“Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel” (2021) Nature Communications
Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel
(2021) Nature Communications, 12 (1), art. no. 926, .
Arnold, W.R.a , Carnevale, L.N.a , Xie, Z.b , Baylon, J.L.c , Tajkhorshid, E.c , Hu, H.b , Das, A.d e
a Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, United States
b Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biochemistry, Center for Biophysics and Quantitative Biology, Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL 61801, United States
d Department of Comparative Biosciences, Department of Biochemistry, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL, United States
e Division of Nutritional Sciences, Neuroscience Program, Department of Bioengineering, Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, United States
Abstract
The endocannabinoid system is a promising target to mitigate pain as the endocannabinoids are endogenous ligands of the pain-mediating receptors—cannabinoid receptors 1 and 2 (CB1 and CB2) and TRPV1. Herein, we report on a class of lipids formed by the epoxidation of N-arachidonoyl-dopamine (NADA) and N-arachidonoyl-serotonin (NA5HT) by epoxygenases. EpoNADA and epoNA5HT are dual-functional rheostat modulators of the endocannabinoid-TRPV1 axis. EpoNADA and epoNA5HT are stronger modulators of TRPV1 than either NADA or NA5HT, and epoNA5HT displays a significantly stronger inhibition on TRPV1-mediated responses in primary afferent neurons. Moreover, epoNA5HT is a full CB1 agonist. These epoxides reduce the pro-inflammatory biomarkers IL-6, IL-1β, TNF-α and nitrous oxide and raise anti-inflammatory IL-10 cytokine in activated microglial cells. The epoxides are spontaneously generated by activated microglia cells and their formation is potentiated in the presence of anandamide. Detailed kinetics and molecular dynamics simulation studies provide evidence for this potentiation using the epoxygenase human CYP2J2. Taken together, inflammation leads to an increase in the metabolism of NADA, NA5HT and other eCBs by epoxygenases to form the corresponding epoxides. The epoxide metabolites are bioactive lipids that are potent, multi-faceted molecules, capable of influencing the activity of CB1, CB2 and TRPV1 receptors. © 2021, The Author(s).
Funding details
Foundation for the National Institutes of HealthFNIHP41 GM104601, R01 AA027065, R01 DK103901, R01 GM101048, R01 GM1155884, R03 DA 04236502, U54 GM087519
American Heart AssociationAHA15SDG25760064
Document Type: Article
Publication Stage: Final
Source: Scopus
“Application of electrical stimulation for peripheral nerve regeneration: Stimulation parameters and future horizons” (2021) Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
Application of electrical stimulation for peripheral nerve regeneration: Stimulation parameters and future horizons
(2021) Interdisciplinary Neurosurgery: Advanced Techniques and Case Management, 24, art. no. 101117, .
Javeed, S.a , Faraji, A.H.a , Dy, C.b , Ray, W.Z.a , MacEwan, M.R.a
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
b Division of Hand and Microsurgery, Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Peripheral nerve trauma impacts both social and occupational quality of life. Patients are typically young and subsequently suffer from lifelong disability. Unlike the central nervous system, the peripheral nervous system has the capacity to regenerate along previous or new connections. Yet, complete functional recovery has been an elusive clinical objective despite the development of advanced microsurgical techniques to repair nerves. In recent decades significant amount of work has expanded the focus towards establishing new facets of adjuvant treatment to improve nerve regeneration. One potential therapy is the application of electric stimulation of peripheral nerves immediately following microsurgical repair. Mounting pre-clinical and clinical evidence demonstrated the efficacy of electrical stimulation in improving nerve regeneration and functional recovery. In this paper, we review the potential therapeutic benefits of electrical stimulation and the current limitations of regeneration after nerve injury. We also summarize the proposed mechanisms of electrical stimulation in increasing the regenerative capacity of peripheral nerves, including evidence from human clinical trials. Finally, we discuss stimulation parameters and safety profiles with an eye towards future treatment strategies. Combining electrical stimulation with conductive scaffolds has the potential to improve successful nerve regeneration and may have profound clinical implications to nerve injury patients. © 2021 The Author(s)
Author Keywords
Axon guidance; Axon regeneration; Bioresorbable; Electrical stimulation; Nerve electrodes; Nerve scaffolds; Peripheral nerve injury
Document Type: Review
Publication Stage: Final
Source: Scopus
“Natural oscillatory modes of 3D deformation of the human brain in vivo” (2021) Journal of Biomechanics
Natural oscillatory modes of 3D deformation of the human brain in vivo
(2021) Journal of Biomechanics, 119, art. no. 110259, .
Escarcega, J.D.a , Knutsen, A.K.b , Okamoto, R.J.a , Pham, D.L.b , Bayly, P.V.a
a Mechanical Engineering and Materials Science, Washington University in St. LouisMO, United States
b Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
Abstract
Natural modes and frequencies of three-dimensional (3D) deformation of the human brain were identified from in vivo tagged magnetic resonance images (MRI) acquired dynamically during transient mild acceleration of the head. Twenty 3D strain fields, estimated from tagged MRI image volumes in 19 adult subjects, were analyzed using dynamic mode decomposition (DMD). These strain fields represented dynamic, 3D brain deformations during constrained head accelerations, either involving rotation about the vertical axis of the neck or neck extension. DMD results reveal fundamental oscillatory modes of deformation at damped frequencies near 7 Hz (in neck rotation) and 11 Hz (in neck extension). Modes at these frequencies were found consistently among all subjects. These characteristic features of 3D human brain deformation are important for understanding the response of the brain in head impacts and provide valuable quantitative criteria for the evaluation and use of computer models of brain mechanics. © 2021 Elsevier Ltd
Author Keywords
Brain mechanics; Dynamic mode decomposition; Natural frequency; Oscillations; Tagged MRI; Traumatic brain injury
Funding details
National Institutes of HealthNIHR01/R56 NS055951, U01 NS112120
Center for Neuroscience and Regenerative MedicineCNRM
Document Type: Article
Publication Stage: Final
Source: Scopus
“Adversity is Linked with Decreased Parent-Child Behavioral and Neural Synchrony” (2021) Developmental Cognitive Neuroscience
Adversity is Linked with Decreased Parent-Child Behavioral and Neural Synchrony
(2021) Developmental Cognitive Neuroscience, 48, art. no. 100937, .
