Arts & Sciences Brown School McKelvey School of Engineering School of Medicine Weekly Publications

WashU weekly Neuroscience publications

“Impact of intrauterine fetal resuscitation with oxygen on oxidative stress in the developing rat brain” (2021) Scientific Reports

Impact of intrauterine fetal resuscitation with oxygen on oxidative stress in the developing rat brain
(2021) Scientific Reports, 11 (1), art. no. 9798, . 

Jiang, J.a d , Giri, T.a , Raghuraman, N.b , Cahill, A.G.c , Palanisamy, A.a b

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Women’s Health, Dell Medical School, The University of Texas at Austin, Austin, TX, United States
d Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

Abstract
Use of maternal oxygen for intrauterine resuscitation is contentious because of the lack of evidence for its efficacy and the possibility of fetal harm through oxidative stress. Because the developing brain is rich in lipids and low in antioxidants, it remains vulnerable to oxidative stress. Here, we tested this hypothesis in a term pregnant rat model with oxytocin-induced fetal distress followed by treatment with either room air or 100% oxygen for 6 h. Fetal brains from both sexes were subjected to assays for biomarkers of oxidative stress (4-hydroxynonenal, protein carbonyl, or 8-hydroxy-2ʹ-deoxyguanosine), expression of genes mediating oxidative stress, and mitochondrial oxidative phosphorylation. Contrary to our hypothesis, maternal hyperoxia was not associated with increased biomarkers of oxidative stress in the fetal brain. However, there was significant upregulation of the expression of select genes mediating oxidative stress, of which some were male-specific. These observations, however, were not accompanied by changes in the expression of proteins from the mitochondrial electron transport chain. In summary, maternal hyperoxia in the setting of acute uteroplacental ischemia-hypoxia does not appear to cause oxidative damage to the developing brain. © 2021, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

“Local field potentials in the parietal reach region reveal mechanisms of bimanual coordination” (2021) Nature Communications

Local field potentials in the parietal reach region reveal mechanisms of bimanual coordination
(2021) Nature Communications, 12 (1), art. no. 2514, . 

Mooshagian, E.a c , Holmes, C.D.b , Snyder, L.H.a b

a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Department of Cognitive Science, University of California San Diego, La Jolla, CA, United States

Abstract
Primates use their arms in complex ways that frequently require coordination between the two arms. Yet the planning of bimanual movements has not been well-studied. We recorded spikes and local field potentials (LFP) from the parietal reach region (PRR) in both hemispheres simultaneously while monkeys planned and executed unimanual and bimanual reaches. From analyses of interhemispheric LFP-LFP and spike-LFP coherence, we found that task-specific information is shared across hemispheres in a frequency-specific manner. This shared information could arise from common input or from direct communication. The population average unit activity in PRR, representing PRR output, encodes only planned contralateral arm movements while beta-band LFP power, a putative PRR input, reflects the pattern of planned bimanual movement. A parsimonious interpretation of these data is that PRR integrates information about the movement of the left and right limbs, perhaps in service of bimanual coordination. © 2021, The Author(s).

Funding details
National Eye InstituteNEIEY-012135
National Institute of Neurological Disorders and StrokeNINDSNS-076206

Document Type: Article
Publication Stage: Final
Source: Scopus

“Relating whole-brain functional connectivity to self-reported negative emotion in a large sample of young adults using group regularized canonical correlation analysis” (2021) NeuroImage

Relating whole-brain functional connectivity to self-reported negative emotion in a large sample of young adults using group regularized canonical correlation analysis
(2021) NeuroImage, 237, art. no. 118137, . 

Tozzi, L.a , Tuzhilina, E.b , Glasser, M.F.c , Hastie, T.J.b , Williams, L.M.a d

a Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, United States
b Department of Statistics, Stanford University, Stanford, United States
c Departments of Radiology and Neuroscience, Washington University, St. Louis, United States
d Sierra-Pacific Mental Illness Research, Education and Clinical Center (MIRECC) Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States

Abstract
The goal of our study was to use functional connectivity to map brain function to self-reports of negative emotion. In a large dataset of healthy individuals derived from the Human Connectome Project (N = 652), first we quantified functional connectivity during a negative face-matching task to isolate patterns induced by emotional stimuli. Then, we did the same in a complementary task-free resting state condition. To identify the relationship between functional connectivity in these two conditions and self-reports of negative emotion, we introduce group regularized canonical correlation analysis (GRCCA), a novel algorithm extending canonical correlations analysis to model the shared common properties of functional connectivity within established brain networks. To minimize overfitting, we optimized the regularization parameters of GRCCA using cross-validation and tested the significance of our results in a held-out portion of the data set using permutations. GRCCA consistently outperformed plain regularized canonical correlation analysis. The only canonical correlation that generalized to the held-out test set was based on resting state data (r = 0.175, permutation test p = 0.021). This canonical correlation loaded primarily on Anger-aggression. It showed high loadings in the cingulate, orbitofrontal, superior parietal, auditory and visual cortices, as well as in the insula. Subcortically, we observed high loadings in the globus pallidus. Regarding brain networks, it loaded primarily on the primary visual, orbito-affective and ventral multimodal networks. Here, we present the first neuroimaging application of GRCCA, a novel algorithm for regularized canonical correlation analyses that takes into account grouping of the variables during the regularization scheme. Using GRCCA, we demonstrate that functional connections involving the visual, orbito-affective and multimodal networks are promising targets for investigating functional correlates of subjective anger and aggression. Crucially, our approach and findings also highlight the need of cross-validation, regularization and testing on held out data for correlational neuroimaging studies to avoid inflated effects. © 2021

Author Keywords
Canonical correlations;  Emotion;  Face-matching;  Functional connectivity;  Negative valence;  Resting state

Funding details
National Institutes of HealthNIHU01MH109985, PAR-14-281

Document Type: Article
Publication Stage: Final
Source: Scopus

“Minimal specifications for non-human primate MRI: Challenges in standardizing and harmonizing data collection” (2021) NeuroImage

Minimal specifications for non-human primate MRI: Challenges in standardizing and harmonizing data collection
(2021) NeuroImage, 236, art. no. 118082, . 

Autio, J.A.a , Zhu, Q.b c , Li, X.b , Glasser, M.F.d e , Schwiedrzik, C.M.f g , Fair, D.A.h , Zimmermann, J.h , Yacoub, E.h , Menon, R.S.i , Van Essen, D.C.e , Hayashi, T.a , Russ, B.j k l , Vanduffel, W.b m n o

a Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
b Laboratory for Neuro- and Psychophysiology, Department of Neurosciences, KU Leuven Medical School, Leuven 3000, Belgium
c Cognitive Neuroimaging Unit, INSERM, CEA, Université Paris-Saclay, NeuroSpin Center, 91191 Gif/Yvette, France
d Departments of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Departments of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
f Neural Circuits and Cognition Lab, European Neuroscience Institute Göttingen – A Joint Initiative of the University Medical Center Göttingen and the Max Planck SocietyGrisebachstraße 537077 Göttingen, Germany
g Perception and Plasticity Group, German Primate Center – Leibniz Institute for Primate Research, 37077 GöttingenKellnerweg 4, Germany
h Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
i Centre for Functional and Metabolic Mapping, Western University, London, ON, Canada
j Department of Psychiatry, New York University Langone, New York City, NY, United States
k Center for the Biomedical Imaging and Neuromodulation, Nathan Kline Institute, Orangeburg, NY, United States
l Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York City, NY, United States
m Leuven Brain Institute, KU Leuven, Leuven 3000, Belgium
n Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, MA 02129, Charlestown, United States
o Department of Radiology, Harvard Medical School, MA 02144, Boston, United States

Abstract
Recent methodological advances in MRI have enabled substantial growth in neuroimaging studies of non-human primates (NHPs), while open data-sharing through the PRIME-DE initiative has increased the availability of NHP MRI data and the need for robust multi-subject multi-center analyses. Streamlined acquisition and analysis protocols would accelerate and improve these efforts. However, consensus on minimal standards for data acquisition protocols and analysis pipelines for NHP imaging remains to be established, particularly for multi-center studies. Here, we draw parallels between NHP and human neuroimaging and provide minimal guidelines for harmonizing and standardizing data acquisition. We advocate robust translation of widely used open-access toolkits that are well established for analyzing human data. We also encourage the use of validated, automated pre-processing tools for analyzing NHP data sets. These guidelines aim to refine methodological and analytical strategies for small and large-scale NHP neuroimaging data. This will improve reproducibility of results, and accelerate the convergence between NHP and human neuroimaging strategies which will ultimately benefit fundamental and translational brain science. © 2021

Author Keywords
MRI;  Multi-site;  Non-human primate;  PRIME-DE;  Standardization

Funding details
Japan Science and Technology AgencyJST
NIH Blueprint for Neuroscience Research
G0C1920N, G0E0520N, G0B8617N
RIKEN
Deutsche ForschungsgemeinschaftDFGBRAINS R01-MH101555, MH-060974, RF1MH117040, SCHW1683/2-1
McDonnell Center for Systems Neuroscience
KU LeuvenC14/17/109
National Institutes of HealthNIH
945539
Japan Agency for Medical Research and DevelopmentAMEDJP20dm037006
Japan Agency for Medical Research and DevelopmentAMED
Japan Science and Technology AgencyJST
European Research CouncilERC
Japan Society for the Promotion of ScienceKAKENJP20K15945
Horizon 2020802482
Canadian Institutes of Health ResearchCIHRFRN-148453
Natural Sciences and Engineering Research Council of CanadaNSERCNSF-2024581, DA048742, EB027061
RF1 MH116978, P50NS098573, MH115357, MH096773, DA04112, DA041148

Document Type: Article
Publication Stage: Final
Source: Scopus

“Multi-objective data-driven optimization for improving deep brain stimulation in Parkinson’s disease” (2021) Journal of Neural Engineering

Multi-objective data-driven optimization for improving deep brain stimulation in Parkinson’s disease
(2021) Journal of Neural Engineering, 18 (4), art. no. 046046, . 

