WashU weekly Neuroscience publications

Prenatal stress exposure and multimodal assessment of amygdala–medial prefrontal cortex connectivity in infants
(2020) Developmental Cognitive Neuroscience, 46, art. no. 100877, .

Humphreys, K.L.^a , Camacho, M.C.^b , Roth, M.C.^a , Estes, E.C.^a

^a Vanderbilt University, Department of Psychology and Human Development, 230 Appleton Place, #552, Nashville, TN 37203, United States
^b Washington University in St. Louis, Department of Psychiatry, 4444 Forest Park Avenue, St. Louis, MO 63110, United States

Abstract
Stressful experiences are linked to neurodevelopment. There is growing interest in the role of stress in the connectivity between the amygdala and medial prefrontal cortex (mPFC), a circuit that subserves automatic emotion regulation. However, the specific timing and mechanisms that underlie the association between stress and amygdala–mPFC connectivity are unclear. Many factors, including variations in fetal exposure to maternal stress, appear to affect early developing brain circuitry. However, few studies have examined the associations of stress and amygdala–mPFC connectivity in early life, when the brain is most plastic and sensitive to environmental influence. In this longitudinal pilot study, we characterized the association between prenatal stress and amygdala–mPFC connectivity in young infants (approximately age 5 weeks). A final sample of 33 women who provided data on preconception and prenatal stress during their pregnancy returned with their offspring for a magnetic resonance imaging scan session, which enabled us to characterize amygdala–mPFC structural and functional connectivity as a function of prenatal stress. Increased prenatal stress was associated with decreased functional connectivity and increased structural connectivity between the amygdala and mPFC. These results provide insight into the influence of prenatal maternal stress on the early development of this critical regulatory circuitry. © 2020 The Author(s)

Author Keywords
Amygdala;  Diffusion weighted imaging;  Infant neuroimaging;  Medial prefrontal cortex;  Prenatal stress;  Resting-state

Funding details
Jacobs Foundation2017-1261-05
Vanderbilt Institute for Clinical and Translational ResearchVICTRVR53419
National Science FoundationNSF

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

Mild traumatic brain injury is associated with effect of inflammation on structural changes of default mode network in those developing chronic pain
(2020) Journal of Headache and Pain, 21 (1), art. no. 135, .

Niu, X.^a b c , Bai, L.^d , Sun, Y.^b , Wang, Y.^b , Bai, G.^e , Yin, B.^f , Wang, S.^d , Gan, S.^b d , Jia, X.^d , Liu, H.^a

^a Department of Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
^b Department of Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
^c Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d The Key Laboratory of Biomedical Information Engineering, Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049, China
^e Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
^f Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

Abstract
Background: Mild traumatic brain injury (mTBI) has a higher prevalence (more than 50%) of developing chronic posttraumatic headache (CPTH) compared with moderate or severe TBI. However, the underlying neural mechanism for CPTH remains unclear. This study aimed to investigate the inflammation level and cortical volume changes in patients with acute PTH (APTH) and further examine their potential in identifying patients who finally developed CPTH at follow-up. Methods: Seventy-seven mTBI patients initially underwent neuropsychological measurements, 9-plex panel of serum cytokines and MRI scans within 7 days post-injury (T-1) and 54 (70.1%) of patients completed the same protocol at a 3-month follow-up (T-2). Forty-two matched healthy controls completed the same protocol at T-1 once. Results: At baseline, mTBI patients with APTH presented significantly increased GM volume mainly in the right dorsal anterior cingulate cortex (dACC) and dorsal posterior cingulate cortex (dPCC), of which the dPCC volume can predict much worse impact of headache on patients’ lives by HIT-6 (β = 0.389, P = 0.007) in acute stage. Serum levels of C-C motif chemokine ligand 2 (CCL2) were also elevated in these patients, and its effect on the impact of headache on quality of life was partially mediated by the dPCC volume (mean [SE] indirect effect, 0.088 [0.0462], 95% CI, 0.01–0.164). Longitudinal analysis showed that the dACC and dPCC volumes as well as CCL2 levels had persistently increased in patients developing CPTH 3 months postinjury. Conclusion: The findings suggested that structural remodelling of DMN brain regions were involved in the progression from acute to chronic PTH following mTBI, which also mediated the effect of inflammation processes on pain modulation. Trial registration: ClinicalTrial.gov ID: NCT02868684; registered 16 August 2016. © 2020, The Author(s).

Author Keywords
Inflammation effect;  Mild traumatic brain injury;  Posttraumatic headache;  Voxel-based morphometry

Funding details
Natural Science Foundation of Zhejiang ProvinceLY19H180003, LY16H180009, LY15H090016
Wenzhou Municipal Science and Technology BureauWMSTBY20140577
National Natural Science Foundation of ChinaNSFC82071993, 81771914

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

Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions
(2020) Scientific Reports, 10 (1), art. no. 20365, .

Egeland, M.T.^a , Tarczyluk-Wells, M.M.^b , Asmar, M.M.^b , Adintori, E.G.^c , Lawrence, R.^c , Snella, E.M.^d , Jens, J.K.^d , Crawford, B.E.^c , Wait, J.C.M.^c , McCullagh, E.^c , Pinkstaff, J.^c , Cooper, J.D.^a b e , Ellinwood, N.M.^d

^a The Lundquist Institute at Harbor-UCLA Medical Center, and David Geffen School of Medicine, UCLA, Torrance, CA, United States
^b King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, United Kingdom
^c BioMarin Pharmaceutical Inc., Novato, CA, United States
^d Iowa State University, Ames, IA, United States
^e Department of Pediatrics, Washington University School of Medicine in St Louis, 660 S Euclid Avenue, Campus, Box 8208, St Louis, MO 63110, United States

Abstract
Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24–30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred. The findings in this study will form the basis of future assessments of therapeutic efficacy in this large animal disease model. © 2020, The Author(s).

