“Structural correlates of commission errors in prospective memory” (2020) Cortex
Structural correlates of commission errors in prospective memory
(2020) Cortex, 124, pp. 44-53.
Scullin, M.K.a , Ball, B.H.b c , Bugg, J.M.b
a Baylor University, United States
b Washington University in St. Louis, United States
c University of Texas, Arlington, United States
Abstract
Prospective memory refers to remembering to perform an intended future action, such as remembering to take medication with breakfast. Historically, the field has focused on failures to initially remember a prospective memory task (omission errors), but interestingly, individuals will occasionally repeat a prospective memory action after it has been completed (e.g., double dosing). These failures in prospective memory deactivation/forgetting are termed commission errors. The current registered study investigated structural neuroimaging correlates of a laboratory measure of commission errors in 47 healthy older adults. Extant theories differed in their predicted outcomes: commission error risk was predicted to be highest in individuals with smaller medial temporal lobe volume (output monitoring theory), larger lateral prefrontal cortex volume (residual activation theory), or a combination of larger medial temporal lobe volume and smaller lateral prefrontal cortex volume (dual mechanisms theory). In registered analyses, we found that a higher number of commission errors was associated with larger medial temporal lobe/hippocampal grey matter volume (supporting dual mechanisms theory), but not with grey or white matter volume in the lateral parietal lobe, frontal pole, or a composite of ventrolateral/dorsolateral prefrontal cortex (not supporting dual mechanisms theory). In post hoc analyses, smaller volume in the lateral orbitofrontal cortex was associated with a higher number of commission errors, possibly indicating that the dual mechanisms theory of PFC control was conceptually correct, but that a different PFC subregion than anticipated exerts control over commission errors. Collectively, the registered and post hoc analysis findings showed a functional dissociation across MTL/PFC regions that was more consistent with the dual mechanisms theory than the alternative theories. © 2019 Elsevier Ltd
Author Keywords
Aging; Commission Error; Hippocampus; Orbitofrontal cortex; Prospective Memory
Document Type: Article
Publication Stage: Final
Source: Scopus
“Association of poorer dietary quality and higher dietary inflammation with greater symptom severity in depressed individuals with appetite loss” (2020) Journal of Affective Disorders
Association of poorer dietary quality and higher dietary inflammation with greater symptom severity in depressed individuals with appetite loss
(2020) Journal of Affective Disorders, 263, pp. 99-106.
Burrows, K.a , Stewart, J.L.a , Antonacci, C.a b , Kuplicki, R.a , Thompson, K.a , Taylor, A.c , Teague, T.K.c d e f , Paulus, M.P.a
a Laureate Institute for Brain Research, Tulsa, OK, United States, United States
b Washington University in St. Louis, St. Louis, MO, United States
c Integrative Immunology Center, School of Community Medicine, The University of Oklahoma, Tulsa, OK, United States
d Departments of Surgery and Psychiatry, School of Community Medicine, The University of Oklahoma, Tulsa, OK, United States
e Department of Biochemistry and Microbiology, The Oklahoma State University Center for Health Sciences, Tulsa, OK, United States
f Department of Pharmaceutical Sciences, The University of Oklahoma College of Pharmacy, Oklahoma City, OK, United States
Abstract
Background: Major depressive disorder (MDD) is the leading cause of years lived with disability; however, little is known about its etiology to inform treatment. For a subset of MDD patients, appetite change and/or bodily inflammation may play a role in exacerbating symptoms. The goal of this study is to examine whether, relative to healthy comparisons (HC), MDD individuals with increased versus decreased appetite symptoms show a differential relationship between diet quality and inflammation. Methods: Unmedicated current MDD (n = 61) varying in appetite change (decrease (MDD-DE): n = 39; increase (MDD-IN): n = 22) and HC (n = 42) completed 24-hour dietary recall and state depression/anxiety measures. Healthy eating and dietary inflammatory indices were calculated from dietary reports. Blood samples measured five inflammation-related biomarkers. Analyses investigated between- and within-group differences in the Healthy Eating Index (HEI), the Dietary Inflammatory Index (DII), inflammation-related blood biomarkers, and symptom severity. Results: While both MDD-DE and MDD-IN exhibited lower HEI scores than HC, only MDD-IN showed higher plasma interleukin-1 receptor antagonist (IL-1RA) and interleukin-6 (IL-6) levels than HC. In contrast, MDD-DE exhibited higher DII scores than MDD-IN and HC. Within MDD-DE, greater symptom severity was associated with lower HEI and higher DII. Limitations: Modest sample sizes and the cross-sectional study design limited power to detect within-MDD effects. Conclusions: Although MDD, regardless of appetite change, is linked to poorer dietary quality, depression severity was related to dietary characteristics only in subjects who reported appetite loss. Thus, increasing the quality of dietary intake could be a treatment target for some individuals with depression. © 2019 Elsevier B.V.
Author Keywords
Appetite change; Dietary inflammatory index; Healthy eating index; Major depressive disorder; Nutrition; Plasma inflammation-related biomarkers
Document Type: Article
Publication Stage: Final
Source: Scopus
“Prevalence and correlates of maladaptive guilt in middle childhood” (2020) Journal of Affective Disorders
Prevalence and correlates of maladaptive guilt in middle childhood
(2020) Journal of Affective Disorders, 263, pp. 64-71.
