WashU weekly Neuroscience publications

Cerebrospinal fluid Aβ42 moderates the relationship between brain functional network dynamics and cognitive intraindividual variability
(2021) Neurobiology of Aging, 98, pp. 116-123. 

Meeker, K.L.^a b , Ances, B.M.^b , Gordon, B.A.^c , Rudolph, C.W.^a , Luckett, P.^b , Balota, D.A.^d , Morris, J.C.^b , Fagan, A.M.^b , Benzinger, T.L.^c , Waring, J.D.^a

^a Department of Psychology, Saint Louis University, St. Louis, MO, United States
^b Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
As Alzheimer’s disease (AD) pathology accumulates, resting-state functional connectivity (rs-fc) within and between brain networks decreases, and fluctuations in cognitive performance known as intraindividual variability (IIV) increase. Here, we assessed the relationship between IIV and anticorrelations in rs-fc between the default mode network (DMN)-dorsal attention network (DAN) in cognitively normal older adults and symptomatic AD participants. We also evaluated the relationship between cerebrospinal fluid (CSF) biomarkers of AD (amyloid-beta [Aβ42] and tau) and IIV-anticorrelation in rs-fc. We observed that cognitive IIV and anticorrelations between DMN × DAN were higher in individuals with AD compared with cognitively normal participants. As DMN × DAN relationship became more positive, cognitive IIV increased, indicating that stronger anticorrelations between networks support more consistent cognitive performance. Moderation analyses indicated that continuous CSF Aβ42, but not CSF total tau, moderated the relationship between cognitive IIV and DMN × DAN, collectively demonstrating that greater amyloid burden and alterations in functional network dynamics are associated with cognitive changes seen in AD. These findings are valuable, as they suggest that amyloid affects cognitive functioning during the early stages of AD. © 2020 Elsevier Inc.

Author Keywords
Alzheimer’s disease;  Anticorrelation;  Aβ42;  Cognitive intraindividual variability;  Functional networks

Funding details
Foundation for Barnes-Jewish Hospital
R01AG057680, R01NR014449, K01AG053474, P01AG00391, R01NR012657, P01AG005681, U19AG032438, R01AG052550, P01AG026276, R01NR012907
Hope Center for Neurological Disorders
UL1 TR000448

Document Type: Article
Publication Stage: Final
Source: Scopus

Adolescent Brain Development and Psychopathology: Introduction to the Special Issue
(2021) Biological Psychiatry, 89 (2), pp. 93-95. 

Leibenluft, E.^a , Barch, D.M.^b

^a Section on Mood Dysregulation and Neuroscience, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States
^b Departments of Psychological and Brain Sciences, Psychiatry, and Radiology, Washington University in St. Louis, St. Louis, MO, United States

Document Type: Note
Publication Stage: Final
Source: Scopus

Psychostimulant use disorder emphasizing methamphetamine and the opioid -dopamine connection: Digging out of a hypodopaminergic ditch
(2021) Journal of the Neurological Sciences, 420, art. no. 117252, . 

Blum, K.^a b c , Cadet, J.L.^a c , Gold, M.S.^c

^a Molecular Neuropsychiatry Research Branch, NIH National Institute on Drug Abuse, Baltimore, MD, United States
^b Graduate College, Western University Health Sciences, Pomona, CA, United States
^c Department of Psychiatry, Washington University, St Louis, MO, United States

Abstract
Background: Approved food and drug administration (FDA) medications to treat Psychostimulant Use Disorder (PUD) are needed. Both acute and chronic neurological deficits related to the neurophysiological effects of these powerfully addictive drugs can cause stroke and alterations in mood and cognition. Objective: This article presents a brief review of the psychiatric and neurobiological sequelae of methamphetamine use disorder, some known neurogenetic associations impacted by psychostimulants, and explores treatment modalities and outcomes. Hypothesis: The authors propose that gentle D2 receptor stimulation accomplished via some treatment modalities can induce dopamine release, causing alteration of D2-directed mRNA and thus enhanced function of D2 receptors in the human. This proliferation of D2 receptors, in turn, will induce the attenuation of craving behavior, especially in genetically compromised high-risk populations. Discussion: A better understanding of the involvement of molecular neurogenetic opioid, mesolimbic dopamine, and psychostimulant connections in “wanting” supports this hypothesis. While both scientific and, clinical professionals search for an FDA approved treatment for PUD the induction of dopamine homeostasis, via activation of the brain reward circuitry, offers treatment for underlying neurotransmitter functional deficits, potential prophylaxis, and support for recovery efforts. Conclusion: Dopamine regulation may help people dig out of their hypodopaminergia ditch. © 2020

Author Keywords
Amphetamines;  Cocaine;  Induction of dopamine homeostasis;  Methamphetamine use disorder (MAUD);  Methamphetamines;  Neurogenetics;  Psychostimulant use disorder (PUD)

Document Type: Review
Publication Stage: Final
Source: Scopus

Body-, eating-, and exercise-related social comparison behavior and disordered eating in college women in the U.S. and Iran: A cross-cultural comparison
(2021) Eating Behaviors, 40, art. no. 101451, . 

Sahlan, R.N.^a , Saunders, J.F.^b , Fitzsimmons-Craft, E.E.^c

^a Department of Clinical Psychology, Iran University of Medical Sciences, Tehran, Iran
^b Department of Psychological Science, Georgia College and State University, Milledgeville, GA, United States
^c Department of Psychiatry, Washington University in St. Louis, United States

Abstract
Wearing of the hijab is associated with lower eating disorder (ED) attitudes and behaviors in women. However, this potential buffering role of the hijab has been questioned in countries, such as Iran, where its wearing is compulsory. Further, cross-cultural comparisons between disordered eating behaviors and correlates in Iranian and U.S. women are lacking. This study examines social-cognitive correlates of disordered eating in U.S. and Iranian women, comparing rates of ED- related social comparison and eating pathology. College women in the U.S. (n = 180) and Iran (n = 384) completed the Body, Eating, and Exercise Comparison Orientation Measure (BEECOM) and the Eating Disorder Examination-Questionnaire (EDE-Q) in one session. One-way analyses of covariance and partial correlations were used to test the mean differences and inter-correlations between the variables among U.S. and Iranian women. U.S. women endorsed higher BEECOM scores and higher levels of overvaluation of weight and shape and dietary restraint compared to Iranians. Most BEECOM subscales and disordered eating symptoms were inter-correlated in each culture. The tendency to engage in exercise comparison was not significantly correlated with excessive exercise for U.S. women. Correlations between variables were stronger for U.S. women compared to Iranian women. While the ED-related social comparison levels were higher for U.S. women, the typical Western patterns of social comparison and disordered eating extend to Iranian women. Eating disorder-related social comparison is a recommended clinical target in both Eastern and Western cultures. © 2020 Elsevier Ltd

Author Keywords
College women;  Disordered eating;  Iran;  Social comparison;  U.S.