Funding details
BioMarin Pharmaceutical

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

Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease
(2020) Acta Neuropathologica Communications, 8 (1), art. no. 196, .

Ibanez, L.^a b , Bahena, J.A.^a b , Yang, C.^a b , Dube, U.^a b , Farias, F.H.G.^a b , Budde, J.P.^a b , Bergmann, K.^a b , Brenner-Webster, C.^a b , Morris, J.C.^c d e , Perrin, R.J.^c d e f , Cairns, N.J.^{c d e f g} , O’Donnell, J.^d , Álvarez, I.^h i , Diez-Fairen, M.^h i , Aguilar, M.^h i , Miller, R.^d , Davis, A.A.^c d , Pastor, P.^h i , Kotzbauer, P.^c d , Campbell, M.C.^d j , Perlmutter, J.S.^c d j , Rhinn, H.^k , Harari, O.^a b c e , Cruchaga, C.^{a b c e l} , Benitez, B.A.^a b

^a Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO 63110, United States
^b NeuroGenomics and Informatics Center, Washington University, St. Louis, MO 63110, United States
^c Hope Center for Neurologic Disorders, Washington University, St. Louis, MO 63110, United States
^d Department of Neurology, Washington University, St. Louis, MO 63110, United States
^e The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, United States
^g College of Medicine and Health, University of Exeter, Exeter, Devon, United Kingdom
^h Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain
ⁱ Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain
^j Departments of Neuroscience and Radiology, Programs in Physical Therapy and Occupational Therapy, Washington University, St. Louis, MO 63110, United States
^k Department of Bioinformatics, Alector, INC, San Francisco, CA 94080, United States
^l Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1–42 (R2 = 2.29%; p = 2.5 × 10−11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1–42 levels (p = 7.3 × 10−04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1–42 plays a role in Parkinson’s disease (p = 1.4 × 10−05) and age at onset (p = 7.6 × 10−06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1–42 (p = 3.8 × 10−06), higher mean cortical binding potentials (p = 5.8 × 10−08), and higher Braak amyloid beta score (p = 4.4 × 10−04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta1–42, and APOE. © 2020, The Author(s).

Author Keywords
Alpha-synuclein;  Amyloid beta;  APOE;  GWAS;  Parkinson disease

Funding details
National Institutes of HealthNIHRF1AG058501, NS097437, NS097799, NS07532, U01AG058922, P01AG003991, RF1AG053303, R01AG044546, R01AG057777, R01NS118146, R01AG058501, NS075321
National Institutes of HealthNIHP01 AG026276
BFG-15-362540, NIRG-11-200110, BAND-14-338165, AARG-16-441560
Hope Center for Neurological Disorders
American Parkinson Disease AssociationAPDA

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

A 26-Year-Old Woman With Diplopia and Nystagmus
(2020) Journal of Neuro-Ophthalmology: The Official Journal of the North American Neuro-Ophthalmology Society, 40 (4), pp. 533-537.

Anderson, W.J., Sharma, A., Guzman, M.A., Chung, S.M.

Departments of Ophthalmology (WJA, MAG, SMC), Pathology (MAG), and Neurology (SMC), Saint Louis University School of Medicine, St. Louis, Missouri; and Department of Radiology (AS), Washington University School of Medicine, St. Louis, Missouri

Abstract
A 26-year-old woman presented for a routine contact lens evaluation but was found to have a subtle right sixth nerve paresis and adducting nystagmus of the left eye. She reported horizontal diplopia on far right gaze as well as subjective right-sided weakness and poor balance for 1 year. Brain and spinal MRI revealed multiple cystic lesions with variable enhancement throughout the posterior fossa and cervical spinal cord. These MRI findings were highly suspicious for an infectious central nervous system process, such as neurocysticercosis; however, primary or metastatic tumors were also important considerations. Tumor location and imaging characteristics were most helpful in differentiating among these etiologies. A brain biopsy ultimately established the diagnosis of a rosette-forming glioneuronal tumor.

Document Type: Article
Publication Stage: Final
Source: Scopus

Reduced Activation of the Synaptic-Type GABAA Receptor Following Prolonged Exposure to Low Concentrations of Agonists: Relationship between Tonic Activity and Desensitization
(2020) Molecular Pharmacology, 98 (6), pp. 762-769.

Pierce, S.R., Germann, A.L., Evers, A.S., Steinbach, J.H., Akk, G.

Department of Anesthesiology (S.R.P., A.L.G., A.S.E., G.A.) and the Taylor Family Institute for Innovative Psychiatric Research (A.S.E., Washington University School of Medicine, St. Louis, MO, United States

Abstract
Synaptic GABAA receptors are alternately exposed to short pulses of a high, millimolar concentration of GABA and prolonged periods of low, micromolar concentration of the transmitter. Prior work has indicated that exposure to micromolar concentrations of GABA can both activate the postsynaptic receptors generating sustained low-amplitude current and desensitize the receptors, thereby reducing the peak amplitude of subsequent synaptic response. However, the precise relationship between tonic activation and reduction of peak response is not known. Here, we have measured the effect of prolonged exposure to GABA or the combination of GABA and the neurosteroid allopregnanolone, which was intended to desensitize a fraction of receptors, on a subsequent response to a high concentration of agonist in human α1β3γ2L receptors expressed in Xenopus oocytes. We show that the reduction in the peak amplitude of the post-exposure test response correlates with the open probability of the preceding desensitizing response. Curve fitting of the inhibitory relationship yielded an IC50 of 12.5 µM and a Hill coefficient of -1.61. The activation and desensitization data were mechanistically analyzed in the framework of a three-state Resting-Active-Desensitized model. Using the estimated affinity, efficacy, and desensitization parameters, we calculated the amount of desensitization that would accumulate during a long (2-minute) application of GABA or GABA plus allopregnanolone. The results indicate that accumulation of desensitization depends on the level of activity rather than agonist or potentiator concentration per se. We estimate that in the presence of 1 µM GABA, approximately 5% of α1β3γ2L receptors are functionally eliminated because of desensitization. SIGNIFICANCE STATEMENT: We present an analytical approach to quantify and predict the loss of activatable GABAA receptors due to desensitization in the presence of transmitter and the steroid allopregnanolone. The findings indicate that the peak amplitude of the synaptic response is influenced by ambient GABA and that changes in ambient concentrations of the transmitter and other GABAergic agents can modify tonically and phasically activated synaptic receptors in opposite directions. Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