Donohue, M.R.a , Tillman, R.a , Perino, M.T.a , Whalen, D.J.a , Luby, J.a , Barch, D.M.a b c
a Department of Psychiatry, Washington University School of Medicine, 4444 Forest Park Avenue, Suite 2100, St. Louis, MO, United States
b Department of Psychology, Washington University, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Maladaptive guilt can develop by age three and is associated with severe affective psychopathology in adolescents and adults. Yet, little is known about its prevalence prior to adolescence, or which children are at greatest risk of developing this symptom. This study examined the prevalence and correlates of maladaptive guilt in middle childhood. Methods: This study examined a large community sample of 9-to 10-year-old children (N = 4485) from the Adolescent Brain and Cognitive Development (ABCD) study. Maladaptive guilt was assessed through the Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5. Parental rejection, family conflict, and parental depression were assessed via questionnaires. Results: In depressed children, a 1-month prevalence of maladaptive guilt of 18.4% and a lifetime prevalence of 30.8% was found. Lifetime rates ranged from 1.8 to 4.1% in children with other psychiatric disorders. Cross-sectionally, maladaptive guilt was associated with lower family income-to-needs, greater family conflict, a history of maternal depression, and greater parental rejection. These findings held when controlling for children’s depressive severity, indicating that these associations are specific to maladaptive guilt. Limitations: Maladaptive guilt was assessed through one item, though many studies of maladaptive guilt measure the symptom in this manner. Conclusions: Findings suggest that it may be beneficial for clinicians to assess for maladaptive guilt beyond the context of assessment for depression, particularly with children of low socioeconomic status and children of depressed mothers, whom this study suggests are at higher risk. Negative family climates and parenting might also be important targets of preventative interventions. © 2019
Author Keywords
Family conflict; Maladaptive guilt; Maternal depression; Negative parenting; Prevalence
Document Type: Article
Publication Stage: Final
Source: Scopus
“Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe Disease)” (2020) Molecular and Cellular Neuroscience
Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe Disease)
(2020) Molecular and Cellular Neuroscience, 102, art. no. 103451, .
Corado, C.R.a , Pinkstaff, J.b , Jiang, X.c , Galban, E.M.d , Fisher, S.J.d , Scholler, O.a , Russell, C.a , Bagel, J.H.d , ODonnell, P.A.d , Ory, D.S.c , Vite, C.H.d , Bradbury, A.M.d
a BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949, United States
b AnaptysBio, Inc., 10421 Pacific Center Court, San Diego, CA 92121, United States
c Washington University, 1 Brookings Drive, St Louis, MO 63130, United States
d University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, United States
Abstract
Globoid cell leukodystrophy (GLD, Krabbe disease, Krabbe’s disease) is caused by genetic mutations in the gene encoding, galactosylceramidase (GALC). Deficiency of this enzyme results in central and peripheral nervous system pathology, and is characterized by loss of myelin and an infiltration of globoid cells. The canine model of GLD provides a translational model which faithfully recapitulates much of the human disease pathology. Targeted lipidomic analysis was conducted in serum and cerebrospinal fluid (CSF) over the lifetime of GLD affected and normal canines, and in brain tissue at humane endpoint to better understand disease progression and identify potential biomarkers of disease. Psychosine, a substrate of GALC and primary contributor to the pathology in GLD, was observed to be significantly elevated in the serum and CSF by 2 or 4 weeks of age, respectively, and steadily increased over the lifetime of affected animals. Importantly, psychosine concentration strongly correlated with disease severity. Galactosylceramide, glucosylceramide, and lactosylceramide were also found to be elevated in the CSF of affected animals and increased with age. Psychosine and galactosylceramide were found to be significantly increased in brain tissue at humane endpoint. This study identified several biomarkers which may be useful in the development of therapeutics for GLD. © 2019 Elsevier Inc.
Author Keywords
Brain lipids; Canine model; Ceramides; Globoid cell leukodystrophy; Liquid chromatography; Mass spectrometry; Sphingolipids
Document Type: Article
Publication Stage: Final
Source: Scopus
“let-7 MicroRNAs Regulate Microglial Function and Suppress Glioma Growth through Toll-Like Receptor 7” (2019) Cell Reports
let-7 MicroRNAs Regulate Microglial Function and Suppress Glioma Growth through Toll-Like Receptor 7
(2019) Cell Reports, 29 (11), pp. 3460-3471.e7.
Buonfiglioli, A.a b , Efe, I.E.b c , Guneykaya, D.b , Ivanov, A.d , Huang, Y.b , Orlowski, E.b , Krüger, C.a , Deisz, R.A.a , Markovic, D.e , Flüh, C.f , Newman, A.G.a , Schneider, U.C.g , Beule, D.d h , Wolf, S.A.i , Dzaye, O.c j , Gutmann, D.H.k , Semtner, M.b , Kettenmann, H.b , Lehnardt, S.a l
a Institute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
b Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany
c Department of Radiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
d Core Unit Bioinformatics, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
e Department of Neurosurgery, Helios Clinics, Berlin, 13125, Germany
f Department of Neurosurgery, University Medical Center Schleswig-Holstein (UKSH), Kiel, 24105, Germany
g Department of Neurosurgery, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
h Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
i Department of Ophthalmology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
j Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
k Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
l Department of Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
Abstract
Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 UUGU motif. In human and murine glioblastoma/glioma, let-7 miRNAs are differentially expressed and reduce murine GL261 glioma growth in the same sequence-specific fashion through microglial TLR7. Taken together, these data establish let-7 miRNAs as key TLR7 signaling activators that serve to regulate the diverse functions of microglia in health and glioma. © 2019 The Author(s)
Buonfiglioli et al. elucidate the role of let-7 miRNAs acting as Toll-like receptor (TLR) ligands in the brain. Select let-7 miRNAs function as signaling molecules to modulate diverse microglial functions and glioma growth through TLR7. These data establish let-7 miRNAs as TLR7 signaling activators of microglia in health and glioma. © 2019 The Author(s)
Author Keywords
glioblastoma; lethal-7; microglia; microRNA; Toll-like receptor 7
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“A metastable subproteome underlies inclusion formation in muscle proteinopathies” (2019) Acta Neuropathologica Communications
A metastable subproteome underlies inclusion formation in muscle proteinopathies
(2019) Acta Neuropathologica Communications, 7 (1), art. no. 197, .