Document Type: Article
Publication Stage: Final
Source: Scopus

Neurovascular trauma: Diagnosis and therapy
(2021) Handbook of Clinical Neurology, 176, pp. 325-344. 

Kansagra, A.P.^a , Balasetti, V.^b , Huang, M.C.^c

^a Departments of Radiology, Neurological Surgery, and Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States

Abstract
Traumatic cerebrovascular injuries are common in both military and civilian populations. Whether such injuries occur in the aftermath of blunt or penetrating trauma has major implications for characteristics, classification, diagnosis, and optimal management of these lesions. Advances in screening methods, including particularly the dramatic rise of high-quality CT angiography, have facilitated early detection of these lesions. Fortunately, these diagnostic advances have occurred alongside improvements in pharmacological treatment and endovascular intervention, which now play an important role alongside surgical intervention in reducing the likelihood of adverse clinical outcomes. While the management of victims of trauma remains challenging, improved understanding of and ability to appropriately manage traumatic cerebrovascular lesions promises to yield better clinical outcomes for these vulnerable patients. Copyright © 2021 Elsevier B.V. All rights reserved.

Author Keywords
Blunt;  Cerebral;  Cerebrovascular;  Cervical;  Penetrating;  Trauma;  Vascular

Document Type: Article
Publication Stage: Final
Source: Scopus

Accelerating Psychometric Screening Tests with Prior Information
(2021) Studies in Computational Intelligence, 914, pp. 305-311. 

Larsen, T.^a , Malkomes, G.^b , Barbour, D.^a

^a Washington University in St. Louis, St. Louis, MO 63130, United States
^b SigOpt, San Francisco, CA 94108, United States

Abstract
Classical methods for psychometric function estimation either require excessive measurements or produce only a low-resolution approximation of the target psychometric function. In this paper, we propose solutions for rapid high-resolution approximation of the psychometric function of a patient given her or his prior exam. We develop a rapid screening algorithm for a change in the psychometric function estimation of a patient. We use Bayesian active model selection to perform an automated pure-tone audiometry test with the goal of quickly finding if the current estimation will be different from the previous one. We validate our methods using audiometric data from the National Institute for Occupational Safety and Health (niosh). Initial results indicate that with a few tones we can (i) detect if the patient’s audiometric function has changed between the two test sessions with high confidence, and (ii) learn high-resolution approximations of the target psychometric function. © 2021, The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Exome-wide rare variant analysis in familial essential tremor
(2021) Parkinsonism and Related Disorders, 82, pp. 109-116. 

Diez-Fairen, M.^a , Houle, G.^b c , Ortega-Cubero, S.^d , Bandres-Ciga, S.^e f , Alvarez, I.^a , Carcel, M.^a , Ibañez, L.^g , Fernandez, M.V.^g , Budde, J.P.^g , Trotta, J.-R.^h , Tonda, R.^h , Chong, J.X.ⁱ , Bamshad, M.J.^i j k , Nickerson, D.A.^k , Aguilar, M.^a , Tartari, J.P.^a , Gironell, A.^l , García-Martín, E.^m , Agundez, J.A.^m , Alonso-Navarro, H.ⁿ , Jimenez-Jimenez, F.J.ⁿ , Fernandez, M.^o p , Valldeoriola, F.^p q , Marti, M.J.^p q , Tolosa, E.^p q , Coria, F.^r , Pastor, M.A.^s , Vilariño-Güell, C.^t , Rajput, A.^u , Dion, P.A.^b v , Cruchaga, C.^g , Rouleau, G.A.^c v , Pastor, P.^a , University of Washington Center for Mendelian Genomics (UWCMG)^w

^a Fundació Docència i Recerca MútuaTerrassa, Movement Disorders Unit, Department of Neurology, University Hospital Mútua Terrassa, Terrassa, Barcelona, Spain
^b Department of Human Genetics, McGill University, Montréal, QC, Canada
^c Montreal Neurological Institute, McGill University, Montréal, QC, Canada
^d Department of Neurology and Neurosurgery, Hospital Universitario de Burgos, Burgos, Spain
^e Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, BethesdaMD, United States
^f Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain
^g NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^h Centre Nacional d’Anàlisis Genòmic (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain & Universitat Pompeu Fabra (UPF), Barcelona, Spain
ⁱ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, United States
^j Seattle Children’s Hospital, Seattle, WA 98105, United States
^k Department of Genome Sciences, University of Washington, Seattle, WA, United States
^l Movement Disorders Unit, Neurology Department, Hospital de Sant Pau and Sant Pau Biomedical Research Institute, Barcelona, 08026, Spain
^m University Institute of Molecular Pathology Biomarkers, UNEx. ARADyAL Instituto de Salud Carlos III, Cáceres, Spain
ⁿ Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain
^o María de Maeztu Unit of Excellence, Institute of Neurosciences, University of Barcelona, Ministry of Science, Innovation and UniversitiesMDM-2017-0729, Spain
^p Parkinson’s Disease & Movement Disorders Unit, Department of Neurology, Hospital Clínic, IDIBAPS, Barcelona, Spain
^q Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic de Barcelona, Barcelona, Spain
^r Clinic for Nervous Disorders, Service of Neurology, Son Espases University Hospital, Palma de Mallorca, Spain
^s Department of Neurology, Clínica Universidad de Navarra, Pamplona, Spain
^t Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
^u Saskatchewan Movement Disorders Program, University of Saskatchewan/Saskatchewan Health Authority, Saskatoon, SK, Canada
^v Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, Canada

Abstract
Introduction: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing. Methods: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes. Results: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders. Conclusions: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes. © 2020 Elsevier Ltd

Author Keywords
Essential tremor;  Genetic risk;  MMP10;  Rare variants;  WES

Funding details
Ministerio de Ciencia e InnovaciónMICINNSAF2013-47939-R
National Heart, Lung, and Blood InstituteNHLBIUM1 HG006493, U24 HG008956
Baylor-Hopkins Center for Mendelian GenomicsBHCMG
National Human Genome Research InstituteNHGRI
MDM-2017-0729

Document Type: Article
Publication Stage: Final
Source: Scopus

Anterior Cingulate Cortex and the Control of Dynamic Behavior in Primates
(2020) Current Biology, 30 (23), pp. R1442-R1454. 