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

Should Patients With Optic Disc Drusen Be Treated With Intraocular Pressure-Lowering Medications?
(2020) Journal of Neuro-Ophthalmology: The Official Journal of the North American Neuro-Ophthalmology Society, 40 (4), pp. 538-543.

Falardeau, J.M., Pineles, S.L., Van Stavern, G.P., Lee, A.G.

Department of Ophthalmology (JMF), Portland, Oregon; Department of Ophthalmology (SLP), UCLA, Los Angeles, California; and Department of Ophthalmology and Visual Sciences (GPVS), Washington University in St. Louis, St. Louis, Missouri

Document Type: Article
Publication Stage: Final
Source: Scopus

Arteritic Orbital Ischemia Producing Afferent and Efferent Pupillary Defects
(2020) Journal of Neuro-Ophthalmology: The Official Journal of the North American Neuro-Ophthalmology Society, 40 (4), pp. 530-532.

Hussain, M., Kini, A., Al Othman, B., Ponce, C.P., Li, H., Lee, A.G.

Texas A&M College of Medicine (MH, AGL), Bryan, Texas; Department of Ophthalmology (AK, BAO, CPP, HL, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Department of Pathology and Genomic Medicine, Ocular Pathology (CPP), Houston Methodist Hospital, Houston, Texas; Community Retina Group (HL), Houston, Texas; The Houston Methodist Research Institute (AGL), Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa. Department of Ophthalmology (JMF), Portland, Oregon; Department of Ophthalmology (SLP), UCLA, Los Angeles, California; and Department of Ophthalmology and Visual Sciences (GPVS), Washington University in St. Louis, St. Louis, Missouri

Abstract
A 67-year-old woman presented with acute loss of vision to no light perception (NLP), a right afferent pupillary defect, and anisocoria with a nonreactive and dilated pupil in the right eye. Fundus examination showed pallid optic disc edema and a central retinal artery occlusion (CRAO) in the right eye. A temporal artery biopsy showed giant cell arteritis (GCA). Orbital involvement in GCA has been reported previously. However the combination of an afferent and efferent pupillary defect, NLP vision, pallid disc edema, and a CRAO in an elderly patient is likely a unique clinical combination that should strongly suggest GCA. Clinicians should be aware of the myriad presentations of GCA, including orbital ischemia.

Document Type: Article
Publication Stage: Final
Source: Scopus

Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and triglial dysfunction
(2020) Proceedings of the National Academy of Sciences of the United States of America, 117 (46), pp. 29101-29112.

Peng, A.Y.T.^a , Agrawal, I.^a , Ho, W.Y.^a , Yen, Y.-C.^a , Pinter, A.J.^a , Liu, J.^a , Phua, Q.X.C.^a , Koh, K.B.^a , Chang, J.-C.^a , Sanford, E.^a , Man, J.H.K.^a , Wong, P.^b c , Gutmann, D.H.^d , Tucker-Kellogg, G.^e f , Ling, S.-C.^c g h

^a Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore117549, Singapore
^b Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore117600, Singapore
^c Program in Neuroscience and Behavior Disorders, Duke-NUS Medical School169857, Singapore
^d Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110
^e Computational Biology Programme, Faculty of Science, National University of Singapore117558, Singapore
^f Department of Biological Sciences, Faculty of Science, National University of Singapore117558, Singapore
^g Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117549 Singapore, Singapore; shuochien@gmail.com
^h Centre for Healthy Longevity, National University Health System117549, Singapore

Abstract
Patients with amyotrophic lateral sclerosis (ALS) can have abnormal TDP-43 aggregates in the nucleus and cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunction contributes to motor neuron degeneration in ALS, the normal function of TDP-43 in astrocytes are largely unknown, and the role of astroglial TDP-43 loss to ALS pathobiology remains to be clarified. Herein, we show that TDP-43-deleted astrocytes exhibit a cell-autonomous increase in GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43-deleted astrocytes resemble A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause loss of motor neurons in the spinal cord or denervation at the neuromuscular junction. In contrast, there is a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting triglial dysfunction mediated by TDP-43 loss in astrocytes. Moreover, mice with astroglial TDP-43 deletion develop motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.

Author Keywords
A1-reactive astrocytes;  amyotrophic lateral sclerosis (ALS);  cell-autonomous;  TDP-43;  triglial dysfunction

Document Type: Article
Publication Stage: Final
Source: Scopus

Motor Control: Memory and Motor Control in the Dorsal Striatum
(2020) Current Biology, 30 (22), pp. R1366-R1368.

Kravitz, A.V., Matikainen-Ankney, B.A.

Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Avenue, CSRB 5536, Saint Louis, MO 63110, United States

Abstract
The dorsal striatum is important for motor control. Yet whether that control encompasses procedural memories, kinematic refinement, or both is still debated. A recent study has shed new light on the role of the dorsal striatum in learned movement sequences and the effort required to refine them. © 2020 Elsevier Inc.