Ciryam, P.a , Antalek, M.b , Cid, F.c , Tartaglia, G.G.c , Dobson, C.M.d , Guettsches, A.-K.e , Eggers, B.f , Vorgerd, M.e , Marcus, K.f , Kley, R.A.g , Morimoto, R.I.b , Vendruscolo, M.d , Weihl, C.C.h
a Department of Neurology, Vagelos College of Physicians, Columbia University, New York, NY, United States
b Rice Institute for Biomedical Research, Department of Molecular Biosciences, Northwestern University, Evanston, IL, United States
c Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
d Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
e Department of Neurology, Heimer Institute of Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
f Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum, Germany
g Department of Neurology, St. Marien Hospital Borken, University of Witten/Herdecke, Borken, Germany
h Department of Neurology and Hope Center for Neurological Disease, Washington University School of Medicine, Saint Louis, MO, United States
Abstract
Protein aggregation is a pathological feature of neurodegenerative disorders. We previously demonstrated that protein inclusions in the brain are composed of supersaturated proteins, which are abundant and aggregation-prone, and form a metastable subproteome. It is not yet clear, however, whether this phenomenon is also associated with non-neuronal protein conformational disorders. To respond to this question, we analyzed proteomic datasets from biopsies of patients with genetic and acquired protein aggregate myopathy (PAM) by quantifying the changes in composition, concentration and aggregation propensity of proteins in the fibers containing inclusions and those surrounding them. We found that a metastable subproteome is present in skeletal muscle from healthy patients. The expression of this subproteome escalate as proteomic samples are taken more proximal to the pathologic inclusion, eventually exceeding its solubility limits and aggregating. While most supersaturated proteins decrease or maintain steady abundance across healthy fibers and inclusion-containing fibers, proteins within the metastable subproteome rise in abundance, suggesting that they escape regulation. Taken together, our results show in the context of a human conformational disorder that the supersaturation of a metastable subproteome underlies widespread aggregation and correlates with the histopathological state of the tissue. © 2019 The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Developmental hypomyelination in Wolfram syndrome: New insights from neuroimaging and gene expression analyses” (2019) Orphanet Journal of Rare Diseases
Developmental hypomyelination in Wolfram syndrome: New insights from neuroimaging and gene expression analyses
(2019) Orphanet Journal of Rare Diseases, 14 (1), art. no. 279, .
Samara, A.a , Rahn, R.a b c , Neyman, O.a , Park, K.Y.a , Samara, A.d , Marshall, B.e , Dougherty, J.a c , Hershey, T.a b f
a Department of Psychiatry, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO 63110, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Genetics, Washington University Medical School, St. Louis, MO 63110, United States
d Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
e Department of Pediatrics, Washington University Medical School, St. Louis, MO 63110, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration. © 2019 The Author(s).
Author Keywords
Hypomyelination; Neurodegeneration; Neurodevelopment; Neuroimaging; Unfolded protein response; WFS1, endoplasmic reticulum stress
Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K+ and water” (2019) The Journal of Cell Biology
SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K+ and water
(2019) The Journal of Cell Biology, 218 (12), pp. 4017-4029.
Li, H.a , Russo, A.a , DiAntonio, A.a b
a Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO
b Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University in St. Louis School of Medicine, St. Louis, MO
Abstract
Glial regulation of extracellular potassium (K+) helps to maintain appropriate levels of neuronal excitability. While channels and transporters mediating K+ and water transport are known, little is understood about upstream regulatory mechanisms controlling the glial capacity to buffer K+ and osmotically obliged water. Here we identify salt-inducible kinase 3 (SIK3) as the central node in a signal transduction pathway controlling glial K+ and water homeostasis in Drosophila Loss of SIK3 leads to dramatic extracellular fluid accumulation in nerves, neuronal hyperexcitability, and seizures. SIK3-dependent phenotypes are exacerbated by K+ stress. SIK3 promotes the cytosolic localization of HDAC4, thereby relieving inhibition of Mef2-dependent transcription of K+ and water transport molecules. This transcriptional program controls the glial capacity to regulate K+ and water homeostasis and modulate neuronal excitability. We identify HDAC4 as a candidate therapeutic target in this pathway, whose inhibition can enhance the K+ buffering capacity of glia, which may be useful in diseases of dysregulated K+ homeostasis and hyperexcitability. © 2019 Li et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Disease-associated mutations in Niemann-Pick type C1 alter ER calcium signaling and neuronal plasticity” (2019) The Journal of Cell Biology
Disease-associated mutations in Niemann-Pick type C1 alter ER calcium signaling and neuronal plasticity
(2019) The Journal of Cell Biology, 218 (12), pp. 4141-4156.