Hoyniak, C.P.a , Quiñones-Camacho, L.E.a , Camacho, M.C.a , Chin, J.H.a , Williams, E.M.a , Wakschlag, L.S.b , Perlman, S.B.a
a Washington University in St. Louis School of Medicine, United States
b Northwestern University, United States
Abstract
Parent-child synchrony—parent-child interaction patterns characterized by contingent social responding, mutual responsivity, and co-regulation—has been robustly associated with adaptive child outcomes. Synchrony has been investigated in both behavioral and biological frameworks. While it has been demonstrated that adversity can influence behavioral parent-child synchrony, the neural mechanisms by which this disruption occurs are understudied. The current study examined the association between adversity, parent-child behavioral synchrony, and parent-child neural synchrony across lateral prefrontal cortical regions using functional near-infrared spectroscopy hyperscanning during a parent-child interaction task that included a mild stress induction followed by a recovery period. Participants included 115 children (ages 4-5) and their primary caregivers. Parent-child behavioral synchrony was quantified as the amount time the dyad was synchronous (e.g., reciprocal communication, coordinated behaviors) during the interaction task. Parent-child neural synchrony was examined as the hemodynamic concordance between parent and child lateral PFC activation. Adversity was examined across two, empirically-derived domains: sociodemographic risk (e.g., family income) and familial risk (e.g., household chaos). Adversity, across domains, was associated with decreased parent-child behavioral synchrony across task conditions. Sociodemographic risk was associated with decreased parent-child neural synchrony in the context of experimentally-induced stress. These findings link adversity to decreased parent-child behavioral and neural synchrony. © 2021 The Author(s)
Author Keywords
Adversity; fNIRS; Parent-Child Neural Synchrony
Funding details
National Science FoundationNSF174745
National Institutes of HealthNIHR01 MH107540
National Institute of Mental HealthNIMHT32 MH100019-06
Document Type: Article
Publication Stage: Final
Source: Scopus
“Autophagy activation and photoreceptor survival in retinal detachment” (2021) Experimental Eye Research
Autophagy activation and photoreceptor survival in retinal detachment
(2021) Experimental Eye Research, 205, art. no. 108492, .
Xiao, J.a , Yao, J.b , Jia, L.b , Ferguson, T.A.c , Weber, S.d , Sundstrom, J.M.d , Wubben, T.J.b , Besirli, C.G.b , Zacks, D.N.b
a Department of Ophthalmology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
b Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, MI, United States
c Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, United States
d Department of Ophthalmology, Penn State College of Medicine, Hershey, PA, United States
Abstract
We assess the effect of autophagy inhibition on photoreceptor (PR) survival during experimental retinal detachment (RD) and examine the and examine the relationship between autophagy and the expression of glycolytic enzymes HK2 and PKM2 in the retina. We find that inhibiting autophagy by genetic knock out of the autophagy activator Atg5 in rod PRs resulted in increased apoptotic and necroptotic cell death during RD, demonstrated by elevated terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, caspase 8 activity, transcript levels of Fas receptor and RIPK3 as compared to controls. The absence of autophagy in rods resulted in downregulation of hexokinase 2 and pyruvate kinase muscle isozyme 2 levels. More than 460 proteins were identified by mass spectroscopy in autophagosomes isolated from detached retinas compared with less than 150 proteins identified in autophagosomes from attached retinas. Among various cellular compartments, proteins from cytoskeleton, cytoplasm and intracellular organelles constituted a large portion of increased autophagosome contents. These proteins represent numerous biological processes, including phototransduction, cell-cell signaling, metabolism and inflammation. Our findings suggest that competent autophagy machinery is necessary for PR homeostasis and improving PR survival during periods of nutrient deprivation. © 2021 Elsevier Ltd
Author Keywords
Aerobic glycolysis; Atg5; Autophagosome; Autophagy; Retinal detachment
Funding details
National Eye InstituteNEIEY-020823, EY007003
Foundation Fighting BlindnessFFB
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Final
Source: Scopus
“Beyond somatosensation: Mrgprs in mucosal tissues” (2021) Neuroscience Letters
Beyond somatosensation: Mrgprs in mucosal tissues
(2021) Neuroscience Letters, 748, art. no. 135689, .
Inclan-Rico, J.M.a b , Kim, B.S.c d e f , Abdus-Saboor, I.b
a Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, United States
c Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
f Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Mas-related G coupled receptors (Mrgprs) are a superfamily of receptors expressed in sensory neurons that are known to transmit somatic sensations from the skin to the central nervous system. Interestingly, Mrgprs have recently been implicated in sensory and motor functions of mucosal-associated neuronal circuits. The gastrointestinal and pulmonary tracts are constantly exposed to noxious stimuli. Therefore, it is likely that neuronal Mrgpr signaling pathways in mucosal tissues, akin to their family members expressed in the skin, might relay messages that alert the host when mucosal tissues are affected by damaging signals. Further, Mrgprs have been proposed to mediate the cross-talk between sensory neurons and immune cells that promotes host-protective functions at barrier sites. Although the mechanisms by which Mrgprs are activated in mucosal tissues are not completely understood, these exciting studies implicate Mrgprs as potential therapeutic targets for conditions affecting the intestinal and airway mucosa. This review will highlight the central role of Mrgpr signaling pathways in the regulation of homeostasis at mucosal tissues. © 2021 The Author(s)
Author Keywords
Airways; GI tract; Mast cells; Mrgprs; Sensory neurons
Funding details
National Institutes of HealthNIH
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSR01-AR070116
National Institute of Dental and Craniofacial ResearchNIDCRR00-DE026807
University of Pennsylvania
Document Type: Review
Publication Stage: Final
Source: Scopus
“A sibling-comparison study of smoking during pregnancy and risk for reading-related problems” (2021) Neurotoxicology and Teratology
A sibling-comparison study of smoking during pregnancy and risk for reading-related problems
(2021) Neurotoxicology and Teratology, 84, art. no. 106961, .
Micalizzi, L.a , Marceau, K.b , Evans, A.S.c , Brick, L.A.d , Palmer, R.H.C.e , Heath, A.C.f , Knopik, V.S.b
a Center for Alcohol and Addiction Studies, Brown University School of Public Health, Box G-S121-5, Providence, RI 02903, United States
b Department of Human Development and Family Studies, Purdue University, 1202 W State Street, West Lafayette, IN 47907, United States
c Concord Comprehensive Neuropsychological Services, 86 Baker Avenue Extension #301, Concord, MA 01742, United States
d Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, 345 Blackstone Blvd, Providence, RI 02906, United States
e Behavioral Genetics of Addiction Laboratory, Department of Psychology, Emory University, 36 Eagle Row, Atlanta, GA 30322, United States
f Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States
Abstract
This research examines the relationship between smoking during pregnancy (SDP) and risk for reading related problems in siblings discordant for exposure to SDP. Data (N = 173 families) were drawn from the Missouri Mothers and Their Children study, a sample, identified using birth records (years 1998–2005), in which mothers changed her smoking behavior between two pregnancies (Child 1 [older sibling]: M = 12.99; Child 2 [younger sibling]: M = 10.19). A sibling comparison approach was used, providing a robust test for the association between SDP and reading related outcomes in school-aged children. Results suggested within-family (i.e., potentially causal) associations between SDP and reading and language/comprehension factor scores, as well as between SDP and specific reading-related skills, including reading accuracy and receptive language, with increased exposure to SDP associated with decreased performance. SDP was not associated with spelling, reading rate, or receptive vocabulary. Initial within-family associations between SDP and word-letter identification, phonetic/decoding skills, and reading comprehension were fully attenuated following partial control for genetic and environmental confounding of the associations. These findings indicate that exposure to SDP is associated with poorer performance on some, but not all skills assessed. © 2021 Elsevier Inc.
