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

WashU weekly Neuroscience publications: September 4, 2022

The CELLO trial: Protocol of a planned phase 4 study to assess the efficacy of Ocrelizumab in patients with radiologically isolated syndrome” (2022) Multiple Sclerosis and Related Disorders

The CELLO trial: Protocol of a planned phase 4 study to assess the efficacy of Ocrelizumab in patients with radiologically isolated syndrome
(2022) Multiple Sclerosis and Related Disorders, 68, art. no. 104143, . 

Longbrake, E.E.a , Hua, L.H.b , Mowry, E.M.c , Gauthier, S.A.d , Alvarez, E.e , Cross, A.H.f , Pei, J.g , Priest, J.g , Raposo, C.g , Hafler, D.A.a , Winger, R.C.g

a Department of Neurology, Yale School of Medicine, New Haven, CT, United States
b Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States
c The Johns Hopkins University School of Medicine, Baltimore, MD, United States
d Weill Cornell Medical College, New York, NY, United States
e Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus, University of Colorado, Aurora, CO, United States
f Washington University School of Medicine, St Louis, MO, United States
g Genentech, Inc., South San Francisco, CA, United States

Abstract
Background: Patients with radiologically isolated syndrome (RIS) exhibit CNS lesions suggestive of multiple sclerosis (MS) in the absence of overt neurological symptoms characteristic of the disease. They may have concurrent brain atrophy, subtle cognitive impairment, and intrathecal inflammation. At least half ultimately develop MS, cementing RIS as preclinical MS for many. However, high-quality data, including immunologic biomarkers, to guide treatment decisions in this population are lacking. Early intervention with ocrelizumab, a humanized monoclonal antibody approved for relapsing and primary progressive MS that targets CD20+ B-cells, may affect disease course and improve long-term outcomes. The objective of this study is to describe the protocol for CELLO, a clinical trial assessing the effect of ocrelizumab on RIS. Methods: The CELLO clinical trial, a phase 4, multicenter, randomized, double-blind, placebo-controlled study conducted as an academic-industry collaboration, aims to (1) assess the efficacy of ocrelizumab in patients with RIS and (2) identify biomarkers indicative of emerging autoimmunity as well as immune recovery after transient B-cell depletion. The study will enroll 100 participants across ≥15 sites. Participants will be aged 18 to 40 years, have RIS (defined as meeting 2017 revised McDonald criteria for dissemination in space), and have either been diagnosed with RIS within the last 5 years or have had new brain lesions identified within 5 years of study entry. A screening program of first-degree relatives of patients with MS will be used to boost recruitment. Eligible patients will be randomized 1:1 to receive 3 courses of ocrelizumab or placebo at baseline, week 24, and week 48. Patients will subsequently be followed up for ≥3 years. The primary outcome is time to development of new radiological or clinical evidence of MS. Secondary and exploratory objectives will investigate neuroimaging, serological and immunologic biomarkers, cognitive function, and patient-reported outcomes. A substudy using single-cell RNA sequencing to characterize blood and CSF immune cells will assess markers associated with conversion to clinical MS. Conclusion: The CELLO study will improve the understanding of B-cell biology in early MS disease pathophysiology, characterize the emergence of CNS autoimmunity, and provide evidence to inform treatment decision-making for individuals with RIS. ClinicalTrials.gov: NCT04877457 © 2022 Elsevier B.V.

Author Keywords
Biomarker;  Clinical trial;  Multiple sclerosis;  Radiologically isolated syndrome

Funding details
UL1 TR001863
National Institutes of HealthNIHK23 NS107624, K23107624, KL2 TR001862
National Multiple Sclerosis SocietyNMSS
Conrad N. Hilton FoundationCNHF
Genentech
Yale University
Biogen
Patient-Centered Outcomes Research InstitutePCORI
National Center for Advancing Translational SciencesNCATS
F. Hoffmann-La Roche
TG Therapeutics
Horizon Pharmaceuticals

Document Type: Article
Publication Stage: Final
Source: Scopus

Relationship of neurite architecture to brain activity during task-based fMRI” (2022) NeuroImage

Relationship of neurite architecture to brain activity during task-based fMRI
(2022) NeuroImage, 262, art. no. 119575, . 

Schifani, C.a , Hawco, C.a b d , Nazeri, A.c , Voineskos, A.N.a b d

a Kimel Family Translational Imaging Genetics Research Laboratory, The Centre for Addiction and Mental Health, Toronto, ON, Canada
b Department of Psychiatry, University of Toronto, Toronto, ON, Canada
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Institute of Medical Science, University of Toronto, Toronto, ON, Canada

Abstract
Functional MRI (fMRI) has been widely used to examine changes in neuronal activity during cognitive tasks. Commonly used measures of gray matter macrostructure (e.g., cortical thickness, surface area, volume) do not consistently appear to serve as structural correlates of brain function. In contrast, gray matter microstructure, measured using neurite orientation dispersion and density imaging (NODDI), enables the estimation of indices of neurite density (neurite density index; NDI) and organization (orientation dispersion index; ODI) in gray matter. Our study explored the relationship among neurite architecture, BOLD (blood-oxygen-level-dependent) fMRI, and cognition, using a large sample (n = 750) of young adults of the human connectome project (HCP) and two tasks that index more cortical (working memory) and more subcortical (emotion processing) targeting of brain functions. Using NODDI, fMRI, structural MRI and task performance data, hierarchical regression analyses revealed that higher working memory- and emotion processing-evoked BOLD activity was related to lower ODI in the right DLPFC, and lower ODI and NDI values in the right and left amygdala, respectively. Common measures of brain macrostructure (i.e., DLPFC thickness/surface area and amygdala volume) did not explain any additional variance (beyond neurite architecture) in BOLD activity. A moderating effect of neurite architecture on the relationship between emotion processing task-evoked BOLD response and performance was observed. Our findings provide evidence that neuro-/social-affective cognition-related BOLD activity is partially driven by the local neurite organization and density with direct impact on emotion processing. In vivo gray matter microstructure represents a new target of investigation providing strong potential for clinical translation. © 2022

Author Keywords
diffusion-weighted MRI;  functional activity;  Gray matter microstructure;  NODDI;  task-related fMRI

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMH
NIH Blueprint for Neuroscience Research
Brain and Behavior Research FoundationBBRF
McDonnell Center for Systems Neuroscience
Centre for Addiction and Mental HealthCAMH
Centre for Addiction and Mental Health FoundationCAMH
Canadian Institutes of Health ResearchIRSC
Canada Foundation for InnovationCFI
University of TorontoU of T

Document Type: Article
Publication Stage: Final
Source: Scopus

Increased persuadability and credulity in people with corpus callosum dysgenesis” (2022) Cortex

Increased persuadability and credulity in people with corpus callosum dysgenesis
(2022) Cortex, 155, pp. 251-263. 

Barnby, J.M.a g , Dean, R.J.a b , Burgess, H.a b , Kim, J.a , Teunisse, A.K.c , Mackenzie, L.a b , Robinson, G.A.a d , Dayan, P.e f , Richards, L.J.a b

a Queensland Brain Institute, University of Queensland, Brisbane, Australia
b Department of Neuroscience, Washington University in St Louis School of Medicine, St. Louis, MO, United States
c Department of Psychology, Macquarie UniversityNSW, Australia
d School of Psychology, University of Queensland, Brisbane, Australia
e Max Planck Institute for Biological Cybernetics, DE, Tübingen, Germany
f University of Tübingen, DE, Tübingen, Germany
g Department of Psychology, Royal Holloway, University of London, London, United Kingdom

Abstract
Corpus callosum dysgenesis is one of the most common congenital neurological malformations. Despite being a clear and identifiable structural alteration of the brain’s white matter connectivity, the impact of corpus callosum dysgenesis on cognition and behaviour has remained unclear. Here we build upon past clinical observations in the literature to define the clinical phenotype of corpus callosum dysgenesis better using unadjusted and adjusted group differences compared with a neurotypical sample on a range of social and cognitive measures that have been previously reported to be impacted by a corpus callosum dysgenesis diagnosis. Those with a diagnosis of corpus callosum dysgenesis (n = 22) demonstrated significantly higher persuadability, credulity, and insensitivity to social trickery than neurotypical (n = 86) participants, after controlling for age, sex, education, autistic-like traits, social intelligence, and general cognition. To explore this further, we examined the covariance structure of our psychometric variables using a machine learning algorithm trained on a neurotypical dataset. The algorithm was then used to test whether these dimensions possessed the capability to discriminate between a test-set of neurotypical and corpus callosum dysgenesis participants. After controlling for age and sex, and with Leave-One-Out-Cross-Validation across 250 training-set bootstrapped iterations, we found that participants with a diagnosis of corpus callosum dysgenesis were best classed within dimension space along the same axis as persuadability, credulity, and insensitivity to social trickery, with a mean accuracy of 71.7%. These results have implications for a) the characterisation of corpus callosum dysgenesis, and b) the role of the corpus callosum in social inference. © 2022 Elsevier Ltd

Author Keywords
Corpus callosum dysgenesis;  Machine learning;  Persuadability;  Phenotyping

Funding details
Alexander von Humboldt-StiftungAvH
Washington University School of Medicine in St. LouisWUSM
Australian Research CouncilARC
National Health and Medical Research CouncilNHMRCAPP1135769, GNT1120615
Max-Planck-GesellschaftMPG

Document Type: Article
Publication Stage: Final
Source: Scopus

MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma” (2022) Experimental and Molecular Pathology

MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma
(2022) Experimental and Molecular Pathology, 128, art. no. 104813, . 