Tiscione, S.A.a , Vivas, O.a , Ginsburg, K.S.b , Bers, D.M.b , Ory, D.S.c , Santana, L.F.a , Dixon, R.E.a , Dickson, E.J.a
a Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA
b Department of Pharmacology, University of California, Davis, Davis, CA
c Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
Abstract
Niemann-Pick type C1 (NPC1) protein is essential for the transport of externally derived cholesterol from lysosomes to other organelles. Deficiency of NPC1 underlies the progressive NPC1 neurodegenerative disorder. Currently, there are no curative therapies for this fatal disease. Given the Ca2+ hypothesis of neurodegeneration, which posits that altered Ca2+ dynamics contribute to neuropathology, we tested if disease mutations in NPC1 alter Ca2+ signaling and neuronal plasticity. We determine that NPC1 inhibition or disease mutations potentiate store-operated Ca2+ entry (SOCE) due to a presenilin 1 (PSEN1)-dependent reduction in ER Ca2+ levels alongside elevated expression of the molecular SOCE components ORAI1 and STIM1. Associated with this dysfunctional Ca2+ signaling is destabilization of neuronal dendritic spines. Knockdown of PSEN1 or inhibition of the SREBP pathway restores Ca2+ homeostasis, corrects differential protein expression, reduces cholesterol accumulation, and rescues spine density. These findings highlight lysosomes as a crucial signaling platform responsible for tuning ER Ca2+ signaling, SOCE, and synaptic architecture in health and disease. © 2019 Tiscione et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Overview of MR Imaging Volumetric Quantification in Neurocognitive Disorders” (2019) Topics in Magnetic Resonance Imaging : TMRI
Overview of MR Imaging Volumetric Quantification in Neurocognitive Disorders
(2019) Topics in Magnetic Resonance Imaging : TMRI, 28 (6), pp. 311-315.
Raji, C.A.a , Ly, M.b , Benzinger, T.L.S.a
a Division of Neuroradiology, Department of Radiology, Mallinckrodt Institute of Radiology at Washington University, St. Louis, MO
b University of Pittsburgh Medical Scientist Training Program, Pittsburgh, United States
Abstract
This review article provides a general overview on the various methodologies for quantifying brain structure on magnetic resonance images of the human brain. This overview is followed by examples of applications in Alzheimer dementia and mild cognitive impairment. Other examples will include traumatic brain injury and other neurodegenerative dementias. Finally, an overview of general principles for protocol acquisition of magnetic resonance imaging for volumetric quantification will be discussed along with the current choices of FDA cleared algorithms for use in clinical practice.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Current Update on Treatment Strategies for Idiopathic Normal Pressure Hydrocephalus” (2019) Current Treatment Options in Neurology
Current Update on Treatment Strategies for Idiopathic Normal Pressure Hydrocephalus
(2019) Current Treatment Options in Neurology, 21 (12), art. no. 65, .
Isaacs, A.M.a b , Williams, M.A.c , Hamilton, M.G.b d
a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
b Division of Neurosurgery, Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
c Adult and Transitional Hydrocephalus and CSF Disorders, Departments of Neurology and Neurological Surgery, University of Washington School of Medicine, Seattle, WA, United States
d Adult Hydrocephalus Program, Department of Clinical Neuroscience, University of Calgary, Foothills Medical Centre – 12th Floor, Neurosurgery, 1403 – 29 Street NW, Calgary, AB T2N 2T9, Canada
Abstract
Purpose of review: Idiopathic normal pressure hydrocephalus (iNPH) is a surgically treatable neurological disorder of the elderly population that is characterized by abnormal ventricular enlargement due to cerebrospinal fluid (CSF) accumulation and gait disturbance, cognitive impairment, or urinary incontinence. The objective of this review is to present the current diagnostic and treatment approaches for iNPH and to discuss some of the postoperative modalities that complement positive surgical outcomes. Recent findings: Although historically reported patient outcomes following iNPH surgery were dismal and highly variable, recent advances in terms of better understanding of the iNPH disease process, better standardization of iNPH diagnostic and treatment processes arising from the adoption of clinical guidelines for diagnosis, treatment and in research methodologies, and availability of long-term follow-up data, have helped reduce the variations to a much improved 73 to 96% reported good outcomes. Summary: With careful evaluation, good patient selection, and advanced surgical techniques, iNPH can be surgically treated to return patients close to their pre-iNPH functional status. Institution of an interdisciplinary effort to rehabilitate patients following surgery may help augment their recovery. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Cerebrospinal fluid; Dementia; Hydrocephalus; Normal pressure hydrocephalus
Document Type: Review
Publication Stage: Final
Source: Scopus
“Introduction Imaging in neurosurgical disease” (2019) Neurosurgical Focus
Introduction Imaging in neurosurgical disease
(2019) Neurosurgical Focus, 47 (6), p. E1.
Osbun, J.W.a , Dacey, R.G.b , Barrow, D.L.c , Saindane, A.M.d , Nimsky, C.e
a Departments of Neurosurgery, Radiology, Neurology, Washington University in St. Louis
b Department of Neurosurgery, Washington University in St. LouisMO
c Department of Neurosurgery, Emory University
d 4Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia; and
e Department of Neurosurgery, University Marburg, Germany
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Resting-state network mapping in neurosurgical practice: a review” (2019) Neurosurgical Focus
Resting-state network mapping in neurosurgical practice: a review
(2019) Neurosurgical Focus, 47 (6), p. E15.
Hacker, C.D.a , Roland, J.L.b , Kim, A.H.a , Shimony, J.S.c , Leuthardt, E.C.a
a Departments of1Neurological Surgery and
b Department of Neurosurgery, University of California, San Francisco, CA, Mexico
c 3Radiology, Washington University School of Medicine, St. Louis, Missouri; and
Abstract
Resting-state functional MRI (rs-fMRI) is a well-established method for studying intrinsic connectivity and mapping the topography of functional networks in the human brain. In the clinical setting, rs-fMRI has been used to define functional topography, typically language and motor systems, in the context of preoperative planning for neurosurgery. Intraoperative mapping of critical speech and motor areas with electrocortical stimulation (ECS) remains standard practice, but preoperative noninvasive mapping has the potential to reduce operative time and provide functional localization when awake mapping is not feasible. Task-based fMRI has historically been used for this purpose, but it can be limited by the young age of the patient, cognitive impairment, poor cooperation, and need for sedation. Resting-state fMRI allows reliable analysis of all functional networks with a single study and is inherently independent of factors affecting task performance. In this review, the authors provide a summary of the theory and methods for resting-state network mapping. They provide case examples illustrating clinical implementation and discuss limitations of rs-fMRI and review available data regarding performance in comparison to ECS. Finally, they discuss novel opportunities for future clinical applications and prospects for rs-fMRI beyond mapping of regions to avoid during surgery but, instead, as a tool to guide novel network-based therapies.