The dorsal striatum is important for motor control. Yet whether that control encompasses procedural memories, kinematic refinement, or both is still debated. A recent study has shed new light on the role of the dorsal striatum in learned movement sequences and the effort required to refine them. © 2020 Elsevier Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

Strategies to improve patient care for obstructive sleep apnea: a report from the American Academy of Sleep Medicine Sleep-Disordered Breathing Collaboration Summit
(2020) Journal of Clinical Sleep Medicine: JCSM : Official Publication of the American Academy of Sleep Medicine, 16 (11), pp. 1933-1937.

Rosen, I.M.^a , Rowley, J.A.^b , Malhotra, R.K.^c , Kristo, D.A.^d , Carden, K.A.^e , Kirsch, D.B.^f , American Academy of Sleep Medicine Board of Directors^g

^a Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^b Wayne State University, Detroit, MI, United States
^c Sleep Medicine Center, Washington University School of Medicine, St. Louis, MO, United States
^d University of Pittsburgh, Pittsburgh, PA, United States
^e Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
^f Sleep Medicine, Atrium Health, Charlotte, North Carolina

Abstract
NONE: In Chicago, Illinois, on Saturday, November 10, 2018, the American Academy of Sleep Medicine hosted 35 representatives from 14 medical societies, nurse practitioner associations and patient advocacy groups for a one-day Sleep-Disordered Breathing Collaboration Summit to discuss strategies to improve the diagnosis and treatment of obstructive sleep apnea. This report provides a brief synopsis of the meeting, identifies current challenges, and highlights potential opportunities for ongoing collaboration. © 2020 American Academy of Sleep Medicine.

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

A Psychometric Evaluation of the Motor-Behavioral Assessment Scale for Use as an Outcome Measure in Rett Syndrome Clinical Trials
(2020) American Journal on Intellectual and Developmental Disabilities, 125 (6), pp. 493-509.

Raspa, M.^a , Bann, C.M.^a , Gwaltney, A.^a , Benke, T.A.^b , Fu, C.^c , Glaze, D.G.^d , Haas, R.^e , Heydemann, P.^f , Jones, M.^g , Kaufmann, W.E.^h , Lieberman, D.ⁱ , Marsh, E.ⁱ , Peters, S.^j , Ryther, R.^k , Standridge, S.^l , Skinner, S.A.^m , Percy, A.K.ⁿ , Neul, J.L.^o

^a Carla M. Bann, RTI International
^b University of Colorado School of Medicine
^c Vanderbilt Kennedy Center
^d Baylor College of Medicine
^e University of California San Diego
^f Rush University Medical Center
^g Benioff Children’s Hospital
^h Walter E. Kaufmann, Greenwood Genetic Center
ⁱ Children’s Hospital Boston
^j Vanderbilt Kennedy Center
^k Robin Ryther, Washington University School of Medicine
^l Shannon Standridge, Cincinnati Children’s Hospital
^m Greenwood Genetic Center
ⁿ University of Alabama at Birmingham
^o Jeffrey L. Neul, Vanderbilt Kennedy Center

Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder that primarily affects females. Recent work indicates the potential for disease modifying therapies. However, there remains a need to develop outcome measures for use in clinical trials. Using data from a natural history study (n = 1,075), we examined the factor structure, internal consistency, and validity of the clinician-reported Motor Behavior Assessment scale (MBA). The analysis resulted in a five-factor model: (1) motor dysfunction, (2) functional skills, (3) social skills, (4) aberrant behavior, and (5) respiratory behaviors. Item Response Theory (IRT) analyses demonstrated that all items had acceptable discrimination. The revised MBA subscales showed a positive relationship with parent reported items, age, and a commonly used measure of clinical severity in RTT, and mutation type. Further work is needed to evaluate this measure longitudinally and to add items related to the RTT phenotype. ©AAIDD.

Author Keywords
clinical trial;  outcome measure;  psychometrics;  Rett syndrome

Document Type: Article
Publication Stage: Final
Source: Scopus

Association between intake of energy and macronutrients and memory impairment severity in US older adults, national health and nutrition examination survey 2011–2014
(2020) Nutrients, 12 (11), art. no. 3559, pp. 1-13.

Liu, Q.^a , Guo, J.^b , Hu, L.^c , Veronese, N.^d , Smith, L.^e , Yang, L.^f g , Cao, C.^h

^a Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, United States
^b Sports and Medicine Integration Center, Capital University of Physical Education and Sports, Beijing, 100191, China
^c Department of Sport and Exercise Science, Zhejiang University, Hangzhou, 310027, China
^d Department of Internal Medicine and Geriatrics, University of Palermo, Palermo, 90133, Italy
^e The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, CB1 1PT, United Kingdom
^f Department of Cancer Epidemiology and Prevention Research, Cancer Care Alberta, Alberta Health Services, Calgary, AB T2S 3C3, Canada
^g Departments of Oncology and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N2, Canada
^h Program in Physical Therapy, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Without a cure, dementia affects about 50 million people worldwide. Understanding the effects of dietary habits, a key lifestyle behavior, on memory impairment is critical to inform early behavioral modification to delay further memory loss and progression to dementia. We examined the associations of total energy intake and energy intake from macronutrients with memory impairment among older US adults using data from the nationally representative National Health and Nutrition Examination Survey study 2011–2014. A total of 3623 participants aged ≥60 years were analyzed. Comparing to those with low total energy intake, individuals with high intake were more likely to have severe memory impairment (OR: 1.52, 95% CI: 1.15 to 2.02; ptrend = 0.005). Specifically, higher energy intake from carbohydrate (OR: 1.59, 95% CI: 1.12 to 2.26) and sugar (OR: 1.54, 95% CI: 1.11 to 2.16) were both significantly associated with the presence of memory impairment. Additionally, higher energy intake from fat, carbohydrate and sugar were significantly associated with more server memory impairment (fat: ptrend = 0.04; carbohydrate: ptrend = 0.03; sugar: ptrend = 0.02). High energy intake, either total or from carbohydrates, fat or sugar, is associated with memory impairment severity in the older US population. No such association was found in energy intake from protein. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Carbohydrates;  Energy intake;  Memory impairment;  Older adults;  Sugar

Funding details
Beijing Municipal Education Commission

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

Dendritic and parallel processing of visual threats in the retina control defensive responses
(2020) Science Advances, 6 (47), .