Connolly, M.J.a , Cole, E.R.a , Isbaine, F.b , De Hemptinne, C.c , Starr, P.A.d , Willie, J.T.e , Gross, R.E.a b f , Miocinovic, S.a f

a Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, United States
b Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, United States
c Department of Neurology, University of Florida, Gainesville, FL 32608, United States
d Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, United States
e Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neurology, Emory University School of Medicine, 12 Executive Park Drive North East, Atlanta, GA 30322, United States

Abstract
Objective. Deep brain stimulation (DBS) is an effective treatment for Parkinson’s disease (PD) but its success depends on a time-consuming process of trial-and-error to identify the optimal stimulation settings for each individual patient. Data-driven optimization algorithms have been proposed to efficiently find the stimulation setting that maximizes a quantitative biomarker of symptom relief. However, these algorithms cannot efficiently take into account stimulation settings that may control symptoms but also cause side effects. Here we demonstrate how multi-objective data-driven optimization can be used to find the optimal trade-off between maximizing symptom relief and minimizing side effects. Approach. Cortical and motor evoked potential data collected from PD patients during intraoperative stimulation of the subthalamic nucleus were used to construct a framework for designing and prototyping data-driven multi-objective optimization algorithms. Using this framework, we explored how these techniques can be applied clinically, and characterized the design features critical for solving this optimization problem. Our two optimization objectives were to maximize cortical evoked potentials, a putative biomarker of therapeutic benefit, and to minimize motor potentials, a biomarker of motor side effects. Main Results. Using this in silico design framework, we demonstrated how the optimal trade-off between two objectives can substantially reduce the stimulation parameter space by 61 ± 19%. The best algorithm for identifying the optimal trade-off between the two objectives was a Bayesian optimization approach with an area under the receiver operating characteristic curve of up to 0.94 ± 0.02, which was possible with the use of a surrogate model and a well-tuned acquisition function to efficiently select which stimulation settings to sample. Significance. These findings show that multi-objective optimization is a promising approach for identifying the optimal trade-off between symptom relief and side effects in DBS. Moreover, these approaches can be readily extended to newly discovered biomarkers, adapted to DBS for disorders beyond PD, and can scale with the development of more complex DBS devices. © 2021 IOP Publishing Ltd.

Author Keywords
Bayesian optimization;  Dbs side effects;  Deep brain stimulation;  Evoked potential;  Pareto set;  Stimulation parameters;  Subthalamic nucleus

Funding details
National Institute of Neurological Disorders and StrokeNINDSK23NS097576

Document Type: Article
Publication Stage: Final
Source: Scopus

“Liver inflammation at the time of spinal cord injury enhances intraspinal pathology, liver injury, metabolic syndrome and locomotor deficits” (2021) Experimental Neurology

Liver inflammation at the time of spinal cord injury enhances intraspinal pathology, liver injury, metabolic syndrome and locomotor deficits
(2021) Experimental Neurology, 342, art. no. 113725, . 

Goodus, M.T.a b , Carson, K.E.a b , Sauerbeck, A.D.a c , Dey, P.d , Alfredo, A.N.a b , Popovich, P.G.a b , Bruno, R.S.e , McTigue, D.M.a b

a The Belford Center for Spinal Cord Injury, Ohio State University, Columbus, OH, United States
b Department of Neuroscience, College of Medicine, Ohio State University, Columbus, OH, United States
c Department of Neurology, Washington University in St. LouisMO, United States
d Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, Punjab, India
e Department of Human Sciences, College of Education and Human Ecology, The Ohio State University, Columbus, OH, United States

Abstract
The current high obesity rates mean that neurological injuries are increasingly sustained on a background of systemic pathology, including liver inflammation, which likely has a negative impact on outcomes. Because obesity involves complex pathology, the effect of hepatic inflammation alone on neurological recovery is unknown. Thus, here we used a gain-of-function model to test if liver inflammation worsens outcome from spinal cord injury (SCI) in rats. Results show liver inflammation concomitant with SCI exacerbated intraspinal pathology and impaired locomotor recovery. Hepatic inflammation also potentiated SCI-induced non-alcoholic steatohepatitis (NASH), endotoxemia and insulin resistance. Circulating and cerebrospinal levels of the liver-derived protein Fetuin-A were higher in SCI rats with liver inflammation, and, when microinjected into intact spinal cords, Fetuin-A caused macrophage activation and neuron loss. Thus, liver inflammation functions as a disease modifying factor to impair recovery from SCI, and Fetuin-A is a potential neuropathological mediator. Since SCI alone induces acute liver inflammation, the liver may be a novel clinical target for improving recovery from SCI. © 2021

Author Keywords
ALT;  Fatty liver disease;  Hepatocyte ballooning;  Iron;  Kupffer cells;  Metabolic syndrome;  Obesity;  TLR4;  TNF;  White matter sparing

Funding details
National Institute of Neurological Disorders and StrokeNINDSP30-NS045758, R01-NS082095
Craig H. Neilsen FoundationCHNF
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

“Feasibility and acceptability of remotely accessed cognitive remediation for schizophrenia in public health settings” (2021) Psychiatry Research

Feasibility and acceptability of remotely accessed cognitive remediation for schizophrenia in public health settings
(2021) Psychiatry Research, 301, art. no. 113956, . 

Medalia, A.a , Saperstein, A.M.b , Stefancic, A.b , Meyler, S.b , Styke, S.b , Qian, M.c , Liu, J.d , Cabassa, L.J.e

a New York State Psychiatric Institute, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, and NewYork-Presbyterian, 1051 Riverside Drive, Box 100, New York, NY 10032, United States
b New York State Psychiatric Institute, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, Box 100, New York, NY 10032, United States
c Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY 10032, United States
d New York State Psychiatric Institute, Mental Health Data Science, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, United States
e Brown School of Social Work, Washington University in St. Louis, Goldfarb Hall, Room 358, Campus Box 1196, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
Cognitive remediation (CR) is an evidence-based therapy used to improve cognition in people with schizophrenia. However, it often requires multiple in-person clinic sessions per week, which can limit scalability. This mixed methods study considered the feasibility and acceptability of a hybrid approach, which allowed for half the sessions to be conducted remotely as homework, without the clinician present. Individuals with schizophrenia were randomized to either all in-clinic or hybrid conditions and completed questionnaires and individual interviews about their experience. CR clinicians provided feedback in complement. Because of limited access to technology, most Hybrid CR participants had to come to clinic to access computers and often sought clinician support to do their homework. Participants in the two conditions were equally satisfied per the Client Satisfaction Questionnaire, and the majority reported perceived benefit and enjoyment. Both CR participants and clinicians identified access to technology as a barrier to program feasibility, while availability of clinician support positively impacted acceptability. Suggestions to improve CR highlighted adopting a flexible approach to providing CR that accounts for participant access to technology, potential benefit from peer interaction, and need for clinician support. © 2021

Author Keywords
Cognitive remediation;  Mixed methods;  Schizophrenia;  Telepsychiatry

Funding details
National Institute of Mental HealthNIMH1 P50 MH 115843- 01

Document Type: Article
Publication Stage: Final
Source: Scopus

“Role of Cilostazol in Prevention of Vasospasm After Aneurysmal Subarachnoid Hemorrhage–A Systematic Review, Meta-Analysis, and Trial Sequential Analysis” (2021) World Neurosurgery

Role of Cilostazol in Prevention of Vasospasm After Aneurysmal Subarachnoid Hemorrhage–A Systematic Review, Meta-Analysis, and Trial Sequential Analysis
(2021) World Neurosurgery, 150, pp. 161-170. 

