WashU weekly Neuroscience publications

Acute disseminated encephalomyelitis associated with a novel paraneoplastic process in hepatic epithelial hemangioendothelioma: A case report
(2020) Clinical Neurology and Neurosurgery, 194, art. no. 105903, . 

Shah, A.S.^a , Yahanda, A.T.^a , Loftspring, M.C.^b , Osbun, J.W.^a

^a Department of Neurosurgery, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, United States
^b Department of Neurology Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, United States

Author Keywords
Acute disseminated encephalomyelitis;  Decompression;  Epithelial hemangioendothelioma;  Hemicraniectomy;  Paraneoplastic syndrome

Document Type: Article
Publication Stage: Final
Source: Scopus

The role of working memory capacity in analytic and multiply-constrained problem-solving in demanding situations
(2020) Quarterly Journal of Experimental Psychology, 73 (6), pp. 920-928. 

Ellis, D.M.^a , Ball, B.H.^{b c} , Kimpton, N.^a , Brewer, G.A.^a

^a Department of Psychology, Arizona State University, Tempe, AZ, United States
^b The University of Texas at Arlington, Arlington, TX, United States
^c Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Working memory processes are important for analytic problem-solving; however, their role in multiply-constrained problem-solving is currently debated. This study explored individual differences in working memory and successful completion of analytic and multiply-constrained problem-solving by having participants solve algebra and compound remote associate (CRAT) problems of varying difficulty under low and high memory demand conditions. Working memory was predictive of both algebra and multiply-constrained problem-solving. Specifically, participants with high working memory solved more problems than those with low working. Memory load did not differentially affect performance for low and high working memory participants. However, for multiply-constrained problem-solving the effect of item difficulty was more detrimental for high-span participants than low-span participants. Together, these findings suggest that working memory processes are important for both types of problem-solving and that participants with low working memory capacity may need to offload internal memory demands onto the environment to efficiently solve problems. © Experimental Psychology Society 2020.

Author Keywords
analytic problem-solving;  compound remote associates;  individual differences;  multiply-constrained problem-solving;  Problem-solving;  working memory

Document Type: Article
Publication Stage: Final
Source: Scopus

Low-dose interleukin-2 reverses behavioral sensitization in multiple mouse models of headache disorders
(2020) Pain, 161 (6), pp. 1381-1398. 

Zhang, J.^{a b c} , Czerpaniak, K.^{a b} , Huang, L.^{a b} , Liu, X.^{a b} , Cloud, M.E.^{a b} , Unsinger, J.^a , Hotchkiss, R.S.^{a d e} , Li, D.^{a b} , Cao, Y.-Q.^{a b}

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States. Dr. Huang is now with the Department of Anesthesiology, New York University Langone Health, New York University Grossman School of Medicine, New York, NY, United States
^c Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
^d Departments of Medicine and
^e Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Headache disorders are highly prevalent and debilitating, with limited treatment options. Previous studies indicate that many proinflammatory immune cells contribute to headache pathophysiology. Given the well-recognized role of regulatory T (Treg) cells in maintaining immune homeostasis, we hypothesized that enhancing Treg function may be effective to treat multiple headache disorders. In a mouse model of chronic migraine, we observed that repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration doubled the number of CD3 T cells in the trigeminal ganglia without altering the number of Treg cells, suggesting a deficiency in Treg-mediated immune homeostasis. We treated mice with low-dose interleukin-2 (ld-IL2) to preferentially expand and activate endogenous Treg cells. This not only prevented the development of NTG-induced persistent sensitization but also completely reversed the established facial skin hypersensitivity resulting from repeated NTG administration. The effect of ld-IL2 was independent of mouse sex and/or strain. Importantly, ld-IL2 treatment did not alter basal nociceptive responses, and repeated usage did not induce tolerance. The therapeutic effect of ld-IL2 was abolished by Treg depletion and was recapitulated by Treg adoptive transfer. Furthermore, treating mice with ld-IL2 1 to 7 days after mild traumatic brain injury effectively prevented as well as reversed the development of behaviors related to acute and chronic post-traumatic headache. In a model of medication overuse headache, Ld-IL2 completely reversed the cutaneous hypersensitivity induced by repeated administration of sumatriptan. Collectively, this study identifies ld-IL2 as a promising prophylactic for multiple headache disorders with a mechanism distinct from the existing treatment options.

Document Type: Article
Publication Stage: Final
Source: Scopus

Editorial: It’s Complicated: Adrenarcheal and Pubertal Hormonal Influence on Brain Development
(2020) Journal of the American Academy of Child and Adolescent Psychiatry, 59 (6), pp. 699-700. 

Botteron, K.N.

Washington University School of Medicine, St LouisMO, United States

Abstract
Recent research has begun to establish the very important role of prepubertal, pubertal, and peripubertal neurodevelopment and the developmental expression of adolescent-onset psychiatric disorders. There are definite changes in the rates and expression of psychiatric disorders during this time period of marked hormonal changes, with increases in rates of both major depression and anxiety disorders, particularly in females, and a sharp increase in risk-taking behavior in both males and females. Recent reports underscore the critical roles that neurodevelopmental changes contribute to the development of psychiatric disorders. Typical pubertal developmental changes, such as generalized growth spurts, breast and genital bodily maturation, and the onset of menstruation are strongly related to developmental changes in hormonal expression. Until recently, however, many behavioral and psychiatric investigations (including neuroimaging investigations) did not measure hormonal levels. Such investigations, by a small number of investigators, have been completed over the past 5 to 10 years. These studies make it clear that we need to substantially increase our understanding of the endocrine-related neurodevelopmental processes in periadolescence and adolescence as they relate to the expression of many psychiatric. Barendse et al.,1 published in this issue, reports some interesting findings that advance our understanding of adrenarcheal brain development, dehydroepiandrosterone (DHEA), and its relationship to anxiety symptoms. © 2020 American Academy of Child and Adolescent Psychiatry

Document Type: Editorial
Publication Stage: Final
Source: Scopus

In utero exposure to transient ischemia-hypoxemia promotes long-term neurodevelopmental abnormalities in male rat offspring
(2020) JCI Insight, 5 (10), . 

Palanisamy, A.^{a b} , Giri, T.^a , Jiang, J.^a , Bice, A.^c , Quirk, J.D.^c , Conyers, S.B.^d , Maloney, S.E.^d , Raghuraman, N.^b , Bauer, A.Q.^c , Garbow, J.R.^c , Wozniak, D.F.^{d e}

^a Department of Anesthesiology
^b Department of Obstetrics and Gynecology
^c Mallinckrodt Institute of Radiology
^d Department of Psychiatry
^e Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI, we confirmed that oxytocin-induced aberrant uterine hypercontractility substantially compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 hour after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders.

Author Keywords
Behavior;  Development;  hypoxia;  Neuroscience;  Radicals

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

On complement, memory, and microglia
(2020) New England Journal of Medicine, 382 (21), pp. 2056-2058. 

Klein, R.S.^{a b}

^a Department of Medicine, Pathology and Immunology, Washington University, School of Medicine, St. Louis, United States
^b Department of Medicine Neurosciences, Washington University, School of Medicine, St. Louis, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

Sex-specific impact of patterns of imageable tumor growth on survival of primary glioblastoma patients
(2020) BMC Cancer, 20 (1), p. 447. 