Author Keywords
Family studies; Language; Reading; Smoking during pregnancy
Funding details
National Institutes of HealthNIHK01DA039288, K01DA048135, K01DA17671, K05AA017688, L30TR001045, P60AA11998, R01AA021492, R01AA09022, R01DA023134, R01DA042742, R01HD049024, R37AA07728
Document Type: Article
Publication Stage: Final
Source: Scopus
“Peripheral sensory stimulation elicits global slow waves by recruiting somatosensory cortex bilaterally” (2021) Proceedings of the National Academy of Sciences of the United States of America
Peripheral sensory stimulation elicits global slow waves by recruiting somatosensory cortex bilaterally
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (8), art. no. e2021252118, .
Rosenthal, Z.P.a b c , Raut, R.V.b d , Bowen, R.M.c e , Snyder, A.Z.c d , Culver, J.P.d e f , Raichle, M.E.c d e , Lee, J.-M.c d e
a Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110, United States
b Graduate Program of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Physics, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Slow waves (SWs) are globally propagating, low-frequency (0.5- to 4-Hz) oscillations that are prominent during sleep and anesthesia. SWs are essential to neural plasticity and memory. However, much remains unknown about the mechanisms coordinating SW propagation at the macroscale. To assess SWs in the context of macroscale networks, we recorded cortical activity in awake and ketamine/xylazine-anesthetized mice using widefield optical imaging with fluorescent calcium indicator GCaMP6f. We demonstrate that unilateral somatosensory stimulation evokes bilateral waves that travel across the cortex with state-dependent trajectories. Under anesthesia, we observe that rhythmic stimuli elicit globally resonant, front-to-back propagating SWs. Finally, photothrombotic lesions of S1 show that somatosensory-evoked global SWs depend on bilateral recruitment of homotopic primary somatosensory cortices. Specifically, unilateral lesions of S1 disrupt somatosensory-evoked global SW initiation from either hemisphere, while spontaneous SWs are largely unchanged. These results show that evoked SWs may be triggered by bilateral activation of specific, homotopically connected cortical networks. © 2021 National Academy of Sciences. All rights reserved.
Author Keywords
Propagation; Slow wave; Somatosensory cortex
Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHF31NS103275, P01NS080675, P30NS098577, R01NS090874, R01NS099429, R37NS110699
American Heart AssociationAHA20PRE34990003
Document Type: Article
Publication Stage: Final
Source: Scopus
“Dynamic Polarization of Rab11a Modulates Crb2a Localization and Impacts Signaling to Regulate Retinal Neurogenesis” (2021) Frontiers in Cell and Developmental Biology
Dynamic Polarization of Rab11a Modulates Crb2a Localization and Impacts Signaling to Regulate Retinal Neurogenesis
(2021) Frontiers in Cell and Developmental Biology, 8, art. no. 608112, .
Clark, B.S.a d , Miesfeld, J.B.a , Flinn, M.A.a b , Collery, R.F.c , Link, B.A.a
a Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
b Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States
c Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin Eye Institute, Milwaukee, WI, United States
d Department of Ophthalmology and Visual Sciences, Department of Developmental Biology, Washington University School of Medicine, St. LouisMO, United States
Abstract
Interkinetic nuclear migration (IKNM) is the process in which pseudostratified epithelial nuclei oscillate from the apical to basal surface and in phase with the mitotic cycle. In the zebrafish retina, neuroepithelial retinal progenitor cells (RPCs) increase Notch activity with apical movement of the nuclei, and the depth of nuclear migration correlates with the probability that the next cell division will be neurogenic. This study focuses on the mechanisms underlying the relationships between IKNM, cell signaling, and neurogenesis. In particular, we have explored the role IKNM has on endosome biology within RPCs. Through genetic manipulation and live imaging in zebrafish, we find that early (Rab5-positive) and recycling (Rab11a-positive) endosomes polarize in a dynamic fashion within RPCs and with reference to nuclear position. Functional analyses suggest that dynamic polarization of recycling endosomes and their activity within the neuroepithelia modulates the subcellular localization of Crb2a, consequently affecting multiple signaling pathways that impact neurogenesis including Notch, Hippo, and Wnt activities. As nuclear migration is heterogenous and asynchronous among RPCs, Rab11a-affected signaling within the neuroepithelia is modulated in a differential manner, providing mechanistic insight to the correlation of IKNM and selection of RPCs to undergo neurogenesis. © Copyright © 2021 Clark, Miesfeld, Flinn, Collery and Link.
Author Keywords
crumbs; endocytosis; interkinetic nuclear migration; neurogenesis; Rab11; recycling endosome
Funding details
P30 EY08126
National Institutes of HealthNIHC06RR016511, F32 HL150958, K99EY030944, P30 EY001931, R00EY027844, R01 EY014167, T32 EY014536, T32 HL134643
National Center for Research ResourcesNCRRG20 RR030956
Vanderbilt-Ingram Cancer CenterVICCP30 CA68485
University of Massachusetts Amherst
E. Matilda Ziegler Foundation for the Blind
Document Type: Article
Publication Stage: Final
Source: Scopus
“Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss” (2021) Frontiers in Cell and Developmental Biology
Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss
(2021) Frontiers in Cell and Developmental Biology, 8, art. no. 628712, .
Holmgren, M.a , Sheets, L.a b
a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans. © Copyright © 2021 Holmgren and Sheets.
Author Keywords
hair cell; hearing loss; lateral line; mitochondria; zebrafish
Funding details
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCDR01-DC-016066
Document Type: Review
Publication Stage: Final
Source: Scopus
“Fine Particle Exposure and Clinical Aggravation in Neurodegenerative Diseases in New York State” (2021) Environmental Health Perspectives
Fine Particle Exposure and Clinical Aggravation in Neurodegenerative Diseases in New York State
(2021) Environmental Health Perspectives, 129 (2), p. 27003.
Nunez, Y.a , Boehme, A.K.b , Weisskopf, M.G.c , Re, D.B.a , Navas-Acien, A.a , van Donkelaar, A.d e , Martin, R.V.d e , Kioumourtzoglou, M.-A.a
a Department of Environmental Health Sciences, Columbia University Mailman School of Public HealthNY, United States
b Department of Epidemiology and Neurology, Columbia UniversityNY, United States
c Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States
d Department of Energy, Environmental and Chemical Engineering, Washington University in St. Louis, St. Louis, MO, United States
e Department of Physics and Atmospheric Science, Dalhousie University, Halifax, NS, Canada
Abstract
BACKGROUND: Adult-onset neurodegenerative diseases affect millions and negatively impact health care systems worldwide. Evidence suggests that air pollution may contribute to aggravation of neurodegeneration, but studies have been limited. OBJECTIVE: We examined the potential association between long-term exposure to particulate matter formula presented in aerodynamic diameter [fine particulate matter (formula presented )] and disease aggravation in Alzheimer’s (AD) and Parkinson’s (PD) diseases and amyotrophic lateral sclerosis (ALS), using first hospitalization as a surrogate of clinical aggravation. METHODS: We used data from the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS 2000-2014) to construct annual county counts of first hospitalizations with a diagnosis of AD, PD, or ALS (total, urbanicity-, sex-, and age-stratified). We used annual formula presented concentrations estimated by a prediction model at a formula presented resolution, which we aggregated to population-weighted county averages to assign exposure to cases based on county of residence. We used outcome-specific mixed quasi-Poisson models with county-specific random intercepts to estimate rate ratios (RRs) for a 1-y formula presented exposure. We allowed for nonlinear exposure-outcome relationships using penalized splines and accounted for potential confounders. RESULTS: We found a positive nonlinear formula presented association that plateaued above formula presented (formula presented , 95% CI: 1.04, 1.14 for a formula presented increase from 8.1 to formula presented ). We also found a linear formula presented positive association (formula presented , 95% CI: 1.01, 1.09 per formula presented increase), and suggestive evidence of an association with AD. We found effect modification by age for PD and ALS with a stronger positive association in patients formula presented of age but found insufficient evidence of effect modification by sex or urbanization level for any of the outcomes. CONCLUSION: Our findings suggest that annual increase in county-level formula presented concentrations may contribute to clinical aggravation of PD and ALS. Importantly, the average annual formula presented concentration in our study was formula presented , below the current American national standards, suggesting the standards may not adequately protect the aging population. https://doi.org/10.1289/EHP7425.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Conscious Sedation versus Local Anesthesia During Thrombectomy for Acute Ischemic Stroke, Do We Have a Winner?” (2021) World Neurosurgery
Conscious Sedation versus Local Anesthesia During Thrombectomy for Acute Ischemic Stroke, Do We Have a Winner?