Bohara, S.a , Garg, K.a , Singh Rajpal, P.M.b , Kasliwal, M.c

a Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
b Department of Anesthesia, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurological Surgery, Case Western Reserve University School of Medicine, Cleveland, OH, United States

Abstract
Objective: Cerebral vasospasm is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). Many drugs have been tried to mitigate cerebral vasospasm and delayed cerebral ischemia. Cilostazol, a selective inhibitor of phosphodiesterase 3, is a promising agent in preventing cerebral vasospasm and delayed cerebral ischemia after aSAH. The objective of this article was to ascertain the effect of cilostazol on cerebral vasospasm after aSAH by performing meta-analysis and trial sequential analysis. Methods: A systematic search of the literature was performed, and all the eligible randomized controlled trials were included in the meta-analysis and trial sequential analysis. Results: A total of 454 articles were identified using the search criteria. Six articles were selected for systematic review and the 4 randomized controlled trials were included in the meta-analysis. The pooled odds ratio for symptomatic vasospasm, new-onset infarct, and angiographic vasospasm was 0.35 (95% confidence interval [CI], 0.21–0.59; P < 0.0001), 0.38 (95% CI, 0.21–0.66; P = 0.0007) and 0.49 (95% CI, 0.31–0.80; P = 0.004), respectively. The pooled risk ratio for unfavorable outcome was 0.52 (95% CI, 0.37–0.74; P = 0.0003). Conclusions: Cilostazol decreases the prevalence of symptomatic vasospasm, new-onset infarct, and angiographic vasospasm when administered after aSAH. Trial sequential analysis increased the precision of our results because the defined thresholds of effect were met by the available studies. However, further studies involving patients from other geographic areas are required to confirm the generalization of the results. © 2021 Elsevier Inc.

Author Keywords
Aneurysm;  Cilostazol;  Delayed cerebral ischemia;  Mortality;  Subarachnoid hemorrhage;  Vasospasm

Document Type: Review
Publication Stage: Final
Source: Scopus

“Effect of peripheral neuropathy on bone mineral density in adults with diabetes: A systematic review of the literature and meta-analysis” (2021) Bone

Effect of peripheral neuropathy on bone mineral density in adults with diabetes: A systematic review of the literature and meta-analysis
(2021) Bone, 147, p. 115932. 

Mohseni, M.a , Hosseinzadeh, P.b , Civitelli, R.a , Eisen, S.c

a Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
b Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
c Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

Abstract
INTRODUCTION: Peripheral neuropathy occurs in two thirds of patients with diabetes mellitus (DM). It can lead to severe pathological changes in the feet, and it increases the risk of fracture more than any other diabetic complication. The objective of this review is to analyze available literature on the effect of peripheral neuropathy on BMD of the foot, spine, or hip. We hypothesize that the presence of diabetic neuropathy leads to lower BMD in adults with diabetes. METHODS: Original studies investigating the effects of diabetic neuropathy on bone density were searched for inclusion in this systematic review. Studies were eligible if they met the following criteria: 1) participants included adults with either Type 1 DM or Type 2 DM; 2) Method used for the diagnosis of neuropathy described in the manuscript 3) DXA scan, ultrasound, or CT scan was used to measure proximal femur, spine, or foot bone mineral density were reported, and 4) bone parameters were analyzed based on the presence and absence of neuropathy. RESULTS: Among the 5 studies that met eligibility criteria, 4 did not find a significant effect of neuropathy on BMD. One study showed a significant negative impact of neuropathy on calcaneal BMD in patients with type 1 diabetes. The meta-analysis did not show a significant effect of peripheral neuropathy on BMDs of proximal femur, spine, and calcaneus in diabetic adults. CONCLUSION: Our study shows no evidence that peripheral neuropathy affects bone density or bone turnover in DM. However, this conclusion should be taken with caution since only a very limited number of studies were available for inclusion in the analysis and included both type 1 and type 2 DM patients. Improved measures of peripheral neuropathy and more advanced imaging technologies are needed to better assess the effect of diabetes on bone health. Copyright © 2021 Elsevier Inc. All rights reserved.

Author Keywords
Bone mineral density;  Diabetes mellitus;  DXA scan;  Neuropathy

Document Type: Article
Publication Stage: Final
Source: Scopus

“Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing” (2021) Developmental Cell

Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing
(2021) Developmental Cell, 56 (10), pp. 1526-1540.e7. 

Chen, T.a , Rohacek, A.M.a , Caporizzo, M.b , Nankali, A.c , Smits, J.J.d , Oostrik, J.d , Lanting, C.P.d , Kücük, E.e , Gilissen, C.e , van de Kamp, J.M.f , Pennings, R.J.E.d , Rakowiecki, S.M.a , Kaestner, K.H.a , Ohlemiller, K.K.g , Oghalai, J.S.c , Kremer, H.d e , Prosser, B.L.b , Epstein, D.J.a

a Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
c The Caruso Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles, CA, United States
d Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, Netherlands
e Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
f Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
g Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
In mammals, sound is detected by mechanosensory hair cells that are activated in response to vibrations at frequency-dependent positions along the cochlear duct. We demonstrate that inner ear supporting cells provide a structural framework for transmitting sound energy through the cochlear partition. Humans and mice with mutations in GAS2, encoding a cytoskeletal regulatory protein, exhibit hearing loss due to disorganization and destabilization of microtubule bundles in pillar and Deiters’ cells, two types of inner ear supporting cells with unique cytoskeletal specializations. Failure to maintain microtubule bundle integrity reduced supporting cell stiffness, which in turn altered cochlear micromechanics in Gas2 mutants. Vibratory responses to sound were measured in cochleae from live mice, revealing defects in the propagation and amplification of the traveling wave in Gas2 mutants. We propose that the microtubule bundling activity of GAS2 imparts supporting cells with mechanical properties for transmitting sound energy through the cochlea. © 2021 Elsevier Inc.

Author Keywords
cochlea;  cochlear mechanics;  cytoskeleton;  Gas2;  hearing loss;  microtubules;  supporting cells

Funding details
National Science FoundationNSF15–48571
National Institutes of HealthNIHR01 DC013774, R01 DC006254, R01 DC014450, R01 HL133080, R01 DC017741
T32 GM008216
Israel National Road Safety AuthorityNRSAT32 DC-00011, F31DC014647

Document Type: Article
Publication Stage: Final
Source: Scopus

“Pre-Clinical Common Data Elements for Traumatic Brain Injury Research: Progress and Use Cases” (2021) Journal of Neurotrauma

Pre-Clinical Common Data Elements for Traumatic Brain Injury Research: Progress and Use Cases
(2021) Journal of Neurotrauma, 38 (10), pp. 1399-1410. 

Laplaca, M.C.a x , Huie, J.R.b , Alam, H.B.c , Bachstetter, A.D.d , Bayir, H.e , Bellgowan, P.F.f , Cummings, D.f , Dixon, C.E.e , Ferguson, A.R.b , Ferland-Beckham, C.g , Floyd, C.L.h , Friess, S.H.i , Galanopoulou, A.S.j , Hall, E.D.d , Harris, N.G.k , Hawkins, B.E.l , Hicks, R.R.m , Hulbert, L.E.n , Johnson, V.E.o , Kabitzke, P.A.p , Lafrenaye, A.D.q , Lemmon, V.P.r , Lifshitz, C.W.s , Lifshitz, J.s , Loane, D.J.t , Misquitta, L.f , Nikolian, V.C.c , Noble-Haeusslein, L.J.u , Smith, D.H.o , Taylor-Burds, C.f , Umoh, N.v , Vovk, O.f , Williams, A.M.c , Young, M.e , Zai, L.J.w

a Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, 313 Ferst Drive, Atlanta, GA 30332, United States
b Brain and Spinal Injury Center, Department of Neurological Surgery, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
c Department of Surgery, University of Michigan, Ann Arbor, MI, United States
d Department of Neuroscience, University of Kentucky, Lexington, KY, United States
e Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
f National Institutes of Health, Bethesda, MD, United States
g Cohen Veterans Bioscience, Cambridge, MA, United States
h Department of Physical Medicine and Rehabilitation, University of Utah, Salt Lake City, UT, United States
i Division of Critical Care Medicine, Washington University in St. Louis, St. Louis, MO, United States
j Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
k Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA, United States
l Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, United States
m One Mind, Rutherford, CA, United States
n Department of Animal Sciences and Industry, Kansas State University, Manhattan, KS, United States
o Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States
p Broad Institute of MIT and Harvard, Cambridge, MA, United States
q Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
r Department of Neurological Surgery, University of Miami, Miami, FL, United States
s Department of Child Health, University of Arizona College of Medicine Phoenix, Phoenix, AZ, United States
t School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
u Departments of Psychology and Neurology, University of Texas at Austin, Austin, TX, United States
v Department of Defense, U.S. Army Medical Research and Materiel Command, Fort Detrick, Frederick, MD, United States
w Lucent Neuroscience, Parker, CO, United States
x San Francisco Veterans Affairs Health Care System, San Francisco, CA, United States

Abstract
Traumatic brain injury (TBI) is an extremely complex condition due to heterogeneity in injury mechanism, underlying conditions, and secondary injury. Pre-clinical and clinical researchers face challenges with reproducibility that negatively impact translation and therapeutic development for improved TBI patient outcomes. To address this challenge, TBI Pre-clinical Working Groups expanded upon previous efforts and developed common data elements (CDEs) to describe the most frequently used experimental parameters. The working groups created 913 CDEs to describe study metadata, animal characteristics, animal history, injury models, and behavioral tests. Use cases applied a set of commonly used CDEs to address and evaluate the degree of missing data resulting from combining legacy data from different laboratories for two different outcome measures (Morris water maze [MWM]; RotorRod/Rotarod). Data were cleaned and harmonized to Form Structures containing the relevant CDEs and subjected to missing value analysis. For the MWM dataset (358 animals from five studies, 44 CDEs), 50% of the CDEs contained at least one missing value, while for the Rotarod dataset (97 animals from three studies, 48 CDEs), over 60% of CDEs contained at least one missing value. Overall, 35% of values were missing across the MWM dataset, and 33% of values were missing for the Rotarod dataset, demonstrating both the feasibility and the challenge of combining legacy datasets using CDEs. The CDEs and the associated forms created here are available to the broader pre-clinical research community to promote consistent and comprehensive data acquisition, as well as to facilitate data sharing and formation of data repositories. In addition to addressing the challenge of standardization in TBI pre-clinical studies, this effort is intended to bring attention to the discrepancies in assessment and outcome metrics among pre-clinical laboratories and ultimately accelerate translation to clinical research. © 2021 Mary Ann Liebert, Inc. publishers.