Whitmire, P.^a , Rickertsen, C.R.^a , Hawkins-Daarud, A.^a , Carrasco, E., Jr^a , Lorence, J.^{a b} , De Leon, G.^a , Curtin, L.^{a c} , Bayless, S.^a , Clark-Swanson, K.^a , Peeri, N.C.^d , Corpuz, C.^e , Lewis-de Los Angeles, C.P.^f , Bendok, B.R.^{a g} , Gonzalez-Cuyar, L.^h , Vora, S.ⁱ , Mrugala, M.M.^j , Hu, L.S.^k , Wang, L.^l , Porter, A.^j , Kumthekar, P.^m , Johnston, S.K.^{a n} , Egan, K.M.^d , Gatenby, R.^o , Canoll, P.^p , Rubin, J.B.^q , Swanson, K.R.^a

^a Precision Neurotherapeutics Innovation Program, Mayo Clinic, AZ, 5777 East Mayo Blvd, Phoenix, 85054, United States
^b School of Life Sciences, Arizona State University, AZ, Tempe, United States
^c Centre for Mathematical Medicine and Biology, University of Nottingham, Nottingham, United Kingdom
^d Cancer Epidemiology Program, Moffitt Cancer Center, FL, Tampa, United States
^e Department of Neurology, Columbia University Medical Center, NY, NY, United States
^f Northwestern University Interdepartmental Neuroscience Program, Northwestern University Feinberg School of Medicine, Chicago, United States
^g Department of Neurologic Surgery, Mayo Clinic, AZ, Phoenix, United States
^h Department of Pathology, Division of Neuropathology, University of Washington, Seattle, WA, USA
ⁱ Department of Radiation Oncology, Mayo Clinic, AZ, Phoenix, United States
^j Department of Neurology, Mayo Clinic, AZ, Phoenix, United States
^k Department of Radiology, Mayo Clinic, AZ, Phoenix, United States
^l Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, United States
^m Department of Neurology, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States
ⁿ Department of Radiology, University of Washington, Seattle, WA, USA
^o Cancer Biology and Evolution Program, Moffitt Cancer Center, FL, Tampa, United States
^p Division of Neuropathology, Department of Pathology and Cell Biology, Columbia University Medical Center, NY, NY, United States
^q Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA

Abstract
BACKGROUND: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. METHODS: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). RESULTS: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR = 1.027, p = 0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR = 1.011, p < 0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p = 0.010 t-test), but tumor size was not correlated with female overall survival (p = 0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p = 0.004, F p = 0.001, t-test). CONCLUSION: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Author Keywords
Biomathematical models;  Glioblastoma;  Neuroimaging;  Sex differences

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients
(2020) Neuro-Oncology, 22 (5), pp. 601-612. 

Lee, E.Q.^{a b} , Weller, M.^c , Sul, J.^d , Bagley, S.J.^e , Sahebjam, S.^f , van den Bent, M.^g , Ahluwalia, M.^h , Campian, J.L.ⁱ , Galanis, E.^j , Gilbert, M.R.^k , Holdhoff, M.^l , Lesser, G.J.^m , Lieberman, F.S.ⁿ , Mehta, M.P.^o , Penas-Prado, M.^k , Schreck, K.C.^l , Strowd, R.E.^m , Vogelbaum, M.A.^f , Walbert, T.^p , Chang, S.M.^q , Nabors, L.B.^r , Grossman, S.^l , Reardon, D.A.^{a b} , Wen, P.Y.^{a b}

^a Dana-Farber Cancer Institute, Boston, MA, United States
^b Harvard Medical School, Boston, MA, United States
^c University Hospital and University of ZurichZurich, Switzerland
^d Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver SpringMD, United States
^e Hospital of the University of Pennsylvania, Philadelphia, PA, United States
^f Moffitt Cancer Center, Tampa, FL, United States
^g Erasmus University Hospital, Rotterdam, Netherlands
^h Cleveland Clinic, Cleveland, OH, United States
ⁱ Washington University, St Louis, MO, United States
^j Mayo Clinic, Rochester, MN, United States
^k Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
^l Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States
^m Wake Forest Baptist Comprehensive Cancer Center, Winston-SalemNC, United States
ⁿ University of Pittsburgh, Pittsburgh, PA, United States
^o Miami Cancer Institute, Miami, FL, United States
^p Henry Ford Health System, Detroit, MI, United States
^q University of California San Francisco, San Francisco, CA, United States
^r University of Alabama at Birmingham, Birmingham, AL, United States

Abstract
Building on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
clinical trials;  eligibility;  exclusion criteria;  inclusion criteria;  primary brain tumor

Document Type: Article
Publication Stage: Final
Source: Scopus

Sleep, fatigue and burnout among physicians: an American Academy of Sleep Medicine position statement
(2020) Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine, 16 (5), pp. 803-805. 

Kancherla, B.S.^a , Upender, R.^b , Collen, J.F.^c , Rishi, M.A.^d , Sullivan, S.S.^e , Ahmed, O.^f , Berneking, M.^g , Flynn-Evans, E.E.^h , Peters, B.R.ⁱ , Abbasi-Feinberg, F.^j , Aurora, R.N.^k , Carden, K.A.^l , Kirsch, D.B.^m , Kristo, D.A.ⁿ , Malhotra, R.K.^o , Martin, J.L.^{p q} , Olson, E.J.^r , Ramar, K.^r , Rosen, C.L.^s , Rowley, J.A.^t , Shelgikar, A.V.^u , Gurubhagavatula, I.^{v w}

^a Department of Pediatrics, Division of Pediatric Pulmonology, Texas Children’s Hospital – Baylor College of Medicine, Houston, TX
^b Department of Neurology, Division of Sleep Medicine, Vanderbilt Medical Center, Nashville, TN, United States
^c Pulmonary, Critical Care and Sleep Medicine Service, Walter Reed National Military Medical Center, Bethesda, MD, United States
^d Department of Pulmonology, Critical Care and Sleep Medicine, Mayo Clinic, Eau Claire, WI, United States
^e SleepEval Research Institute, Palo Alto, CA, Mexico
^f Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of MedicineNY
^g Concentra, Inc., Grand RapidsMI
^h Fatigue Countermeasures Laboratory, Human Systems Integration Division, NASA Ames Research Center, Moffett FieldCA
ⁱ Sleep Disorders Center, Virginia Mason Medical Center, Seattle, WA, United States
^j Sleep Medicine, Millennium Physician Group, Fort Myers, FL, United States
^k Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
^l Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
^m Sleep Medicine, Atrium Health, Charlotte, North Carolina
ⁿ University of Pittsburgh, Pittsburgh, PA, United States
^o Sleep Medicine Center, Washington University School of Medicine, St. Louis, MO, United States
^p Veteran Affairs Greater Los Angeles Healthcare System, North HillsCA
^q David Geffen School of Medicine at the University of California, Los Angeles, CA, Mexico
^r Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN
^s Department of Pediatrics, Case Western Reserve University, University Hospitals – Cleveland Medical Center, Cleveland, OH, United States
^t Wayne State University, Detroit, MI, United States
^u University of Michigan Sleep Disorders Center, University of Michigan, Ann Arbor, MI, United States
^v Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^w Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, United States

Abstract
None: Physician burnout is a serious and growing threat to the medical profession and may undermine efforts to maintain a sufficient physician workforce to care for the growing and aging patient population in the United States. Burnout involves a host of complex underlying associations and potential for risk. While prevalence is unknown, recent estimates of physician burnout are quite high, approaching 50% or more, with midcareer physicians at highest risk. Sleep deprivation due to shift-work schedules, high workload, long hours, sleep interruptions, and insufficient recovery sleep have been implicated in the genesis and perpetuation of burnout. Maladaptive attitudes regarding sleep and endurance also may increase the risk for sleep deprivation among attending physicians. While duty-hour restrictions have been instituted to protect sleep opportunity among trainees, virtually no such effort has been made for attending physicians who have completed their training or practicing physicians in nonacademic settings. It is the position of the American Academy of Sleep Medicine that a critical need exists to evaluate the roles of sleep disruption, sleep deprivation, and circadian misalignment in physician well-being and burnout. Such evaluation may pave the way for the development of effective countermeasures that promote healthy sleep, with the goal of reducing burnout and its negative impacts such as a shrinking physician workforce, poor physician health and functional outcomes, lower quality of care, and compromised patient safety. © 2020 American Academy of Sleep Medicine.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Local Perturbations of Cortical Excitability Propagate Differentially Through Large-Scale Functional Networks
(2020) Cerebral Cortex (New York, N.Y. : 1991), 30 (5), pp. 3352-3369. 