Gray, A.a , Cui, T.b , Bell, E.H.b , McElroy, J.c , Sebastian, E.b , Li, F.d , Geurts, M.e , Liu, K.a , Robe, P.f , Haque, S.J.b , Chakravarti, A.b

a The Ohio State University College of Medicine, Columbus, OH, United States
b Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, OH, United States
c The Ohio State University Center for Biostatistics, Department of Biomedical Informatics, Columbus, OH, United States
d Institute for Informatics, Washington University School of Medicine, St. Louis, MO, United States
e Erasmus Medical Center Cancer Institute, Rotterdam, Netherlands
f Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands

Abstract
Purpose: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of <15 months, while only 3–5% of patients survive longer than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. In this study, we identified the association between miR-575 expression and overall survival (OS) of primary GBM patients and undertook functional studies to discern the contribution of miR-575 to GBM tumorigenesis. Methods: Total RNAs were isolated from 254 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies. To determine the association between miR-575 and patients’ prognosis, Kaplan-Meier, univariable and multivariable Cox regression analyses were performed. Cell proliferation, colony formation, migration assays were conducted to investigate the function of miR-575 in vitro and in vivo. In silico target gene network analysis was performed to identify the putative targets of miR-575 in GBM, which were further verified by luciferase reporter assay, as well as qPCR and immunoblotting. Results: Our clinical data (n = 254) show that miR-575 is associated with worse GBM OS by univariable analysis (UVA, HR = 1.27, p-value<0.001) and multivariable (MVA, HR = 1.23, p = 0.007) analysis incorporating critical clinical variables. Functional studies indicated that overexpression of miR-575 significantly increased cell proliferation and migration of GBM cells in vitro, as well as tumor growth in vivo. Subsequent in silico target gene network and mechanistic studies identified CDKN1B/p27 and PTEN, as potential targets of miR-575 in GBM. MicroRNA-575 can also regulate the activity of AKT and ERK pathways in GBM. Conclusion: miR-575 has prognostic value in GBM, with higher expression associating with worse OS of patients, and contributes to GBM tumorigenesis by regulating multiple signaling pathways in GBM. © 2022

Author Keywords
CDKN1B/p27;  Glioblastoma;  MicroRNA-575;  Oncogene;  PTEN;  Tumor progression

Funding details
National Cancer InstituteNCI1RC2CA148190, R01CA108633, R01CA1145128, R01CA11522358, R01CA169368, R01CA188228, U10CA180850-01
Ohio State UniversityOSUP30 CA016058

Document Type: Article
Publication Stage: Final
Source: Scopus

Quiescence during burst suppression and postictal generalized EEG suppression are distinct patterns of activity” (2022) Clinical Neurophysiology

Quiescence during burst suppression and postictal generalized EEG suppression are distinct patterns of activity
(2022) Clinical Neurophysiology, 142, pp. 125-132. 

Kafashan, M.a , Brian Hickman, L.a b , Labonte, A.K.a c , Huels, E.R.d e , Maybrier, H.f , Guay, C.S.a g h , Subramanian, S.i , Farber, N.B.i , Ching, S.j k , Hogan, R.E.l , Kelz, M.B.m , Avidan, M.S.a i , Mashour, G.A.e , Palanca, B.J.A.a j k n

a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
c Neuroscience Graduate Program, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States
e Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States
f Psychological & Brain Sciences Department, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
g Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
h Picower Institute for Learning & Memory, Massachusetts Institute of Technology, Cambridge, MA, United States
i Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
j Department of Electrical & Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
k Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
l Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
m Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
n Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: Periods of low-amplitude electroencephalographic (EEG) signal (quiescence) are present during both anesthetic-induced burst suppression (BS) and postictal generalized electroencephalographic suppression (PGES). PGES following generalized seizures induced by electroconvulsive therapy (ECT) has been previously linked to antidepressant response. The commonality of quiescence during both BS and PGES motivated trials to recapitulate the antidepressant effects of ECT using high doses of anesthetics. However, there have been no direct electrographic comparisons of these quiescent periods to address whether these are distinct entities. Methods: We compared periods of EEG quiescence recorded from two human studies: BS induced in 29 healthy adult volunteers by isoflurane general anesthesia and PGES in 11 patients undergoing right unilateral ECT for treatment-resistant depression. An automated algorithm allowed detection of EEG quiescence based on a 10-microvolt amplitude threshold. Spatial, spectral, and temporal analyses compared quiescent epochs during BS and PGES. Results: The median (interquartile range) voltage for quiescent periods during PGES was greater than during BS (1.81 (0.22) microvolts vs 1.22 (0.33) microvolts, p < 0.001). Relative power was greater for quiescence during PGES than BS for the 1–4 Hz delta band (p < 0.001), at the expense of power in the theta (4–8 Hz, p < 0.001), beta (13–30 Hz, p = 0.04) and gamma (30–70 Hz, p = 0.006) frequency bands. Topographic analyses revealed that amplitude across the scalp was consistently higher for quiescent periods during PGES than BS, whose voltage was within the noise floor. Conclusions: Quiescent epochs during PGES and BS have distinct patterns of EEG signals across voltage, frequency, and spatial domains. Significance: Quiescent epochs during PGES and BS, important neurophysiological markers for clinical outcomes, are shown to have distinct voltage and frequency characteristics. © 2022 International Federation of Clinical Neurophysiology

Author Keywords
Anesthesia;  Burst suppression;  Electroconvulsive therapy;  Electroencephalography;  Major depressive disorder;  Postictal generalized electroencephalographic suppression;  Seizures

Funding details
National Institutes of HealthNIHTR002344
National Institute of Mental HealthNIMHK01 MH128663
James S. McDonnell FoundationJSMF
McDonnell Center for Systems Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios” (2022) Cell

High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios
(2022) Cell, 185 (18), pp. 3426-3440.e19. Cited 1 time.

Byrska-Bishop, M.a , Evani, U.S.a , Zhao, X.b c d , Basile, A.O.a , Abel, H.J.e f , Regier, A.A.e f , Corvelo, A.a , Clarke, W.E.a g , Musunuri, R.a , Nagulapalli, K.a , Fairley, S.h , Runnels, A.a , Winterkorn, L.a , Lowy, E.h , Eichler, E.E.l , Korbel, J.O.l , Lee, C.l , Marschall, T.l , Devine, S.E.l , Harvey, W.T.l , Zhou, W.l , Mills, R.E.l , Rausch, T.l , Kumar, S.l , Alkan, C.l , Hormozdiari, F.l , Chong, Z.l , Chen, Y.l , Yang, X.l , Lin, J.l , Gerstein, M.B.l , Kai, Y.l , Zhu, Q.l , Yilmaz, F.l , Xiao, C.l , Paul Flicekh , Germer, S.a , Brand, H.b c d i , Hall, I.M.e f j k , Talkowski, M.E.b c d i , Narzisi, G.a , Zody, M.C.a , Human Genome Structural Variation Consortiumm

a New York Genome Center, New York, NY 10013, United States
b Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
c Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
d Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
e McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, United States
f Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
g Outlier Informatics Inc., Saskatoon, SK S7H 1L4, Canada
h European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
i Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
j Center for Genomic Health, Yale University School of Medicine, New Haven, CT 06510, United States
k Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, United States

Abstract
The 1000 Genomes Project (1kGP) is the largest fully open resource of whole-genome sequencing (WGS) data consented for public distribution without access or use restrictions. The final, phase 3 release of the 1kGP included 2,504 unrelated samples from 26 populations and was based primarily on low-coverage WGS. Here, we present a high-coverage 3,202-sample WGS 1kGP resource, which now includes 602 complete trios, sequenced to a depth of 30X using Illumina. We performed single-nucleotide variant (SNV) and short insertion and deletion (INDEL) discovery and generated a comprehensive set of structural variants (SVs) by integrating multiple analytic methods through a machine learning model. We show gains in sensitivity and precision of variant calls compared to phase 3, especially among rare SNVs as well as INDELs and SVs spanning frequency spectrum. We also generated an improved reference imputation panel, making variants discovered here accessible for association studies. © 2022 The Authors

Author Keywords
1000 Genomes Project;  INDEL;  population genetics;  reference imputation panel;  SNV;  structural variation;  trio sequencing;  whole-genome sequencing

Funding details
National Institutes of HealthNIHU24HG007497
National Institute of Mental HealthNIMHMH115957
National Human Genome Research InstituteNHGRIUM1HG008901
U.S. National Library of MedicineNLM
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDHD081256, UM1HG008853, UM1HG008895
Wellcome TrustWTWT104947/Z/14/Z
European Molecular Biology LaboratoryEMBL

Document Type: Article
Publication Stage: Final
Source: Scopus

Sequence grammar underlying the unfolding and phase separation of globular proteins” (2022) Molecular Cell

Sequence grammar underlying the unfolding and phase separation of globular proteins
(2022) Molecular Cell, 82 (17), pp. 3193-3208.e8. 