Kim, T.^a b , Shen, N.^a , Hsiang, J.-C.^a b , Johnson, K.P.^a b , Kerschensteiner, D.^a c d e

^a John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
^b Graduate Program in Neuroscience, Washington University School of Medicine, MO, Saint Louis 63110, United States
^c Department of Neurosciences, Washington University School of Medicine, MO, Saint Louis 63110, United States
^d Department of Biomedical Engineering, Washington University School of Medicine, MO, Saint Louis 63110, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, MO, Saint Louis 63110, United States

Abstract
Approaching predators cast expanding shadows (i.e., looming) that elicit innate defensive responses in most animals. Where looming is first detected and how critical parameters of predatory approaches are extracted are unclear. In mice, we identify a retinal interneuron (the VG3 amacrine cell) that responds robustly to looming, but not to related forms of motion. Looming-sensitive calcium transients are restricted to a specific layer of the VG3 dendrite arbor, which provides glutamatergic input to two ganglion cells (W3 and OFFα). These projection neurons combine shared excitation with dissimilar inhibition to signal approach onset and speed, respectively. Removal of VG3 amacrine cells reduces the excitation of W3 and OFFα ganglion cells and diminishes defensive responses of mice to looming without affecting other visual behaviors. Thus, the dendrites of a retinal interneuron detect visual threats, divergent circuits downstream extract critical threat parameters, and these retinal computations initiate an innate survival behavior. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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

A walking dance to improve gait speed for people with Parkinson disease: A pilot study
(2020) Neurodegenerative Disease Management, 10 (5), pp. 301-308.

Harrison, E.C.^a , Earhart, G.M.^a b c , Leventhal, D.^d , Quinn, L.^e , Mazzoni, P.^a

^a Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
^b Program in Physical Therapy, Washington University School of Medicine, St Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
^d Dance for PD^®, Mark Morris Dance Group, Brooklyn, NY 11217, United States
^e Department of Movement Science and Kinesiology, Teachers College, Columbia University, New York City, NY 10027, United States

Abstract
Aim: To determine the effectiveness of a targeted dance intervention to improve walking speed for people with Parkinson disease (PD) by increasing motor motivation. Materials & methods: 11 participants with PD participated in a 6-week pilot study in which they learned a contemporary dance composed of walking steps and designed to mimic everyday walking. 1 h classes occurred twice-weekly. Results: Pre-and post-intervention assessments revealed a significant increase in gait speed (t9 = 3.30; p = 0.009), cadence (t9 = 2.345; p = 0.044), and stride length (t9 = 3.757; p = 0.005), and a significant decrease (improvement) in single support time variability (t9 =-2.744; p = 0.022). There were no significant changes in other measures of gait variability nor in motor symptoms, mood and anxiety, extent of life-space mobility, or quality of life. No adverse events were reported. Conclusion: Joywalk provides preliminary evidence that a targeted physical intervention for people with PD may specifically counter bradykinesia. © 2020 Future Medicine Ltd.

Author Keywords
bradykinesia;  dance;  gait speed;  motivation;  Parkinson disease;  reward

Document Type: Article
Publication Stage: Final
Source: Scopus

The Language of Recollection in Support of Recognition Memory Decisions
(2020) Zeitschrift fur Psychologie / Journal of Psychology, 228 (4), pp. 291-295. Cited 1 time.

Dobbins, I.G.^a , Kantner, J.^b

^a Department of Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, MO 63130-4899, United States
^b Department of Psychology, California State University, Northridge, CA, United States

Abstract
Researchers often augment recognition memory decisions with confidence ratings or reports of Remember and Know experiences. While important, these ratings are subject to variation in interpretation and misspecification. Here we review recent findings from a verbal reports as data procedure in which subjects justify, in their own words, the basis of recognition. The application of a language pattern classifier to these justifications demonstrates that it: (a) is sensitive to the presence of recollection, (b) tracks individual differences in recognition accuracy, and (c) generalizes in a theoretically meaningful way to justifications from a separate experiment. More broadly, this approach should be useful for any cognitive decision task in which competing theories suggest different explicit bases underlying the judgments, or for which the explicit versus implicit basis of the decisions is in question. © 2020 Hogrefe Publishin.

Author Keywords
language classifier;  recognition memory;  recollection;  statistical learning

Document Type: Article
Publication Stage: Final
Source: Scopus

Reactivity of Judgments of Learning in a Levels-of-Processing Paradigm
(2020) Zeitschrift fur Psychologie / Journal of Psychology, 228 (4), pp. 278-290. Cited 1 time.

Tekin, E., Roediger, H.L.

Department of Psychological and Brain Sciences, Washington University in St. Louis, One Brookings Drive, St Louis, MO 63130-4899, United States

Abstract
Recent studies have shown that judgments of learning (JOLs) are reactive measures in paired-associate learning paradigms. However, evidence is scarce concerning whether JOLs are reactive in other paradigms. In old/new recognition experiments, we investigated the reactivity effects of JOLs in a levels-of-processing (LOP) paradigm. In Experiments 1 and 2, for each word, subjects saw a yes/no orienting question followed by the target word and a response. Then, they either did or did not make a JOL. The yes/no questions were about target words appearances, rhyming properties, or category memberships. In Experiment 3, for each word, subjects gave a pleasantness rating or counted the letter ? e . Our results revealed that JOLs enhanced recognition across all orienting tasks in Experiments 1 and 2, and for the ecounting task in Experiment 3. This reactive effect was salient for shallow tasks, attenuating but not eliminating ? the LOP effect after making JOLs. We conclude that JOLs are reactive in LOP paradigms and subjects encode words more effectively when providing JOLs. © 2020 Hogrefe Publishin.