Author Keywords
big data;  common data elements;  missing value analysis;  pre-clinical;  reproducibility

Funding details
California Institute of TechnologyCIT
National Institute of Neurological Disorders and StrokeNINDSR21 NS096515-02S1, R01 NS091062-03S1
Center for Information TechnologyCIT
U.S. Department of DefenseDOD
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

“The coding and long noncoding single-cell atlas of the developing human fetal striatum” (2021) Science

The coding and long noncoding single-cell atlas of the developing human fetal striatum
(2021) Science, 372 (6542), art. no. abf5759, . 

Bocchi, V.D.a b , Conforti, P.a b , Vezzoli, E.a b , Besusso, D.a b k , Cappadona, C.a b , Lischetti, T.a b , Galimberti, M.a b , Ranzani, V.b , Bonnal, R.J.P.b , Simone, M.D.b l , Rossetti, G.b , He, X.c , Kamimoto, K.d e f , Espuny-Camacho, I.a b m , Faedo, A.a b n , Gervasoni, F.b g , Vuono, R.c o , Morris, S.A.d e f , Chen, J.h , Felsenfeld, D.i j , Pavesi, G.a , Barker, R.A.c

a Dipartimento di Bioscienze, Università Degli Studi di Milano, Milan, Italy
b Istituto Nazionale Genetica Molecolare, Ingm, Milan, Italy
c WT-MRC Cambridge Stem Cell Institute and Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
f Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
g Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università Degli Studi di Milano, Milan, Italy
h Chdi Management/CHDI Foundation, New York, NY, United States
i Department of Biomedical Sciences for Health, Università Degli Studi di Milano, Milan, 20133, Italy
j Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090 Milan, Italy
k Ifomfirc Institute of Molecular Oncology, Milan, Italy
l Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
m Université de Liège, Giga Stem Cells, Quartier Hôpital 15, Liège, B-4000, Belgium
n OpenZone, Bresso, Milan, 20091, Italy
o Medway School of Pharmacy, University of Kent, Chatham, Kent, United Kingdom

Abstract
Deciphering how the human striatum develops is necessary for understanding the diseases that affect this region. To decode the transcriptional modules that regulate this structure during development, we compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons (D1- A nd D2-MSNs) arise from a common progenitor and that lineage commitment is established during the postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. We then uncovered cell type-specific gene regulatory networks that we validated through in silico perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment. © 2021 American Association for the Advancement of Science. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Emergence of developmental delay in infants and toddlers with an fmr1 mutation” (2021) Pediatrics

Emergence of developmental delay in infants and toddlers with an fmr1 mutation
(2021) Pediatrics, 147 (5), art. no. e2020011528, . 

Wheeler, A.C.a , Gwaltney, A.a , Raspa, M.a , Okoniewski, K.C.a , Berry-Kravis, E.b , Botteron, K.N.c , Budimirovic, D.d , Hazlett, H.C.e , Hessl, D.f , Losh, M.g , Martin, G.E.h , Rivera, S.M.f i , Roberts, J.E.j , Bailey, D.B.a

a Research Triangle Institute International, Research Triangle Park, NC, United States
b Department of Pediatrics, Rush Medical College, Chicago, IL, United States
c Departments of Psychiatry and Radiology, School of Medicine, Washington University, St Louis, MO, United States
d Kennedy Krieger Institute, Baltimore, MD, United States
e Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
f Department of Psychiatry and Behavioral Sciences, MIND Institute, Sacramento, CA, United States
g School of Communication, Northwestern University, Evanston, IL, United States
h Department of Communication Sciences and Disorders, St. John’s University, Staten Island, NY, United States
i Department of Psychology, College of Letters and Science, University of California, Davis, Davis, CA, United States
j Department of Psychology, University of South Carolina, Columbia, SC, United States

Abstract
BACKGROUND: Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options. METHODS: Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of >500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children ,5 years of age. RESULTS: Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over early childhood at around half the rate of their typically developing peers; girls with a full mutation showed growth at around three-quarters of the rate of their typically developing peers. Although children with a premutation were mostly typical in their developmental profiles and trajectories, mild but significant delays in fine motor skills by 18 months were detected. CONCLUSIONS: Children with the FMR1 gene full mutation demonstrate significant developmental challenges within the first 2 years of life, suggesting that earlier identification is needed to facilitate earlier implementation of interventions and therapeutics to maximize effectiveness. © 2021 by the American Academy of Pediatrics.

Funding details
National Institutes of HealthNIH1R01HD056031, R01MH90194, P30-HD003110, R01MH1075732, R01HD038819, R01MH091131
H324B010041

Document Type: Article
Publication Stage: Final
Source: Scopus

“Presymptomatic detection and intervention for autism spectrum disorder” (2021) Pediatrics

Presymptomatic detection and intervention for autism spectrum disorder
(2021) Pediatrics, 147 (5), art. no. e2020032250, . 

MacDuffie, K.E.a b , Estes, A.M.a , Harrington, L.T.a , Peay, H.L.c , Piven, J.d , Pruett Jr, J.R.e , Wolff, J.J.f , Wilfond, B.S.g

a Departments of Speech and Hearing Sciences, University of Washington, Seattle, WA, United States
b Treuman Katz Center for Pediatric Bioethics, Seattle Children’s Research Institute, Seattle, WA, United States
c Research Triangle Institute International, Research Triangle Park, NC, United States
d Carolina Institute for Developmental Disabilities, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
e School of Medicine, Washington University, St Louis, MO, United States
f Department of Educational Psychology, University of Minnesota, Minneapolis, MN, United States
g Departments of Pediatrics, University of Washington, Seattle, WA, United States

Abstract
Universal screening for autism spectrum disorder (ASD) is recommended during pediatric primary care visits in the first 2 years of life. However, many children are missed by initial screening and not diagnosed with ASD until years later. Research efforts are underway to develop and evaluate new objective measures of risk for ASD that can be used in infancy, before symptoms emerge. Initial studies with these tests, particularly MRI-based screening for infants at high familial risk, have shown promise but have not yet been evaluated in clinical trials. We present the study design for a hypothetical clinical trial that would combine presymptomatic detection and intervention for ASD and consider, through commentaries from diverse perspectives, the ethical issues that should be anticipated in advance of beginning such trials. Commentators Drs Pruett and Piven address the social value of the proposed research and importance of researcher-bioethicist collaborations. Drs Estes and Wolff discuss the clinical potential and challenges of developing presymptomatic interventions for infants at risk for ASD. Dr Harrington takes a neurodiversity view of presymptomatic prediction and intervention and their implications for autistic identity and quality of life. Finally, Drs MacDuffie, Peay and Wilfond consider the potential risks and benefits that must be evaluated and weighed in the next phases of research on presymptomatic detection and intervention for ASD. © 2021 by the American Academy of Pediatrics.

Funding details
National Institute of Mental HealthNIMHR01 MH118362, F32MH118689

Document Type: Article
Publication Stage: Final
Source: Scopus

“Beyond the AJR: ‘MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468 individuals worldwide”‘ (2021) American Journal of Roentgenology

Beyond the AJR: ‘MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468 individuals worldwide’
(2021) American Journal of Roentgenology, 216 (5), p. 1170. 

Raji, C.A.a b , Benzinger, T.L.S.a c

a Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, 4525 Scott Ave, St. Louis, MO 63110, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO, United States

Document Type: Note
Publication Stage: Final
Source: Scopus

“Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas” (2021) New England Journal of Medicine

Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas
(2021) New England Journal of Medicine, 384 (17), pp. 1613-1622. Cited 1 time.