Ruff, K.M.a , Choi, Y.H.b , Cox, D.b , Ormsby, A.R.b , Myung, Y.c d e , Ascher, D.B.c d e , Radford, S.E.f , Pappu, R.V.a , Hatters, D.M.b

a Department of Biomedical Engineering, Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Biochemistry and Pharmacology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia
c Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
d Structural Biology and Bioinformatics, Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC 3010, Australia
e Systems and Computational Biology, Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia
f Astbury Centre for Structural and Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom

Abstract
Aberrant phase separation of globular proteins is associated with many diseases. Here, we use a model protein system to understand how the unfolded states of globular proteins drive phase separation and the formation of unfolded protein deposits (UPODs). We find that for UPODs to form, the concentrations of unfolded molecules must be above a threshold value. Additionally, unfolded molecules must possess appropriate sequence grammars to drive phase separation. While UPODs recruit molecular chaperones, their compositional profiles are also influenced by synergistic physicochemical interactions governed by the sequence grammars of unfolded proteins and cellular proteins. Overall, the driving forces for phase separation and the compositional profiles of UPODs are governed by the sequence grammars of unfolded proteins. Our studies highlight the need for uncovering the sequence grammars of unfolded proteins that drive UPOD formation and cause gain-of-function interactions whereby proteins are aberrantly recruited into UPODs. © 2022 The Authors

Author Keywords
barnase;  chaperonin-containing T-complex;  Cry2;  molecular condensate;  protein deposit;  protein folding;  protein misfolding;  protein quality control;  proteostasis;  SOD1;  superoxide dismutase 1;  TRiC

Funding details
National Institutes of HealthNIH5R01NS056114
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0241
Wellcome TrustWT204963
Australian Research CouncilARC
National Health and Medical Research CouncilNHMRCDP170103093

Document Type: Article
Publication Stage: Final
Source: Scopus

Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait” (2022) Stroke

Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait
(2022) Stroke, 53 (9), pp. 2887-2895. 

Wang, Y.a , Guilliams, K.P.b , Fields, M.E.c , Fellah, S.a , Binkley, M.M.a , Reis, M.d , Vo, K.D.d , Chen, Y.a , Ying, C.d , Blinder, M.e , King, A.A.f , Hulbert, M.L.c , An, H.a , Lee, J.-M.a , Ford, A.L.a

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Division of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Division of Pediatric Hematology/Oncology, Washington University School of Medicine, St. Louis, MO, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Division of Hematology/Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
f Program in Occupational Therapy and Departments of Pediatrics and Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function. Methods: As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics. Results: Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P=0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P=0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P=0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P=0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P=0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P=0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P=0.053) and correlated with SCI volume (ρ=0.49, P=0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia. Conclusions: Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
hemodynamics;  ischemia;  neuroimaging;  oxygen;  sickle cell trait

Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIK23HL136904, R01 HL129241
National Institute of Neurological Disorders and StrokeNINDS1K23NS099472-01

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain Structure and Function Predict Adherence to an Exercise Intervention in Older Adults” (2022) Medicine and Science in Sports and Exercise

Brain Structure and Function Predict Adherence to an Exercise Intervention in Older Adults
(2022) Medicine and Science in Sports and Exercise, 54 (9), pp. 1483-1492. 

Morris, T.P.a , Burzynska, A.b , Voss, M.c , Fanning, J.d , Salerno, E.A.e , Prakash, R.f , Gothe, N.P.g h , Whitfield-Gabrieli, S.a i , Hillman, C.H.a j , McAuley, E.g h , Kramer, A.F.a g

a Department of Psychology, Northeastern University, Boston, MA, United States
b Department of Human Development and Family Studies, Colorado State University, Fort Collins, CO, United States
c Deptartment of Psychology, University of Iowa, Iowa City, IA, United States
d Department of Health and Exercise Science, Wake Forest University, Winston-Salem, NC, United States
e Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Department of Psychology, Ohio State University, Columbus, OH, United States
g Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
h Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, United States
i McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States
j Department of Physical Therapy, Movement, and Rehabilitation Sciences, Northeastern University, Boston, MA, United States

Abstract
Introduction Individual differences in brain structure and function in older adults are potential proxies of brain reserve or maintenance and may provide mechanistic predictions of adherence to exercise. We hypothesized that multimodal neuroimaging features would predict adherence to a 6-month randomized controlled trial of exercise in 131 older adults (age, 65.79 ± 4.65 yr, 63% female), alone and in combination with psychosocial, cognitive, and health measures. Methods Regularized elastic net regression within a nested cross-validation framework was applied to predict adherence to the intervention in three separate models (brain structure and function only; psychosocial, health, and demographic data only; and a multimodal model). Results Higher cortical thickness in somatosensory and inferior frontal regions and less surface area in primary visual and inferior frontal regions predicted adherence. Higher nodal functional connectivity (degree count) in default, frontoparietal, and attentional networks and less nodal strength in primary visual and temporoparietal networks predicted exercise adherence (r = 0.24, P = 0.004). Survey and clinical measures of gait and walking self-efficacy, biological sex, and perceived stress also predicted adherence (r = 0.17, P = 0.056); however, this prediction was not significant when tested against a null test statistic. A combined multimodal model achieved the highest predictive strength (r = 0.28, P = 0.001). Conclusions Our results suggest that there is a substantial utility of using brain-based measures in future research into precision and individualized exercise interventions older adults. © Lippincott Williams & Wilkins.

Author Keywords
AEROBIC EXERCISE;  AGING;  BRAIN RESERVE;  FUNCTIONAL CONNECTIVITY;  MACHINE LEARNING;  PREDICTION

Funding details
National Institutes of HealthNIHR37 AG025667
National Institute on AgingNIA

Document Type: Article
Publication Stage: Final
Source: Scopus

A phase-II clinical trial of targeted cerebral near infrared spectroscopy using standardized treatment guidelines to improve brain oxygenation in preterm infants (BOx-II): A study protocol” (2022) Contemporary Clinical Trials

A phase-II clinical trial of targeted cerebral near infrared spectroscopy using standardized treatment guidelines to improve brain oxygenation in preterm infants (BOx-II): A study protocol
(2022) Contemporary Clinical Trials, 120, art. no. 106886, . 

Vesoulis, Z.a , Hopper, A.b , Fairchild, K.c , Zanelli, S.c , Chalak, L.d , Noroozi, M.a , Liu, J.e , Chock, V.e

a Washington University, St. Louis, MO, United States
b Loma Linda University, Loma Linda, CA, United States
c University of Virginia, Charlottesville, VA, United States
d University of Texas Southwest, Dallas, TX, United States
e Stanford University, Palo Alto, CA, United States

Abstract
Background: Mortality and brain injury are common adverse outcomes in infants born <28 weeks. Conventional pulse oximetry may not detect subclinical changes prior to deterioration and fails to detect changes within the brain. Increasing evidence supports the use of cerebral near-infrared spectroscopy (NIRS) in the early care of preterm infants, yet the impact of specific interventions on cerebral oxygenation and the relationship between cerebral hypoxia and brain injury on MRI remain to be determined. Methods/design: 100 infants <28 completed weeks of gestation will be recruited for a prospective, multicenter intervention trial. After informed consent, infants will undergo cerebral NIRS monitoring starting within 6 h of birth and continuing through 72 h. Infants with persistent cerebral desaturation will receive interventions following a standard treatment algorithm selected by the provider based on the patient’s clinical condition. Providers will record the timing and choice of intervention(s) and term equivalent brain MRI will be performed for survivors. There are three objectives of this study: 1) to identify the relationship between cerebral hypoxia burden and brain injury on term-equivalent MRI. 2) to identify most common interventions after cerebral hypoxia, and 3) to quantify frequency of occult cerebral hypoxia events. Discussion: There is increasing evidence for the role of early cerebral NIRS monitoring in the neuroprotective care of preterm infants. This phase-II trial will provide essential data to improve the intervention approach, model the effect size of interventions on a wider extent of brain injury, and quantify the discrepancy between measurements of systemic and cerebral hypoxia. © 2022 Elsevier Inc.

Author Keywords
Guidelines;  Hypoxia;  MRI;  NIRS;  Prematurity

Funding details
National Institutes of HealthNIHUL1 TR001085
Medtronic
Stanford UniversitySU
Edwards LifesciencesELC
Cerebral Palsy Alliance Research FoundationCPARFPRG01719

Document Type: Article
Publication Stage: Final
Source: Scopus

Association between antidepressant use and ED or hospital visits in outpatients with SARS-CoV-2” (2022) Translational Psychiatry

Association between antidepressant use and ED or hospital visits in outpatients with SARS-CoV-2
(2022) Translational Psychiatry, 12 (1), p. 341. 