Author Keywords
judgments of learning;  levels of processing;  metacognition;  reactivity

Document Type: Article
Publication Stage: Final
Source: Scopus

Prospective Associations between Plasma Amyloid-Beta 42/40 and Frailty in Community-Dwelling Older Adults
(2020) Journal of Prevention of Alzheimer’s Disease, .

Lu, W.-H.^a , Giudici, K.V.^a , Rolland, Y.^a b , Guyonnet, S.^a b , Li, Y.^c d , Bateman, R.J.^c , de Souto Barreto, P.^a b , Vellas, B.^a b , MAPT/DSA Group^e

^a Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital (CHU Toulouse), Toulouse, France
^b UPS/Inserm UMR1027, University of Toulouse III, Toulouse, France
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Brain amyloid-beta (Aβ) plaques, a hallmark of the pathophysiology of Alzheimer’s disease, have been associated with frailty. Whether the plasma Aβ markers show similar relationship with frailty is unknown. OBJECTIVES: To investigate the prospective associations between plasma Aβ42/40 ratio and overtime frailty in community-dwelling older adults. METHODS: From the 5-year Multidomain Alzheimer Preventive Trial (MAPT), we included 477 adults ≥70 years with available data on plasma Aβ42/40 ratio (lower is worse). Fried frailty phenotype (robust, pre-frail and frail) was assessed at the same time-point of plasma Aβ measures and after until the end of follow-up. The outcomes of interest were the change in the frailty phenotype over time (examined by mixed-effect ordinal logistic regressions) and incident frailty (examined by Cox proportional hazard models). RESULTS: Plasma Aβ42/40 did not show significant associations with incident frailty; however, after adjusting for Apolipoprotein E (APOE) ε4 genotype, people in the lower quartile of plasma Aβ42/40 (≤0.103) had higher risk of incident frailty (HR=2.63; 95% CI, 1.00 to 6.89), compared to those in the upper quartile (>0.123). Exploratory analysis found a significant association between the lower quartile of plasma Aβ42/40 and incident frailty among APOE ε4 non-carriers (HR=3.48; 95% CI, 1.19 to 10.16), but not among carriers. No associations between plasma Aβ42/40 and evolution of frailty were observed. CONCLUSION: No significant associations between plasma Aβ42/40 and frailty were found when APOE ε4 status was not accounted into the model. Nevertheless, APOE ε4 non-carriers with high Aβ burden might be more susceptible to develop frailty. © 2020, Serdi and Springer Nature Switzerland AG.

Author Keywords
amyloid-beta;  biomarker;  Frailty;  neurodegeneration;  older adults

Funding details
Association pour la Recherche sur le CancerARC
National Institute on AgingNIA
Avid Radiopharmaceuticals
National Institutes of HealthNIHR56AG061900, RF1AG061900
Ministère des Affaires Sociales et de la Santé
Centre Hospitalier Universitaire de Toulouse
European Regional Development FundFEDERMP0022856
Les Laboratories Pierre Fabre

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

Associations between delirium and electroencephalographic markers: Notes from the field
(2020) Clinical Neurophysiology, .

Palanca, B.J.A.^a b c , Guay, C.S.^a

^a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Funding details
National Institute on AgingNIA
National Institutes of HealthNIHR01AG057901

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

An analysis of within-subject and population level risk related to substance use and mental health outcomes among adolescents in the PATH study
(2020) Drug and Alcohol Dependence, art. no. 108385, .

Li, X., Borodovsky, J.T., Kasson, E.M., Fentem, A., Cavazos-Rehg, P.A.

Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110, United States

Abstract
Introduction: The objective of this study was to understand how adolescent substance use patterns may lead to negative mental health outcomes. Methods: Data from adolescents (12–17 years old at baseline, Wave 1) who participated in the first 3 waves of the Population Assessment of Health and Tobacco (PATH) study were used. Self-reported data on past 30-day substance use and internalizing/externalizing problems were used to conduct within-subject (fixed-effects model) and population-averaged (GEE model) analyses. Results: In both within-subject and between-subject analyses, the use of other illicit drugs (e.g., opioids, cocaine, prescription drugs for non-medical use) was positively associated with internalizing problems (within-subject estimate, AOR: 1.65, 95 % CI = 1.36–2.01; between-subject estimate, AOR: 1.53, 95 % CI = 1.32–1.78) and alcohol use was positively associated with externalizing problems (within-subject estimate, AOR: 1.66, 95 % CI = 1.43–1.93; between-subject estimate, AOR: 1.67, 95 % CI = 1.48–1.89). Additionally, within-subject analysis suggested that alcohol, marijuana, and other illicit drugs were associated with increased odds of comorbid internalizing and externalizing problems (ranging from marijuana, AOR: 1.18, – alcohol, AOR: 1.58). Discussion: Using within-subject and between-subject comparisons, this study demonstrated associations between adolescent substance use and internalizing and externalizing problems. Results suggest not only the need for individual level assessment and early intervention, but also the development and implementation of public health policy aimed at preventing or mitigating the negative effects of substance use in adolescence to promote improved mental health outcomes for this at-risk group. © 2020 Elsevier B.V.

Author Keywords
Externalizing problems;  Internalizing problems;  Mental health;  PATH;  Substance use

Funding details
National Institutes of HealthNIH
National Institute on Alcohol Abuse and AlcoholismNIAAAF32AA027941
National Institutes of HealthNIHK02 DA043657
National Institute on Alcohol Abuse and AlcoholismNIAAA
National Institutes of HealthNIHK02 DA043657
National Institute on Alcohol Abuse and AlcoholismNIAAAF32AA027941

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

Reward Functioning Abnormalities in Adolescents at High Familial Risk for Depressive Disorders
(2020) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, .