(2021) World Neurosurgery, 146, pp. 383-384.
Anadani, M.a , Audibert, G.b , Gory, B.c d
a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Anesthesiology and Surgical Intensive Care, Université de Lorraine, Nancy, France
c Department of Diagnostic and Therapeutic Neuroradiology, Université de Lorraine, Nancy, France
d IADI, INSERM U1254, Université de Lorraine, Nancy, France
Document Type: Article
Publication Stage: Final
Source: Scopus
“The role of mental imagery in Parkinson’s disease rehabilitation” (2021) Brain Sciences
The role of mental imagery in Parkinson’s disease rehabilitation
(2021) Brain Sciences, 11 (2), art. no. 185, pp. 1-14.
Abraham, A.a b , Duncan, R.P.c d , Earhart, G.M.c d e
a Department of Physical Therapy, Faculty of Health Sciences, Ariel University, Ariel, 4077625, Israel
b Navigation and Accessibility Research Center of Ariel University (NARCA), Ariel University, Ariel, 4077625, Israel
c Washington University in St. Louis School of Medicine, St. Louis, MO 63108, United States
d Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
e Department of Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
Abstract
Parkinson’s disease (PD) is a disabling neurodegenerative disease whose manifestations span motor, sensorimotor, and sensory domains. While current therapies for PD include pharma-cological, invasive, and physical interventions, there is a constant need for developing additional approaches for optimizing rehabilitation gains. Mental imagery is an emerging field in neuroreha-bilitation and has the potential to serve as an adjunct therapy to enhance patient function. Yet, the literature on this topic is sparse. The current paper reviews the motor, sensorimotor, and sensory domains impacted by PD using gait, balance, and pain as examples, respectively. Then, mental imagery and its potential for PD motor and non-motor rehabilitation is discussed, with an emphasis on its suitability for addressing gait, balance, and pain deficits in people with PD. Lastly, future research directions are suggested. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Dynamic neuro-cognitive imagery; Mental imagery; Motor; Motor imagery; Parkinson’s disease; Rehabilitation; Sensorimotor; Sensory
Funding details
National Institutes of HealthNIHK23 HD100569, R61 AT010753
Document Type: Article
Publication Stage: Final
Source: Scopus
“Survival Predictors of Heart Rate Variability After Myocardial Infarction With and Without Low Left Ventricular Ejection Fraction” (2021) Frontiers in Neuroscience
Survival Predictors of Heart Rate Variability After Myocardial Infarction With and Without Low Left Ventricular Ejection Fraction
(2021) Frontiers in Neuroscience, 15, art. no. 610955, .
Hayano, J.a , Ueda, N.a , Kisohara, M.a , Yuda, E.b , Carney, R.M.c , Blumenthal, J.A.d
a Department of Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
b Tohoku University Graduate School of Engineering, Sendai, Japan
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Duke University Medical Center, Durham, NC, United States
Abstract
Background: Heart rate variability (HRV) and heart rate (HR) dynamics are used to predict the survival probability of patients after acute myocardial infarction (AMI), but the association has been established in patients with mixed levels of left ventricular ejection fraction (LVEF). Objective: We investigated whether the survival predictors of HRV and HR dynamics depend on LVEF after AMI. Methods: We studied 687 post-AMI patients including 147 with LVEF ≤35% and 540 with LVEF >35%, of which 23 (16%) and 22 (4%) died during the 25 month follow-up period, respectively. None had an implanted cardioverter-defibrillator. From baseline 24 h ECG, the standard deviation (SDNN), root mean square of successive difference (rMSSD), percentage of successive difference >50 ms (pNN50) of normal-to-normal R-R interval, ultra-low (ULF), very-low (VLF), low (LF), and high (HF) frequency power, deceleration capacity (DC), short-term scaling exponent (α1), non-Gaussianity index (λ25s), and the amplitude of cyclic variation of HR (Acv) were calculated. Results: The predictors were categorized into three clusters; DC, SDNN, α1, ULF, VLF, LF, and Acv as Cluster 1, λ25s independently as Cluster 2, and rMSSD, pNN50, and HF as Cluster 3. In univariate analyses, mortality was best predicted by indices belonging to Cluster 1 regardless of LVEF. In multivariate analyses, however, mortality in patients with low LVEF was best predicted by the combinations of Cluster 1 predictors or Cluster 1 and 3 predictors, whereas in patients without low LVEF, it was best predicted by the combinations of Cluster 1 and 2 predictors. Conclusion: The mortality risk in post-AMI patients with low LVEF is predicted by indices reflecting decreased HRV or HR responsiveness and cardiac parasympathetic dysfunction, whereas in patients without low LVEF, the risk is predicted by a combination of indices that reflect decreased HRV or HR responsiveness and indicator that reflects abrupt large HR changes suggesting sympathetic involvement. © Copyright © 2021 Hayano, Ueda, Kisohara, Yuda, Carney and Blumenthal.
Author Keywords
heart rate dynamics; heart rate variability; left ventricular ejection fraction; mortality; myocardial Infarction; redundancy; risk stratification; survival
Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBI
Document Type: Article
Publication Stage: Final
Source: Scopus
“Free Flap Reconstruction of the Anterior Skull Base: A Systematic Review” (2021) Journal of Neurological Surgery, Part B: Skull Base
Free Flap Reconstruction of the Anterior Skull Base: A Systematic Review
(2021) Journal of Neurological Surgery, Part B: Skull Base, .