Fritz, B.A.a , Hoertel, N.b c d , Lenze, E.J.e , Jalali, F.f , Reiersen, A.M.e

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Hôpital Corentin-Celton, Issy-les-Moulineaux, Assistance Publique-Hôpitaux de Paris92130, France
c Paris, France
d Institut de psychiatrie et neurosciences de Paris (IPNP), INSERM, Paris, France
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
f Department of Gastroenterology, Saddleback Medical Group, Laguna HillsCA, United States

Abstract
Antidepressants have previously been associated with better outcomes in patients hospitalized with COVID-19, but their effect on clinical deterioration among ambulatory patients has not been fully explored. The objective of this study was to assess whether antidepressant exposure was associated with reduced emergency department (ED) or hospital visits among ambulatory patients with SARS-CoV-2 infection. This retrospective cohort study included adult patients (N = 25 034) with a positive SARS-CoV-2 test performed in a non-hospital setting. Logistic regression analyses tested associations between home use of antidepressant medications and a composite outcome of ED visitation or hospital admission within 30 days. Secondary exposures included individual antidepressants and antidepressants with functional inhibition of acid sphingomyelinase (FIASMA) activity. Patients with antidepressant exposure were less likely to experience the primary composite outcome compared to patients without antidepressant exposure (adjusted odds ratio [aOR] 0.89, 95% CI 0.79-0.99, p = 0.04). This association was only observed with daily doses of at least 20 mg fluoxetine-equivalent (aOR 0.87, 95% CI 0.77-0.99, p = 0.04), but not with daily doses lower than 20 mg fluoxetine-equivalent (aOR 0.94, 95% CI 0.80-1.11, p = 0.48). In exploratory secondary analyses, the outcome incidence was also reduced with exposure to selective serotonin reuptake inhibitors (aOR 0.87, 95% CI 0.75-0.99, p = 0.04), bupropion (aOR 0.70, 95% CI 0.55-0.90, p = 0.005), and FIASMA antidepressant drugs (aOR 0.87, 95% CI 0.77-0.99, p = 0.03). Antidepressant exposure was associated with a reduced incidence of emergency department visitation or hospital admission among SARS-CoV-2 positive patients, in a dose-dependent manner. These data support the FIASMA model of antidepressants’ effects against COVID-19. © 2022. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Natural locus coeruleus dynamics during feeding” (2022) Science Advances

Natural locus coeruleus dynamics during feeding
(2022) Science Advances, 8 (33), p. eabn9134. 

Sciolino, N.R.a , Hsiang, M.a , Mazzone, C.M.a , Wilson, L.R.a , Plummer, N.W.a , Amin, J.a , Smith, K.G.a , McGee, C.A.b , Fry, S.A.a , Yang, C.X.a , Powell, J.M.a , Bruchas, M.R.c , Kravitz, A.V.d , Cushman, J.D.a , Krashes, M.J.e , Cui, G.a , Jensen, P.a

a Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle ParkNC, United States
b Comparative Medicine, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle ParkNC, United States
c Departments of Anesthesiology and Pharmacology, Center for the Neurobiology of Addiction, Pain, Emotion, University of Washington, Seattle, WA, United States
d Department of Psychiatry, Washington University, St. Louis, MO, United States
e National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States

Abstract
Recent data demonstrate that noradrenergic neurons of the locus coeruleus (LC-NE) are required for fear-induced suppression of feeding, but the role of endogenous LC-NE activity in natural, homeostatic feeding remains unclear. Here, we found that LC-NE activity was suppressed during food consumption, and the magnitude of this neural response was attenuated as mice consumed more pellets throughout the session, suggesting that LC responses to food are modulated by satiety state. Visual-evoked LC-NE activity was also attenuated in sated mice, suggesting that satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Last, we found that activation of the LC to the lateral hypothalamus pathway suppresses feeding and enhances avoidance and anxiety-like responding. Our findings suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., satiety).

Document Type: Article
Publication Stage: Final
Source: Scopus

GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein” (2022) Science (New York, N.Y.)

GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein
(2022) Science (New York, N.Y.), 377 (6608), p. eabk0637. 

Diaz-Ortiz, M.E.a b , Seo, Y.a , Posavi, M.a , Carceles Cordon, M.a , Clark, E.a , Jain, N.a c , Charan, R.a d , Gallagher, M.D.a e , Unger, T.L.a , Amari, N.a , Skrinak, R.T.a , Davila-Rivera, R.a , Brody, E.M.a , Han, N.a , Zack, R.a , Van Deerlin, V.M.f , Tropea, T.F.a , Luk, K.C.f , Lee, E.B.f , Weintraub, D.g h , Chen-Plotkin, A.S.a

a Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, United States
c Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO, United States
d Cambridge, MA, United States
e Whitehead Institute for Biomedical Research, Cambridge, MA, United States
f Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
g Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
h Parkinson’s Disease Research, Education and Clinical Center (PADRECC), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States

Abstract
Many risk loci for Parkinson’s disease (PD) have been identified by genome-wide association studies (GWASs), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel single-nucleotide polymorphism rs199347) to GPNMB through colocalization analyses of expression quantitative trait locus and PD risk signals, confirmed by allele-specific expression studies in the human brain. In cells, glycoprotein nonmetastatic melanoma protein B (GPNMB) coimmunoprecipitated and colocalized with α-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of GPNMB resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 731 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating with disease severity. Thus, GPNMB represents a PD risk gene with potential for biomarker development and therapeutic targeting.

Document Type: Article
Publication Stage: Final
Source: Scopus

Machine Learning Quantifies Accelerated White-Matter Aging in Persons With HIV” (2022) The Journal of Infectious Diseases

Machine Learning Quantifies Accelerated White-Matter Aging in Persons With HIV
(2022) The Journal of Infectious Diseases, 226 (1), pp. 49-58. 

Petersen, K.J.a , Strain, J.a , Cooley, S.a , Vaida, F.b , Ances, B.M.a

a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Department of Family and Preventive Medicine, University of California, San Diego, CA, United States

Abstract
BACKGROUND: Persons with HIV (PWH) undergo white matter changes, which can be quantified using the brain-age gap (BAG), the difference between chronological age and neuroimaging-based brain-predicted age. Accumulation of microstructural damage may be accelerated in PWH, especially with detectable viral load (VL). METHODS: In total, 290 PWH (85% with undetectable VL) and 165 HIV-negative controls participated in neuroimaging and cognitive testing. BAG was measured using a Gaussian process regression model trained to predict age from diffusion magnetic resonance imaging in publicly available normative controls. To test for accelerated aging, BAG was modeled as an age × VL interaction. The relationship between BAG and global neuropsychological performance was examined. Other potential predictors of pathological aging were investigated in an exploratory analysis. RESULTS: Age and detectable VL had a significant interactive effect: PWH with detectable VL accumulated +1.5 years BAG/decade versus HIV-negative controls (P = .018). PWH with undetectable VL accumulated +0.86 years BAG/decade, although this did not reach statistical significance (P = .052). BAG was associated with poorer global cognition only in PWH with detectable VL (P < .001). Exploratory analysis identified Framingham cardiovascular risk as an additional predictor of pathological aging (P = .027). CONCLUSIONS: Aging with detectable HIV and cardiovascular disease may lead to white matter pathology and contribute to cognitive impairment. © The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
aging;  brain age;  diffusion tensor imaging;  HIV;  machine learning;  MRI;  white matter

Document Type: Article
Publication Stage: Final
Source: Scopus

Top 10 Research Themes for Dystonia in Cerebral Palsy: A Community-Driven Research Agenda” (2022) Neurology

Top 10 Research Themes for Dystonia in Cerebral Palsy: A Community-Driven Research Agenda
(2022) Neurology, 99 (6), pp. 237-245. 

Gilbert, L.A.a , Fehlings, D.L.b , Gross, P.c f , Kruer, M.C.d , Kwan, W.c , Mink, J.W.e , Shusterman, M.f , Aravamuthan, B.R.a

a The Department of Neurology, Washington University School of Medicine, St. Louis Children’s HospitalMO, United States
b Department of Pediatrics, University of Toronto, Holland Bloorview Kids Rehabilitation HospitalON, Canada
c Department of Population Health Sciences, University of Utah, Salt Lake City, United States
d Departments of Child Health, Neurology, Genetics, and Cellular and Molecular Medicine, College of Medicine-Phoenix, University of Arizona, Cerebral Palsy and Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, United States
e Department of Neurology, University of Rochester, School of Medicine and DentistryNY, United States
f The Cerebral Palsy Research Network, Salt Lake City, UT, United States

Abstract
Dystonia in cerebral palsy (DCP) is a common, debilitating, but understudied condition. The CP community (people with CP and caregivers) is uniquely equipped to help determine the research questions that best address their needs. We developed a community-driven DCP research agenda using the well-established James Lind Alliance methodology. CP community members, researchers, and clinicians were recruited through multiple advocacy, research, and professional organizations. To ensure shared baseline knowledge, participants watched webinars outlining our current knowledge on DCP prepared by a Steering Group of field experts (cprn.org/research-cp-dystonia-edition). Participants next submitted their remaining uncertainties about DCP. These were vetted by the Steering Group and consolidated to eliminate redundancy to generate a list of unique uncertainties, which were then prioritized by the participants. The top-prioritized uncertainties were aggregated into themes through iterative consensus-building discussions within the Steering Group. 166 webinar viewers generated 67 unique uncertainties. 29 uncertainties (17 generated by community members) were prioritized higher than their randomly matched pairs. These were coalesced into the following top 10 DCP research themes: (1) develop new treatments; (2) assess rehabilitation, psychological, and environmental management approaches; (3) compare effectiveness of current treatments; (4) improve diagnosis and severity assessments; (5) assess the effect of mixed tone (spasticity and dystonia) in outcomes and approaches; (6) assess predictors of treatment responsiveness; (7) identify pathophysiologic mechanisms; (8) characterize the natural history; (9) determine the best treatments for pain; and (10) increase family awareness. This community-driven research agenda reflects the concerns most important to the community, both in perception and in practice. We therefore encourage future DCP research to center around these themes. Furthermore, noting that community members (not clinicians or researchers) generated the majority of top-prioritized uncertainties, our results highlight the important contributions community members can make to research agendas, even beyond DCP. © American Academy of Neurology.