Belleau, E.L.^a b , Kremens, R.^a b , Ang, Y.-S.^a b , Pisoni, A.^c , Bondy, E.^d , Durham, K.^e , Auerbach, R.P.^e f , Pizzagalli, D.A.^a b

^a Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, MA, United States
^b Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^c Department of Psychology and Neuroscience, Duke University, Durham, NC, United States
^d Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^e Department of Psychiatry, Columbia University, New York, NY, United States
^f Division of Clinical Developmental Neuroscience, Sackler Institute, New York, NY, United States

Abstract
Background: A parental history of major depressive disorder (MDD) is an established risk factor for MDD in youth, and clarifying the mechanisms related to familial risk transmission is critical. Aberrant reward processing is a promising biomarker of MDD risk; accordingly, the aim of this study was to test behavioral measures of reward responsiveness and underlying frontostriatal resting activity in healthy adolescents both with (high-risk) and without (low-risk) a maternal history of MDD. Methods: Low-risk and high-risk 12- to 14-year-old adolescents completed a probabilistic reward task (n = 74 low-risk, n = 27 high-risk) and a resting-state functional magnetic resonance imaging scan (n = 61 low-risk, n = 25 high-risk). Group differences in response bias toward reward and resting ventral striatal and medial prefrontal cortex (mPFC) fractional amplitude of low-frequency fluctuations (fALFFs) were examined. Computational modeling was applied to dissociate reward sensitivity from learning rate. Results: High-risk adolescents showed a blunted response bias compared with low-risk adolescents. Computational modeling analyses revealed that relative to low-risk adolescents, high-risk adolescents exhibited reduced reward sensitivity but similar learning rate. Although there were no group differences in ventral striatal and mPFC fALFFs, groups differed in their relationships between mPFC fALFFs and response bias. Specifically, among high-risk adolescents, higher mPFC fALFFs correlated with a blunted response bias, whereas there was no fALFFs–response bias relationship among low-risk youths. Conclusions: High-risk adolescents exhibit reward functioning impairments, which are associated with mPFC fALFFs. The blunted response bias–mPFC fALFFs association may reflect an excessive mPFC-mediated suppression of reward-driven behavior, which may potentiate MDD risk. © 2020 Society of Biological Psychiatry

Author Keywords
Adolescence;  Depression;  Familial risk;  Fractional amplitude of low-frequency fluctuation;  Frontostriatal;  Reward

Funding details
Harvard Medical SchoolHMS
Klingenstein Third Generation FoundationKTGF
McLean Hospital
Dana Foundation
National Institute of Mental HealthNIMHU01MH108168, R01MH119771, 1K23MH122668, 5R01MH108602, R37MH068376
Agency for Science, Technology and ResearchA*STAR
Takeda Pharmaceuticals International
National Institute of Mental HealthNIMH
Dana Foundation
Brain and Behavior Research FoundationBBRF

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

Delay discounting, cognitive ability, and personality: What matters?
(2020) Psychonomic Bulletin and Review, .

Yeh, Y.-H., Myerson, J., Green, L.

Department of Psychological and Brain Sciences, Washington University in St. Louis, Campus Box 1125, St. Louis, MO 63130, United States

Abstract
Steep delay discounting is associated with problems such as addiction, obesity, and risky sexual behavior that are frequently described as reflecting impulsiveness and lack of self-control, but it may simply indicate poor cognitive functioning. The present investigation took advantage of the unique opportunity provided by the Human Connectome Project (N=1,206) to examine the relation between delay discounting and 11 cognitive tasks as well as the Big Five fundamental personality traits. With income level and education statistically controlled, discounting was correlated with only four of the 11 cognitive abilities evaluated, although the rs were all small (<.20). Importantly, the two discounting measures loaded on their own factor. Discounting was not correlated with Neuroticism or Conscientiousness, traits related to psychometric impulsiveness and self-control. These findings suggest that steep delay discounting is not simply an indicator of poor cognitive functioning or psychometric impulsiveness but an important individual difference characteristic in its own right. © 2020, The Psychonomic Society, Inc.

Author Keywords
Cognitive ability;  Decision-making;  Discounting;  Human Connectome Project;  Personality

Funding details
National Institute on AgingNIA
National Institutes of HealthNIHR01AG058885
National Institutes of HealthNIH
McDonnell Center for Systems Neuroscience

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

Lurasidone and Risk for Metabolic Syndrome: Results from Short and Long-term Clinical Studies in Patients with Schizophrenia
(2020) CNS Spectrums, .

Tocco, M.^a , Newcomer, J.W.^b c , Mao, Y.^a , Pikalov, A.^a , Loebel, A.^a

^a Sunovion Pharmaceuticals Inc., 84 Waterford Dr, Marlborough, MA 01752, United States
^b Thriving Mind South Florida, Miami, FL, United States
^c Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, United States