Author Keywords
BOLD = blood oxygen level–dependent; ECS = electrocortical stimulation; fMRI; fMRI = functional MRI; functional connectivity; functional mapping; MLP = multilayer perceptron; resting state; rs-fMRI = resting-state fMRI; RSN = resting-state network; TMS = transcranial magnetic stimulation
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“20th Century Hearing Devices: Going, Going, Nearly Gone” (2019) Hearing Journal
20th Century Hearing Devices: Going, Going, Nearly Gone
(2019) Hearing Journal, 72 (12), pp. 10-13.
Uchanski, R.M.a , Sarli, C.C.b
a Becker Medical Library s Translational Research Support Division, Washington University School of Medicine, St. Louis, MO, United States
b Otolaryngology Department, Program in Audiology and Communication Sciences
Document Type: Article
Publication Stage: Final
Source: Scopus
“Neural Processes of Proactive and Reactive Controls Modulated by Motor-Skill Experiences” (2019) Frontiers in Human Neuroscience
Neural Processes of Proactive and Reactive Controls Modulated by Motor-Skill Experiences
(2019) Frontiers in Human Neuroscience, 13, art. no. 404, .
Yu, Q.a b , Chau, B.K.H.b , Lam, B.Y.H.b , Wong, A.W.K.c d , Peng, J.b e , Chan, C.C.H.b f
a Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
b Applied Cognitive Neuroscience Laboratory, Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong
c Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Education, Shaoguan University, Shaoguan, China
f University Research Facility in Behavioral and Systems Neuroscience, The Hong Kong Polytechnic University, Hong Kong
Abstract
This study investigated the experience of open and closed motor skills on modulating proactive and reactive control processes in task switching. Fifty-four participants who were open-skilled (n = 18) or closed-skilled athletes (n = 18) or non-athletic adults (n = 18) completed a cued task-switching paradigm task. This task tapped into proactive or reactive controls of executive functions under different validity conditions. Electroencephalograms of the participants were captured during the task. In the 100% validity condition, the open-skilled participants showed significantly lower switch cost of response time than the closed-skilled and control participants. Results showed that the open-skilled participants had less positive-going parietal cue-locked P3 in the switch than repeat trials. Participants in the control group showed more positive-going cue-locked P3 in the switch than repeat trials, whereas the closed-skilled participants had no significant differences between the two types of trials. In the 50% validity condition, the open- and closed-skilled participants had less switch cost of response time than the control participants. Participants in the open- and closed-skilled groups showed less positive-going parietal stimulus-locked P3 in the switch than repeat trials, which was not the case for those in the control group. Our findings confirm the dissociation between proactive and reactive controls in relation to their modulations by the different motor-skill experiences. Both proactive and reactive controls of executive functions could be strengthened by exposing individuals to anticipatory or non-anticipatory enriched environments, suggesting proactive and reactive controls involved in motor-skill development seem to be transferable to domain-general executive functions. © Copyright © 2019 Yu, Chau, Lam, Wong, Peng and Chan.
Author Keywords
ERP; motor skills; proactive control; reactive control; task switching
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell” (2019) Nature Metabolism
Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell
(2019) Nature Metabolism, 1 (11), pp. 1110-1126.
Menegaz, D.a , Hagan, D.W.b , Almaça, J.a , Cianciaruso, C.c , Rodriguez-Diaz, R.a , Molina, J.a , Dolan, R.M.b , Becker, M.W.b , Schwalie, P.C.c d , Nano, R.e , Lebreton, F.f , Kang, C.g h , Sah, R.g h , Gaisano, H.Y.i , Berggren, P.-O.j k l , Baekkeskov, S.c m , Caicedo, A.a j n o , Phelps, E.A.b c
a Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
b J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
c Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
d Swiss Institute of Bioinformatics, Lausanne, Switzerland
e Pancreatic Islet Processing Facility, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
f Cell Isolation and Transplantation Center, Faculty of Medicine, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
g Center for Cardiovascular Research and Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States
h Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, United States
i Department of Medicine, University of Toronto, Toronto, ON, Canada
j Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
k The Rolf Luft Research Center for Diabetes & Endocrinology, Karolinska Institutet, Stockholm, Sweden
l Division of Integrative Biosciences and Biotechnology, WCU Program, University of Science and Technology, Pohang, South Korea
m Departments of Medicine and Microbiology/Immunology, Diabetes Center, University of California San Francisco, San Francisco, CA, United States
n Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, United States
o Program in Neuroscience, Miller School of Medicine, University of Miami, Miami, FL, United States
Abstract
Pancreatic beta cells synthesize and secrete the neurotransmitter GABA (γ-aminobutyric acid) as a paracrine and autocrine signal to help regulate hormone secretion and islet homeostasis. Islet GABA release has classically been described as a secretory-vesicle-mediated event. Yet, a limitation of the hypothesized vesicular GABA release from islets is the lack of expression of a vesicular GABA transporter in beta cells. Consequentially, GABA accumulates in the cytosol. Here, we provide evidence that the human beta cell effluxes GABA from a cytosolic pool in a pulsatile manner, imposing a synchronizing rhythm on pulsatile insulin secretion. The volume regulatory anion channel, functionally encoded by LRRC8A or Swell1, is critical for pulsatile GABA secretion. GABA content in beta cells is depleted and secretion is disrupted in islets from patients with type 1 and type 2 diabetes, suggesting that loss of GABA as a synchronizing signal for hormone output may correlate with diabetes pathogenesis. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Gtf2i and Gtf2ird1 mutation do not account for the full phenotypic effect of the Williams syndrome critical region in mouse models” (2019) Human Molecular Genetics
Gtf2i and Gtf2ird1 mutation do not account for the full phenotypic effect of the Williams syndrome critical region in mouse models
(2019) Human Molecular Genetics, 28 (20), pp. 3443-3465.