Monosov, I.E.^{a b c d e} , Haber, S.N.^f g , Leuthardt, E.C.^b d , Jezzini, A.^a

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
^c Department of Electrical Engineering, Washington University, St. Louis, MO 63130, United States
^d Department of Neurosurgery School of Medicine, Washington University, St. Louis, MO 63110, United States
^e Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14627, United States
^g Basic Neuroscience, McLean Hospital, Harvard Medical School, Belmont, MA 02478, United States

Abstract
The brain mechanism for controlling continuous behavior in dynamic contexts must mediate action selection and learning across many timescales, responding differentially to the level of environmental uncertainty and volatility. In this review, we argue that a part of the frontal cortex known as the anterior cingulate cortex (ACC) is particularly well suited for this function. First, the ACC is interconnected with prefrontal, parietal, and subcortical regions involved in valuation and action selection. Second, the ACC integrates diverse, behaviorally relevant information across multiple timescales, producing output signals that temporally encapsulate decision and learning processes and encode high-dimensional information about the value and uncertainty of future outcomes and subsequent behaviors. Third, the ACC signals behaviorally relevant information flexibly, displaying the capacity to represent information about current and future states in a valence-, context-, task- and action-specific manner. Fourth, the ACC dynamically controls instrumental- and non-instrumental information seeking behaviors to resolve uncertainty about future outcomes. We review electrophysiological and circuit disruption studies in primates to develop this point, discuss its relationship to novel therapeutics for neuropsychiatric disorders in humans, and conclude by relating ongoing research in primates to studies of medial frontal cortical regions in rodents. Monosov and colleagues review how dynamic and risky decisions, foraging and information seeking are controlled by value, valence, and context sensitive neurons in the anterior cingulate cortex © 2020 Elsevier Inc.

Funding details
McKnight FoundationMH045573, R01CA203861, MH106435
National Institute of Mental HealthNIMHR01MH110594, R01MH116937

Document Type: Review
Publication Stage: Final
Source: Scopus

Hidden Hearing Loss: Mixed Effects of Compensatory Plasticity
(2020) Current Biology, 30 (23), pp. R1433-R1436. 

Barbour, D.L.

Laboratory of Sensory Neuroscience and Neuroengineering, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Hidden hearing loss manifests as speech perception difficulties with normal hearing thresholds. A new study shows that neural compensation induced by this disorder may actually improve speech perception under narrow conditions within an overall profile of degradation. © 2020 Elsevier Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

Activation of the archaeal ion channel MthK is exquisitely regulated by temperature
(2020) eLife, 9, . 

Jiang, Y.^a b , Idikuda, V.^a b , Chowdhury, S.^a b , Chanda, B.^a b

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States
^b Center for the Investigation of Membrane Excitability Diseases (CIMED), St. Louis, United States

Abstract
Physiological response to thermal stimuli in mammals is mediated by a structurally diverse class of ion channels, many of which exhibit polymodal behavior. To probe the diversity of biophysical mechanisms of temperature-sensitivity, we characterized the temperature-dependent activation of MthK, a two transmembrane calcium-activated potassium channel from thermophilic archaebacteria. Our functional complementation studies show that these channels are more efficient at rescuing K+ transport at 37°C than at 24°C. Electrophysiological activity of the purified MthK is extremely sensitive (Q10 >100) to heating particularly at low-calcium concentrations whereas channels lacking the calcium-sensing RCK domain are practically insensitive. By analyzing single-channel activities at limiting calcium concentrations, we find that temperature alters the coupling between the cytoplasmic RCK domains and the pore domain. These findings reveal a hitherto unexplored mechanism of temperature-dependent regulation of ion channel gating and shed light on ancient origins of temperature-sensitivity. © 2020, Jiang et al.

Author Keywords
allosteric coupling;  archaebacteria;  calcium activation;  ion channels;  molecular biophysics;  RCK domain;  structural biology;  thermo-sensing

Document Type: Article
Publication Stage: Final
Source: Scopus

Pituitary gland recovery following fully endoscopic transsphenoidal surgery for nonfunctioning pituitary adenoma: Results of a prospective multicenter study
(2020) Journal of Neurosurgery, 133 (6), pp. 1732-1738. Cited 2 times.

Little, A.S.^a , Gardner, P.A.^b , Fernandez-Miranda, J.C.^c , Chicoine, M.R.^d , Barkhoudarian, G.^e , Prevedello, D.M.^f , Yuen, K.C.J.^g , Kelly, D.F.^e

^a Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, United States
^b Department of Neurosurgery, University of PittsburghPA, United States
^c Department of Neurosurgery, Stanford University, Palo Alto, CA, United States
^d Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States
^e Pacific Brain Tumor Center and Pituitary Disorders Program, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA, United States
^f Department of Neurological Surgery, Ohio State University, Columbus, OH, United States
^g Department of Neuroendocrinology, Barrow Neurological Institute, Phoenix, AZ, United States

Abstract
OBJECTIVE Recovery from preexisting hypopituitarism after transsphenoidal surgery for pituitary adenoma is an important outcome to investigate. Furthermore, pituitary function has not been thoroughly evaluated after fully endoscopic surgery, and benchmark outcomes have not been clearly established. Here, the authors characterize pituitary gland outcomes with a focus on gland recovery following endoscopic transsphenoidal removal of clinically nonfunctioning adenomas. METHODS This multicenter prospective study was conducted at 6 US pituitary centers among adult patients with nonfunctioning pituitary macroadenomas who had undergone endoscopic endonasal pituitary surgery. Pituitary gland function was evaluated 6 months after surgery. RESULTS The 177 enrolled patients underwent fully endoscopic transsphenoidal surgery; 169 (95.5%) of them were available for follow-up. Ninety-five (56.2%) of the 169 patients had had a preoperative deficiency in at least one hormone axis, and 20/95 (21.1%) experienced recovery in at least one axis at the 6-month follow-up. Patients with adrenal insufficiency were more likely to recover (10/34 [29.4%]) than were those with hypothyroidism (8/72 [11.1%]) or male hypogonadism (5/50 [10.0%]). At the 6-month follow-up, 14/145 (9.7%) patients had developed at least one new deficiency. The study did not identify any predictors of gland recovery (p ≥0.20). Permanent diabetes insipidus was observed in 4/166 (2.4%) patients. Predictors of new gland dysfunction included a larger tumor size (p = 0.009) and Knosp grade 3 and 4 (p = 0.051). CONCLUSIONS Fully endoscopic pituitary surgery resulted in improvement of pituitary gland function in a substantial minority of patients. The deficiency from which patients were most likely to recover was adrenal insufficiency. Overall rates of postoperative permanent diabetes insipidus were low. This study provides multicenter benchmark neuroendocrine clinical outcome data for the endoscopic technique. © AANS 2020.