Funding details
U.S. Department of DefenseDOD1K08NS117850-01A1, 5K12NS098482-02, R01-NS106298-02
National Institute of Neurological Disorders and StrokeNINDS5R01NS106298-03
University of Utah
Acorda Therapeutics

Document Type: Article
Publication Stage: Final
Source: Scopus

Neuroimaging Findings in CHANTER Syndrome: A Case Series” (2022) American Journal of Neuroradiology

Neuroimaging Findings in CHANTER Syndrome: A Case Series
(2022) American Journal of Neuroradiology, 43 (8), pp. 1136-1141. 

Mallikarjun, K.S.a , Parsons, M.S.a , Nigogosyan, Z.a , Goyal, M.S.a , Eldaya, R.W.a b

a Mallinckrodt Institute of Radiology, Washington University, School of Medicine, Ringgold Standard Institution, St. Louis, MO, United States
b MD Anderson Cancer Center, Diagnostic Imaging Division, Houston, TX, United States

Abstract
Recently, a distinct clinicoradiologic entity involving cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) on MR imaging was identified. Patients present in an unresponsive state following exposure to drugs of abuse. Very little information exists regarding this entity, particularly in the radiology literature. We identify and describe 3 patients at our institution with similar clinical and radiographic findings. Multifocal restricted diffusion in the brain is typically associated with poor outcomes. By contrast, CHANTER involves intraventricular obstructive hydrocephalus that, when treated, can lead to substantial recovery. This novel syndrome should be on the differential in patients who present in an unresponsive state after recent opioid use in the context of the above imaging findings. Additional diagnoses on the differential can include ischemic stroke, hypoxic-ischemic encephalopathy, “chasing the dragon,” leukoencephalopathy, opioid-associated amnestic syndrome, and pediatric opioid-use-associated neurotoxicity with cerebellar edema. © 2022 American Society of Neuroradiology. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

The Structural Basis of Long-Term Potentiation in Hippocampal Synapses, Revealed by Electron Microscopy Imaging of Lanthanum-Induced Synaptic Vesicle Recycling” (2022) Frontiers in Cellular Neuroscience

The Structural Basis of Long-Term Potentiation in Hippocampal Synapses, Revealed by Electron Microscopy Imaging of Lanthanum-Induced Synaptic Vesicle Recycling
(2022) Frontiers in Cellular Neuroscience, 16, art. no. 920360, . 

Heuser, J.E.

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Hippocampal neurons in dissociated cell cultures were exposed to the trivalent cation lanthanum for short periods (15–30 min) and prepared for electron microscopy (EM), to evaluate the stimulatory effects of this cation on synaptic ultrastructure. Not only were characteristic ultrastructural changes of exaggerated synaptic vesicle turnover seen within the presynapses of these cultures—including synaptic vesicle depletion and proliferation of vesicle-recycling structures—but the overall architecture of a large proportion of the synapses in the cultures was dramatically altered, due to large postsynaptic “bulges” or herniations into the presynapses. Moreover, in most cases, these postsynaptic herniations or protrusions produced by lanthanum were seen by EM to distort or break or “perforate” the so-called postsynaptic densities (PSDs) that harbor receptors and recognition molecules essential for synaptic function. These dramatic EM observations lead us to postulate that such PSD breakages or “perforations” could very possibly create essential substrates or “tags” for synaptic growth, simply by creating fragmented free edges around the PSDs, into which new receptors and recognition molecules could be recruited more easily, and thus, they could represent the physical substrate for the important synaptic growth process known as “long-term potentiation” (LTP). All of this was created simply in hippocampal dissociated cell cultures, and simply by pushing synaptic vesicle recycling way beyond its normal limits with the trivalent cation lanthanum, but we argued in this report that such fundamental changes in synaptic architecture—given that they can occur at all—could also occur at the extremes of normal neuronal activity, which are presumed to lead to learning and memory. Copyright © 2022 Heuser.

Author Keywords
endocytosis;  hippocampal synapses;  lanthanum;  long-term potentiation;  postsynaptic densities (PSDs);  synaptic vesicle

Funding details
National Institute of Neurological Disorders and StrokeNINDS
National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Final
Source: Scopus

miRNA Expression Is Increased in Serum from Patients with Semantic Variant Primary Progressive Aphasia” (2022) International Journal of Molecular Sciences

miRNA Expression Is Increased in Serum from Patients with Semantic Variant Primary Progressive Aphasia
(2022) International Journal of Molecular Sciences, 23 (15), . 

Serpente, M.a , Ghezzi, L.b , Fenoglio, C.c , Buccellato, F.R.a d , Fumagalli, G.G.a , Rotondo, E.a , Arcaro, M.a , Arighi, A.a , Galimberti, D.a d

a Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, 20122, Italy
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, 20122, Italy
d Department of Biomedical, Surgical and Dental Sciences, Dino Ferrari Center, University of Milan, Milan, 20122, Italy

Abstract
Primary progressive aphasia (PPA) damages the parts of the brain that control speech and language. There are three clinical PPA variants: nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). The pathophysiology underlying PPA variants is not fully understood, including the role of micro (mi)RNAs which were previously shown to play a role in several neurodegenerative diseases. Using a two-step analysis (array and validation through real-time PCR), we investigated the miRNA expression pattern in serum from 54 PPA patients and 18 controls. In the svPPA cohort, we observed a generalized upregulation of miRNAs with miR-106b-5p and miR-133a-3p reaching statistical significance (miR-106b-5p: 2.69 ± 0.89 mean ± SD vs. 1.18 ± 0.28, p &lt; 0.0001; miR-133a-3p: 2.09 ± 0.10 vs. 0.74 ± 0.11 mean ± SD, p = 0.0002). Conversely, in lvPPA, the majority of miRNAs were downregulated. GO enrichment and KEGG pathway analyses revealed that target genes of both miRNAs are involved in pathways potentially relevant for the pathogenesis of neurodegenerative diseases. This is the first study that investigates the expression profile of circulating miRNAs in PPA variant patients. We identified a specific miRNA expression profile in svPPA that could differentiate this pathological condition from other PPA variants. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort.

Author Keywords
circulating miRNAs;  gene expression;  logopenic variant PPA;  semantic variant primary progressive aphasia (svPPA)

Document Type: Article
Publication Stage: Final
Source: Scopus

Observational Study of Neuroimaging Biomarkers of Severe Upper Limb Impairment After Stroke” (2022) Neurology

Observational Study of Neuroimaging Biomarkers of Severe Upper Limb Impairment After Stroke
(2022) Neurology, 99 (4), pp. E402-E413. 

Hayward, K.S.a , Ferris, J.K.b , Lohse, K.R.c , Borich, M.R.d , Borstad, A.e , Cassidy, J.M.f , Cramer, S.C.g h i , Dukelow, S.P.i , Findlater, S.E.j , Hawe, R.L.j , Liew, S.-L.k , Neva, J.L.l , Stewart, J.C.m , Boyd, L.A.b

a Departments of Physiotherapy, Medicine, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Heidelberg, VIC, Australia
b Rehabilitation Sciences Graduate Research Program, University of British Columbia, Vancouver, BC, Canada
c Physical Therapy and Neurology, Washington University School of Medicine, Saint Louis, MO, United States
d Division of Physical Therapy, Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, GA, United States
e School of Health Sciences, Department of Physical Therapy, College of St. Scholastica, Duluth, MN, United States
f Department of Allied Health Sciences, University of North Carolina, Chapel Hill, NC, United States
g Department of Neurology, University of California Los Angeles, United States
h California Rehabilitation Institute, Los Angeles, CA, United States
i Department of Clinical Neurosciences, Cumming School of Medicine, University of CalgaryAB, Canada
j School of Kinesiology, University of Minnesota, Minneapolis, United States
k Chan Div. of Occup. Sci. and Occup. Ther., Biokinesiology and Phys. Ther., Biomed. Eng., and Neurol., Usc Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, United States
l Université de Montréal, École de Kinésiologie et des Sciences de l’Activité Physique, Faculté de Médecine, Centre de Recherche de l’Institut Universitaire de Gériatrie de MontréalQC, Canada
m Physical Therapy Program, Department of Exercise Science, University of South Carolina, Colombia