Friedman, G.K.a d h , Johnston, J.M.d , Bag, A.K.i , Bernstock, J.D.a , Li, R.e h , Aban, I.f , Kachurak, K.a h , Nan, L.a , Kang, K.-D.a , Totsch, S.a , Schlappi, C.a , Martin, A.M.a , Pastakia, D.j r , McNall-Knapp, R.a , Sait, S.F.m , Khakoo, Y.m n , Karajannis, M.A.l , Woodling, K.m p , Palmer, J.D.k , Osorio, D.S.o p , Leonard, J.q , Abdelbaki, M.S.h p s , Madan-Swain, A.a , Atkinson, T.P.b h , Whitley, R.J.c h , Fiveash, J.B.g , Markert, J.M.d h

a Department of Pediatrics, Divisions of Pediatric Hematology-Oncology
b Pediatric Allergy and Immunology
c Pediatric Infectious Disease
d Departments of Neurosurgery
e Pathology
f Biostatistics
g Radiation Oncology
h University of Alabama at Birmingham and Children’s of Alabama, United States
i St. Jude Children’s Research Hospital, Department of Diagnostic Imaging, Memphis, United States
j Department of Pediatrics, Vanderbilt University Medical Center, Nashville, United States
k The Department of Neurosurgery, Harvard Medical School, Brigham and Women’s Hospital and Boston Children’s Hospital, Boston, United States
l The Department of Pediatrics, Albert Einstein College of Medicine
m Departments of Pediatrics
n Neurology
o Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, United States
p Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant
q Department of Pediatric Neurosurgery
r And Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center, Nationwide Children’s Hospital
s Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis, United States

Abstract
BACKGROUND Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or “cold,” with few tumorinfiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaqueforming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- A nd post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumorinfiltrating lymphocytes. CONCLUSIONS Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically “cold” tumors to “hot.” (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.). © 2021 Massachussetts Medical Society. All rights reserved.

Funding details
U.S. Food and Drug AdministrationFDANCT02457845
Rally Foundation
University of Alabama at BirminghamUABP30CA008748, P30CA013148
National Institutes of HealthNIHUL1TR003096
Kaul Pediatric Research InstituteKPRI
National Cancer InstituteNCI
Swedish Cancer Foundation
U.S. Food and Drug AdministrationFDAR01FD005379
U.S. Department of DefenseDODW81XWH-15-1-0108
National Center for Advancing Translational SciencesNCATS
Andrew McDonough B+ FoundationAMBF

Document Type: Article
Publication Stage: Final
Source: Scopus

“Re-examining age differences in the Stroop effect: The importance of the trees in the forest (plot)” (2021) Psychology and Aging

Re-examining age differences in the Stroop effect: The importance of the trees in the forest (plot)
(2021) Psychology and Aging, 36 (2), pp. 214-231. 

Nicosia, J., Cohen-Shikora, E.R., Balota, D.A.

Department of Psychological and Brain Sciences, Washington University in St. Louis

Abstract
Despite several meta-analyses suggesting that age differences in attentional control are “greatly exaggerated,” there have been multiple reports of disproportionate age differences in the Stroop effect. The Stroop task is widely accepted as the gold standard for assessing attentional control and has been critical in comparisons across development and in studies of neuropsychological patient groups. However, accounting for group differences in processing speed is a notorious challenge in interpreting reaction time (RT) data. Within the aging literature, prior meta-analyses have relied on Brinley and State-Trace techniques to account for overall processing speed differences in evaluating the effects of within-participant manipulations. Such analyses are based on mean performance per group per study and have been criticized as potentially being insensitive to within-participant manipulations. In order to further examine possible age differences in Stroop performance, we amassed a dataset from 33 different computerized, color-naming Stroop task studies with available trial-level data from 2,896 participants. We conducted meta-regression analyses on a wide set of dependent measures that control for general slowing, tested for publication bias, and examined four potential methodological moderators. We also conducted linear mixed-effect modeling allowing the intercept to vary randomly for each participant, thereby accounting for individual differences in processing speed. All analyses, with the exception of the Brinley and State-Trace techniques, produced clear evidence supporting a disproportionate age difference in the Stroop effect above and beyond the effects of general slowing. Discussion highlights the importance of trial-level data in accounting for group differences in processing speed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Document Type: Article
Publication Stage: Final
Source: Scopus

“Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau” (2021) Alzheimer’s and Dementia

Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau
(2021) Alzheimer’s and Dementia, . 

Butt, O.H.a , Meeker, K.L.a , Wisch, J.K.a , Schindler, S.E.a , Fagan, A.M.a b c , Benzinger, T.L.S.d , Cruchaga, C.b c e , Holtzman, D.M.a b c , Morris, J.C.a b c , Ances, B.M.a b c d

a Department of Neurology, Washington University in Saint Louis, Saint Louis, MO, United States
b Knight Alzheimer Disease Research Center, Washington University in Saint Louis, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University in Saint Louis, St. Louis, MO, United States
d Department of Radiology, Washington University in Saint Louis, Saint Louis, MO, United States
e Department of Psychiatry, Washington University in Saint Louis, Saint Louis, MO, United States

Abstract
Introduction: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer’s disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aβ) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aβ accumulation. Methods: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aβ per cerebrospinal fluid (CSF) or amyloid positron emission tomography. Results: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P =.02), with significant weighting on linear regression toward CSF total tau (P =.03) and CSF phosphorylated tau at codon 181 (P =.03), but not CSF Aβ42. Discussion: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau. © 2021 the Alzheimer’s Association

Author Keywords
apolipoprotein E;  functional connectivity;  preclinical Alzheimer’s disease;  resting state;  tau

Funding details
Hope Center for Neurological Disorders
National Institute on AgingNIAP01 AG026276

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

“Maternal stress and depression are associated with respiratory phenotypes in urban children” (2021) Journal of Allergy and Clinical Immunology

Maternal stress and depression are associated with respiratory phenotypes in urban children
(2021) Journal of Allergy and Clinical Immunology, . 

Ramratnam, S.K.a , Lockhart, A.b , Visness, C.M.b , Calatroni, A.b , Jackson, D.J.a , Gergen, P.J.c , Bacharier, L.B.d , O’Connor, G.T.e , Sandel, M.T.e , Kattan, M.f , Wood, R.A.g , Gern, J.E.a , Inner-City Asthma Consortiumh

a Department of Pediatrics, University of Wisconsin – Madison, Madison, Wis, United States
b Rho Federal Systems Division, Inc., Chapel Hill, NC, United States
c National Institute of Allergy and Infectious Diseases, Rockville, Md, United States
d Department of Pediatrics, Washington University School of Medicine and St Louis Children’s Hospital, St Louis, Mo, United States
e Department of Medicine, Boston University School of Medicine, Boston, MA, United States
f Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States
g Department of Pediatrics, Johns Hopkins University Medical Center, Baltimore, Md, United States

Abstract
Background: Prenatal and early-life exposure to maternal stress and depression is linked to development of recurrent wheezing in young children. Objective: We sought to determine whether maternal stress and depression in early life are associated with nonatopic wheezing phenotype in urban children. Methods: The Urban Environment and Childhood Asthma Study examined a birth cohort of children at high risk for asthma in low-income neighborhoods. Prenatal and postnatal (through age 3 years) maternal stress and depression scores were compared with respiratory phenotypes through age 10 years (multinomial regression), self-reported colds (linear regression), and detection of respiratory viruses (Poisson regression). Results: Scores for maternal depression, and, to a lesser extent, maternal perceived stress, were positively related to multiple wheezing phenotypes. In particular, cumulative measures of maternal depression in the first 3 years were related to the moderate-wheeze-low-atopy phenotype (odds ratio, 1.13; [1.05, 1.21]; P <.01). Considering indicators of respiratory health that were used to identify the phenotypes, there were multiple positive associations between early-life scores for maternal stress and depression and increased wheezing illnesses, but no consistent relationships with lung function and some inverse relationships with allergic sensitization. Cumulative maternal stress and depression scores were associated with cumulative number of respiratory illnesses through age 3 years. Conclusions: Among high-risk, urban children, maternal stress and depression in early life were positively associated with respiratory illnesses and a moderate-wheeze-low-atopy phenotype. These results suggest that treating stress and depression in expectant and new mothers could reduce viral respiratory illnesses and recurrent wheeze during the preschool years and some forms of childhood asthma. © 2021 American Academy of Allergy, Asthma & Immunology

Author Keywords
allergic sensitization;  Asthma;  atopy;  maternal depression;  pediatrics;  wheeze

Funding details
National Institutes of HealthNIHUM1AI114271-01, NO1-AI-254821, NO1-AI-25496, UM2AI117870, HHSN272200900052C, HHSN272201000052I
National Center for Research ResourcesNCRRM01RR00533, UL1TR001079, 1UL1RR025771, M01RR00071, 1UL1RR024156, 5UL1RR024992-02, RR00052, UL1TR000040
National Institute of Allergy and Infectious DiseasesNIAID
National Heart, Lung, and Blood InstituteNHLBI
Johns Hopkins UniversityJHU
Sanofi Genzyme
Boehringer IngelheimBI
Sanofi
Pfizer
National Heart, Lung, and Blood InstituteNHLBI
National Institutes of HealthNIH
Astellas Pharma
National Institute of Allergy and Infectious DiseasesNIAID

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

“De-identification procedures for magnetic resonance images and the impact on structural brain measures at different ages” (2021) Human Brain Mapping

De-identification procedures for magnetic resonance images and the impact on structural brain measures at different ages
(2021) Human Brain Mapping, . 