Author Keywords
Endoscopic surgery;  Hypopituitarism;  Nonfunctioning adenoma;  Pituitary surgery;  Transsphenoidal surgery

Document Type: Review
Publication Stage: Final
Source: Scopus

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients
(2020) Science Advances, 6 (49), . 

Bryant, L.^a , Li, D.^a , Cox, S.G.^b , Marchione, D.^c , Joiner, E.F.^d , Wilson, K.^c , Janssen, K.^c , Lee, P.^e , March, M.E.^a , Nair, D.^a , Sherr, E.^f , Fregeau, B.^f , Wierenga, K.J.^g , Wadley, A.^g , Mancini, G.M.S.^h , Powell-Hamilton, N.ⁱ , van de Kamp, J.^j , Grebe, T.^k , Dean, J.^l , Ross, A.^l , Crawford, H.P.^m , Powis, Z.ⁿ , Cho, M.T.^o , Willing, M.C.^p , Manwaring, L.^p , Schot, R.^h , Nava, C.^q r , Afenjar, A.^s , Lessel, D.^t u , Wagner, M.^v w x , Klopstock, T.^y z aa , Winkelmann, J.^v x aa ab , Catarino, C.B.^y , Retterer, K.^o , Schuette, J.L.^ac , Innis, J.W.^ac , Pizzino, A.^ad ae , Lüttgen, S.^af , Denecke, J.^af , Strom, T.M.^v x , Monaghan, K.G.^o , Yuan, Z.-F.^c , Dubbs, H.^ad ae , Bend, R.^ag , Lee, J.A.^ag , Lyons, M.J.^ag , Hoefele, J.^x , Günthner, R.^ah ai , Reutter, H.^aj , Keren, B.^r , Radtke, K.^ak , Sherbini, O.^ad ae , Mrokse, C.^ak , Helbig, K.L.^ak , Odent, S.^al , Cogne, B.^am an , Mercier, S.^am an , Bezieau, S.^am an , Besnard, T.^am an , Kury, S.^am an , Redon, R.^an , Reinson, K.^ao ap , Wojcik, M.H.^aq ar , Õunap, K.^ao ap , Ilves, P.^as , Innes, A.M.^at , Kernohan, K.D.^au av , Costain, G.^aw , Meyn, M.S.^aw ax , Chitayat, D.^aw ay , Zackai, E.^az , Lehman, A.^ba , Kitson, H.^bb , Martin, M.G.^bc bd , Martinez-Agosto, J.A.^be bf , Nelson, S.F.^be bg , Palmer, C.G.S.^be bh , Papp, J.C.^be , Parker, N.H.^bi , Sinsheimer, J.S.^bj , Vilain, E.^bk , Wan, J.^be , Yoon, A.J.^be , Zheng, A.^be , Brimble, E.^bl , Ferrero, G.B.^bm , Radio, F.C.^bn , Carli, D.^bm , Barresi, S.^bn , Brusco, A.^bo , Tartaglia, M.^bn , Thomas, J.M.^bp , Umana, L.^bq , Weiss, M.M.^j , Gotway, G.^bq , Stuurman, K.E.^h , Thompson, M.L.^br , McWalter, K.^o , Stumpel, C.T.R.M.^bs , Stevens, S.J.C.^bs , Stegmann, A.P.A.^bs , Tveten, K.^bt , Vøllo, A.^bu , Prescott, T.^bt , Fagerberg, C.^bv , Laulund, L.W.^bw , Larsen, M.J.^bv , Byler, M.^bx , Lebel, R.R.^bx , Hurst, A.C.^by , Dean, J.^by , Schrier Vergano, S.A.^bz , Norman, J.^ca , Mercimek-Andrews, S.^aw , Neira, J.^cb , Van Allen, M.I.^ba cc , Longo, N.^cd , Sellars, E.^ce , Louie, R.J.^ag , Cathey, S.S.^ag , Brokamp, E.^cf , Heron, D.^r , Snyder, M.^cg , Vanderver, A.^ad ae , Simon, C.^d , de la Cruz, X.^ch ci , Padilla, N.^ch , Crump, J.G.^b , Chung, W.^cj , Garcia, B.^b c , Hakonarson, H.H.^a , Bhoj, E.J.^a , DDD Study^ck , Care4Rare Canada Consortium^cl , CAUSES Study^cm , Undiagnosed Diseases Network^cn