Abstract
Background and ObjectivesIt is difficult to predict poststroke outcome for individuals with severe motor impairment because both clinical tests and corticospinal tract (CST) microstructure may not reliably indicate severe motor impairment. Here, we test whether imaging biomarkers beyond the CST relate to severe upper limb (UL) impairment poststroke by evaluating white matter microstructure in the corpus callosum (CC). In an international, multisite hypothesis-generating observational study, we determined if (1) CST asymmetry index (CST-AI) can differentiate between individuals with mild-moderate and severe UL impairment and (2) CC biomarkers relate to UL impairment within individuals with severe impairment poststroke. We hypothesized that CST-AI would differentiate between mild-moderate and severe impairment, but CC microstructure would relate to motor outcome for individuals with severe UL impairment.MethodsSeven cohorts with individual diffusion imaging and motor impairment (Fugl-Meyer Upper Limb) data were pooled. Hand-drawn regions-of-interest were used to seed probabilistic tractography for CST (ipsilesional/contralesional) and CC (prefrontal/premotor/motor/sensory/posterior) tracts. Our main imaging measure was mean fractional anisotropy. Linear mixed-effects regression explored relationships between candidate biomarkers and motor impairment, controlling for observations nested within cohorts, as well as age, sex, time poststroke, and lesion volume.ResultsData from 110 individuals (30 with mild-moderate and 80 with severe motor impairment) were included. In the full sample, greater CST-AI (i.e., lower fractional anisotropy in the ipsilesional hemisphere, p < 0.001) and larger lesion volume (p = 0.139) were negatively related to impairment. In the severe subgroup, CST-AI was not reliably associated with impairment across models. Instead, lesion volume and CC microstructure explained impairment in the severe group beyond CST-AI (p’s < 0.010).DiscussionWithin a large cohort of individuals with severe UL impairment, CC microstructure related to motor outcome poststroke. Our findings demonstrate that CST microstructure does relate to UL outcome across the full range of motor impairment but was not reliably associated within the severe subgroup. Therefore, CC microstructure may provide a promising biomarker for severe UL outcome poststroke, which may advance our ability to predict recovery in individuals with severe motor impairment after stroke. © American Academy of Neurology.

Funding details
National Institutes of HealthNIHK24 HD074722, R01 NS059909
Canadian Institutes of Health ResearchIRSCK01 HD091283, MOP-106662, R01 NR105591
State Government of Victoria

Document Type: Article
Publication Stage: Final
Source: Scopus

Adolescent Mental Health and Family Economic Hardships: The Roles of Adverse Childhood Experiences and Family Conflict” (2022) Journal of Youth and Adolescence

Adolescent Mental Health and Family Economic Hardships: The Roles of Adverse Childhood Experiences and Family Conflict
(2022) Journal of Youth and Adolescence, . 

Barnhart, S.a , Garcia, A.R.a , Karcher, N.R.b

a University of Kentucky, 619 Patterson Office Tower, Lexington, KY 40506-0027, United States
b Washington University School of Medicine, Box 1125, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
Rising and economically disproportionate rates of adverse mental health outcomes among children and youth warrant research investigating the complex pathways stemming from socioeconomic status. While adverse childhood experiences (ACEs) have been considered a possible mechanism linking socioeconomic status (SES) and child and youth psychopathology in previous studies, less is understood about how family environments might condition these pathways. Using data from a longitudinal, multiple-wave study, the present study addresses this gap by examining the direct relationships between family economic status and youth internalizing and externalizing symptoms, if ACEs mediate these relationships, and if conflictual family environments moderate these direct and indirect relationships. The data were obtained from 5510 youth participants [mean age at baseline = 9.52 (SD = 0.50), 47.7% female, 2.1% Asian, 10.3% Black, 17.6% Hispanic, 9.8% Multiracial/Multiethnic, 60.2% White] and their caretakers from the baseline, 1-year, and 2-year follow up waves. Conditional process analysis assessed the direct, indirect, and moderated relationships in separate, equivalent models based on youth- versus caregiver-raters of ACEs and youth psychopathology to capture potential differences based on the rater. The results of both the youth- and caregiver-rated models indicated that lower family economic status directly predicted higher levels of externalizing symptoms, and ACEs indirectly accounted for higher levels of internalizing and externalizing symptoms. Additionally, family conflict moderated some, but not all, of these relationships. The study’s findings highlight that lower family economic status and ACEs, directly and indirectly, contribute to early adolescent psychopathology, and conflictual family environments can further intensify these relationships. Implementing empirically supported policies and interventions that target ACEs and family environments may disrupt deleterious pathways between SES and youth psychopathology. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Adolescent Brain Cognitive Development Study®;  Adverse childhood experiences;  Child and adolescent mental health;  Economic adversity;  Family conflict

Funding details
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
National Institute of Mental HealthNIMHK23MH121792-01

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

A multidisciplinary Prematurity Research Cohort Study” (2022) PloS One

A multidisciplinary Prematurity Research Cohort Study
(2022) PloS One, 17 (8), p. e0272155. 

Stout, M.J.a , Chubiz, J.b , Raghuraman, N.b , Zhao, P.b , Tuuli, M.G.c , Wang, L.V.d , Cahill, A.G.e , Cuculich, P.S.f , Wang, Y.b , Jungheim, E.S.g , Herzog, E.D.h , Fay, J.i , Schwartz, A.L.j , Macones, G.A.e , England, S.K.b

a Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States
b Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Obstetrics and Gynecology, Brown University, Providence, RI, United States
d Department of Medical Engineering, California Institute of Technology, Pasadena, CA, United States
e Department of Women’s Health, University of Texas at Austin, Austin, TX, United States
f Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, United States
g Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, United States
h Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
i Department of Biology, University of Rochester, Rochester, NY, United States
j Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: Worldwide, 10% of babies are born preterm, defined as a live birth before 37 weeks of gestation. Preterm birth is the leading cause of neonatal death, and survivors face lifelong risks of adverse outcomes. New approaches with large sample sizes are needed to identify strategies to predict and prevent preterm birth. The primary aims of the Washington University Prematurity Research Cohort Study were to conduct three prospective projects addressing possible causes of preterm birth and provide data and samples for future research. STUDY DESIGN: Pregnant patients were recruited into the cohort between January 2017 and January 2020. Consenting patients were enrolled into the study before 20 weeks’ gestation and followed through delivery. Participants completed demographic and lifestyle surveys; provided maternal blood, placenta samples, and cord blood; and participated in up to three projects focused on underlying physiology of preterm birth: cervical imaging (Project 1), circadian rhythms (Project 2), and uterine magnetic resonance imaging and electromyometrial imaging (Project 3). RESULTS: A total of 1260 participants were enrolled and delivered during the study period. Of the participants, 706 (56%) were Black/African American, 494 (39%) were nulliparous, and 185 (15%) had a previous preterm birth. Of the 1260 participants, 1220 (97%) delivered a live infant. Of the 1220 with a live birth, 163 (14.1%) had preterm birth, of which 74 (6.1%) were spontaneous preterm birth. Of the 1220 participants with a live birth, 841 participated in cervical imaging, 1047 contributed data and/or samples on circadian rhythms, and 39 underwent uterine magnetic resonance imaging. Of the 39, 25 underwent electromyometrial imaging. CONCLUSION: We demonstrate feasibility of recruiting and retaining a diverse cohort in a complex prospective, longitudinal study throughout pregnancy. The extensive clinical, imaging, survey, and biologic data obtained will be used to explore cervical, uterine, and endocrine physiology of preterm birth and can be used to develop novel approaches to predict and prevent preterm birth.

Document Type: Article
Publication Stage: Final
Source: Scopus

Internalizing Symptoms and Adverse Childhood Experiences Associated With Functional Connectivity in a Middle Childhood Sample” (2022) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Internalizing Symptoms and Adverse Childhood Experiences Associated With Functional Connectivity in a Middle Childhood Sample
(2022) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, . 

Albertina, E.A., Barch, D.M., Karcher, N.R.

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

Abstract
Background: Research has found overlapping associations in adults of resting-state functional connectivity (RSFC) to both internalizing disorders (e.g., depression, anxiety) and a history of traumatic events. The present study aimed to extend this previous research to a younger sample by examining RSFC associations with both internalizing symptoms and adverse childhood experiences (ACEs) in middle childhood. Methods: We used generalized linear mixed models to examine associations between a priori within- and between-network RSFC with child-reported internalizing symptoms and ACEs using the Adolescent Brain Cognitive Development dataset (N = 10,168, mean age = 9.95 years, SD = 0.627). Results: We found that internalizing symptoms and ACEs were associated with both multiple overlapping and unique RSFC network patterns. Both ACEs and internalizing symptoms were associated with a reduced anticorrelation between the default mode network and the dorsal attention network. However, internalizing symptoms were uniquely associated with lower within-network default mode network connectivity, while ACEs were uniquely associated with both lower between-network connectivity of the auditory network and cingulo-opercular network, and higher within-network frontoparietal network connectivity. Conclusions: The present study points to overlap in the RSFC associations with internalizing symptoms and ACEs, as well as important areas of specificity in RSFC associations. Many of the RSFC associations found have been previously implicated in attentional control functions, including modulation of attention to sensory stimuli. This may have critical importance in understanding internalizing symptoms and outcomes of ACEs. © 2022 Society of Biological Psychiatry

Author Keywords
ABCD;  Adverse childhood experiences;  Internalizing symptoms;  Middle childhood;  Mood disorders;  Resting-state functional connectivity

Funding details
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
National Institute of Mental HealthNIMHK23MH121792-01, L30 MH120574-01
National Institute on Drug AbuseNIDAU01 DA041120

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

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2” (2022) Genetics in Medicine

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2
(2022) Genetics in Medicine, . 