Buimer, E.E.L.a , Schnack, H.G.a , Caspi, Y.a , van Haren, N.E.M.a b , Milchenko, M.c , Pas, P.a , Hulshoff Pol, H.E.a , Brouwer, R.M.a , Alzheimer’s Disease Neuroimaging Initiatived

a UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
b Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, Rotterdam, Netherlands
c Department of Radiology, Washington University School of Medicine, Mallinckrodt Institute of Radiology, Saint Louis, MO, United States

Abstract
Surface rendering of MRI brain scans may lead to identification of the participant through facial characteristics. In this study, we evaluate three methods that overwrite voxels containing privacy-sensitive information: Face Masking, FreeSurfer defacing, and FSL defacing. We included structural T1-weighted MRI scans of children, young adults and older adults. For the young adults, test–retest data were included with a 1-week interval. The effects of the de-identification methods were quantified using different statistics to capture random variation and systematic noise in measures obtained through the FreeSurfer processing pipeline. Face Masking and FSL defacing impacted brain voxels in some scans especially in younger participants. FreeSurfer defacing left brain tissue intact in all cases. FSL defacing and FreeSurfer defacing preserved identifiable characteristics around the eyes or mouth in some scans. For all de-identification methods regional brain measures of subcortical volume, cortical volume, cortical surface area, and cortical thickness were on average highly replicable when derived from original versus de-identified scans with average regional correlations >.90 for children, young adults, and older adults. Small systematic biases were found that incidentally resulted in significantly different brain measures after de-identification, depending on the studied subsample, de-identification method, and brain metric. In young adults, test–retest intraclass correlation coefficients (ICCs) were comparable for original scans and de-identified scans with average regional ICCs >.90 for (sub)cortical volume and cortical surface area and ICCs >.80 for cortical thickness. We conclude that apparent visual differences between de-identification methods minimally impact reliability of brain measures, although small systematic biases can occur. © 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Author Keywords
aged;  brain;  child;  data anonymization;  humans;  longitudinal studies;  magnetic resonance imaging;  privacy;  reproducibility of results;  young adult

Funding details
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO024.001.003
U.S. Department of DefenseDODW81XWH
1220012
National Institute on AgingNIA
AbbVie
Alzheimer’s Drug Discovery FoundationADDF
National Institutes of HealthNIHU01 AG024904
U.S. Department of DefenseDOD
Eli Lilly and Company
Genentech
National Institute of Biomedical Imaging and BioengineeringNIBIB
Northern California Institute for Research and EducationNCIRE
Alzheimer’s AssociationAA
Canadian Institutes of Health ResearchCIHR
Alzheimer’s Disease Neuroimaging InitiativeADNI
National Institute on AgingNIA
AbbVie
Alzheimer’s Drug Discovery FoundationADDF
National Institutes of HealthNIHU01 AG024904
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO
U.S. Department of DefenseDODW81XWH
1220012
Biogen
National Institute of Biomedical Imaging and BioengineeringNIBIB
BioClinica
Alzheimer’s AssociationAA
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO024.001.003
Ministry of Education, Culture, Sports, Science and TechnologyMonbusho

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

“Slow recovery from fast inactivation of Nav1.3 channels: a common gating mechanism shared in sweet- and sour-sensing cells” (2021) Pflugers Archiv European Journal of Physiology

Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Funding details
National Institute of Neurological Disorders and StrokeNINDS
National Institutes of HealthNIHNS-100695

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

“Quantitative muscle echointensity: A practical approach using ultrasound to evaluate children with suspected neuromuscular disorders” (2021) Muscle and Nerve

a Neuromuscular Division, Departments of Neurology and Pediatrics, Washington University, St. Louis, MO, United States
b Neuromuscular Division, Department of Neurology, Duke University, Durham, NC, United States

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

“T-box transcription factor 21 is expressed in terminal Schwann cells at the neuromuscular junction” (2021) Muscle and Nerve

T-box transcription factor 21 is expressed in terminal Schwann cells at the neuromuscular junction
(2021) Muscle and Nerve, . 

Jablonka-Shariff, A., Broberg, C., Rios, R., Snyder-Warwick, A.K.

Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Introduction/Aims: Terminal Schwann cells (tSCs) are nonmyelinating Schwann cells present at the neuromuscular junction (NMJ) with multiple integral roles throughout their lifespan. There is no known gene differentiating tSCs from myelinating Schwann cells, making their isolation and investigation challenging. In this work we investigated genes expressed within tSCs. Methods: A novel dissection technique was utilized to isolate the tSC-containing NMJ band from the sternomastoid muscles of S100-GFP mice. RNA was isolated from samples containing: (a) NMJ bands (tSCs with nerve and muscle), (b) nerve, and (c) muscle, and microarray genetic expression analysis was conducted. Data were validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescent staining. To identify genes specific to tSCs compared with other NMJ components, analysis of variance and rank-order analysis were performed using the Partek Genomic Suite. Results: Microarray analysis of the tSC-enriched NMJ band revealed upregulation (by 4- to 12-fold) of several genes unique to the NMJ compared with muscle or nerve parts alone (P <.05). Among these genes, Tbx21 (or T-bet) was identified, which showed a 12-fold higher expression at the NMJ compared with sciatic nerve (P <.002). qRT-PCR analysis showed Tbx21 mRNA expression was over ninefold higher (P <.05) in the NMJ relative to muscle and nerve. Tbx21 protein colocalized with tSCs and was not noted in myelinating SCs from sciatic nerve. Discussion: We found TBX21 to be expressed in tSCs. Additional studies will be performed to determine the functional significance of TBX21 in tSCs. These studies may enhance the investigative tools available to modulate tSCs to improve motor recovery after nerve injury. © 2021 Wiley Periodicals LLC.

Author Keywords
nerve injury;  neuromuscular junction;  reinnervation;  T-BET;  TBX21;  terminal Schwann cell

Funding details
National Institutes of HealthNIHK08NS096232
National Institute of Neurological Disorders and StrokeNINDS
Plastic Surgery FoundationPSF

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

“Pipeline embolization of proximal middle cerebral artery aneurysms: A multicenter cohort study” (2021) Interventional Neuroradiology

Pipeline embolization of proximal middle cerebral artery aneurysms: A multicenter cohort study
(2021) Interventional Neuroradiology, . 

Lauzier, D.C.a , Root, B.K.a , Kayan, Y.b , Almandoz, J.E.D.b , Osbun, J.W.a c d , Chatterjee, A.R.a c d , Whaley, K.L.e , Tipps, M.E.e , Moran, C.J.a c , Kansagra, A.P.a c d

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Division of Neurointerventional Radiology, Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
e Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, United States

Abstract
Background and purpose: Flow diversion of aneurysms located in the M1 segment and middle cerebral artery bifurcation with Pipeline embolization device is sometimes performed, but further study is needed to support its regular use in aneurysm treatment. Here, we report measures of safety and efficacy for Pipeline embolization in the proximal middle cerebral artery in a multi-center cohort. Materials and methods: Clinical and angiographic data of eligible patients were retrospectively obtained from participating centers and assessed for key clinical and angiographic outcomes. Additional details were extracted for patients with complications. Results: In our multi-center cohort, complete aneurysm occlusion was achieved in 71% (17/24) of treated aneurysms. There were no deaths or disabling strokes, but non-disabling ischemic strokes occurred in 8% (2/24) of patients. For aneurysms in the M1 segment, complete aneurysm occlusion was observed in 75% (12/16) of aneurysms, aneurysm volume reduction was observed in 100% (16/16) of aneurysms, and non-disabling ischemic strokes occurred in 13% (2/16) of patients. For aneurysms at the middle cerebral artery bifurcation, complete aneurysm occlusion was observed in 63% (5/8) of aneurysms, aneurysm volume reduction occurred in 88% (7/8) of aneurysms, and ischemic or hemorrhagic complications occurred in 0% (0/8) of patients. Conclusion: Pipeline embolization of cerebral aneurysms in the M1 segment and middle cerebral artery bifurcation demonstrated a 71% rate of complete aneurysm occlusion. There were no deaths or disabling strokes, but there was an 8% rate of non-disabling ischemic strokes. © The Author(s) 2021.

Author Keywords
aneurysm;  endovascular;  Middle cerebral artery;  pipeline embolization device

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

“Differential effects of the novel neurosteroid hypnotic (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile on electroencephalogram activity in male and female rats” (2021) British Journal of Anaesthesia

Differential effects of the novel neurosteroid hypnotic (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile on electroencephalogram activity in male and female rats
(2021) British Journal of Anaesthesia, . 