Kopp, N.a b , McCullough, K.a b , Maloney, S.E.b c , Dougherty, J.D.a b c
a Department of Genetics
b Department of Psychiatry
c Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA
Abstract
Williams syndrome (WS) is a neurodevelopmental disorder caused by a 1.5-1.8 Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of WS include cardiovascular problems, craniofacial dysmorphology, deficits in visual-spatial cognition and a characteristic hypersocial personality. There are still no genes in the region that have been consistently linked to the cognitive and behavioral phenotypes, although human studies and mouse models have led to the current hypothesis that the general transcription factor 2 I family of genes, GTF2I and GTF2IRD1, are responsible. Here we test the hypothesis that these two transcription factors are sufficient to reproduce the phenotypes that are caused by deletion of the WS critical region (WSCR). We compare a new mouse model with loss of function mutations in both Gtf2i and Gtf2ird1 to an established mouse model lacking the complete WSCR. We show that the complete deletion (CD) model has deficits across several behavioral domains including social communication, motor functioning and conditioned fear that are not explained by loss of function mutations in Gtf2i and Gtf2ird1. Furthermore, transcriptome profiling of the hippocampus shows changes in synaptic genes in the CD model that are not seen in the double mutants. Thus, we have thoroughly defined a set of molecular and behavioral consequences of complete WSCR deletion and shown that genes or combinations of genes beyond Gtf2i and Gtf2ird1 are necessary to produce these phenotypic effects. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Evaluating glial and neuronal blood biomarkers GFAP and UCH-L1 as gradients of brain injury in concussive, subconcussive and non-concussive trauma: A prospective cohort study” (2019) BMJ Paediatrics Open
Evaluating glial and neuronal blood biomarkers GFAP and UCH-L1 as gradients of brain injury in concussive, subconcussive and non-concussive trauma: A prospective cohort study
(2019) BMJ Paediatrics Open, 3 (1), art. no. e000473, .
Papa, L.a , Zonfrillo, M.R.b , Welch, R.D.c , Lewis, L.M.d , Braga, C.F.e , Tan, C.N.a , Ameli, N.J.a , Lopez, M.A.a , Haeussler, C.A.a , Mendez Giordano, D.a , Giordano, P.A.a , Ramirez, J.f , Mittal, M.K.g
a Department of Emergency Medicine, Orlando Regional Medical Center, Orlando, FL, United States
b Hasbro Children’s Hospital, Providence, RI, United States
c Wayne State University School of Medicine, Detroit, MI, United States
d Division of Emergency Medicine, Washington University in St. Louis, Saint Louis, MO, United States
e Department of Family Medicine and Community Health, Robert Wood Johnson University Hospital, New Brunswick, NJ, United States
f Department of Pediatric Emergency Medicine, Arnold Palmer Hospital for Children, Orlando, FL, United States
g Division of Emergency Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
Abstract
Objectives To evaluate the ability of glial fibrillary acidic protein (GFAP) and ubiquitin C-Terminal hydrolase (UCH-L1) to detect concussion in children and adult trauma patients with a normal mental status and assess biomarker concentrations over time as gradients of injury in concussive and non-concussive head and body trauma. Design Large prospective cohort study. Setting Three level I trauma centres in the USA. Participants Paediatric and adult trauma patients of all ages, with and without head trauma, presenting with a normal mental status (Glasgow Coma Scale score of 15) within 4 hours of injury. Rigorous screening for concussive symptoms was conducted. Of 3462 trauma patients screened, 751 were enrolled and 712 had biomarker data. Repeated blood sampling was conducted at 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 hours postinjury in adults. Main outcomes Detection of concussion and gradients of injury in children versus adults by comparing three groups of patients: (1) those with concussion; (2) those with head trauma without overt signs of concussion (non-concussive head trauma controls) and (3) those with peripheral (body) trauma without head trauma or concussion (non-concussive body trauma controls). Results A total of 1904 samples from 712 trauma patients were analysed. Within 4 hours of injury, there were incremental increases in levels of both GFAP and UCH-L1 from non-concussive body trauma (lowest), to mild elevations in non-concussive head trauma, to highest levels in patients with concussion. In concussion patients, GFAP concentrations were significantly higher compared with body trauma controls (p<0.001) and with head trauma controls (p<0.001) in both children and adults, after controlling for multiple comparisons. However, for UCH-L1, there were no significant differences between concussion patients and head trauma controls (p=0.894) and between body trauma and head trauma controls in children. The AUC for initial GFAP levels to detect concussion was 0.80 (0.73-0.87) in children and 0.76 (0.71-0.80) in adults. This differed significantly from UCH-L1 with AUCs of 0.62 (0.53-0.72) in children and 0.69 (0.64-0.74) in adults. Conclusions In a cohort of trauma patients with normal mental status, GFAP outperformed UCH-L1 in detecting concussion in both children and adults. Blood levels of GFAP and UCH-L1 showed incremental elevations across three injury groups: from non-concussive body trauma, to non-concussive head trauma, to concussion. However, UCH-L1 was expressed at much higher levels than GFAP in those with non-concussive trauma, particularly in children. Elevations in both biomarkers in patients with non-concussive head trauma may be reflective of a subconcussive brain injury. This will require further study. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
biomarkers; blood test; concussion; glial fibrillary acidic protein (GFAP); mild traumatic brain injury; paediatric; subconcussive, head trauma, trauma, children; Ubiquitin C-Terminal hydrolase (UCH-L1)
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease” (2019) Aging Cell
Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease
(2019) Aging Cell, art. no. e13078, .