Lai, A.a b c o , Soucy, A.a c o , El Achkar, C.M.b d , Barkovich, A.J.e , Cao, Y.f o , DiStefano, M.g h o , Evenson, M.f o , Guerrini, R.i o , Knight, D.b o , Lee, Y.-S.f o , Mefford, H.C.j o , Miller, D.T.a c o , Mirzaa, G.k l o , Mochida, G.a c o , Rodan, L.H.a c d o , Patel, M.g o , Smith, L.b o , Spencer, S.m o , Walsh, C.A.a c d g o , Yang, E.n o , Yuskaitis, C.J.b d , Yu, T.a d g o , Poduri, A.b d g o , Achkar, C.o , Barkovich, J.o , Chelly, J.o , Engle, E.o , Hong, W.o , Koh, H.o , Lassiter, R.o , Marsh, E.o , Pinsky, R.o , Shain, C.o , Yuan, B.o , Yuskaitis, C.o , ClinGen Brain Malformation Variant Curation Expert Panelp

a Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA
b Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Boston, MA
c Department of Pediatrics, Harvard Medical School, Boston, MA
d Department of Neurology, Harvard Medical School, Boston, MA
e Department of Radiology, University of California, San Francisco, CA
f Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO
g Broad Institute of MIT and Harvard, Cambridge, MA
h Precision Health Program, Geisinger, Danville, PA
i Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Department of Neuroscience, Meyer Children’s University Hospital, University of Florence, Florence, Italy
j Center for Pediatric Neurological Disease Research, St. Jude Hospital, Memphis, TN, United States
k Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, United States
l Department of Pediatrics, University of Washington, Seattle, WA, United States
m Division of Reproductive Genetics, Northwestern Medicine, Chicago, IL
n Department of Radiology, Boston Children’s Hospital and Harvard Medical School, Boston, MA

Abstract
Purpose: Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families. Methods: The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations. We selected the genes AKT3, MTOR, PIK3CA, and PIK3R2 as the first set of genes to provide additional specifications to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation guidelines, which currently focus solely on germline variants. Results: A total of 24 of the original 28 ACMG/AMP criteria required modification. Several modifications used could be applied to other genes and disorders in which somatic variants play a role: 1) using variant allele fraction differences as evidence that somatic mutagenesis occurred as a proxy for de novo variation, 2) incorporating both somatic and germline evidence, and 3) delineating phenotype on the basis of variable tissue expression. Conclusion: We have established a framework for rigorous interpretation of somatic mosaic variants, addressing issues unique to somatic variants that will be applicable to many genes and conditions. © 2022 American College of Medical Genetics and Genomics

Author Keywords
AKT3;  MTOR;  PIK3CA;  PIK3R2;  Somatic mosaicism

Funding details
Howard Hughes Medical InstituteHHMI
National Institute of Neurological Disorders and StrokeNINDSR01NS035129
National Institute of Child Health and Human DevelopmentNICHDU24HD093487

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

Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes” (2022) Nature Genetics

Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
(2022) Nature Genetics, . 