Dang, R.P.a , Ettyreddy, A.R.a , Rizvi, Z.b , Doering, M.c , Mazul, A.L.a , Zenga, J.d , Jackson, R.S.a , Pipkorn, P.a
a Department of Otolaryngology-Head and Neck Surgery, Washington University, School of Medicine, 660 South Euclid Avenue, Louis, MO 63110, United States
b Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA, United States
c School of Medicine, Washington University in Saint Louis, Saint Louis, MO, United States
d Department of Otolaryngology-Head and Neck Surgery, Medical College of Wisconsin, Milwaukee, WI, United States
Abstract
Objectives Given the limitations in the available literature, the precise indications, techniques, and outcomes of anterior skull base free flap reconstruction remain uncertain. The objective of this study was to perform a systematic review of published literature and evaluate indications, methods, and complications for anterior skull base free flap reconstruction. Methods A systematic review of the literature was performed using a set of search criteria to identify patients who underwent free flap reconstruction of the anterior skull base. Articles were reviewed for inclusion based on relevance, with the primary outcome being surgical complications. Results After a comprehensive search, 406 articles were obtained and 16 articles were ultimately found to be relevant to this review-79 patients undergoing free flap reconstruction were identified. Overall complication rates were 17.7% (95% confidence interval [CI]: 16.6-33.1%) for major complications and 19.0% (95% CI: 17.8-35.5%) for minor complications. Conclusion Microvascular reconstruction of the anterior skull base is feasible with high reliability reported in the literature. © 2021 Wolters Kluwer Medknow Publications. All rights reserved.
Author Keywords
anterior; free flap; reconstruction; skull base; systematic review
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
“Focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN)” (2021) MethodsX
Focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN)
(2021) MethodsX, 8, art. no. 101266, .
Ye, D.a , Chen, H.b c
a Department of Mechanical Engineering and Material Science, Washington University in St. Louis, Saint Louis, MO 63130, United States
b Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
c Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United States
Abstract
The blood-brain barrier (BBB) is the major obstacle for brain drug delivery and limits the treatment options for central nervous system diseases. To circumvent the BBB, we introduce focused ultrasound-mediated intranasal brain drug delivery (FUSIN). FUSIN utilizes the nasal route for direct nose-to-brain drug administration, bypassing the BBB and minimizing systemic exposure to the major organs, such as heart, lung, liver, and kidney [1]. It also uses transcranial ultrasound energy focused at a targeted brain region to induce microbubble cavitation, enhancing the transport of intranasally administered agents at the FUS-targeted brain location. FUSIN is unique because it can achieve noninvasive and localized brain drug delivery with minimized systemic toxicity to other major organs. The goal of this paper is to provide a detailed protocol for FUSIN delivery to the mouse brain. • FUSIN delivery utilizes the nose-to-brain pathway for brain drug delivery. • FUSIN utilizes FUS combined with microbubble to significantly enhance the delivery efficiency of intranasally administered drugs to the FUS targeted brain regions. • FUSIN achieves efficient brain delivery with minimized systemic exposure in the major organs. © 2021 The Authors
Author Keywords
Blood-brain barrier; Brain drug delivery; Focused ultrasound; Focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN); Intranasal administration; Microbubbles
Funding details
800CW-BSA
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981
Document Type: Article
Publication Stage: Final
Source: Scopus
“Treatment of sacroiliac joint laxity-induced coronal imbalance with the kickstand rod technique” (2021) British Journal of Neurosurgery
Treatment of sacroiliac joint laxity-induced coronal imbalance with the kickstand rod technique
(2021) British Journal of Neurosurgery, .
Zhang, J.K., Dibble, C.F., Cashin, J., Hajji, S., Dorward, I., Hawasli, A.H.
Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Considerations of the sacroiliac joint (SIJ) and its role in causing lower back and limb pain have taken a secondary role ever since Mixter and Barr’s hallmark article in 1934 on the herniated nucleus pulposus. However, recent literature has highlighted the contribution of sacroiliac joint degeneration in the development of failed back surgery syndrome (FBSS), especially in patients undergoing lumbar or lumbosacral spinal fusion surgeries. Many reports have studied the anatomy, physiology, and clinical significance of the sacroiliac joint, but none have linked its dysfunction with other spinal deformities. Case Description: A 63-year-old female with a history of multiple complex instrumented spinal fusions presented to our institution with progressive leftward coronal imbalance despite successful arthrodesis from T3 through S1. She was initially treated with decompression and reimplantation, but adjacent segment disease at the SIJ led to laxity, distal failure, and a worsening coronal deformity. A mechanical fall after her decompression surgery led to a dramatically increased coronal imbalance, which was ultimately treated using Lenke’s kickstand rod technique. At 3.5 years follow up, the patient’s coronal balance remains stable. Conclusion: Few studies have related SIJ degeneration and laxity with spinal deformity. Our case describes SIJ degeneration that evolved to joint laxity, which ultimately produced a leftward coronal imbalance according to the adjacent segment disease mechanism. Additionally, we describe the use of a kickstand rod to effectively correct the coronal imbalance, reduce pain levels, promote SIJ arthrodesis, and prevent further SIJ-related issues without significant complications over 3 years post-operation. © 2021 The Neurosurgical Foundation.
Author Keywords
Coronal imbalance; joint hypermobility; kickstand rod; pseudarthrosis; sacroiliac joint; spinal deformity; spinal fusion
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Understanding barriers to treatment among individuals not engaged in treatment who misuse opioids: A structural equation modeling approach” (2021) Substance Abuse
Understanding barriers to treatment among individuals not engaged in treatment who misuse opioids: A structural equation modeling approach
(2021) Substance Abuse, .
Cavazos-Rehg, P.a , Xu, C.a , Krauss, M.J.a , Min, C.a , Winograd, R.b , Grucza, R.a , Bierut, L.J.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Missouri Institute of Mental Health, University of Missouri St. Louis, St. Louis, MO, United States
Abstract
Background: Many individuals misusing opioids do not enter into treatment. The question of who enters into treatment for their opioid abuse and under what circumstances is complex and shaped by multiple factors. The objective of the current study is to explore the risk factors for wide-ranging and numerous barriers to treatment among social media users. Method: Opioid-related forums within a popular social media platform were used to recruit non-treatment engaged individuals (≥15 years) who had misused opioids in the past month (n = 144; 66% male; median age 28). Four treatment barrier factors were identified utilizing principle component analysis: (1) stigma, (2) awareness, (3) attitudinal, and (4) denial. A structural equation model (SEM) was then created to explore the risk factors for different types of barriers to OUD treatment. Results: The most common barriers among participants not engaged in treatment for their opioid misuse were the belief that one should be able to help themselves with their condition (66%), treatment was too expensive (63%), and worries about being labeled or judged (57%). Additionally, SEM results demonstrate stigma barriers, awareness, and attitudinal barriers were associated with mental health comorbidities, opioid abuse and dependence severity, and treatment history. Denial barriers, however, were only associated with treatment history, and structural/financial barriers were only associated with opioid abuse and dependence severity. Conclusions: Our research findings are relevant for underscoring the wide-ranging and numerous barriers to treatment faced by individuals misusing opioids that are especially concentrated among those who also struggle with comorbid mental illness. © 2021 Taylor & Francis Group, LLC.
Author Keywords
anxiety; comorbidity; depression; opioids; Social media; treatment barriers
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Guilty, Innocent, or Just Not Proven? Bayesian Verdicts in the Case of Inhibitory Deficits” (2021) Experimental Aging Research
Guilty, Innocent, or Just Not Proven? Bayesian Verdicts in the Case of Inhibitory Deficits
(2021) Experimental Aging Research, .