Lee, J.a b , Kim, D.-E.a , Griffin, P.b , Sheehan, P.W.b , Kim, D.-H.a , Musiek, E.S.b , Yoon, S.-Y.a
a Department of Brain Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
b Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
Abstract
A promising new therapeutic target for the treatment of Alzheimer’s disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ1-42 (fAβ1-42) than at CT12. BMAL1 directly drives transcription of REV-ERB proteins, which are implicated in microglial activation. Interestingly, pharmacological inhibition of REV-ERBs with the small molecule antagonist SR8278 or genetic knockdown of REV-ERBs-accelerated microglial uptake of fAβ1-42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2-like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev-erbα in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque-associated increases in disease-associated microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aβ clearance and neuroinflammation by targeting REV-ERBs and provides new insights into the role of REV-ERBs in AD. © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Author Keywords
Alzheimer’s disease; circadian; microglia; REV-ERBs; SR8278
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1” (2019) Annals of Clinical and Translational Neurology
Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1
(2019) Annals of Clinical and Translational Neurology, .
Payne, J.M.a b , Hearps, S.J.C.a , Walsh, K.S.c , Paltin, I.d , Barton, B.e f g , Ullrich, N.J.h , Haebich, K.M.a , Coghill, D.a b , Gioia, G.A.c , Cantor, A.i , Cutter, G.j , Tonsgard, J.H.k , Viskochil, D.l , Rey-Casserly, C.m , Schorry, E.K.n , Ackerson, J.D.o , Klesse, L.p , Fisher, M.J.d , Gutmann, D.H.q , Rosser, T.r , Packer, R.J.c , Korf, B.s , Acosta, M.T.c t , North, K.N.a b , the NF Clinical Trials Consortiumu
a Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia
b Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
c Center for Neuroscience and Behavioral Medicine, Children’s National Health System, Washington, DC, United States
d Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
e Kids Neuroscience Centre, The Children’s Hospital at Westmead, Westmead, NSW, Australia
f Children’s Hospital Education Research Institute, The Children’s Hospital at Westmead, Westmead, NSW, Australia
g The University of Sydney Children’s Hospital Westmead Clinical School, University of Sydney, Westmead, NSW, Australia
h Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
i Department of Preventative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
j School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States
k Division of Neurology, The University of Chicago Medicine Comer Children’s Hospital, Chicago, IL, United States
l Department of Genetics, University of Utah, Salt Lake City, UT, United States
m Center for Neuropsychology, Boston Children’s Hospital, Boston, MA, United States
n Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
o Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
p Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States
q Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
r Department of Neurology, Children’s Hospital of Los Angeles, Los Angeles, CA, United States
s Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
t National Institutes of Health, National Human Genome Research Institute, Bethesda, MD, United States
Abstract
Objective: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. Methods: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. Results: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. Interpretation: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design. © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“Children’s Facial Muscular Movements and Risk for Early Psychopathology: Assessing Clinical Utility” (2019) Behavior Therapy
Children’s Facial Muscular Movements and Risk for Early Psychopathology: Assessing Clinical Utility
(2019) Behavior Therapy, .
Grabell, A.S.a , Jones, H.M.b , Wilett, A.E.b , Bemis, L.M.b , Wakschlag, L.S.c , Perlman, S.B.d
a University of Massachusetts, Amherst, United States
b University of Pittsburgh School of Medicine
c Northwestern University Feinberg School of Medicine
d Washington University School of Medicine in St. Louis
Abstract
Standardized developmentally based assessment systems have transformed the capacity to identify transdiagnostic behavioral markers of mental disorder risk in early childhood, notably, clinically significant irritability and externalizing behaviors. However, behavior-based instruments that both differentiate risk for persistent psychopathology from normative misbehavior, and are feasible for community clinicians to implement, are in nascent phases of development. Young children’s facial expressions during frustration challenges may form the basis for novel assessments tools that are flexible, quick, and easy to implement as markers of psychopathology to complement validated questionnaires. However, the accuracy of facial expressions to correctly classify young children falling above and below clinical cut-offs is unknown. Our goal was to test how facial expressions during frustration, defined by different facial muscular movements, related to individual differences in irritability and externalizing behaviors and discriminated children with clinically significant levels from peers. Participants were 79 children (ages 3–7) who completed a short, moderately frustrating computer task while facial expressions were recorded. Only negative facial expressions that included eye constriction related to irritability and externalizing behaviors and were clinically discriminating. Moreover, these expressions significantly discriminated children with and without clinically significant irritability and externalizing symptoms with high Area Under the Curve (AUC) values (>.75) indicating good clinical utility. In contrast, expressions without eye constriction showed no clinical utility. The presence of negative expressions with eye constriction in response to a short frustration prompt may serve as an indicator of early psychopathology, raising the potential for novel assessment tools that may enhance precision of early identification. © 2019
Author Keywords
child; facial expression; psychopathology; risk assessment; ROC curve
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Sleep Measure Validation in a Pediatric Neurocritical Care Acquired Brain Injury Population” (2019) Neurocritical Care
Sleep Measure Validation in a Pediatric Neurocritical Care Acquired Brain Injury Population
(2019) Neurocritical Care, .