Rosenthal, Z.P.^{a b c} , Raut, R.V.^{b d} , Yan, P.^c , Koko, D.^c , Kraft, A.W.^e , Czerniewski, L.^{c f} , Acland, B.^{b g} , Mitra, A.^{a b d} , Snyder, L.H.^{f g} , Bauer, A.Q.^{d f} , Snyder, A.Z.^{c d} , Culver, J.P.^{d f h} , Raichle, M.E.^{c d f g} , Lee, J.-M.^{c d f}

^a Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, 63110, USA
^b Graduate Program of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
^d Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
^e Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, MA, Boston, 02115, United States
^f Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, 63110, USA
^g Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA
^h Department of Physics, Washington University School of Medicine, St. Louis, MO, 63110, USA

Abstract
Electrophysiological recordings have established that GABAergic interneurons regulate excitability, plasticity, and computational function within local neural circuits. Importantly, GABAergic inhibition is focally disrupted around sites of brain injury. However, it remains unclear whether focal imbalances in inhibition/excitation lead to widespread changes in brain activity. Here, we test the hypothesis that focal perturbations in excitability disrupt large-scale brain network dynamics. We used viral chemogenetics in mice to reversibly manipulate parvalbumin interneuron (PV-IN) activity levels in whisker barrel somatosensory cortex. We then assessed how this imbalance affects cortical network activity in awake mice using wide-field optical neuroimaging of pyramidal neuron GCaMP dynamics as well as local field potential recordings. We report 1) that local changes in excitability can cause remote, network-wide effects, 2) that these effects propagate differentially through intra- and interhemispheric connections, and 3) that chemogenetic constructs can induce plasticity in cortical excitability and functional connectivity. These findings may help to explain how focal activity changes following injury lead to widespread network dysfunction. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

Author Keywords
calcium imaging;  excitability;  functional connectivity;  inhibition;  parvalbumin interneuron

Document Type: Article
Publication Stage: Final
Source: Scopus

Pattern Similarity Analyses of FrontoParietal Task Coding: Individual Variation and Genetic Influences
(2020) Cerebral Cortex (New York, N.Y. : 1991), 30 (5), pp. 3167-3183. 

Etzel, J.A.^a , Courtney, Y.^{b c} , Carey, C.E.^{a d} , Gehred, M.Z.^{a e} , Agrawal, A.^f , Braver, T.S.^a

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, USA
^b Department of Biology, Kent State University, Kent, OH 44243, USA
^c Division of Medical Sciences, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, United States
^d Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, United States
^e Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, United States
^f Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA

Abstract
Pattern similarity analyses are increasingly used to characterize coding properties of brain regions, but relatively few have focused on cognitive control processes in FrontoParietal regions. Here, we use the Human Connectome Project (HCP) N-back task functional magnetic resonance imaging (fMRI) dataset to examine individual differences and genetic influences on the coding of working memory load (0-back, 2-back) and perceptual category (Face, Place). Participants were grouped into 105 monozygotic twin, 78 dizygotic twin, 99 nontwin sibling, and 100 unrelated pairs. Activation pattern similarity was used to test the hypothesis that FrontoParietal regions would have higher similarity for same load conditions, while Visual regions would have higher similarity in same perceptual category conditions. Results confirmed this highly robust regional double dissociation in neural coding, which also predicted individual differences in behavioral performance. In pair-based analyses, anatomically selective genetic relatedness effects were observed: relatedness predicted greater activation pattern similarity in FrontoParietal only for load coding and in Visual only for perceptual coding. Further, in related pairs, the similarity of load coding in FrontoParietal regions was uniquely associated with behavioral performance. Together, these results highlight the power of task fMRI pattern similarity analyses for detecting key coding and heritability features of brain regions. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
heritability;  N-back;  prefrontal;  twins;  working memory

Document Type: Article
Publication Stage: Final
Source: Scopus

The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse AD Models
(2020) Cells, 9 (5), . 

Bécot, A.^a , Pardossi-Piquard, R.^a , Bourgeois, A.^a , Duplan, E.^a , Xiao, Q.^b , Diwan, A.^{c d} , Lee, J.-M.^b , Lauritzen, I.^a

^a Laboratory of Excellence DistALZ, 660 route des Lucioles 06650 Valbonne, France
^b Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, City, Missouri, 63110, USA
^c Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
^d John Cochran Veterans Affairs Medical Center, St. Louis, MO 63106, USA

Abstract
: Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

Author Keywords
3xTgAD mice;  AAV8;  Alzheimer’s disease;  C99;  cathepsins;  lysosomes;  TFEB;  βCTF

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease
(2020) Frontiers in Neurology, 11, art. no. 370, . 

Black, K.J.^{a b} , Acevedo, H.K.^a , Koller, J.M.^a

^a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^b Departments of Neurology, Radiology and Neuroscience, Washington University in St. Louis, St. Louis, MO, United States

Abstract
We propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled based on clinical effects, but clinical measurements are influenced by confounding factors. The new method proposes to measure the effect objectively based on the timing of the known response of several brain regions to exogenous levodopa. Such responses are robust and can be quantified using perfusion MRI. Here we present simulation studies based on published clinical dose-response data and an intravenous levodopa infusion. Standard pharmacokinetic-pharmacodynamic methods were used to model the response. Then the effect site rate constant ke was estimated from simulated response data plus Gaussian noise. Predicted time – effect curves sampled at times consistent with phMRI differ substantially based on clinical severity. Estimated ke from noisy input data was recovered with good accuracy. These simulation results support the feasibility of levodopa phMRI hysteresis mapping to measure the severity of dopamine denervation objectively and simultaneously in all brain regions with a robust imaging response to exogenous levodopa. © Copyright © 2020 Black, Acevedo and Koller.

Author Keywords
ASL;  drug discovery and development;  hysteresis;  levodopa;  pharmacodynamics;  pharmacokinetic-pharmacodynamic modeling;  pharmacological biomarkers;  phMRI

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Light-evoked glutamate transporter EAAT5 activation coordinates with conventional feedback inhibition to control rod bipolar cell output
(2020) Journal of Neurophysiology, 123 (5), pp. 1828-1837. 