^a Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^b Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, CA, 90033, United States
^c Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^d Vagelos College of Physicians and Surgeons, Columbia University, NY, NY 10032, United States
^e Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^f Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
^g Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL 32224, United States
^h Department of Clinical Genetics, Erasmus University Medical Center, CN Rotterdam, 3015, Netherlands
ⁱ Department of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE 19810, USA
^j Department of Clinical Genetics, VU Medical Center, Amsterdam, Netherlands
^k Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, United States
^l Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, United Kingdom
^m Clinical and Metabolic Genetics, Cook Children’s Medical Center, Fort Worth, United States
ⁿ Department of Emerging Genetic Medicine, Ambry Genetics, Aliso Viejo, CA 92656, USA
^o GeneDx, 207 Perry Parkway, Gaithersburg, United States
^p Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA
^q UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Sorbonne Universités ,UPMC Univ Paris 06, Paris, France
^r AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, F-75013, France
^s CRMR des malformations et maladies congénitales du cervelet et CRMR déficience intellectuelle, hôpital Trousseau, AP-HP, Service de génétique, France
^t Institute of Human Genetics, University Medical Center Hamburg-EppendorfHamburg 20246, Germany
^u Undiagnosed Disease Program at the University Medical Center Hamburg-Eppendorf (UDP-UKE), Martinistrasse 52Hamburg 20246, Germany
^v Helmholtz Zentrum München, Munich, Germany
^w Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany
^x Institut für Humangenetik, Technische Universität München, Munich, Germany
^y Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians University, Ziemssenstr. 1a, Munich, 80336, Germany
^z German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^aa Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
^ab Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
^ac Division of Genetics, Metabolism, Genomic Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, United States
^ad Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^ae Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^af Department of Pediatrics, University Medical Center EppendorfHamburg 20246, Germany
^ag Greenwood Genetic Center, SC 29646, Greenwood, United States
^ah Department of Nephrology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
^ai Institute of Human Genetics, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
^aj Department of Neonatology and Pediatric Intensive Care, Children’s Hospital, University Hospital Bonn & Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
^ak Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA
^al CHU Rennes, Service de Génétique Clinique, CNRS UMR6290, University Rennes1, Rennes, France
^am CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, Nantes, 44093, France
^an INSERM, CNRS, UNIV Nantes, CHU Nantes, l’institut du thorax, Nantes, 44007, France
^ao Department of Clinical Genetics, United Laboratories, Tartu University HospitalTartu, Estonia
^ap Institute of Clinical Medicine, University of TartuTartu, Estonia
^aq Division of Genetics and Genomics and Division of Newborn Medicine, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^ar Broad Institute, Cambridge, MA 02142, United States
^as Radiology Department of Tartu University Hospital and Institute of Clinical Medicine, University of TartuTartu, Estonia
^at Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
^au Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H8L1, Canada
^av Newborn Screening Ontario (NSO), Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
^aw Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada
^ax Center for Human Genomics and Precision Medicine, School of Medicine and Public Health, University of Wisconsin – Madison, Madison, WI 53705, United States
^ay Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, ON, Canada
^az Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^ba Department of Medical Genetics, University of British Columbia, Vancouver, Canada
^bb Department of Pediatrics, University of British Columbia, Vancouver, Canada
^bc Division of Gastroenterology and Nutrition, Department of Pediatrics, Mattel Children’s Hospital, Los Angeles, CA 90095, USA
^bd Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
^be Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
^bf Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
^bg Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
^bh Institute for Society and Genetics, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
^bi David Geffen School of Medicine, Los Angeles, CA 90095, USA
^bj Institute for Society and Genetics, Departments of Human Genetics, Biomathematics, and Biostatistics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
^bk Center for Genetic Medicine Research, Children’s National Medical CenterWA, United States
^bl Department of Neurology and Neurological Sciences, Stanford Medicine, Stanford, CA 94305, USA
^bm Department of Public Health and Pediatrics, University of Torino, Turin, Italy
^bn Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy
^bo Department of Medical Sciences, University of Torino, Turin, Italy
^bp Pediatrics and Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, United States
^bq Genetics and Metabolism, UT Southwestern Medical Center, Dallas, TX 75390, United States
^br HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
^bs Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands
^bt Department of Medical Genetics, Telemark Hospital Trust, Skien, 3710, Norway
^bu Department of Pediatrics, Hospital of Østfold, Norway
^bv Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
^bw H.C. Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
^bx SUNY Upstate Medical University, Syracuse, NY 13210, USA
^by University of Alabama at Birmingham, Birmingham, AL 35294, USA
^bz Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, United States
^ca INTEGRIS Pediatric Neurology, Oklahoma City, United States
^cb Department of Human Genetics, Emory University, Atlanta, GA 30322, United States
^cc Medical Genetics Programs, Provincial Health Shared Services BC and Vancouver Island Health Shared Services BC, Canada
^cd Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, United States
^ce University of Arkansas for Medical Sciences, Little Rock, United States
^cf Vanderbilt University, Nashville, United States
^cg Child Neurology, UT Southwestern Medical Center, Dallas, TX 75390, United States
^ch Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
^ci Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
^cj Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, NY, NY 10032, United States

Abstract
Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation. 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

dmPFC-vlPAG projection neurons contribute to pain threshold maintenance and antianxiety behaviors
(2020) Journal of Clinical Investigation, 130 (12), pp. 6555-6570. 

Yin, J.-B.^a b c d , Liang, S.-H.^a e , Li, F.^a f , Zhao, W.-J.^a f , Bai, Y.^a c , Sun, Y.^a c e , Wu, Z.-Y.^a c , Ding, T.^g , Sun, Y.^f , Liu, H.-X.^a , Lu, Y.-C.^a , Zhang, T.^a , Huang, J.^a , Chen, T.^a , Li, H.^a c , Chen, Z.-F.^c , Cao, J.^h , Ren, R.^d , Peng, Y.-N.^d , Yang, J.^d , Zang, W.-D.^h , Li, X.ⁱ , Dong, Y.-L.^a , Li, Y.-Q.^a d h

^a Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi’an, China
^b Department of Neurology, 960th Hospital of PLA, Jinan, China
^c Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, United States
^d Key Laboratory of Brain Science Research and Transformation in the Tropical Environment of Hainan Province, Haikou, China
^e Department of Human Anatomy, Binzhou Medical College, Yantai, China
^f Cadet Brigade, Xijing Hospital, Fourth Military Medical University, Xi’an, China
^g Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi’an, China
^h Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
ⁱ Department of Orthopaedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Abstract
The dorsal medial prefrontal cortex (dmPFC) has been recognized as a key cortical area for nociceptive modulation. However, the underlying neural pathway and the function of specific cell types remain largely unclear. Here, we show that lesions in the dmPFC induced an algesic and anxious state. Using multiple tracing methods including a rabies-based transsynaptic tracing method, we outlined an excitatory descending neural pathway from the dmPFC to the ventrolateral periaqueductal gray (vlPAG). Specific activation of the dmPFC/vlPAG neural pathway by optogenetic manipulation produced analgesic and antianxiety effects in a mouse model of chronic pain. Inhibitory neurons in the dmPFC were specifically activated using a chemogenetic approach, which logically produced an algesic and anxious state under both normal and chronic pain conditions. Antagonists of the GABAA receptor (GABAAR) or mGluR1 were applied to the dmPFC, which produced analgesic and antianxiety effects. In summary, the results of our study suggest that the dmPFC/vlPAG neural pathway might participate in the maintenance of pain thresholds and antianxiety behaviors under normal conditions, while silencing or suppressing the dmPFC/vlPAG pathway might be involved in the initial stages and maintenance of chronic pain and the emergence of anxiety-like behaviors. © 2020, American Society for Clinical Investigation.

Funding details
China Postdoctoral Science Foundation2019TQ0135
Fourth Military Medical UniversityFMMU2015D06
2018153
National Natural Science Foundation of ChinaNSFC81801099, 31871061, 81620108008, 31671087

Document Type: Article
Publication Stage: Final
Source: Scopus

A ventrolateral medulla-midline thalamic circuit for hypoglycemic feeding
(2020) Nature Communications, 11 (1), art. no. 6218, . 