Myerson, J.a , Featherston, K.G.a , Flores, C.b , Lilienthal, L.c , Bui, Y.d , Hale, S.a
a Department of Psychological Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Stanford Introductory Studies – Thinking Matters, Stanford University, Stanford, CA, United States
c Department of Psychology, Penn State Altoona, Altoona, PA, United States
d Exponent, Inc, Los Angeles, CA, United States
Abstract
Background: This study addresses two issues: Whether age-related differences in working memory (WM) can be studied in online samples, and whether such differences reflect an inhibitory deficit. Currently, the evidence is mixed, but the playing field was not level because traditional statistics cannot provide evidence for the null hypothesis. Experiment 1: MTurk workers (ages 19–74) performed simple and complex visuospatial WM tasks to determine whether a secondary task affected the rate of age-related decline. Performance on both tasks replicated previous laboratory studies, establishing that age-related differences in WM can be studied online. Bayesian analyses revealed it is ten times as likely that there is no inhibitory deficit on visuospatial WM tasks as that there is. Experiment 2: The effects of irrelevant location information on visuospatial WM were examined in older (M age = 64.0) and younger (M age = 25.0) MTurk workers. Irrelevant locations produced interference, but both groups were equally affected. Bayesian analyses provided support for the null hypothesis of no age difference. Conclusions: The results of both experiments on working memory not only revealed equivalent visuospatial inhibitory function in older and younger adults, they also demonstrated that age-related differences in visuospatial WM can be effectively studied online as well as in the laboratory. © 2021 Taylor & Francis Group, LLC.
Funding details
National Institutes of HealthNIHR01AG058885
National Institute on AgingNIA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“MR Elastography demonstrates reduced white matter shear stiffness in early-onset hydrocephalus” (2021) NeuroImage: Clinical
MR Elastography demonstrates reduced white matter shear stiffness in early-onset hydrocephalus
(2021) NeuroImage: Clinical, 30, art. no. 102579, .
Wagshul, M.E.a , McAllister, J.P.b , Limbrick, D.D., Jr.b c , Yang, S.a , Mowrey, W.d , Goodrich, J.T.e , Meiri, A.a , Morales, D.M.b , Kobets, A.e , Abbott, R.e
a Albert Einstein College of Medicine, Gruss MRRC, Departments of Radiology and Physiology & Biophysics, Bronx, NY, United States
b Saint Louis Children’s Hospital and the Department of Neurosurgery, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Pediatrics, Washington University, School of Medicine, United States
d Albert Einstein College of Medicine, Department of Epidemiology and Population Health, Bronx, NY, United States
e Montefiore Medical Center, Department of Neurosurgery, Bronx, NY, United States
Abstract
Introduction: Hydrocephalus that develops early in life is often accompanied by developmental delays, headaches and other neurological deficits, which may be associated with changes in brain shear stiffness. However, noninvasive approaches to measuring stiffness are limited. Magnetic Resonance Elastography (MRE) of the brain is a relatively new noninvasive imaging method that provides quantitative measures of brain tissue stiffness. Herein, we aimed to use MRE to assess brain stiffness in hydrocephalus patients compared to healthy controls, and to assess its associations with ventricular size, as well as demographic, shunt-related and clinical outcome measures. Methods: MRE was collected at two imaging sites in 39 hydrocephalus patients and 33 healthy controls, along with demographic, shunt-related, and clinical outcome measures including headache and quality of life indices. Brain stiffness was quantified for whole brain, global white matter (WM), and lobar WM stiffness. Group differences in brain stiffness between patients and controls were compared using two-sample t-tests and multivariable linear regression to adjust for age, sex, and ventricular volume. Among patients, multivariable linear or logistic regression was used to assess which factors (age, sex, ventricular volume, age at first shunt, number of shunt revisions) were associated with brain stiffness and whether brain stiffness predicts clinical outcomes (quality of life, headache and depression). Results: Brain stiffness was significantly reduced in patients compared to controls, both unadjusted (p ≤ 0.002) and adjusted (p ≤ 0.03) for covariates. Among hydrocephalic patients, lower stiffness was associated with older age in temporal and parietal WM and whole brain (WB) (beta (SE): −7.6 (2.5), p = 0.004; −9.5 (2.2), p = 0.0002; −3.7 (1.8), p = 0.046), being female in global and frontal WM and WB (beta (SE): −75.6 (25.5), p = 0.01; −66.0 (32.4), p = 0.05; −73.2 (25.3), p = 0.01), larger ventricular volume in global, and occipital WM (beta (SE): −11.5 (3.4), p = 0.002; −18.9 (5.4), p = 0.0014). Lower brain stiffness also predicted worse quality of life and a higher likelihood of depression, controlling for all other factors. Conclusions: Brain stiffness is reduced in hydrocephalus patients compared to healthy controls, and is associated with clinically-relevant functional outcome measures. MRE may emerge as a clinically-relevant biomarker to assess the neuropathological effects of hydrocephalus and shunting, and may be useful in evaluating the effects of therapeutic alternatives, or as a supplement, of shunting. © 2021 The Authors
Author Keywords
MR Elastography; Pediatric hydrocephalus; Quality of life; Shear stiffness; Shunting; White matter stiffness
Document Type: Article
Publication Stage: Final
Source: Scopus
“Obesity and White Matter Neuroinflammation Related Edema in Alzheimer’s Disease Dementia Biomarker Negative Cognitively Normal Individuals” (2021) Journal of Alzheimer’s Disease
Obesity and White Matter Neuroinflammation Related Edema in Alzheimer’s Disease Dementia Biomarker Negative Cognitively Normal Individuals
(2021) Journal of Alzheimer’s Disease, 79 (4), pp. 1801-1811.
Ly, M.a , Raji, C.A.b c , Yu, G.Z.a , Wang, Q.b , Wang, Y.b , Schindler, S.E.c , An, H.b , Samara, A.d , Eisenstein, S.A.b d , Hershey, T.b c d e , Smith, G.f , Klein, S.f , Liu, J.g , Xiong, C.g , Ances, B.M.c , Morris, J.C.c , Benzinger, T.L.S.b
a University of Pittsburgh Medical Scientist Training Program, Pittsburgh, PA, United States
b Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
e Department of Psychological Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States
f Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO, United States
g Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer’s disease (AD) dementia. Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR=0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N=62) or overweight and obese (BMI ≥25, N=42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL. Results: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha=0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers. Conclusion: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly. © 2021 – IOS Press. All rights reserved.
Author Keywords
Alzheimer’s disease; neuroinflammation imaging; obesity
Funding details
KL2 TR000450
National Institutes of HealthNIHP01AG003991, P01AG026276, P50AG005681
Radiological Society of North AmericaRSNA
Document Type: Article
Publication Stage: Final
Source: Scopus
“Environmental Risk Factors and Psychotic-like Experiences in Children Aged 9–10” (2021) Journal of the American Academy of Child and Adolescent Psychiatry
Environmental Risk Factors and Psychotic-like Experiences in Children Aged 9–10
(2021) Journal of the American Academy of Child and Adolescent Psychiatry, .