Bligard, G.W.^a , DeBrecht, J.^a , Smith, R.G.^b , Lukasiewicz, P.D.^{a c}

^a Department of Ophthalmology and Visual Sciences, Washington University, Campus Box 8096, St. Louis, MO 63110, United States
^b Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, United States
^c Department of Neuroscience, Washington University, St. Louis, MO, United States

Abstract
In the retina, modulation of the amplitude of dim visual signals primarily occurs at axon terminals of rod bipolar cells (RBCs). GABA and glycine inhibitory neurotransmitter receptors and the excitatory amino acid transporter 5 (EAAT5) modulate the RBC output. EAATs clear glutamate from the synapse, but they also have a glutamate-gated chloride conductance. EAAT5 acts primarily as an inhibitory glutamate-gated chloride channel. The relative role of visually evoked EAAT5 inhibition compared with GABA and glycine inhibition has not been addressed. In this study, we determine the contribution of EAAT5-mediated inhibition onto RBCs in response to light stimuli in mouse retinal slices. We find differences and similarities in the two forms of inhibition. Our results show that GABA and glycine mediate nearly all lateral inhibition onto RBCs, as EAAT5 is solely a mediator of RBC feedback inhibition. We also find that EAAT5 and conventional GABA inhibition both contribute to feedback inhibition at all stimulus intensities. Finally, our in silico modeling compares and contrasts EAAT5-mediated to GABA- and glycine-mediated feedback inhibition. Both forms of inhibition have a substantial impact on synaptic transmission to the postsynaptic AII amacrine cell. Our results suggest that the late phase EAAT5 inhibition acts with the early phase conventional, reciprocal GABA inhibition to modulate the rod signaling pathway between rod bipolar cells and their downstream synaptic targets. NEW & NOTEWORTHY Excitatory amino acid transporter 5 (EAAT5) glutamate transporters have a chloride channel that is strongly activated by glutamate, which modulates excitatory signaling. We found that EAAT5 is a major contributor to feedback inhibition on rod bipolar cells. Inhibition to rod bipolar cells is also mediated by GABA and glycine. GABA and glycine mediate the early phase of feedback inhibition, and EAAT5 mediates a more delayed inhibition. Together, inhibitory transmitters and EAAT5 coordinate to mediate feedback inhibition, controlling neuronal output. Copyright © 2020 the American Physiological Society

Author Keywords
EAAT5;  Glucose transporter;  Retina;  Rod bipolar cell

Document Type: Article
Publication Stage: Final
Source: Scopus

Disrupting flight increases sleep and identifies a novel sleep-promoting pathway in Drosophila
(2020) Science Advances, 6 (19), art. no. eaaz2166, . 

Melnattur, K.^a , Zhang, B.^b , Shaw, P.J.^a

^a Department of Neuroscience, Washington University School of Medicine, Campus Box 8108, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b Division of Biological Sciences, University of Missouri, Columbia, MO 65211, United States

Abstract
Sleep is plastic and is influenced by ecological factors and environmental changes. The mechanisms underlying sleep plasticity are not well understood. We show that manipulations that impair flight in Drosophila increase sleep as a form of sleep plasticity. We disrupted flight by blocking the wing-expansion program, genetically disrupting flight, and by mechanical wing perturbations. We defined a new sleep regulatory circuit starting with specific wing sensory neurons, their target projection neurons in the ventral nerve cord, and the neurons they connect to in the central brain. In addition, we identified a critical neuropeptide (burs) and its receptor (rickets) that link wing expansion and sleep. Disrupting flight activates these sleep-promoting projection neurons, as indicated by increased cytosolic calcium levels, and stably increases the number of synapses in their axonal projections. These data reveal an unexpected role for flight in regulating sleep and provide new insight into how sensory processing controls sleep need. Copyright © 2020 The Authors.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Clinical Research in the National Football League: The Player Scientific and Medical Research Protocol
(2020) Current Sports Medicine Reports, 19 (5), pp. 168-174. 

Mack, C.^a , Matava, M.^b , Zeidler, K.^a , Sills, A.^{c d} , Solomon, G.^{c d}

^a IQVIA Research Triangle Park
^b Department of Orthopedic Surgery, Washington University School of Medicine St. Louis, MO, Norway
^c Department of Neurological Surgery, Vanderbilt University School of Medicine Nashville, TN
^d National Football League, NY, NY

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

American Society of Hematology 2020 guidelines for sickle cell disease: Prevention, diagnosis, and treatment of cerebrovascular disease in children and adults
(2020) Blood Advances, 4 (8), pp. 1554-1588. Cited 1 time.

DeBaun, M.R.^a , Jordan, L.C.^b , King, A.A.^c , Schatz, J.^d , Vichinsky, E.^e , Fox, C.K.^{f g} , McKinstry, R.C.^{h i} , Telfer, P.^j , Kraut, M.A.^k , Daraz, L.^l , Kirkham, F.J.^{m n o} , Murad, M.H.^l

^a Department of Pediatrics, Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
^b Division of Pediatric Neurology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
^c Program in Occupational Therapy, Division of Hematology, Department of Pediatrics, Division of Hematology, Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Psychology, University of South Carolina, Columbia, SC, United States
^e Children’s Hospital Oakland Research Institute, Oakland, CA, United States
^f Department of Neurology, University of California San Francisco, San Francisco, CA, United States
^g Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
^h Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
ⁱ Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
^j Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, United Kingdom
^k Department of Radiology, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
^l Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, United States
^m Developmental Neurosciences Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
ⁿ Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
^o Department of Child Health, University Hospital Southampton, Southampton, United Kingdom

Abstract
Background: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan. Objective: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD. Methods: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations. Results: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle-and high-income settings. Conclusions: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sβ0 (HbSβ0) thalassemia living in low-middle-income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSβ0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD. © 2020 by The American Society of Hematology

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Proteinopathy and longitudinal changes in functional connectivity networks in Parkinson disease
(2020) Neurology, 94 (7), pp. e718-e728. 

Campbell, M.C.^a , Jackson, J.J.^b , Koller, J.M.^b , Snyder, A.Z.^b , Kotzbauer, P.T.^b , Perlmutter, J.S.^b

^a From the Departments of Neurology (M.C.C., A.Z.S., P.T.K., J.S.P.), Radiology (M.C.C., A.Z.S., J.S.P.), Psychiatry (J.M.K.), and Neuroscience (J.S.P.), Program in Occupational Therapy (J.S.P.), and Program in Physical Therapy (J.S.P.), Washington University School of Medicine; and Department of Psychological and Brain Sciences (J.J.J.), Washington University in St. Louis, MO. meghanc@wustl.edu
^b From the Departments of Neurology (M.C.C., A.Z.S., P.T.K., J.S.P.), Radiology (M.C.C., A.Z.S., J.S.P.), Psychiatry (J.M.K.), and Neuroscience (J.S.P.), Program in Occupational Therapy (J.S.P.), and Program in Physical Therapy (J.S.P.), Washington University School of Medicine; and Department of Psychological and Brain Sciences (J.J.J.), Washington University in St. Louis, MO

Abstract
OBJECTIVE: To evaluate resting-state functional connectivity as a potential prognostic biomarker of Parkinson disease (PD) progression. The study examined longitudinal changes in cortical resting-state functional connectivity networks in participants with PD compared to controls as well as in relation to baseline protein measures and longitudinal clinical progression. METHODS: Individuals with PD without dementia (n = 64) and control participants (n = 27) completed longitudinal resting-state MRI scans and clinical assessments including full neuropsychological testing after overnight withdrawal of PD medications (“off”). A total of 55 participants with PD and 20 control participants also completed baseline β-amyloid PET scans and lumbar punctures for CSF protein levels of α-synuclein, β-amyloid, and tau. Longitudinal analyses were conducted with multilevel growth curve modeling, a type of mixed-effects model. RESULTS: Functional connectivity within the sensorimotor network and the interaction between the dorsal attention network with the frontoparietal control network decreased significantly over time in participants with PD compared to controls. Baseline CSF α-synuclein protein levels predicted decline in the sensorimotor network. The longitudinal decline in the dorsal attention-frontoparietal internetwork strength correlated with the decline in cognitive function. CONCLUSIONS: These results indicate that α-synuclein levels may influence longitudinal declines in motor-related functional connectivity networks. Further, the interaction between cortical association networks declines over time in PD prior to dementia onset and may serve as a prognostic marker for the development of dementia. © 2019 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Making the Case for Disordered Proteins and Biomolecular Condensates in Bacteria
(2020) Trends in Biochemical Sciences, . 