Sofia Beas, B.^a , Gu, X.^b , Leng, Y.^a , Koita, O.^a , Rodriguez-Gonzalez, S.^a , Kindel, M.^a , Matikainen-Ankney, B.A.^c , Larsen, R.S.^d , Kravitz, A.V.^c e , Hoon, M.A.^b , Penzo, M.A.^a

^a Unit on the Neurobiology of Affective Memory, National Institute of Mental Health, Bethesda, MD, United States
^b Molecular Genetics Section, National Institute of Dental and Craniofacial Research, Bethesda, MD, United States
^c National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States
^d Allen Institute for Brain Science, Seattle, WA, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Marked deficits in glucose availability, or glucoprivation, elicit organism-wide counter-regulatory responses whose purpose is to restore glucose homeostasis. However, while catecholamine neurons of the ventrolateral medulla (VLMCA) are thought to orchestrate these responses, the circuit and cellular mechanisms underlying specific counter-regulatory responses are largely unknown. Here, we combined anatomical, imaging, optogenetic and behavioral approaches to interrogate the circuit mechanisms by which VLMCA neurons orchestrate glucoprivation-induced food seeking behavior. Using these approaches, we found that VLMCA neurons form functional connections with nucleus accumbens (NAc)-projecting neurons of the posterior portion of the paraventricular nucleus of the thalamus (pPVT). Importantly, optogenetic manipulations revealed that while activation of VLMCA projections to the pPVT was sufficient to elicit robust feeding behavior in well fed mice, inhibition of VLMCA–pPVT communication significantly impaired glucoprivation-induced feeding while leaving other major counterregulatory responses intact. Collectively our findings identify the VLMCA–pPVT–NAc pathway as a previously-neglected node selectively controlling glucoprivation-induced food seeking. Moreover, by identifying the ventrolateral medulla as a direct source of metabolic information to the midline thalamus, our results support a growing body of literature on the role of the PVT in homeostatic regulation. © 2020, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Funding details
National Institute of General Medical SciencesNIGMSFi2GM128811
National Institute of Mental HealthNIMH1ZIAMH002950
National Institute of Dental and Craniofacial ResearchNIDCR

Document Type: Article
Publication Stage: Final
Source: Scopus

Hearing Loss in Children: A Review
(2020) JAMA, 324 (21), pp. 2195-2205. 

Lieu, J.E.C.^a , Kenna, M.^b c , Anne, S.^d , Davidson, L.^a

^a Department of Otolaryngology-Head and Neck Surgery, Washington University in St Louis, St Louis, MO, United States
^b Department of Otolaryngology and Communication Enhancement, Boston Children’s Hospital, Boston, MA
^c Department of Otolaryngology, Head and Neck Surgery, Harvard Medical School, Boston, MA
^d Head and Neck Institute, Cleveland Clinic, Cleveland, OH, United States

Abstract
Importance: Hearing loss in children is common and by age 18 years, affects nearly 1 of every 5 children. Without hearing rehabilitation, hearing loss can cause detrimental effects on speech, language, developmental, educational, and cognitive outcomes in children. Observations: Consequences of hearing loss in children include worse outcomes in speech, language, education, social functioning, cognitive abilities, and quality of life. Hearing loss can be congenital, delayed onset, or acquired with possible etiologies including congenital infections, genetic causes including syndromic and nonsyndromic etiologies, and trauma, among others. Evaluation of hearing loss must be based on suspected diagnosis, type, laterality and degree of hearing loss, age of onset, and additional variables such as exposure to cranial irradiation. Hearing rehabilitation for children with hearing loss may include use of hearing aids, cochlear implants, bone anchored devices, or use of assistive devices such as frequency modulating systems. Conclusions and Relevance: Hearing loss in children is common, and there has been substantial progress in diagnosis and management of these cases. Early identification of hearing loss and understanding its etiology can assist with prognosis and counseling of families. In addition, awareness of treatment strategies including the many hearing device options, cochlear implant, and assistive devices can help direct management of the patient to optimize outcomes.

Document Type: Article
Publication Stage: Final
Source: Scopus

Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway
(2020) Nature Communications, 11 (1), art. no. 6164, . 

Smith, S.E.^a b , Chen, X.^a , Brier, L.M.^b c , Bumstead, J.R.^c d , Rensing, N.R.^e , Ringel, A.E.^f , Shin, H.^a , Oldenborg, A.^a , Crowley, J.R.^g , Bice, A.R.^c , Dikranian, K.^a , Ippolito, J.E.^c , Haigis, M.C.^f , Papouin, T.^a , Zhao, G.^a , Wong, M.^e , Culver, J.P.^c d h , Bonni, A.^a

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^b MD-PhD Program, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63105, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, United States
^g Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^h Department of Physics, Washington University in St. Louis, St. Louis, MO 63105, United States

Abstract
Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional α2-Na/K ATPase knockout triggers spontaneous cortical spreading depression events that are associated with EEG low voltage activity events, which correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that α2-Na/K ATPase loss alters metabolic gene expression with consequent serine and glycine elevation in the brain. A serine- and glycine-free diet rescues the transient motor impairment in conditional α2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic α2-Na/K ATPase that triggers episodic motor paralysis in mice. © 2020, The Author(s).

Funding details
U54 HD087011
P41 GM103422
T32 GM07200
NS051255, NS041021
U54CA224088, P30 NS098577, R01 NS099429
Intellectual and Developmental Disabilities Research CenterIDDRCR01 NS056872
Glenn Foundation for Medical Research
P30 DK020579, P30 DK056341
Intellectual and Developmental Disabilities Research CenterIDDRC
American Cancer SocietyACS130373-PF-17-132-01-CCG
G. Harold and Leila Y. Mathers Charitable FoundationF30 NS100217

Document Type: Article
Publication Stage: Final
Source: Scopus

Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study
(2020) The American Journal of Psychiatry, 177 (12), pp. 1168-1178. 

Correll, C.U., Newcomer, J.W., Silverman, B., DiPetrillo, L., Graham, C., Jiang, Y., Du, Y., Simmons, A., Hopkinson, C., McDonnell, D., Kahn, R.S.

Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y. (Correll); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. (Correll); Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll); Thriving Mind South Florida, Miami (Newcomer); Department of Psychiatry, Washington University School of Medicine, St. Louis (Newcomer); Alkermes, Inc., Waltham, Mass. (Silverman, DiPetrillo, Graham, Jiang, Du, Simmons, Hopkinson); Alkermes Pharma Ireland, Dublin (McDonnell); and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Kahn)

Abstract
OBJECTIVE: A combination of olanzapine and the opioid receptor antagonist samidorphan is under development for the treatment of schizophrenia and bipolar I disorder. The single-tablet combination treatment is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. In this phase 3 double-blind trial, the authors evaluated the weight profile of combined olanzapine/samidorphan compared with olanzapine in patients with schizophrenia. METHODS: Adults (ages 18‒55 years) with schizophrenia were randomly assigned to receive either combination treatment with olanzapine and samidorphan or olanzapine treatment for 24 weeks. Primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. The key secondary endpoint was the proportion of patients with ≥7% weight gain. Waist circumference and fasting metabolic laboratory parameters were also measured. RESULTS: Of 561 patients who underwent randomization (olanzapine/samidorphan combination, N=280; olanzapine, N=281), 538 had at least one postbaseline weight assessment. At week 24, the least squares mean percent weight change from baseline was 4.21% (SE=0.68) in the olanzapine/samidorphan group and 6.59% (SE=0.67) in the olanzapine group (the difference of -2.38% [SE=0.76] was significant). Significantly fewer patients in the olanzapine/samidorphan combination group compared with the olanzapine group had weight gain ≥10% (17.8% and 29.8%, respectively; number needed to treat [NNT]=7.29; odds ratio=0.50) and weight gain ≥7% (27.5% and 42.7%, respectively; NNT=6.29; odds ratio=0.50). Increases in waist circumference were smaller in the olanzapine/samidorphan combination group compared with the olanzapine group. Schizophrenia symptom improvement was similar between treatment groups. Adverse events (in ≥10% of the groups) in the olanzapine/samidorphan and olanzapine groups included weight gain (24.8% and 36.2%), somnolence (21.2% and 18.1%), dry mouth (12.8% and 8.0%), and increased appetite (10.9% and 12.3%). Metabolic changes were small and similar between treatments. CONCLUSIONS: Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine and was well tolerated. The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy.

