Publications

Hope Center member publications

List of publications for the week of April 5, 2021

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

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

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

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

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