Joksimovic, S.M.a , Sampath, D.b , Krishnan, K.c , Covey, D.F.c d , Jevtovic-Todorovic, V.a , Raol, Y.H.e , Todorovic, S.M.a f

a Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States
b Department of Neuroscience and Experimental Therapeutics, Texas A&M University System, College Station, TX, United States
c Department of Developmental Biology, Washington University School of Medicine, St LouisMO, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St LouisMO, United States
e Department of Pediatrics, Division of Neurology, Translational Epilepsy Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States
f Neuroscience Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States

Abstract
Background: We recently showed that a neurosteroid analogue, (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rats. The aim of the present study was to evaluate the hypnotic and anaesthetic potential of 3β-OH further using electroencephalography. Methods: We used behavioural assessment and cortical electroencephalogram (EEG) spectral power analysis to examine hypnotic and anaesthetic effects of 3β-OH (30 and 60 mg kg−1) administered intraperitoneally or intravenously to young adult male and female rats. Results: We found dose-dependent sex differences in 3β-OH-induced hypnosis and EEG changes. Both male and female rats responded similarly to i.p. 3β-OH 30 mg kg−1. However, at the higher dose (60 mg kg−1, i.p.), female rats had two-fold longer duration of spontaneous immobility than male rats (203.4 [61.6] min vs 101.3 [32.1] min), and their EEG was suppressed in the low-frequency range (2–6 Hz), in contrast to male rats. Although a sex-dependent hypnotic effect was not confirmed after 30 mg kg−1 i.v., female rats appeared more sensitive to 3β-OH with relatively small changes within delta (1–4 Hz) and alpha (8–13 Hz) bands. Finally, 3β-OH had a rapid onset of action and potent hypnotic/anaesthetic effect after 60 mg kg−1 i.v. in rats of both sexes; however, all female rats and only half of the male rats reached burst suppression, an EEG pattern usually associated with profound inhibition of thalamocortical networks. Conclusions: Based on its behavioural effects and EEG signature, 3β-OH is a potent hypnotic in rats, with female rats being more sensitive than male rats. © 2021 The Authors

Author Keywords
anaesthesia;  electroencephalogram;  hypnosis;  neurosteroid;  power spectral density;  sex differences

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

“Brain Biomarkers: Follow-Up of RNA Expression Discovery Approach: CSF Assays for Neurogranin, SNAP-25, and VILIP-1” (2021) Neuromethods

Brain Biomarkers: Follow-Up of RNA Expression Discovery Approach: CSF Assays for Neurogranin, SNAP-25, and VILIP-1
(2021) Neuromethods, 168, pp. 181-221. 

Herries, E.M.a , Brada, N.b , Sutphen, C.L.c , Fagan, A.M.c , Ladenson, J.H.b

a Departments of Neurology and of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Neurology, Knight Alzheimer’s Disease Research Center, Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Here, we describe our methods for identifying biomarkers of neurological disease that have the potential to evaluate patients with probable Alzheimer’s disease (AD) and efficacy of novel therapeutics. We report a follow-up to our RNA expression discovery approach in mice to identify potential brain biomarkers. The gene expression approach identified 26 genes as having reasonable abundance and specificity and with human homologs known at the time. This chapter describes our follow-up in developing and evaluating the assays for the proteins expressed by these genes. We then present validated working assays for three analytes: VILIP-1 (visinin-like protein 1), a robust marker of neurodegeneration; synaptosomal-associated protein-25 (SNAP-25) and two different assays for neurogranin (Ng), as biomarkers of synaptic pathology, that we have utilized for studying AD, and which have demonstrated diagnostic utility. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Alzheimer’s disease;  Biomarker;  Cerebrospinal fluid;  Neurogranin;  Single Molecule Counting™ immunoassays;  SNAP-25;  VILIP-1

Document Type: Book Chapter
Publication Stage: Final
Source: Scopus

“Neurological diseases and COVID-19: prospective analyses using the UK Biobank” (2021) Acta Neurologica Belgica

Neurological diseases and COVID-19: prospective analyses using the UK Biobank
(2021) Acta Neurologica Belgica, . 

Veronese, N.a , Smith, L.b , Barbagallo, M.a , Giannelli, G.c , Caruso, M.G.c , Cisternino, A.M.c , Notarnicola, M.c , Cao, C.d e , Waldhoer, T.f , Yang, L.g h

a Geriatric Unit, Department of Internal Medicine and Geriatrics, University of Palermo, Palermo, Italy
b The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, United Kingdom
c National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, Italy
d Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
e Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, United States
f Department of Epidemiology, Centre for Public Health, Medical University of Vienna, Vienna, Austria
g Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, Canada
h Departments of Oncology and Community Health Sciences, University of Calgary, Calgary, Canada

Abstract
COVID-19 (Coronavirus disease-19) may present with neurological signs, but whether people already affected by neurological conditions are at a higher risk of contracting COVID-19 is still not known. We, therefore, aimed to investigate the association of previously diagnosed neurological conditions with COVID-19. 502,536 community-dwelling UK Biobank participants (54.4% male, mean age 56.6 ± 10.3 years) were included. Among these, 57,463 participants had a diagnosis of neurological conditions (11.43%) and a total of 1326 COVID-19-positive cases were identified (0.26%). Neurological conditions were identified through medical history and linkage to data on hospital admissions (ICD-10 code G00–G99). COVID-19 presence was diagnosed using the data provided by Public Health England. The association of previous diagnosis of neurological conditions with COVID-19 was evaluated through logistic regressions, adjusted for potential confounders, reported as odds ratios (ORs) with their 95% confidence intervals (CIs). Nerve, nerve root and plexus disorders (G50–G59) were the most common conditions identified. The presence of COVID-19 was almost doubled in neurological conditions compared to the general population (0.45 vs. 0.24%, p < 0.0001). Previously diagnosed neurological conditions were associated with 60% higher odds of COVID-19 positive in the multivariable-adjusted model (OR = 1.6, 95% CI 1.4–1.8). Other degenerative diseases of the nervous system, extrapyramidal and movement disorders, polyneuropathies and other disorders of the peripheral nervous system, cerebral palsy and other paralytic syndromes were significantly associated with a higher odds of COVID-19. The presence of neurological conditions was associated with a significantly higher likelihood of COVID-19 compared to the general population. © 2021, The Author(s).

Author Keywords
COVID-19;  Neurological conditions;  UK Biobank

Funding details
Università degli Studi di Palermo

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

“Spatial neglect treatment: The brain’s spatial-motor Aiming systems” (2021) Neuropsychological Rehabilitation

Spatial neglect treatment: The brain’s spatial-motor Aiming systems
(2021) Neuropsychological Rehabilitation, . 

Barrett, A.M.a b h , Goedert, K.M.c , Carter, A.R.d e , Chaudhari, A.f g

a Neurorehabilitation Division, Emory Brain Health Center, Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
b Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health System, Decatur, GA, United States
c Department of Psychology, Seton Hall University, South Orange, NJ, United States
d Neurorehabilitation Division, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
e Program in Occupational Therapy, Washington University in Saint Louis, Saint Louis, MO, United States
f Department of Neurology, University of California Irvine, Irvine, CA, United States
g Kessler Foundation, West Orange, NJ, United States
h Kessler Foundation, West Orange, NJ, United States

Abstract
Animal and human literature supports spatial-motor “Aiming” bias, a frontal-subcortical syndrome, as a core deficit in spatial neglect. However, spatial neglect treatment studies rarely assess Aiming errors. Two knowledge gaps result: spatial neglect rehabilitation studies fail to capture the impact on motor-exploratory aspects of functional disability. Also, across spatial neglect treatment studies, discrepant treatment effects may also result from sampling different proportions of patients with Aiming bias. We review behavioural evidence for Aiming spatial neglect, and demonstrate the importance of measuring and targeting Aiming bias for treatment, by reviewing literature on Aiming spatial neglect and prism adaptation treatment, and presenting new preliminary data on bromocriptine treatment. Finally, we review neuroanatomical and network disruption that may give rise to Aiming spatial neglect. Because Aiming spatial neglect predicts prism adaptation treatment response, assessment may broaden the ability of rehabilitation research to capture functionally-relevant disability. Frontal brain lesions predict both the presence of Aiming spatial neglect, and a robust response to some spatial neglect interventions. Research is needed that co-stratifies spatial neglect patients by lesion location and Aiming spatial neglect, to personalize spatial neglect rehabilitation and perhaps even open a path to spatial retraining as a means of promoting better mobility after stroke. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
frontal lobe syndrome;  motor-intention;  Spatial neglect

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

“International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery” (2021) International Journal of Stroke

International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery
(2021) International Journal of Stroke, . 