Author Keywords
Antipsychotic Agents;  Olanzapine;  Samidorphan;  Schizophrenia;  Weight Gain

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease
(2020) Neurology: Genetics, 6 (6), art. no. e517, . 

Park, Y.H.^a b c , Hodges, A.^d , Simmons, A.^d , Lovestone, S.^e , Weiner, M.W.^f g j , Kim, S.^ap , Saykin, A.J.^a b h , Nho, K.^a b i , Aisen, P.^k , Petersen, R.^l , Jack, C.R., Jr.^l , Jagust, W.^m , Trojanowki, J.Q.ⁿ , Toga, A.W.^k , Beckett, L.^o , Green, R.C.^p , Saykin, A.J.^q , Morris, J.^r , Shaw, L.M.ⁿ , Khachaturian, Z.^s , Sorensen, G.^t , Carrillo, M.^u , Kuller, L.^v , Raichle, M.^r , Paul, S.^w , Davies, P.^x , Fillit, H.^y , Hefti, F.^z , Holtzman, D.^r , Marcel Mesulam, M.^aa , Potter, W.^ab , Snyder, P.^ac , Hendrix, J.^u , Vasanthakumar, A.^ad , Montine, T.^ae , Rafii, M.^k , Chow, T.^k , Raman, R.^k , Jimenez, G.^k , Donohue, M.^k , Gessert, D.^k , Harless, K.^k , Salazar, J.^k , Cabrera, Y.^k , Walter, S.^k , Hergesheimer, L.^k , Beckett, L.^o , Harvey, D.^o , Donohue, M.^af , Bernstein, M.^l , Fox, N.^ag , Thompson, P.^ah , Schuff, N.^j , DeCArli, C.^o , Borowski, B.^l , Gunter, J.^l , Senjem, M.^l , Vemuri, P.^l , Jones, D.^l , Kantarci, K.^l , Ward, C.^l , Koeppe, R.A.^ai , Foster, N.^aj , Reiman, E.M.^ak , Chen, K.^ak , Mathis, C.^v , Landau, S.^m , Cairns, N.J.^r , Franklin, E.^r , Lee, V.ⁿ , Korecka, M.ⁿ , Figurski, M.^ap , Crawford, K.^k , Neu, S.^k , Foroud, T.M.^q , Potkin, S.^al , Shen, L.^q , Faber, K.^q , Kim, S.^q , Nho, K.^q , Albert, M.^am , Frank, R.^an , Hsiao, J.^ao , AddNeuroMed consortium and the Alzheimer’s Disease Neuroimaging Initiative^ap

^a Department of Radiology and Imaging Sciences, Indiana University, School of Medicine, Indianapolis, United States
^b Indiana Alzheimer Disease Center, Indiana University, School of Medicine, Indianapolis, United States
^c Department of Neurology, Seoul National University Bundang Hospital, Seoul National University, College of Medicine, Seongnam, South Korea
^d Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, United Kingdom
^e Department of Psychiatry, University of Oxford, United Kingdom
^f Department of Radiology, Medicine, and Psychiatry, University of California, San Francisco, United States
^g Department of Veterans Affairs Medical Center, San Francisco, CA, United States
^h Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, United States
ⁱ Center for Computational Biology and Bioinformatics, Indiana University, School of Medicine, Indianapolis, United States
^j UC San Francisco, United States
^k University of Southern California, United States
^l Mayo Clinic, Rochester, United States
^m UC Berkeley
ⁿ University of Pennsylvania, United States
^o UC Davis
^p Brigham and Women’s Hospital, Harvard Medical School, United States
^q Indiana University, United States
^r Washington University St. Louis, United States
^s Prevent Alzheimer’s Disease 2020
^t Siemens
^u Alzheimer’s Association
^v University of Pittsburgh, United States
^w Cornell University, United States
^x Albert Einstein College of Medicine, Yeshiva University, United States
^y AD Drug Discovery Foundation
^z Acumen Pharmaceuticals
^aa Northwestern University, United States
^ab National Institute of Mental Health
^ac Brown University, United States
^ad AbbVie
^ae University of Washington, United States
^af UC San Diego, United States
^ag University of London, United Kingdom
^ah UCLA, School of Medicine
^ai University of Michigan, United States
^aj University of Utah, United States
^ak Banner Alzheimer’s Institute, United States
^al UC Irvine, United States
^am Johns Hopkins University, United States
^an Richard Frank Consulting
^ao National Institute on Aging