Cohan, M.C., Pappu, R.V.

Department of Biomedical Engineering and Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Intrinsically disordered proteins/regions (IDPs/IDRs) contribute to a diverse array of molecular functions in eukaryotic systems. There is also growing recognition that membraneless biomolecular condensates, many of which are organized or regulated by IDPs/IDRs, can enable spatial and temporal regulation of complex biochemical reactions in eukaryotes. Motivated by these findings, we assess if (and how) membraneless biomolecular condensates and IDPs/IDRs are functionally involved in key cellular processes and molecular functions in bacteria. We summarize the conceptual underpinnings of condensate assembly and leverage these concepts by connecting them to recent findings that implicate specific types of condensates and IDPs/IDRs in important cellular level processes and molecular functions in bacterial systems. © 2020 Elsevier Ltd

Author Keywords
cellular organization;  glass transitions;  phase separation aided percolation;  phase transitions;  stickers and spacers

Document Type: Review
Publication Stage: Article in Press
Source: Scopus

Does weather trigger urologic chronic pelvic pain syndrome flares? A case-crossover analysis in the multidisciplinary approach to the study of the chronic pelvic pain research network
(2020) Neurourology and Urodynamics, . 

Li, J.^{a b c} , Yu, T.^{a b d} , Javed, I.^{a b} , Siddagunta, C.^{a b} , Pakpahan, R.^a , Langston, M.E.^{a e} , Dennis, L.K.^f , Kingfield, D.M.^g , Moore, D.J.^h , Andriole, G.L.ⁱ , Lai, H.H.^{i j} , Colditz, G.A.^a , Sutcliffe, S.^a

^a Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Brown School at Washington University, St. Louis, MO, United States
^c STATinMED Research, Plano, TX, United States
^d engage2Health, Health Advocate, Westlake Village, CA, United States
^e Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States
^f Department of Epidemiology & Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, United States
^g Cooperative Institute for Research in Environmental Sciences, University of Colorado, NOAA/OAR/ESRL/Global Systems Laboratory, Boulder, CO, United States
^h School of Natural Resources and the Environment, University of Arizona, Tucson, AZ, United States
ⁱ Division of Urological Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: To investigate whether meteorological factors (temperature, barometric pressure, relative humidity, ultraviolet index [UVI], and seasons) trigger flares in male and female urologic chronic pelvic pain patients. Methods: We assessed flare status every 2 weeks in our case-crossover study of flare triggers in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain 1-year longitudinal study. Flare symptoms, flare start date, and exposures in the 3 days preceding a flare or the date of questionnaire completion were assessed for the first three flares and at three randomly selected nonflare times. We linked these data to daily temperature, barometric pressure, relative humidity, and UVI values by participants’ first 3 zip code digits. Values in the 3 days before and the day of a flare, as well as changes in these values, were compared to nonflare values by conditional logistic regression. Differences in flare rates by astronomical and growing seasons were investigated by Poisson regression in the full study population. Results: A total of 574 flare and 792 nonflare assessments (290 participants) were included in the case-crossover analysis, and 966 flare and 5389 nonflare (409 participants) were included in the full study analysis. Overall, no statistically significant associations were observed for daily weather, no patterns of associations were observed for weather changes, and no differences in flare rates were observed by season. Conclusions: We found minimal evidence to suggest that weather triggers flares, although we cannot rule out the possibility that a small subset of patients is susceptible. © 2020 Wiley Periodicals, Inc.

Author Keywords
bladder pain syndrome;  chronic pelvic pain syndrome;  chronic prostatitis;  flare;  interstitial cystitis;  trigger

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy
(2020) Genetics in Medicine, . 

Singh, S.^a , Gupta, A.^{b c} , Zech, M.^{d e} , Sigafoos, A.N.^{b f} , Clark, K.J.^{b f} , Dincer, Y.^{g h} , Wagner, M.^{d e} , Humberson, J.B.ⁱ , Green, S.^j , van Gassen, K.^a , Brandt, T.^k , Schnur, R.E.^k , Millan, F.^k , Si, Y.^k , Mall, V.^{g l} , Winkelmann, J.^{d e m n} , Gavrilova, R.H.^{b o p} , Klee, E.W.^{b c o} , Engleman, K.^q , Safina, N.P.^q , Slaugh, R.^r , Bryant, E.M.^s , Tan, W.-H.^t , Granadillo, J.^r , Misra, S.N.^s , Schaefer, G.B.^j , Towner, S.ⁱ , Brilstra, E.H.^a , Koeleman, B.P.C.^a

^a Department of Genetics, University Medical Centre Utrecht, Utrecht, Netherlands
^b Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
^c Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
^d Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany
^e Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
^f Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
^g Lehrstuhl für Sozialpädiatrie, Technische Universität München, Munich, Germany
^h Zentrum für Humangenetik und Laboratoriumsdiagnostik (MVZ), Martinsried, Germany
ⁱ Department of Pediatrics, University of Virginia, Charlottesville, VA, United States
^j Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^k GeneDx, Gaithersburg, MD, United States
^l kbo-Kinderzentrum München, Munich, Germany
^m Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany
ⁿ Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
^o Departments of Clinical Genomics and Neurology, Mayo Clinic, Rochester, MN, United States
^p Department of Neurology, Mayo Clinic, Rochester, MN, United States
^q Division of Clinical Genetics, Children’s Mercy Kansas City, University of Missouri Kansas City School of Medicine, Kansas city, MO, United States
^r Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^s Ann & Robert H. Lurie Children’s Hospital, Epilepsy Center, Chicago, IL, United States
^t Division of Genetics and Genomics, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States

Abstract
Purpose: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. Conclusion: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients. © 2020, The Author(s).

Author Keywords
developmental disorder;  epilepsy;  neurodevelopmental disorder;  NR4A2;  seizures

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7
(2020) Genetics in Medicine, . 