Poppert Cordts, K.M.a b , Hall, T.A.b c , Hartman, M.E.d , Luther, M.c , Wagner, A.b , Piantino, J.e , Guilliams, K.P.d f , Guerriero, R.M.f , Jara, J.c , Williams, C.N.c g
a Department of Psychiatry, University of Nebraska Medical Center, Omaha, NE, United States
b Division of Pediatric Psychology, Department of Pediatrics, Institute on Development and Disability, Oregon Health and Science University and Doernbecher Children’s Hospital, Portland, OR, United States
c Pediatric Critical Care and Neurotrauma Recovery Program, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States
d Division of Pediatric Critical Care, Department of Pediatrics, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United States
e Division of Pediatric Neurology, Department of Pediatrics, Oregon Health and Science University and Doernbecher Children’s Hospital, Portland, OR, United States
f Division of Pediatric and Developmental Neurology, Department of Neurology, Washington University School of Medicine, St Louis Children’s Hospital, St. Louis, MO, United States
g Division of Pediatric Critical Care, Department of Pediatrics, Oregon Health and Science University and Doernbecher Children’s Hospital, Portland, OR, United States
Abstract
Background/Objective: Lingering morbidities including physical, cognitive, emotional, and psychosocial sequelae, termed the Post-Intensive Care Syndrome, persist years after pediatric neurocritical care (PNCC) hospitalization. Sleep disturbances impact other Post-Intensive Care Syndrome domains and are under-evaluated to date due to a lack of appropriate measurement tools. The present study evaluated the validity of the Sleep Disturbance Scale for Children (SDSC) to address the growing need for assessing sleep problems after PNCC. Methods: We conducted a prospective observational study of youth aged 3–17 years with acquired brain injury (N = 69) receiving care through longitudinal PNCC programs at two tertiary academic medical centers. Parents completed the SDSC and provided proxy reports of internalizing symptoms, health-related quality of life (HRQOL), fatigue, pain behavior, and cognitive function within 3 months of hospital discharge. Evidence for the validity of the SDSC was established by utilizing the full sample for psychosocial measure comparisons and by comparing SDSC outcomes by severity (Low Risk, Mild-Moderate Risk, and High Risk defined by reported standardized T-scores). Results: Internal consistency of the SDSC was good (α =.81). Within the full sample, increased sleep disturbances on the SDSC were significantly correlated with Post-Intensive Care Syndrome measures, including worse physical (r =.65), psychological (r =.62), and cognitive (r = −.74) sequelae. Youth in the High Risk group evidenced greater dysfunction in mental acuity, pain behavior, internalizing symptoms, and social engagement. Findings revealed both statistically and clinically significant impacts of sleep disturbances as measured by the SDSC on HRQOL. Conclusions: The SDSC is a valid and reliable measure for assessing sleep disturbances in children after PNCC. Results support the use of the SDSC to measure sleep disturbances after PNCC. Targeted interventions for sleep disturbances may be key to overall patient recovery. © 2019, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.
Author Keywords
Brain injury; Critical care; Hospitalization; Outcomes; Pediatric; Quality of life; Sleep
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Binding and intracellular transport of 25-hydroxycholesterol by Niemann-Pick C2 protein” (2019) Biochimica et Biophysica Acta – Biomembranes
Binding and intracellular transport of 25-hydroxycholesterol by Niemann-Pick C2 protein
(2019) Biochimica et Biophysica Acta – Biomembranes, art. no. 183063, .
Petersen, D.a , Reinholdt, P.b , Szomek, M.a , Hansen, S.K.a , Poongavanam, V.b , Dupont, A.a , Heegaard, C.W.c , Krishnan, K.d , Fujiwara, H.d , Covey, D.F.d e , Ory, D.S.f , Kongsted, J.b , Wüstner, D.a
a Department of Biochemistry and Molecular Biology, Odense M, DK-5230, Denmark
b Department of Physics, Chemistry and Pharmacy, Odense M, DK-5230, Denmark
c Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, C, DK-8000, Denmark
d Department of Developmental Biology, Washington University, St. Louis, MO 63110, United States
e Taylor Family Institute for Innovative Psychiatric Research, Washington University, St. Louis, MO 63110, United States
f Department of Medicine, Washington University, St. Louis, MO 63110, United States
Abstract
Side-chain oxidized cholesterol derivatives, like 25-hydroxycholesterol (25-OH-Chol) are important regulators of cellular cholesterol homeostasis. How transport of oxysterols through the endo-lysosomal pathway contributes to their biological function is not clear. The Niemann-Pick C2 protein (NPC2) is a small lysosomal sterol transfer protein required for export of cholesterol from late endosomes and lysosomes (LE/LYSs). Here, we show that 25-hydroxy-cholestatrienol, (25-OH-CTL), an intrinsically fluorescent analogue of 25-OH-Chol, becomes trapped in LE/LYSs of NPC2-deficient fibroblasts, but can efflux from the cells even in the absence of NPC2 upon removal of the sterol source. Fluorescence recovery after photobleaching (FRAP) of 25-OH-CTL in endo-lysosomes was rapid and extensive and only partially dependent on NPC2 function. Using quenching of NPC2’s intrinsic fluorescence, we show that 25-OH-Chol and 25-OH-CTL can bind to NPC2 though with lower affinity compared to cholesterol and its fluorescent analogues, cholestatrienol (CTL) and dehydroergosterol (DHE). This is confirmed by calculations of binding energies which additionally show that 25-OH-CTL can bind in two orientations to NPC2, in stark contrast to cholesterol and its analogues. We conclude that NPC2’s affinity for all sterols is energetically favored over their self-aggregation in the lysosomal lumen. Lysosomal export of 25-OH-Chol is not strictly dependent on the NPC2 protein. © 2019 Elsevier B.V.
Author Keywords
Binding; Electronic structure calculation; Fluorescence; Free energy calculation; Lysosome
Document Type: Article
Publication Stage: Article in Press
Source: Scopus