Lindgren, A.G.a b , Braun, R.G.c , Juhl Majersik, J.d , Clatworthy, P.e , Mainali, S.f , Derdeyn, C.P.g , Maguire, J.h , Jern, C.i j , Rosand, J.k , Cole, J.W.l m , Lee, J.-M.n , Khatri, P.o , Nyquist, P.p , Debette, S.q r , Keat Wei, L.s , Rundek, T.t , Leifer, D.u , Thijs, V.v , Lemmens, R.w x , Heitsch, L.n , Prasad, K.y , Jimenez Conde, J.z aa , Dichgans, M.ab , Rost, N.S.k , Cramer, S.C.ac ad , Bernhardt, J.v , Worrall, B.B.ae , Fernandez-Cadenas, I.af , International Stroke Genetics Consortiumag

a Department of Clinical Sciences Lund, Neurology, –SPiCloseGreaterLund University, Lund, Sweden
b Department of Neurology, Skåne University Hospital, Lund, Sweden
c Department of Neurology, University of Maryland, Baltimore, MD, United States
d Department of Neurology, University of Utah, Salt Lake Cit, UT, United States
e Department of Neurology, North Bristol NHS Trust, Bristol, United Kingdom
f Department of Neurology, -SPiCloseGreaterThe Ohio State University, Columbus, OH, United States
g Department of Radiology, University of Iowa, Iowa City, IA, United States
h Faculty of Health, University of Technology Sydney, Ultimo, NSW, Australia
i Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
j Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
k Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
l Neurology Service, Baltimore Veterans Affairs Medical Center, Baltimore, MD, United States
m Department of Neurology, -SPiCloseGreaterUniversity of Maryland School of Medicine, Baltimore, MD, United States
n Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
o Department of Neurology and Rehabilitation Sciences, University of Cincinnati, Cincinnati, OH, United States
p Anesthesiology/Critical Care Medicine, Neurosurgery, and General Internal Medicine, -SPiCloseGreaterJohns Hopkins School of Medicine, Baltimore, MD, United States
q Bordeaux Population Health, Inserm U1219, University of Bordeaux, Bordeaux, France
r Neurology Department, Bordeaux University Hospital, Bordeaux, France
s Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Perak, Malaysia
t Department of Neurology, -SPiCloseGreaterUniversity of Miami Miller School of Medicine, Miami, FL, United States
u Department of Neurology, Weill Cornell Medicine, New York, NY, United States
v Stroke Theme, Florey Institute of Neuroscience and Mental Health, Melbourne, Vic, Australia
w Department of Neuroscience, University of Leuven, Leuven, Belgium
x Department of Neurology, University Hospitals Leuven, Leuven, Belgium
y Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
z Neurology Department, Neurovascular Research Group, Institut Hospital del Mar d’Investigació Mèdica, Barcelona, Spain
aa Universitat Autònoma de Barcelona, Barcelona, Spain
ab Institute for Stroke and Dementia Research, University Hospital, LMU, Munich, Germany
ac Department of Neurology, UCLA, Los Angeles, CA, United States
ad California Rehabilitation Institute, Los Angeles, CA, United States
ae Department of Neurology, University of Virginia, Charlottesville, VA, United States
af Stroke Pharmacogenomics and Genetics Group, Sant Pau Biomedical Research Institute, Barcelona, Spain

Abstract
Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium. © 2021 World Stroke Organization.

Author Keywords
Data collection;  genetics;  ischemic stroke;  outcome;  phenotype;  recovery;  standardization

Funding details
VetenskapsrådetVR2018–02543, 2019–01757
1841918N
Department of Biotechnology, Ministry of Science and Technology, IndiaDBT
Instituto de Salud Carlos IIIISCIII
National Institute of Child Health and Human DevelopmentNICHDK12HD093427
Sparbanksstiftelsen Färs and Frosta
European Regional Development FundERDF
National Institutes of HealthNIHKL2TR003016, R01-NS105150, R21-NS106480, R01-NS114045, U24-NS107237, R01-NS085419, U24-NS107230, R01-NS100178, U24-NS107222
Region Skåne
Lunds Universitet
Skånes universitetssjukhusSUS
U.S. Department of Veterans AffairsVA
American Heart AssociationAHA15GPSG23770000, 17IBDG3300328
National Institute of Neurological Disorders and StrokeNINDSR01-NS082285, K23NS099487-01, U19-NS115388, 5U10NS086606, R01-NS086905

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

“Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease” (2021) Nature Genetics

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease
(2021) Nature Genetics, . 

Liu, G.a b c , Peng, J.a b d , Liao, Z.a b , Locascio, J.J.a b e , Corvol, J.-C.f , Zhu, F.a b , Dong, X.a b , Maple-Grødem, J.g h , Campbell, M.C.i , Elbaz, A.j , Lesage, S.f , Brice, A.f , Mangone, G.f , Growdon, J.H.e , Hung, A.Y.e , Schwarzschild, M.A.e , Hayes, M.T.a k , Wills, A.-M.e , Herrington, T.M.e , Ravina, B.l , Shoulson, I.m , Taba, P.n , Kõks, S.o p , Beach, T.G.q , Cormier-Dequaire, F.f , Alves, G.g h r , Tysnes, O.-B.s t , Perlmutter, J.S.i u v , Heutink, P.w , Amr, S.S.x , van Hilten, J.J.y , Kasten, M.z aa , Mollenhauer, B.ab ac , Trenkwalder, C.ac ad , Klein, C.ae , Barker, R.A.af ag , Williams-Gray, C.H.af , Marinus, J.y , van Hilten, J.J.y , Scherzer, C.R.a b e k , International Genetics of Parkinson Disease Progression (IGPP) Consortiumah

a Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United States
b Precision Neurology Program of Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
c School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, China
d School of Computer Science, Northwestern Polytechnical University, Xi’an, Shaanxi, China
e Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
f Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Institut National de Santé et en Recherche Médicale, Centre National de Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Centre d’Investigation Clinique Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France
g The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway
h Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
i Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, MO, United States
j Paris-Saclay University, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Inserm, Gustave Roussy, ‘Exposome and heredity’ team, Centre de researche en épidémiologie et santé des populations (CESP), Villejuif, France
k Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
l Praxis Precision Medicines, Cambridge, MA, United States
m Department of Neurology, Center for Health + Technology, University of Rochester, Rochester, NY, United States
n Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia
o Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
p Perron Institute for Neurological and Translational Science, Perth, WA, Australia
q Banner Sun Health Research Institute, Sun City, AZ, United States
r Department of Neurology, Stavanger University Hospital, Stavanger, Norway
s Department of Neurology, Haukeland University Hospital, Bergen, Norway
t Department of Clinical Medicine, University of Bergen, Bergen, Norway
u Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
v Program of Physical Therapy and Program of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
w German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany
x Translational Genomics Core of Partners HealthCare Personalized Medicine, Cambridge, MA, United States
y Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
z Institute of Neurogenetics, University of Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany
aa Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
ab Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
ac Paracelsus-Elena-Klinik, Kassel, Germany
ad Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
ae Institute of Neurogenetics, University of Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany
af John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
ag Wellcome – MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom

Abstract
A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10−11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10−8) and WWOX (HR = 2.12, P = 2.37 × 10−8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
2019QN01Y139
National Institutes of HealthNIHU01NS100603, U01NS095736
National Institute on AgingNIAR01NS115144
Fundamental Research Funds for the Central Universities19ykpy146
National Institute of Neurological Disorders and StrokeNINDS
Shenzhen Fundamental Research ProgramJCYJ20190807161601692
K23NS099380
National Natural Science Foundation of ChinaNSFC31900475
Evelyn Trust
ZonMw
NIHR Cambridge Biomedical Research Centre146281
Bristol-Myers SquibbBMS
Wellcome TrustWT203151/Z/16/Z
H. Lundbeck A/S
Cure Parkinson’s TrustCPT
Parkinson’s UK
Rosetrees TrustA1519 M654
Deutsche Parkinson VereinigungDPV
American Parkinson Disease AssociationAPDA
Deutsche ForschungsgemeinschaftDFG
Medical Research CouncilMRC
Amyotrophic Lateral Sclerosis AssociationALSA
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
MR/R007446/1
AbbVie
Sanofi Genzyme
Pfizer
National Institutes of HealthNIH
Center for Protein Therapeutics, University at BuffaloCPT
European CommissionEC
Biogen
Novo Nordisk
Perron Institute for Neurological and Translational Science
U.S. Department of DefenseDOD
Medical Research CouncilMRC

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

“How Zebrafish Can Drive the Future of Genetic-based Hearing and Balance Research” (2021) JARO – Journal of the Association for Research in Otolaryngology

How Zebrafish Can Drive the Future of Genetic-based Hearing and Balance Research
(2021) JARO – Journal of the Association for Research in Otolaryngology, . 

Sheets, L.a , Holmgren, M.a , Kindt, K.S.b

a Department of Otolaryngology–Head & Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Section On Sensory Cell Development and Function, National Institutes On Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United States

Abstract
Over the last several decades, studies in humans and animal models have successfully identified numerous molecules required for hearing and balance. Many of these studies relied on unbiased forward genetic screens based on behavior or morphology to identify these molecules. Alongside forward genetic screens, reverse genetics has further driven the exploration of candidate molecules. This review provides an overview of the genetic studies that have established zebrafish as a genetic model for hearing and balance research. Further, we discuss how the unique advantages of zebrafish can be leveraged in future genetic studies. We explore strategies to design novel forward genetic screens based on morphological alterations using transgenic lines or behavioral changes following mechanical or acoustic damage. We also outline how recent advances in CRISPR-Cas9 can be applied to perform reverse genetic screens to validate large sequencing datasets. Overall, this review describes how future genetic studies in zebrafish can continue to advance our understanding of inherited and acquired hearing and balance disorders. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Author Keywords
genetic screening;  genetics;  hearing and balance;  zebrafish

Funding details
National Institute on Deafness and Other Communication DisordersNIDCD1ZIADC000085-01, R01-DC-016066

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