Castilla-Vallmanya, L.^a , Selmer, K.K.^{b c} , Dimartino, C.^{d bk} , Rabionet, R.^a , Blanco-Sánchez, B.^{d bk} , Yang, S.^e , Reijnders, M.R.F.^f , van Essen, A.J.^g , Oufadem, M.^{d bk} , Vigeland, M.D.^{h i} , Stadheim, B.^h , Houge, G.^j , Cox, H.^k , Kingston, H.^{l m} , Clayton-Smith, J.^{l m} , Innis, J.W.ⁿ , Iascone, M.^o , Cereda, A.^o , Gabbiadini, S.^o , Chung, W.K.^p , Sanders, V.^{q r} , Charrow, J.^q , Bryant, E.^q , Millichap, J.^q , Vitobello, A.^{s t} , Thauvin, C.^{s u} , Mau-Them, F.T.^{s t} , Faivre, L.^{t u} , Lesca, G.^{v w} , Labalme, A.^v , Rougeot, C.^x , Chatron, N.^{v w} , Sanlaville, D.^{v w} , Christensen, K.M.^y , Kirby, A.^y , Lewandowski, R.^z , Gannaway, R.^z , Aly, M.^{d bk} , Lehman, A.^aa , Clarke, L.^aa , Graul-Neumann, L.^ab , Zweier, C.^ac , Lessel, D.^ad , Lozic, B.^ae , Aukrust, I.^j , Peretz, R.^af , Stratton, R.^af , Smol, T.^{ag ah} , Dieux-Coëslier, A.^ag , Meira, J.^ai , Wohler, E.^aj , Sobreira, N.^aj , Beaver, E.M.^ak , Heeley, J.^ak , Briere, L.C.^al , High, F.A.^al , Sweetser, D.A.^al , Walker, M.A.^am , Keegan, C.E.ⁿ , Jayakar, P.^an , Shinawi, M.^ao , Kerstjens-Frederikse, W.S.^g , Earl, D.L.^ap , Siu, V.M.^aq , Reesor, E.^aq , Yao, T.^aq , Hegele, R.A.^aq , Vaske, O.M.^ar , Rego, S.^as , Shapiro, K.A.^at , Wong, B.^at , Gambello, M.J.^au , McDonald, M.^av , Karlowicz, D.^av , Colombo, R.^{aw ax} , Serretti, A.^ay , Pais, L.^az , O’Donnell-Luria, A.^az , Wray, A.^ba , Sadedin, S.^bb , Chong, B.^bb , Tan, T.Y.^{bb bc} , Christodoulou, J.^{bb bc} , White, S.M.^{bb bc} , Slavotinek, A.^bd , Barbouth, D.^be , Morel Swols, D.^be , Parisot, M.^{bf bg} , Bole-Feysot, C.^{bf bg} , Nitschké, P.^{d bh} , Pingault, V.^{d bi bk} , Munnich, A.^{d bi} , Cho, M.T.^e , Cormier-Daire, V.^{d bi bj} , Balcells, S.^a , Lyonnet, S.^{d bi bk} , Grinberg, D.^a , Amiel, J.^{d bi bk} , Urreizti, R.^a , Gordon, C.T.^{d bk} , Undiagnosed Diseases Network, Care4Rare Canada Consortium^bk

^a Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona; CIBERER, IRSJD, Barcelona, Spain
^b Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital and the University of Oslo, Oslo, Norway
^c The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway
^d Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
^e GeneDx, Gaithersburg, MD, United States
^f Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands
^g Department of Genetics, University Medical Center Groningen, Groningen, Netherlands
^h Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
ⁱ Institute of Clinical Medicine, University of Oslo, Oslo, Norway
^j Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
^k West Midlands Regional Genetics Service, Birmingham Women’s NHS Foundation Trust, Birmingham Women’s Hospital, Edgbaston, Birmingham, United Kingdom
^l Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Academic Health Sciences Centre, Manchester, United Kingdom
^m Division of Evolution and Genomic Sciences, University of Manchester, School of Biological Sciences, Manchester, United Kingdom
ⁿ Departments of Human Genetics, Pediatrics and Internal Medicine, University of Michigan, Ann Arbor, MI, United States
^o Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy
^p Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, United States
^q Ann & Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, United States
^r Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^s UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France
^t INSERM UMR1231 GAD, Dijon, France
^u Centre de Reference maladies rares “Anomalies du Developpement et syndrome malformatifs” de l’Est, Centre de Genetique, Hopital d’Enfants, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France
^v Department of Medical Genetics, Lyon Hospices Civils, Lyon, France
^w Institut NeuroMyoGène, CNRS UMR 5310 – INSERM U1217, Université de Lyon, Lyon, France
^x Hôpital Femme Mère Enfant, Service de Neuropédiatrie, Bron, France
^y Saint Louis University School of Medicine, St. Louis, MO, United States
^z Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
^aa Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada
^ab Institute of Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany
^ac Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
^ad Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
^ae Department of Pediatrics, University Hospital Centre Split; University of Split, School of medicine, Split, Croatia
^af Driscoll Children’s Hospital, Corpus Christi, TX, United States
^ag Institut de Génétique Médicale, CHU Lille, Lille, France
^ah Université de Lille, EA 7364 – RADEME – Maladies RAres du DEveloppement embryonnaire et du MEtabolisme, Lille, France
^ai Division of Medical Genetics, University Hospital Professor Edgard Santos/ Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
^aj McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, United States
^ak Mercy Kids Genetics, Mercy Children’s Hospital, St. Louis, MO, United States
^al Division of Medical Genetics & Metabolism, Massachusetts General Hospital for Children, Boston, MA, United States
^am Department of Pediatric Neurology, Massachusetts General Hospital for Children, Boston, MA, United States
^an Division of Genetics and Metabolism, Nicklaus Children’s Hospital, Miami, FL, United States
^ao Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, United States
^ap Seattle Children’s Hospital, Seattle, WA, United States
^aq University of Western Ontario, London, ON, Canada
^ar Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, United States
^as Institute for Human Genetics, University of California San Francisco, San Francisco, CA, United States
^at Cortica Healthcare, San Diego, CA, United States
^au Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, GA, United States
^av Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
^aw Faculty of Medicine, Catholic University, IRCCS Policlinico Gemelli, Rome, Italy
^ax Center for the Study of Rare Hereditary Diseases (CeSMER), Niguarda Ca’ Granda Metropolitan Hospital, Milan, Italy
^ay Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
^az Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, United States
^ba Royal Children’s Hospital, Melbourne, Australia
^bb Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia
^bc Department of Paediatrics, University of Melbourne, Melbourne, Australia
^bd Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
^be Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, United States
^bf Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker INSERM UMR1163, Paris, France
^bg INSERM US24/CNRS UMS3633, Paris Descartes-Sorbonne Paris Cité University, Paris, France
^bh Bioinformatics Platform, INSERM UMR 1163, Institut Imagine, Paris, France
^bi Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
^bj Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, Institut Imagine, Paris, France
^bk Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France

Abstract
Purpose: Somatic variants in tumor necrosis factor receptor–associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. Methods: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. Results: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay–malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. Conclusion: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies. © 2020, American College of Medical Genetics and Genomics.

Author Keywords
blepharophimosis;  craniofacial development;  intellectual disability;  patent ductus arteriosus;  TRAF7

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

In vivo characterization of emerging white matter microstructure in the fetal brain in the third trimester
(2020) Human Brain Mapping, . 

Jaimes, C.^{a b c} , Machado-Rivas, F.^{a c} , Afacan, O.^{a c} , Khan, S.^{a c} , Marami, B.^{a c} , Ortinau, C.M.^e , Rollins, C.K.^{c d} , Velasco-Annis, C.^a , Warfield, S.K.^{a c} , Gholipour, A.^{a c}

^a Department of Radiology, Boston Children’s Hospital, Boston, MA, United States
^b Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children’s Hospital, Boston, MA, United States
^c Harvard Medical School, Boston, MA, United States
^d Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^e Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
The third trimester of pregnancy is a period of rapid development of fiber bundles in the fetal white matter. Using a recently developed motion-tracked slice-to-volume registration (MT-SVR) method, we aimed to quantify tract-specific developmental changes in apparent diffusion coefficient (ADC), fractional anisotropy (FA), and volume in third trimester healthy fetuses. To this end, we reconstructed diffusion tensor images from motion corrected fetal diffusion magnetic resonance imaging data. With an approved protocol, fetal MRI exams were performed on healthy pregnant women at 3 Tesla and included multiple (2–8) diffusion scans of the fetal head (1–2 b = 0 s/mm2 images and 12 diffusion-sensitized images at b = 500 s/mm2). Diffusion data from 32 fetuses (13 females) with median gestational age (GA) of 33 weeks 4 days were processed with MT-SVR and deterministic tractography seeded by regions of interest corresponding to 12 major fiber tracts. Multivariable regression analysis was used to evaluate the association of GA with volume, FA, and ADC for each tract. For all tracts, the volume and FA increased, and the ADC decreased with GA. Associations reached statistical significance for: FA and ADC of the forceps major; volume and ADC for the forceps minor; FA, ADC, and volume for the cingulum; ADC, FA, and volume for the uncinate fasciculi; ADC of the inferior fronto-occipital fasciculi, ADC of the inferior longitudinal fasciculi; and FA and ADC for the corticospinal tracts. These quantitative results demonstrate the complex pattern and rates of tract-specific, GA-related microstructural changes of the developing white matter in human fetal brain. © 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.