Karcher, N.R.a , Schiffman, J.b c , Barch, D.M.d
a Washington University School of Medicine, St. Louis, MO, United States
b University of Maryland, Baltimore County
c University of CaliforniaIrvine
d Washington University in St. LouisMO, United States
Abstract
Objective: Research implicates environmental risk factors, including correlates of urbanicity, deprivation, and environmental toxins, in psychotic-like experiences (PLEs). The current study examined associations between several types of environmental risk factors and PLEs in school-age children, whether these associations were specific to PLEs or generalized to other psychopathology, and examined possible neural mechanisms for significant associations. Method: The current study used cross-sectional data from 10,328 children 9–10 years old from the Adolescent Brain Cognitive Development (ABCD) Study. Hierarchical linear models examined associations between PLEs and geocoded environmental risk factors and whether associations generalized to internalizing/externalizing symptoms. Mediation models examined evidence of structural magnetic resonance imaging abnormalities (eg, intracranial volume) potentially mediating associations between PLEs and environmental risk factors. Results: Specific types of environmental risk factors, namely, measures of urbanicity (eg, drug offense exposure, less perception of neighborhood safety), deprivation (eg, overall deprivation, poverty rate), and lead exposure risk, were associated with PLEs. These associations showed evidence of stronger associations with PLEs than internalizing/externalizing symptoms (especially overall deprivation, poverty, drug offense exposure, and lead exposure risk). There was evidence that brain volume mediated between 11% and 25% of associations of poverty, perception of neighborhood safety, and lead exposure risk with PLEs. Conclusion: Although in the context of cross-sectional analyses, this evidence is consistent with neural measures partially mediating the association between PLEs and environmental exposures. This study also replicated and extended recent findings of associations between PLEs and environmental exposures, finding evidence for specific associations with correlates of urbanicity, deprivation, and lead exposure risk. © 2020 American Academy of Child and Adolescent Psychiatry
Author Keywords
deprivation; lead exposure; MRI; psychotic-like experiences; urbanicity
Funding details
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
National Institute on Drug AbuseNIDAMH014677, R01-MH112612, R34-MH110506, U01 DA041120
Maryland Department of Health and Mental HygieneDHMH14-13717G/M00B4400214
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Spatially constrained kinetic modeling with dual reference tissues improves 18F-flortaucipir PET in studies of Alzheimer disease” (2021) European Journal of Nuclear Medicine and Molecular Imaging
Spatially constrained kinetic modeling with dual reference tissues improves 18F-flortaucipir PET in studies of Alzheimer disease
(2021) European Journal of Nuclear Medicine and Molecular Imaging, .
Zhou, Y.a , Flores, S.a , Mansor, S.a , Hornbeck, R.C.a , Tu, Z.a , Perlmutter, J.S.a b , Ances, B.c , Morris, J.C.b c , Gropler, R.J.a , Benzinger, T.L.S.a b c
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8225, 510 S. Kingshighway Blvd, St Louis, MO 63110, United States
b Departments of Neurology and Neuroscience, Programs of Physical Therapy and Occupational Therapy, Washington University School of Medicine, Saint Louis, MO, United States
c Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
Abstract
Purpose: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues. Methods: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVREP, 0.7–2.9 min) and late phase (SUVRLP, 80–105 min) to approximate R1 and DVR, respectively. Results: The percent coefficients of variation of R1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVRLP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVRLP, and cerebellum-based SUVREP and R1 provided higher Cohen’s effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals. Conclusion: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R1 and DVR, respectively, for dynamic 18F-flortaucipir PET studies. Cerebellum-based SUVREP and CS-based SUVRLP may be used to simplify 18F-flortaucipir PET study. © 2021, Springer-Verlag GmbH Germany, part of Springer Nature.
Author Keywords
18F-Flortaucipir PET; Alzheimer disease; Dual reference tissues; Logan plot; Spatially constrained kinetic modeling; SRTM; SUVR
Funding details
National Institutes of HealthNIH1RO1HL150891-01, 2P01AG003991-36, P01AG026276, P41EB025815, P50 AG05681, U01AG042791, U19 AG032438-08
Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Comparison of deep phenotyping features of UCPPS with and without Hunner lesion: A MAPP-II Research Network Study” (2021) Neurourology and Urodynamics
Comparison of deep phenotyping features of UCPPS with and without Hunner lesion: A MAPP-II Research Network Study
(2021) Neurourology and Urodynamics, .
Lai, H.H.a , Newcomb, C.b , Harte, S.c , Appleby, D.b , Ackerman, A.L.d , Anger, J.T.d , Nickel, J.C.e , Gupta, P.f , Rodriguez, L.V.g , Landis, J.R.b , Clemens, J.Q.f , The MAPP Research Networkh
a Departments of Surgery (Urology) and Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
b Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
c Departments of Anesthesiology and Internal Medicine-Rheumatology, University of Michigan, Ann Arbor, MI, United States
d Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
e Department of Urology, Queen’s University, Kingston, ON, Canada
f Department of Urology, University of Michigan, Ann Arbor, MI, United States
g Departments of Urology, and Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, United States
Abstract
Objective: To use the phenotyping data from the MAPP-II Symptom Patterns Study (SPS) to compare the systemic features between urologic chronic pelvic pain syndrome (UCPPS) with Hunner lesion (HL) versus those without HL. Methods: We performed chart review on 385 women and 193 men with UCPPS who enrolled in the MAPP-II SPS. 223 had cystoscopy and documentation of HL status. Among them, 12.5% had HL and 87.5% did not. Results: UCPPS participants with HL were older, had increased nocturia, higher Interstitial Cystitis Symptom and Problem Indexes, and were more likely to report “painful urgency” compared with those without HL. On the other hand, UCPPS without HL reported more intense nonurologic pain, greater distribution of pain outside the pelvis, greater numbers of comorbid chronic overlapping pain conditions, higher fibromyalgia-like symptoms, and greater pain centralization, and were more likely to have migraine headache than those with HL. UCPPS without HL also had higher anxiety, perceived stress, and pain catastrophizing than those with HL. There were no differences in sex distribution, UCPPS symptom duration, intensity of urologic pain, distribution of genital pain, pelvic floor tenderness on pelvic examination, quality of life, depression, pain characteristics (nociceptive pain vs. neuropathic pain), mechanical hypersensitivity in the suprapubic area during quantitative sensory testing, and 3-year longitudinal pain outcome and urinary outcome between the two groups. Conclusions: UCPPS with HL displayed more bladder-centric symptom profiles, while UCPPS without HL displayed symptoms suggesting a more systemic pain syndrome. The MAPP-II SPS phenotyping data showed that Hunner lesion is a distinct phenotype from non-Hunner lesion. © 2021 Wiley Periodicals LLC
Author Keywords
chronic prostatitis; clinical phenotyping; Hunner lesion; interstitial cystitis; personalized medicine; ulcerative interstitial cystitis
Funding details
National Institutes of HealthNIHDK082315, DK082316, DK082325, DK082333, DK082342, DK082344, DK082345, DK082370, DK103227, DK103260, DK103271
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease” (2021) Neuromuscular Disorders
Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease
(2021) Neuromuscular Disorders, .
