester, NY, United States
b Center for Health and Technology, Rochester, NY, United States
c Department of Neurology, University of California Irvine, Orange, CA, United States
d Department of Pediatric Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
e Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
f Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
g Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, United States
h Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
i NEuroMuscular Omnicentre (NEMO), Piazza Ospedale Maggiore 3, Milan, Italy
Abstract
Introduction: The Spinal Muscular Atrophy Health Index (SMA-HI) is a multifaceted, disease-specific, patient-reported outcome to measure an SMA patient’s perception of their disease burden. In preparation for upcoming therapeutic trials, we examine the validity, reliability, and usability of the SMA-HI in adults, teenagers, and children with SMA. Methods: Using data from a cross-sectional study of 359 international adult patients with SMA, we identified the most relevant symptoms to include in the SMA-HI. We utilized factor analysis, patient interviews with adults and minors (age 8-15 years), known-group validity testing, and test-retest reliability assessments to evaluate and refine the SMA-HI. Results: The SMA-HI measures overall disease burden and 15 areas of SMA health. Fifteen adult patients and five patients, age 8 to 15 years, participated in semistructured qualitative interviews and found the SMA-HI to be comprehensive, easily completed, and to have clear meaning. The final SMA-HI and its subscales demonstrated good internal consistency (Cronbach α = 0.77-0.96), high test-retest reliability (intraclass correlation coefficient = 0.60-0.96), and an ability to differentiate between SMA groups with different disease severities affecting areas such as employment and ambulation (P <.0001 for both). Discussion: This research provides evidence that the SMA-HI is a valid, relevant, and reliable outcome measure to assess multifaceted patient-reported disease burden in older children, teenagers, and adults with SMA. The SMA-HI provides an opportunity for researchers and clinicians to measure a SMA patient’s perception of their health and determine relevant changes in response to therapeutic intervention or disease progression. © 2021 Wiley Periodicals LLC.
Author Keywords
disease burden; patient-reported outcome measure; quality of life; spinal muscular atrophy; symptom assessment; therapeutic trial
Funding details
National Institutes of HealthNIH
Centers for Disease Control and PreventionCDC
U.S. Food and Drug AdministrationFDA
National Institute of Neurological Disorders and StrokeNINDS4K23NS091511, 7R01FD006071‐02, DD19‐002, R01NS104010
Spinal Muscular Atrophy FoundationSMAF
Amyotrophic Lateral Sclerosis AssociationALSA
Friedreich’s Ataxia Research AllianceFARA
Muscular Dystrophy AssociationMDA
Biogen
Parent Project Muscular DystrophyPPMD
Patient-Centered Outcomes Research InstitutePCORI
CSL Behring
PTC TherapeuticsPTC
AveXis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“OCT Angiography Findings in Preclinical Alzheimer’s Disease: 3-Year Follow-Up” (2021) Ophthalmology
OCT Angiography Findings in Preclinical Alzheimer’s Disease: 3-Year Follow-Up
(2021) Ophthalmology, .
O’Bryhim, B.E.a , Lin, J.B.a b , Van Stavern, G.P.a , Apte, R.S.a
a Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA, United States
Funding details
Starr FoundationTSF
National Institutes of HealthNIHUL1 TR002345, TR002344, GM07200
Research to Prevent BlindnessRPB
P30 AG066444
P01 AG03991
P01 AG026276
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Neural regulation of bone marrow adipose tissue” (2021) Best Practice and Research: Clinical Endocrinology and Metabolism
Neural regulation of bone marrow adipose tissue
(2021) Best Practice and Research: Clinical Endocrinology and Metabolism, art. no. 101522, .
Zhang, X.a b , Hassan, M.G.c d , Scheller, E.L.a b
a Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, United States
b Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
c Department of Orthodontics, Faculty of Oral and Dental Medicine, South Valley University, Qena, Egypt
d Department of Orthodontics, Faculty of Dentistry, October 6 University, Giza, Egypt
Abstract
Bone marrow adipose tissue (BMAT) is an important cellular component of the skeleton. Understanding how it is regulated by the nervous system is crucial to the study of bone and bone marrow related diseases. BMAT is innervated by sympathetic and sensory axons in bone and fluctuations in local nerve density and function may contribute to its distinct physiologic adaptations at various skeletal sites. BMAT is directly responsive to adrenergic signals. In addition, neural regulation of surrounding cells may modify BMAT-specific responses, providing many potential avenues for both direct and indirect neural regulation of BMAT metabolism. Lastly, BMAT and peripheral adipose tissues share the same autonomic pathways across the central neuraxis and regulation of BMAT may occur in diverse clinical settings of neurologic and metabolic disease. This review will highlight what is known and unknown about the neural regulation of BMAT and discuss opportunities for future research in the field. © 2021 Elsevier Ltd
Author Keywords
adrenergic receptor; bone; bone marrow adipocyte; mesenchymal stem cell; nervous system; neurotransmitter
Funding details
National Institutes of HealthNIHU01-DK116317
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
“Clinical and Paraclinical Measures Associated with Outcome in Cerebral Amyloid Angiopathy with Related Inflammation” (2021) Journal of Alzheimer’s Disease: JAD
Clinical and Paraclinical Measures Associated with Outcome in Cerebral Amyloid Angiopathy with Related Inflammation
(2021) Journal of Alzheimer’s Disease: JAD, 80 (1), pp. 133-142.
Plotzker, A.S.a b , Henson, R.L.a b , Fagan, A.M.a b , Morris, J.C.a b , Day, G.S.c
a The Charles F. and Joanne Knight Alzheimer Disease Research Center, St. Louis, MO, USA
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
c Department of Neurology, Mayo Clinic, FL, Jacksonville, United States
Abstract
BACKGROUND: Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable. OBJECTIVE: To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone. METHODS: Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging (MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31-513). RESULTS: Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p = 0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p = 0.04), or lower CSF Aβ40 at presentation (rho = -0.83; p = 0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p = 0.03) or higher late ARIA-E scores (rho = 0.70; p = 0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p = 0.66). CONCLUSION: Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness.
Author Keywords
Alzheimer’s disease; amyloid-beta related angiitis; biomarkers; cerebral amyloid angiopathy; inflammation; treatment outcome
Document Type: Article
Publication Stage: Final
Source: Scopus