Author Keywords
developing white matter;  diffusion tensor imaging;  diffusion weighted MRI;  fetal brain;  fetal MRI;  tract-specific analysis;  tractography;  white matter microstructure

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome
(2020) Laboratory Investigation, . 

Mahadevan, J.^a , Morikawa, S.^a , Yagi, T.^a , Abreu, D.^a , Lu, S.^a , Kanekura, K.^{a b} , Brown, C.M.^a , Urano, F.^{a c}

^a Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
^c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Our results indicate that molecular pathways regulated by MANF are promising therapeutic targets for regenerative therapy of ER stress-related disorders, including diabetes, retinal degeneration, neurodegeneration, and Wolfram syndrome. © 2020, The Author(s).

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage
(2020) Annals of Neurology, . 

Falcone, G.J.^a , Kirsch, E.^a , Acosta, J.N.^a , Noche, R.B.^a , Leasure, A.^a , Marini, S.^b , Chung, J.^b , Selim, M.^c , Meschia, J.F.^d , Brown, D.L.^e , Worrall, B.B.^f , Tirschwell, D.L.^g , Jagiella, J.M.^h , Schmidt, H.ⁱ , Jimenez-Conde, J.^{j k} , Fernandez-Cadenas, I.^l , Lindgren, A.^{m n} , Slowik, A.^h , Gill, D.^o , Holmes, M.^{p q} , Phuah, C.-L.^r , Petersen, N.H.^a , Matouk, MD, C.N.^s , Gunel, M.^s , Sansing, L.^t , Bennett, D.^q , Chen, Z.^q , Sun, L.L.^u , Clarke, R.^a , Walters, R.G.^{p q} , Gill, T.M.^v , Biffi, A.^{b w x y} , Kathiresan, S.^{b w aa} , Langefeld, C.D.^ab , Woo, D.^ac , Rosand, J.^{b w z ad} , Sheth, K.N.^a , Anderson, C.D.^{b w z ad} , For the International Stroke Genetics Consortium^ae

^a Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, United States
^b Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, United States
^c Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, United States
^d Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^e Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI, United States
^f Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA, United States
^g Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA, United States
^h Department of Neurology, Jagiellonian University Medical College, Kraków, Poland
ⁱ Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz, Austria
^j Neurovascular Research Unit, Department of Neurology, Institut Municipal d’Investigacio’ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
^k Program in Inflammation and Cardiovascular Disorders, Institut Municipal d’Investigacio’ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
^l Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
^m Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
ⁿ Department of Neurology, Skåne University Hospital, Lund, Sweden
^o Department of Epidemiology and Biostatistics and Department of Stroke Medicine, Imperial College London, London, United Kingdom
^p Medical Research Council Population Health Research Unit, University of Oxford, Oxford, United Kingdom
^q Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Medical Research Council Population Health Research Unit, University of Oxford, Oxford, United Kingdom
^r Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^s Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
^t Division of Vascular Neurology and Stroke, Department of Neurology, Yale School of Medicine, New Haven, CT, United States
^u Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
^v Department of Internal Medicine, Geriatric Medicine, Yale School of Medicine, New Haven, CT, United States
^w Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
^x Division of Behavioral Neurology, Department of Neurology, MGH, Boston, MA, United States
^y Division of Psychiatry, Department of Psychiatry, MGH, Boston, MA, United States
^z Department of Neurology, MGH, Boston, MA, United States
^aa Cardiovascular Disease Prevention Center, MGH, Boston, MA, United States
^ab Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States
^ac Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^ad Henry and Allison McCance Center for Brain Health, MGH, Boston, MA, United States

Abstract
Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p &lt; 1.00 × 10-100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85–0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81–0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p &gt; 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively. Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020. © 2020 American Neurological Association

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

For Whom Do Cochlear Implants Work Best?
(2020) JAMA Otolaryngology – Head and Neck Surgery, . 

Shew, M., Herzog, J.A., Buchman, C.A.

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, 660 South Euclid Avenue, St Louis, MO 63110, United States

Document Type: Editorial
Publication Stage: Article in Press
Source: Scopus

In vivo evolution of biopsy-proven inflammatory demyelination quantified by R2t* mapping
(2020) Annals of Clinical and Translational Neurology, . 

Xiang, B.^a , Wen, J.^a , Lu, H.-C.^b , Schmidt, R.E.^b , Yablonskiy, D.A.^a , Cross, A.H.^c

^a Department of Radiology, Washington University, St. Louis, MO 63110, United States
^b Department of Pathology & Immunology, Washington University, St. Louis, MO 63110, United States
^c Department of Neurology, Washington University, St. Louis, MO 63110, United States

Abstract
A 35-year-old man with an enhancing tumefactive brain lesion underwent biopsy, revealing inflammatory demyelination. We used quantitative Gradient-Recalled-Echo (qGRE) MRI to visualize and measure tissue damage in the lesion. Two weeks after biopsy, qGRE showed significant R2t* reduction in the left optic radiation and surrounding tissue, consistent with the histopathological and clinical findings. qGRE was repeated 6 and 14 months later, demonstrating partially recovered optic radiation R2t*, in concert with improvement of the hemianopia to ultimately involve only the lower right visual quadrant. These results support qGRE metrics as in vivo biomarkers for tissue damage and longitudinal monitoring of demyelinating disease. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

Genetic and environmental risk structure of internalizing psychopathology in youth
(2020) Depression and Anxiety, . 

Hettema, J.M.^{a b} , Bourdon, J.L.^{a c} , Sawyers, C.^a , Verhulst, B.^b , Brotman, M.A.^d , Leibenluft, E.^d , Pine, D.S.^d , Roberson-Nay, R.^a

^a Department of Psychiatry, Virginia Institute for Psychiatry and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
^b Department of Psychiatry, Texas A&M Health Science Center, Bryan, TX, United States
^c Department of Psychiatry, Brown School of Social Work, Washington University, St. Louis, MO, United States
^d Emotion and Development Branch, National Institute of Mental Health Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States

Abstract
Background: Internalizing disorders (IDs), consisting of syndromes of anxiety and depression, are common, debilitating conditions often beginning early in life. Various trait-like psychological constructs are associated with IDs. Our prior analysis identified a tripartite model of Fear/Anxiety, Dysphoria, and Positive Affect among symptoms of anxiety and depression and the following constructs in youth: anxiety sensitivity, fearfulness, behavioral activation and inhibition, irritability, neuroticism, and extraversion. The current study sought to elucidate their overarching latent genetic and environmental risk structure. Methods: The sample consisted of 768 juvenile twin subjects ages 9–14 assessed for the nine, abovementioned measures. We compared two multivariate twin models of this broad array of phenotypes. Results: A hypothesis-driven, common pathway twin model reflecting the tripartite structure of the measures were fit to these data. However, an alternative independent pathway model provided both a better fit and more nuanced insights into their underlying genetic and environmental risk factors. Conclusions: Our findings suggest a complex latent genetic and environmental structure to ID phenotypes in youth. This structure, which incorporates both clinical symptoms and various psychological traits, informs future phenotypic approaches for identifying specific genetic and pathophysiological mechanisms underlying ID risk. © 2020 Wiley Periodicals, Inc.