Abstract
Objective To determine whether transcriptional risk scores (TRSs), a summation of polarized expression levels of functional genes, reflect the risk of Alzheimer disease (AD). Methods Blood transcriptome data were from Caucasian participants, which included AD, mild cognitive impairment, and cognitively normal controls (CN) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 661) and AddNeuroMed (n = 674) cohorts. To calculate TRSs, we selected functional genes that were expressed under the control of the AD risk loci and were identified as being responsible for AD by using Bayesian colocalization and mendelian randomization methods. Regression was used to investigate the association of the TRS with diagnosis (AD vs CN) and MRI biomarkers (entorhinal thickness and hippocampal volume). Regression was also used to evaluate whether expression of each functional gene was associated with AD diagnosis. Results The TRS was significantly associated with AD diagnosis, hippocampal volume, and entorhinal cortical thickness in the ADNI. The association of the TRS with AD diagnosis and entorhinal cortical thickness was also replicated in AddNeuroMed. Among functional genes identified to calculate the TRS, CD33 and PILRA were significantly upregulated, and TRAPPC6A was significantly downregulated in patients with AD compared with CN, all of which were identified in the ADNI and replicated in AddNeuroMed. Conclusions The blood-based TRS is significantly associated with AD diagnosis and neuroimaging biomarkers. In blood, CD33 and PILRA were known to be associated with uptake of β-amyloid and herpes simplex virus 1 infection, respectively, both of which may play a role in the pathogenesis of AD. Classification of evidence The study is rated Class III because of the case control design and the risk of spectrum bias. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Funding details
National Institute on AgingNIA
Takeda Pharmaceutical Company
GE Healthcare
Eli Lilly and Company
H. Lundbeck A/S
U.S. Department of DefenseDODW81XWH-14-2-0151
Merck
Johnson and Johnson Pharmaceutical Research and DevelopmentJ&JPRD
University of Southern CaliforniaUSC
National Institute on AgingNIAP30 AG10133, R03 AG054936, R01 AG19771, R01 LM011360
U.S. Department of DefenseDODW81XWH-12-2-0012
Servier
Genentech
South London and Maudsley NHS Foundation Trust
Indiana Clinical and Translational Sciences InstituteCTSI
Coins for Alzheimer’s Research TrustCART
Alzheimer’s Drug Discovery FoundationADDF
2020R1C1C1013718
Pfizer
National Institute of Biomedical Imaging and BioengineeringNIBIB
BioClinica
Bristol-Myers SquibbBMS
Novartis Pharmaceuticals CorporationNPC
Eisai Incorporated
Alzheimer’s Disease Neuroimaging InitiativeADNI
AbbVie
Fujirebio US
Janssen Alzheimer Immunotherapy Research And Development
National Center for Advancing Translational SciencesNCATSUL1 TR001108, K01 AG049050
National Institutes of HealthNIHU01 AG024904
U.S. National Library of MedicineNLMR01 LM012535
National Institute of General Medical SciencesNIGMSP50GM115318
Biogen
Northern California Institute for Research and EducationNCIRE
Alzheimer’s Disease Neuroimaging InitiativeADNI
Alzheimer’s AssociationAA
IXICO
National Research Foundation of KoreaNRF

Document Type: Article
Publication Stage: Final
Source: Scopus

The Comprehensive Aphasia Test in Hungarian [CAT-H – új eljárás az afázia magyar nyelvû diagnosztikájában]
(2020) Ideggyogyaszati Szemle, 73 (11-12), pp. 405-416. 

Zakariás, L.^a b c , Rózsa, S.^d , Lukács, Á.^c e

^a Eötvös Loránd Tudományegyetem, Bárczi Gusztáv Gyógypedagógiai KarBudapest, Hungary
^b Országos Orvosi Rehabilitációs IntézetBudapest, Hungary
^c Budapest, Hungary
^d Washington University, School of Medicine, Department of Psychiatry, St. Louis, United States
^e Budapesti Mûszaki és Gazdaságtudományi Egyetem, Kognitív Tudományi TanszékBudapest, Hungary

Abstract
Background and purpose: In this paper we present the Comprehensive Aphasia Test-Hungarian (CAT-H; Zakariás and Lukács, in preparation), an assessment tool newly adapted to Hungarian, currently under standardisation. The test is suitable for the assessment of an acquired language disorder, post-stroke aphasia. The aims of this paper are to present 1) the main characteristics of the test, its areas of application, and the process of the Hungarian adaptation and standardisation, 2) the first results from a sample of Hungarian people with aphasia and healthy controls. Methods: Ninety-nine people with aphasia, mostly with unilateral, left hemisphere stroke, and 19 neurologically intact control participants were administered the CAT-H. In addition, we developed a questionnaire assessing demographic and clinical information. The CAT-H consists of two parts, a Cognitive Screening Test and a Language Test. Results: People with aphasia performed significantly worse than the control group in all language and almost all cognitive subtests of the CAT-H. Consistent with our expectations, the control group performed close to ceiling in all subtests, whereas people with aphasia exhibited great individual variability both in the language and the cognitive subtests. In addition, we found that age, time post-onset, and type of stroke were associated with cognitive and linguistic abilities measured by the CAT-H. Conclusion: Our results and our experiences clearly show that the CAT-H provides a comprehensive profile of a person’s impaired and intact language abilities and can be used to monitor language recovery as well as to screen for basic cognitive deficits in aphasia. We hope that the CAT-H will be a unique resource for rehabilitation professionals and aphasia researchers in aphasia assessment and diagnostics in Hungary.

Background and purpose: A tanulmányban egy újonnan adaptált, jelenleg sztenderdizáció alatt álló logopédiai vizsgálóeljárást, a Comprehensive Aphasia Test magyar változatát (CAT-H; Zakariás & Lukács, elôkészületben) mutatjuk be. A CAT-H a stroke következtében kialakuló szerzett nyelvi zavarok, az afáziák vizsgálatára alkalmas. A tanulmány célja a teszt fôbb jellemzôinek, alkalmazási területeinek, a magyar adaptáció és sztenderdizáció folyamatának, valamint az afáziás személyek tesztben nyújtott teljesítményének bemutatása és egészséges kontrollcsoporttal való összehasonlítása. Methods: Kutatásunkban 99, többségében egyoldali, bal féltekei stroke utáni afáziát mutató személy és 19, neurológiai kórtörténettel nem rendelkezô kontrollszemély vett részt. A vizsgálati személyekkel a klinikai gyakorlatban használatos tesztek mellett a CAT-H battériát vettük fel, amit egy általunk összeállított demográfiai és klinikai kérdôívvel egészítettünk ki. A CAT-H két részbôl, egy kognitív szûrôvizsgálatból és egy átfogó nyelvi tesztbôl áll. Results: Az afáziás csoport teljesítménye vala­mennyi nyelvi és szinte az összes kognitív területen jelentôsen elmaradt az egészséges kontrollcsoportétól. Várakozásainkkal összhangban a kontrollcsoport plafonközeli teljesítményt nyújtott valamennyi területen, míg az afáziás csoportra nagymértékû egyéni variabilitás volt jellemzô a nyelvi és a kognitív szubtesztekben egyaránt. Kapcsolatot találtunk az életkor, az agyi történés óta eltelt idô és a stroke típusa, valamint a teszttel mérhetô egyes kognitív és nyelvi képességek között. Conclusion: Eredményeink és elôzetes tapasztalataink szerint a teszt alkalmas a nyelvi profil feltárására, a nyelvi képességekben történô változások nyomonkövetésére és a kognitív alapképességek zavarainak szûrésére afáziában. Reményeink szerint a teszt sokoldalú felhasználhatóságának köszönhetôen egyedül­álló módon fogja segíteni az afázia hazai diagnosztikáját, az afáziás személyek ellátásában és rehabilitációjában dolgozó szakemberek, valamint az afáziakutatók mun­káját.

Author Keywords
aphasia;  aphasia battery;  assessment;  cognitive and linguistic abilities;  stroke

Document Type: Article
Publication Stage: Final
Source: Scopus