Moore, U.a , Gordish, H.b c , Diaz-Manera, J.d e , James, M.K.a , Mayhew, A.G.a , Guglieri, M.a , Fernandez-Torron, R.a , Rufibach, L.E.f , Feng, J.b , Blamire, A.M.g , Carlier, P.G.h , Spuler, S.i , Day, J.W.j , Jones, K.J.k , Bharucha-Goebel, D.X.l m , Salort-Campana, E.n , Pestronk, A.o , Walter, M.C.p , Paradas, C.q , Stojkovic, T.r , Mori-Yoshimura, M.s , Bravver, E.t , Pegoraro, E.u , Lowes, L.P.v , Mendell, J.R.v , Bushby, K.a , Straub, V.a , Jain COS Consortiumw
a The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Central Parkway, Newcastle upon Tyne, United Kingdom
b Center for Translational Science, Division of Biostatistics and Study Methodology, Children’s National Health SystemWashington, DC, United States
c Pediatrics, Epidemiology and Biostatistics, George Washington UniversityWashington, DC, United States
d Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain
e Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau
f The Jain Foundation, Seattle, Washington DC, United States
g Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, United Kingdom
h AIM & CEA NMR Laboratory, Institute of Myology, Pitié-Salpêtrière University Hospital, Paris, 47-83, France
i Charite Muscle Research Unit, Experimental and Clinical Research Center, a Joint Cooperation of the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany
j Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
k The Children’s Hospital at Westmead, and The University of Sydney, Australia
l Department of Neurology Children’s National Health SystemWashington, DC, United States
m National Institutes of Health (NINDS), Bethesda, MD, United States
n Service des maladies neuromusculaire et de la SLA, Hôpital de La Timone, Marseille, France
o Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
p Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Germany
q Neuromuscular Unit, Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, Spain
r Centre de référence des maladies neuromusculaires, Institut de Myologie, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France
s Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
t Neuroscience Institute, Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, NC, United States
u Department of Neuroscience, University of Padova, Italy
v The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
Abstract
This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation’s international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments. © 2021 The Authors
Author Keywords
[16] Clinical neurology examination; [176] All neuromuscular disease; [185] Muscle disease; [21] Clinical trials methodology; [54] Cohort study
Funding details
MR/S005021/1
Jain Foundation
Biogen
Medical Research CouncilMRC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1)” (2021) Acta Neuropathologica
Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1)
(2021) Acta Neuropathologica, .
Fisher, M.J.a , Jones, D.T.W.b c , Li, Y.d , Guo, X.e , Sonawane, P.S.f , Waanders, A.J.a w , Phillips, J.J.g , Weiss, W.A.h , Resnick, A.C.f , Gosline, S.i x , Banerjee, J.i , Guinney, J.i , Gnekow, A.j , Kandels, D.j , Foreman, N.K.k , Korshunov, A.l , Ryzhova, M.m , Massimi, L.n ab , Gururangan, S.o , Kieran, M.W.p y , Wang, Z.q z , Fouladi, M.r aa , Sato, M.s , Øra, I.t , Holm, S.u , Markham, S.J.a , Beck, P.b c , Jäger, N.b c , Wittmann, A.b , Sommerkamp, A.C.b c , Sahm, F.l , Pfister, S.M.b c v , Gutmann, D.H.e
a Division of Oncology, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, United States
b Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
c Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
d Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, United States
e Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, United States
f Division of Neurosurgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
g Departments of Pathology, University of California, San Francisco, CA, United States
h Departments of Neurology, University of California, San Francisco, CA, United States
i Sage Bionetworks, Seattle, WA, United States
j Faculty of Medicine, University Augsburg, Augsburg, Germany
k University of Colorado, Denver, CO, United States
l Department of Neuropathology, Heidelberg University, Heidelberg, Germany
m Department of Neuropathology, NN Burdenko Neurosurgical Research Centre, Moscow, Russian Federation
n Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy
o Department of Neurosurgery, UF Health Shands Hospital, Gainesville, FL, United States
p Department of Pediatrics, Dana-Farber Cancer Institute, Boston, MA, United States
q Division of Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, United States
r Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
s Division of Hematology/Oncology, University of Iowa Stead Family Children’s Hospital, Iowa City, IA, United States
t Lund University Cancer Center, Lund University, Lund, Sweden
u Karolinska University Hospital, Stockholm, Sweden
v Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
w Division of Hematology/Oncology, Lurie Children’s Hospital of Chicago, Chicago, IL, United States
x Pacific Northwest National Laboratory, Seattle, WA, United States
y Bristol Myers Squibb, Lawrenceville, NJ, United States
z Division of Hematology and Oncology, Children’s Hospital of Richmond, Richmond, VA, United States
aa Division of Hematology and Oncology, Nationwide Children’s Hospital, Columbus, OH, United States
ab Pediatric Neurosurgery, A. Gemelli Hospital, Rome, Italy
Abstract
Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.
Author Keywords
FGFR1; Methylation; Neurofibromatosis; Pediatric brain tumor; Pilocytic astrocytoma
Funding details
Children’s Tumor FoundationCTF2015-18-004
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Mining reported adverse events induced by potential opioid-drug interactions” (2020) JAMIA Open
Mining reported adverse events induced by potential opioid-drug interactions
(2020) JAMIA Open, 3 (1), pp. 104-112.
Chen, J.a , Wu, G.b , Michelson, A.b , Vesoulis, Z.c , Bogner, J.d , Corrigan, J.D.d , Payne, P.R.O.b , Li, F.b c
a Department of Biostatistics, The Ohio State University, Columbus, OH, United States
b Institute for Informatics (I2), Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, OH, United States
Abstract
Objective: Opioid-based analgesia is routinely used in clinical practice for the management of pain and alleviation of suffering at the end of life. It is well-known that opioid-based medications can be highly addictive, promoting not only abuse but also life-threatening overdoses. The scope of opioid-related adverse events (AEs) beyond these well-known effects remains poorly described. This exploratory analysis investigates potential AEs from drug-drug interactions between opioid and nonopioid medications (ODIs). Materials and Methods: In this study, we conduct an initial exploration of the association between ODIs and severe AEs using millions of AE reports available in FDA Adverse Event Reporting System (FAERS). The odds ratio (OR)-based analysis and visualization are proposed for single drugs and pairwise ODIs to identify associations between AEs and ODIs of interest. Moreover, the multilabel (multi-AE) learning models are employed to evaluate the feasibility of AE prediction of polypharmacy. Results: The top 12 most prescribed opioids in the FAERS are identified. The OR-based analysis identifies a diverse set of AEs associated with individual opioids. Moreover, the results indicate many ODIs can increase the risk of severe AEs dramatically. The area under the curve values of multilabel learning models of ODIs for oxycodone varied between 0.81 and 0.88 for 5 severe AEs. Conclusions: The proposed data analysis and visualization are useful for mining FAERS data to identify novel polypharmacy associated AEs, as shown for ODIs. This approach was successful in recapitulating known drug interactions and also identified new opioid-specific AEs that could impact prescribing practices. © The Author(s) 2020.
Author Keywords
Adverse drug effects; Opioid; Opioid-drug interaction
Funding details
Washington University in St. LouisWUSTL
Department of Pediatrics, University of Florida
Document Type: Article
Publication Stage: Final
Source: Scopus