Author Keywords
anxiety;  child;  depression;  fear;  genetics;  twin study

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading
(2020) Molecular Psychiatry, . 

Xu, Y.^a , Du, S.^{a b} , Marsh, J.A.^c , Horie, K.^d , Sato, C.^d , Ballabio, A.^{e f g h} , Karch, C.M.^{c i} , Holtzman, D.M.^{d i} , Zheng, H.^{a b e}

^a Huffington Center on Aging, Baylor College of Medicine, Houston, TX, United States
^b Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
^c Department of Psychiatry, 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 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
^f Dan and Jan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, United States
^g Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy
^h Department of Medical and Translational Sciences, Federico II University, Naples, Italy
ⁱ Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Neurofibrillary tangles (NFTs) composed of hyperphosphorylated and misfolded tau protein are a pathological hallmark of Alzheimer’s disease and other tauopathy conditions. Tau is predominantly an intraneuronal protein but is also secreted in physiological and pathological conditions. The extracellular tau has been implicated in the seeding and propagation of tau pathology and is the prime target of the current tau immunotherapy. However, truncated tau species lacking the microtubule-binding repeat (MTBR) domains essential for seeding have been shown to undergo active secretion and the mechanisms and functional consequences of the various extracellular tau are poorly understood. We report here that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, plays an essential role in the lysosomal exocytosis of selected tau species. TFEB loss of function significantly reduced the levels of interstitial fluid (ISF) tau in PS19 mice expressing P301S mutant tau and in conditioned media of mutant tau expressing primary neurons, while the secretion of endogenous wild-type tau was not affected. Mechanistically we found that TFEB regulates the secretion of truncated mutant tau lacking MTBR and this process is dependent on the lysosomal calcium channel TRPML1. Consistent with the seeding-incompetent nature of the truncated tau and supporting the concept that TFEB-mediated lysosomal exocytosis promotes cellular clearance, we show that reduced ISF tau in the absence of TFEB is associated with enhanced intraneuronal pathology and accelerated spreading. Our results support the idea that TFEB-mediated tau exocytosis serves as a clearance mechanism to reduce intracellular tau under pathological conditions and that effective tau immunotherapy should devoid targeting these extracellular tau species. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Regaining access to marginal knowledge in a classroom setting
(2020) Applied Cognitive Psychology, . 

Butler, A.C.^a , Black-Maier, A.C.^b , Campbell, K.^c , Marsh, E.J.^d , Persky, A.M.^c

^a Department of Education and Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Friday Institute for Educational Innovation, North Carolina State University, Raleigh, NC, United States
^c Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^d Department of Psychology and Neuroscience, Duke University, Durham, NC, United States

Abstract
Students learn large amounts of information, but not all of it is remembered after courses end – meaning that valuable class time is often spent reviewing background material. Crucially, laboratory research suggests different strategies will be effective when reactivating previously learned information (i.e. marginal knowledge), as opposed to learning new information. In two experiments, we evaluated whether these laboratory results translated to the classroom. Topics from prior courses were tested to document which information students could no longer retrieve. Half were assigned to a not-tested control and half to the intervention; for these topics, students answered multiple-choice questions (without feedback) that gave them the chance to recognize the information they had failed to retrieve. Weeks later, students completed a final assessment on all topics. Crucially, multiple-choice testing increased the retrieval of previously forgotten information, providing the first classroom demonstration of the reactivation of marginal knowledge. © 2020 John Wiley & Sons, Ltd.

Author Keywords
long-term retention;  marginal knowledge;  multiple-choice testing;  remediation

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Admitting Low-Risk Patients With Intracerebral Hemorrhage to a Neurological Step-Down Unit Is Safe, Results in Shorter Length of Stay, and Reduces Intensive Care Utilization: A Retrospective Controlled Cohort Study
(2020) Neurohospitalist, . 

Laws, L.^a , Lee, F.^b , Kumar, A.^b , Dhar, R.^a

^a Department of Neurology, Washington University in St. LouisMO, United States
^b Department of Neurology, St. Louis UniversityMO, United States

Abstract
Background and Purpose: Patients suffering intracerebral hemorrhage (ICH) are at risk for early neurologic deterioration and are often admitted to intensive care units (ICU) for observation. There is limited data on the safety of admitting low-risk patients with ICH to a non-ICU setting. We hypothesized that admitting such patients to a neurologic step-down unit (SDU) is safe and less resource-intensive. Methods: We performed a retrospective analysis of patients with primary ICH admitted to our SDU. We compared this cohort to a control group of ICH patients admitted to a neurologic-ICU (NICU) at a partner institution. We analyzed patients with supratentorial ICH ≤15 cc, Glasgow Coma Scale ≥ 13, National Institutes of Health Stroke Scale ≤ 10, and no to minimal intraventricular hemorrhage. Primary end points were (re-)admission to an NICU and rates of hematoma expansion (HE). We also compared total NICU days and hospital length of stay (LOS). Results: Eighty patients with ICH were admitted to the SDU. Only 2 required transfer to the NICU for complications related to ICH, including 1 for HE. Seventy-four SDU patients met inclusion criteria and were compared to 58 patients admitted to an NICU. There was no difference in rates of NICU (re-)admission (7 vs 2, P =.17) or rates of HE (3 vs 5, P =.28). Median NICU days were 0 versus 1 (P <.001). Step-down unit admission was associated with shorter LOS (3 vs 4 days, P =.05). Conclusions: Select patients with ICH can be safely admitted to an SDU. This may reduce LOS and ICU utilization. We also propose criteria for admitting patients with ICH to an SDU. © The Author(s) 2020.

Author Keywords
intensive care unit utilization;  intracerebral hemorrhage;  neurologic intensive care unit;  step-down unit;  transitional care unit

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Continuous Electroencephalography Monitoring in Critically Ill Infants and Children
(2020) Pediatric Neurology, . 

Griffith, J.L., Tomko, S.T., Guerriero, R.M.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Continuous video electroencephalography (CEEG) monitoring of critically ill infants and children has expanded rapidly in recent years. Indications for CEEG include evaluation of patients with altered mental status, characterization of paroxysmal events, and detection of electrographic seizures, including monitoring of patients with limited neurological examination or conditions that put them at high risk for electrographic seizures (e.g., cardiac arrest or extracorporeal membrane oxygenation cannulation). Depending on the inclusion criteria and clinical characteristics of the population studied, the percentage of pediatric patients with electrographic seizures varies from 7% to 46% and with electrographic status epilepticus from 1% to 23%. There is also evidence that epileptiform and background CEEG patterns may provide important information about prognosis in certain clinical populations. Quantitative EEG techniques are emerging as a tool to enhance the value of CEEG to provide real-time bedside data for management and prognosis. Continued research is needed to understand the clinical value of seizure detection and identification of other CEEG patterns on the outcomes of critically ill infants and children. © 2020 Elsevier Inc.

Author Keywords
Critical care;  Electroencephalographic monitoring;  Electroencephalography;  Intensive care unit;  Quantitative electroencephalography;  Seizure;  Status epilepticus

Document Type: Review
Publication Stage: Article in Press
Source: Scopus