Abstract
Objective: To assess the effects of treatment with lurasidone on risk for metabolic syndrome (MetS) in patients with schizophrenia. Methods: Rates of metabolic syndrome during treatment with lurasidone (40-160 mg/d) were analyzed using pooled, short-term data from three randomized, double-blind, placebo-controlled studies (vs olanzapine and quetiapine XR); long-term data from two active-comparator-controlled studies (vs risperidone and quetiapine XR); and data from two open-label studies in which patients were switched from olanzapine or risperidone to lurasidone. Results: MetS was defined based on the National Cholesterol Education Program criteria. In short-term studies, the odds of meeting criteria for MetS at week 6 LOCF (adjusted for baseline metabolic syndrome status) was similar for the lurasidone and placebo groups (OR = 1.18; [95% CI, 0.81-1.71]; P = .39), but the odds (vs placebo) were significantly greater for olanzapine (OR = 2.81; [95% CI, 1.53-5.15]; P .001) and quetiapine (OR = 3.49; [95% CI, 1.93-6.29]; P .0001). No dose effect was observed for lurasidone across the dose range of 40-160 mg/d. In long-term studies, the odds of MetS after 12 months of treatment was significantly higher for risperidone compared with lurasidone (OR = 2.12; 95% CI, 1.15-3.90; P = .016) and for quetiapine XR compared with lurasidone (OR = 3.92; 95% CI, 1.15-13.40; P = .029). In open-label extension studies, the rate of MetS decreased in patients switched to lurasidone after 6 weeks of treatment with olanzapine or 12 months of treatment with risperidone. Conclusion: In this analysis of lurasidone clinical trials, the odds of developing metabolic syndrome were minimal during short- and long-term treatment with lurasidone (40-160 mg/d). Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc.

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

LDLRAD3 is a receptor for Venezuelan equine encephalitis virus
(2020) Nature, .

Ma, H.^a , Kim, A.S.^a b , Kafai, N.M.^a b , Earnest, J.T.^a , Shah, A.P.^a , Case, J.B.^a , Basore, K.^b , Gilliland, T.C.^c , Sun, C.^c , Nelson, C.A.^b , Thackray, L.B.^a , Klimstra, W.B.^c , Fremont, D.H.^b d e f , Diamond, M.S.^a b e f

^a Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
^c Department of Immunology, Center for Vaccine Research University of Pittsburgh, Pittsburgh, PA, United States
^d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, United States
^e Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Program, Washington University School of Medicine, St Louis, MO, United States
^f Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Venezuelan equine encephalitis virus (VEEV) is a neurotropic alphavirus transmitted by mosquitoes that causes encephalitis and death in humans1. VEEV is a biodefence concern because of its potential for aerosol spread and the current lack of sufficient countermeasures. The host factors that are required for VEEV entry and infection remain poorly characterized. Here, using a genome-wide CRISPR–Cas9-based screen, we identify low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3)—a highly conserved yet poorly characterized member of the scavenger receptor superfamily—as a receptor for VEEV. Gene editing of mouse Ldlrad3 or human LDLRAD3 results in markedly reduced viral infection of neuronal cells, which is restored upon complementation with LDLRAD3. LDLRAD3 binds directly to VEEV particles and enhances virus attachment and internalization into host cells. Genetic studies indicate that domain 1 of LDLRAD3 (LDLRAD3(D1)) is necessary and sufficient to support infection by VEEV, and both anti-LDLRAD3 antibodies and an LDLRAD3(D1)–Fc fusion protein block VEEV infection in cell culture. The pathogenesis of VEEV infection is abrogated in mice with deletions in Ldlrad3, and administration of LDLRAD3(D1)–Fc abolishes disease caused by several subtypes of VEEV, including highly virulent strains. The development of a decoy-receptor fusion protein suggests a strategy for the prevention of severe VEEV infection and associated disease in humans. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
Defense Threat Reduction AgencyDTRAHDTRA1-15-1-0047, HDTRA1-15-1-0013
National Institutes of HealthNIHR01 AI143673, R01 AI095436, HHSN272201700060C, U19 AI142759, T32 AI007172, U19 AI142790

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

A Chinese version of the Measure of Stroke Environment (MOSE): psychometric evaluation in stroke survivors
(2020) Disability and Rehabilitation, .

Wang, W.^a , Babulal, G.M.^b , Lin, B.^a , Mei, Y.^a , Zhang, L.^a , Liu, Q.^a , Guo, Y.^a , Zhang, Z.^a

^a School of Nursing and Health, Zhengzhou University, Zhengzhou, China
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: To translate the MOSE from English to Chinese and investigate the psychometric properties of the Chinese-translated version of the Measure of Stroke Environment (MOSE). Materials and methods: The MOSE was translated into Chinese using a cultural adaptation process. To validate this Chinese version, 311 stroke survivors were recruited to complete the questionnaire. The psychometric properties of the MOSE were evaluated by determining item analysis, test–retest reliability, internal consistency, content validity, construct validity, and floor/ceiling effects, respectively. Results: The MOSE was translated without any major difficulties. Regarding psychometric performances, a moderate level of correlation between the items and the domains (r > 0.4), and the significant differences in items between the high group and the low group were tested by independent sample t-tests (p < 0.05). The test–retest reliability was excellent (Intraclass Coefficient Correlation = 0.938). Very high internal consistency was also observed (Cronbach’s α = 0.945, split-half reliability = 0.778). An acceptable I-CVI ranged from 0.714 to 1.000 and a high S-CVI of 0.973. Correlations with the subscales of the WHODAS 2.0 were significant in similar domains reflecting good convergent validity. No floor or ceiling effects were observed. Conclusion: This study provides psychometric evidence supporting the use of the Chinese version of the MOSE among stroke survivors.IMPLICATIONS FOR REHABILITATION The Measure of Stroke Environment was translated into Chinese through a rigorous cultural adaptation process. MOSE-C is now a reliable and valid tool for Chinese-speaking survivors who have suffered from a stroke. It is necessary to assess the perceived environmental barriers of stroke survivors and develop targeted intervention programs in China. © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
environment;  MOSE;  participation;  psychometrics;  Stroke

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

Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus
(2020) JAMA Pediatrics, .

Sullivan, W.^a , Reeves, B.C.^a , Duy, P.Q.^a , Nelson-Williams, C.^b , Dong, W.^b , Jin, S.C.^c , Kahle, K.T.^a

^a Department of Neurosurgery, Yale School of Medicine, New Haven, CA, United States
^b Department of Genetics, Yale University School of Medicine, New Haven, CA, United States
^c Department of Genetics, Washington University School of Medicine, St Louis, MI, United States

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