Zhou, X.a b , Feliciano, P.c , Shu, C.a b , Wang, T.d e f , Astrovskaya, I.c , Hall, J.B.c , Obiajulu, J.U.a b , Wright, J.R.c , Murali, S.C.d g , Xu, S.X.c , Brueggeman, L.h , Thomas, T.R.h , Marchenko, O.c , Fleisch, C.c , Barns, S.D.c , Snyder, L.A.G.c , Han, B.c , Chang, T.S.i , Turner, T.N.j , Harvey, W.T.d , Nishida, A.k , O’Roak, B.J.k , Geschwind, D.H.i , Adams, A.n , Amatya, A.c , Andrus, A.o , Bashar, A.c , Berman, A.p , Brown, A.q , Camba, A.r , Gulsrud, A.C.r , Krentz, A.D.s , Shocklee, A.D.t , Esler, A.u , Lash, A.E.c , Fanta, A.v , Fatemi, A.w , Fish, A.x , Goler, A.c , Gonzalez, A.y , Gutierrez, A., Jr.y , Hardan, A.z , Hess, A.aa , Hirshman, A.n , Holbrook, A.c , Ace, A.J.c , Griswold, A.J.ab , Gruber, A.J.s , Jarratt, A.ac , Jelinek, A.ad , Jorgenson, A.ac , Juarez, A.P.ae , Kim, A.x , Kitaygorodsky, A.b , Luo, A.af , Rachubinski, A.L.ag , Wainer, A.L.n , Daniels, A.M.c , Mankar, A.c , Mason, A.ah , Miceli, A.p , Milliken, A.ai , Morales-Lara, A.aj , Stephens, A.N.c , Nguyen, A.N.c , Nicholson, A.ae , Paolicelli, A.M.ak , McKenzie, A.P.q , Gupta, A.R.v , Raven, A.x , Rhea, A.al , Simon, A.am , Soucy, A.an , Swanson, A.p , Sziklay, A.ah , Tallbull, A.ag , Tesng, A.ac , Ward, A.al , Zick, A.x , Hilscher, B.A.ao , Bell, B.al , Enright, B.ap , Robertson, B.E.c , Hauf, B.aq , Jensen, B.c , Lobisi, B.y , Vernoia, B.M.c , Schwind, B.c , VanMetre, B.q , Erickson, C.A.ad , Sullivan, C.A.W.v , Albright, C.aa , Anglo, C.ao , Buescher, C.h , Bradley, C.C.al , Campo-Soria, C.ac , Cohen, C.c , Colombi, C.x , Diggins, C.c , Edmonson, C.q , Rice, C.E.ar , Fassler, C.ad , Gray, C.aq , Gunter, C.as , Walston, C.H.aq , Klaiman, C.as , Leonczyk, C.n , Martin, C.L.at , Lord, C.r , Taylor, C.M.at , McCarthy, C.al , Ochoa-Lubinoff, C.au , Ortiz, C.al , Pierre, C.n , Rosenberg, C.R.ag , Rigby, C.c , Roche, C.al , Shrier, C.al , Smith, C.ah , Van Wade, C.al , White-Lehman, C.c , Zaro, C.ai , Zha, C.y , Bentley, D.o , Correa, D.y , Sarver, D.E.av , Giancarla, D.y , Amaral, D.G.ao , Howes, D.ac , Istephanous, D.ac , Coury, D.L.aa , Li, D.ao , Limon, D.am , Limpoco, D.af , Phillips, D.n , Rambeck, D.ac , Rojas, D.z , Srishyla, D.ac , Stamps, D.av , Montes, D.V.c , Cho, D.aw , Cho, D.c , Fox, E.A.aw , Bahl, E.h , Berry-Kravis, E.au , Blank, E.ad , Bower, E.ah , Brooks, E.c , Courchesne, E.ah , Dillon, E.q , Doyle, E.al , Given, E.aa , Grimes, E.p , Jones, E.c , Fombonne, E.J.af , Kryszak, E.aa , Wodka, E.L.q , Lamarche, E.aq , Lampert, E.ad , Butter, E.M.aa , O’Connor, E.c , Ocampo, E.n , Orrick, E.z , Perez, E.c , Ruzzo, E.i , Singer, E.c , Matthews, E.T.ai , Pedapati, E.V.ad , Fazal, F.af , Miller, F.K.x , Aberbach, G.ai , Baraghoshi, G.o , Duhon, G.am , Hooks, G.ac , Fischer, G.J.s , Marzano, G.am , Schoonover, G.o , Dichter, G.S.aq , Tiede, G.aa , Cottrell, H.t , Kaplan, H.E.ah , Ghina, H.aw , Hutter, H.q , Koene, H.v , Schneider, H.L.y , Lechniak, H.n , Li, H.au , Morotti, H.af , Qi, H.ah , Richardson, H.al , Zaydens, H.c , Zhang, H.ah , Zhao, H.ah , Arriaga, I.r , Tso, I.F.ax , Acampado, J.c , Gerdts, J.A.aw , Beeson, J.au , Brown, J.c , Comitre, J.y , Cordova, J.ag , Delaporte, J.t , Cubells, J.F.ar , Harris, J.F.ap , Gong, J.z , Gunderson, J.ac , Hernandez, J.c , Judge, J.x , Jurayj, J.v , Law, J.K.c , Manoharan, J.c , Montezuma, J.al , Neely, J.q , Orobio, J.am , Pandey, J.ay , Piven, J.aq , Polanco, J.ad , Polite, J.c , Rosewater, J.y , Scherr, J.aa , Sutcliffe, J.S.az , McCracken, J.T.r , Tjernagel, J.c , Toroney, J.c , Veenstra-Vanderweele, J.ba , Wang, J.ah , Ahlers, K.aw , Schweers, K.A.n , Baalman, K.am , Beard, K.ac , Callahan, K.av , Coleman, K.ah , Fitzgerald, K.D.x , Dent, K.at , Diehl, K.c , Gonring, K.au , Pawlowski, K.G.ai , Hirst, K.t , Pierce, K.L.ah , Murillo, K.r , Murray, K.aq , Nowell, K.t , O’Brien, K.ad , Pama, K.q , Real, K.aq , Singer, K.at , Smith, K.ao , Stephenson, K.aa , Tsai, K.r , Abbeduto, L.ao , Cartner, L.A.c , Beeson, L.af , Carpenter, L.al , Casten, L.h , Coppola, L.af , Cordiero, L.ag , DeMarco, L.ay , Pacheco, L.D.af , Corzo, L.F.au , Shulman, L.H.aj , Walsh, L.K.at , Lesher, L.o , Herbert, L.M.y , Prock, L.M.ai , Malloch, L.av , Mann, L.c , Grosvenor, L.P.c , Simon, L.ac , Soorya, L.V.n , Wasserburg, L.ac , Yeh, L.n , Huang-Storms, L.Y.af , Alessandri, M.y , Popp, M.A.s , Baer, M.au , Beckwith, M.ap , Casseus, M.ap , Coughlin, M.ai , Currin, M.aq , Cutri, M.y , Mallardi, M.D.c , DuBois, M.ac , Dunlevy, M.as , Butler, M.E.c , Frayne, M.z , Gwynette, M.L.F.bb , Ghaziuddin, M.x , Haley, M.r , Heyman, M.ak , Hojlo, M.ai , Jordy, M.aq , Morrier, M.J.ar , Kowanda, M.c , Koza, M.q , Lopez, M.ap , McTaggart, M.q , Norris, M.aa , Hale, M.N.y , O’Neil, M.aj , Printen, M.n , Rayos, M.y , Sabiha, M.c , Sahin, M.bc , Sarris, M.c , Shir, M.ah , Siegel, M.bd , Steele, M.z , Sweeney, M.t , Tafolla, M.r , Valicenti-McDermott, M.aj , Verdi, M.bd , Dennis, M.Y.be , Alvarez, N.q , Bardett, N.p , Berger, N.n , Calderon, N.n , Decius, N.y , Gonzalez, N.ap , Harris, N.p , Lawson, N.c , Lillie, N.ac , Lo, N.c , Long, N.aa , Russo-Ponsaran, N.M.n , Madi, N.ad , Mccoy, N.ad , Nagpal, N.c , Rodriguez, N.ao , Russell, N.aa , Shah, N.c , Takahashi, N.t , Targalia, N.ag , Newman, O.ac , Ousley, O.Y.ar , Heydemann, P.au , Manning, P.ad , Carbone, P.S.o , Bernier, R.A.aw , Gordon, R.A.n , Shaffer, R.C.ad , Annett, R.D.av , Clark, R.D.aq , Jou, R.v , Landa, R.J.q , Earl, R.K.aw , Libove, R.z , Marini, R.c , Doan, R.N.an , Goin-Kochel, R.P.am , Rana, R.c , Remington, R.c , Shikov, R.q , Schultz, R.T.ay , Aberle, S.af , Birdwell, S.t , Boland, S.v , Booker, S.ad , Carpenter, S.p , Chintalapalli, S.x , Conyers, S.al , D’Ambrosi, S.al , Eldred, S.aa , Francis, S.ac , Ganesan, S.c , Hepburn, S.ag , Horner, S.ay , Hunter, S.t , Brewster, S.J.bf , Lee, S.J.n , Jacob, S.ac , Jean, S.c , Hyun, S.bg , Kramer, S.h , Friedman, S.L.ag , Licona, S.n , Littlefield, S.z , Kanne, S.M.t bh , Mastel, S.af , Mathai, S.as , Melnyk, S.ad , Michaels, S.q , Mohiuddin, S.x , Palmer, S.ay , Plate, S.ay , Qiu, S.ak , Randall, S.ad , Sandhu, S.r , Santangelo, S.bd , Shah, S.c , Skinner, S.bi , Thompson, S.ao , White, S.av , White, S.as , Xiao, S.c , Xu, S.ah , Xu, S.c , Chen, T.ah , Greene, T.c , Ho, T.aw , Ibanez, T.aa , Koomar, T.h , Pramparo, T.ah , Rutter, T.aw , Shaikh, T.ag , Tran, T.au , Yu, T.W.an , Galbraith, V.al , Gazestani, V.bj , Myers, V.J.c , Ranganathan, V.ay , Singh, V.q , Weaver, W.C.at , CaI, W.ac , Chin, W.c , Yang, W.S.r , Choi, Y.B.bg , Warren, Z.E.ae , Michaelson, J.J.h , Volfovsky, N.c , Eichler, E.E.d g , Shen, Y.b l , Chung, W.K.a c m , The SPARK Consortiumbk

a Department of Pediatrics, Columbia University Medical Center, New York, NY, United States
b Department of Systems Biology, Columbia University Medical Center, New York, NY, United States
c Simons Foundation, New York, NY, United States
d Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, United States
e Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
f Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center; Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Beijing, China
g Howard Hughes Medical Institute, University of Washington, Seattle, WA, United States
h Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
i Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
j Department of Genetics, Washington University, St. Louis, MO, United States
k Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, United States
l Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, United States
m Department of Medicine, Columbia University Medical Center, New York, NY, United States
n Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, United States
o Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
p Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, United States
q Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, MD, United States
r Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, United States
s PreventionGenetics, Marshfield, WI, United States
t Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri, Columbia, MO, United States
u Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
v Child Study Center, Yale School of Medicine, New Haven, CT, United States
w Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, United States
x Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
y Department of Psychology, University of Miami’s Center for Autism and Related Disabilities (UM-CARD), Coral Gables, FL, United States
z Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
aa Division of Pediatric Psychology and Neuropsychology, Nationwide Children’s Hospital (Child Development Center), Columbus, OH, United States
ab John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States
ac Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
ad Department of Psychiatry and Behavioral Neuroscience, Cincinnati Children’s Hospital Medical Center – Research Foundation, Cincinnati, OH, United States
ae Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
af Department of Psychiatry, Oregon Health & Science University, Portland, OR, United States
ag Department of Pediatrics, JFK Partners/University of Colorado School of Medicine, Aurora, CO, United States
ah Department of Neurosciences, University of California, San Diego and SARRC Phoenix, La Jolla, CA, United States
ai Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
aj Department of Pediatrics, Montefiore Medical Center and The Albert Einstein College of Medicine, Bronx, NY, United States
ak Department of Psychiatry, Weill Cornell Medicine, White Plains, NY, United States
al Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States
am Department of Pediatrics, Texas Children’s Hospital (Baylor College of Medicine), Houston, TX, United States
an Department of Medicine, Boston Children’s Hospital, Boston, MA, United States
ao MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA, United States
ap Children’s Specialized Hospital, Toms River, NJ, United States
aq Department of Psychiatry, University of North Carolina (UNC, TEACCH, CIDD), Chapel Hill, NC, United States
ar Department of Psychiatry and Behavioral Sciences, Emory University and Marcus Autism Center, Atlanta, GA, United States
as Department of Pediatrics, Emory University and Marcus Autism Center, Atlanta, GA, United States
at Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA, United States
au Department of Pediatrics, Rush University Medical Center, Chicago, IL, United States
av Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, United States
aw Department of Psychiatry and Behavioral Sciences, University of Washington/Seattle Children’s Autism Center, Seattle, WA, United States
ax Department of Psychology, University of Michigan, Ann Arbor, MI, United States
ay Center for Autism Research, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
az Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
ba Department of Psychiatry, Columbia University Medical Center, New York, NY, United States
bb Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
bc Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
bd Maine Medical Center Research Institute, Scarborough, ME, United States
be Genome Center, MIND Institute, Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, United States
bf Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA, United States
bg Center for Autism and the Developing Brain (CADB), Weill Cornell Medicine, White Plains, NY, United States
bh Department of Health Psychology, University of Missouri, Columbia, MO, United States
bi Greenwood Genetic Center, Greenwood, SC, United States
bj Department of Pediatrics, University of California, San Diego and SARRC Phoenix, La Jolla, CA, United States

Abstract
To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P &lt; 2.5 × 10−6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10−6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes. © 2022, The Author(s).

Funding details
National Institutes of HealthNIH1K99MH117165, 606450, 644038, DC014489, MH105527, R01GM120609
Howard Hughes Medical InstituteHHMI
National Institute of Mental HealthNIMH608045, 810018EE, R01MH101221
Simons FoundationSF
Simons Foundation Autism Research InitiativeSFARI

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

Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci” (2022) Molecular Psychiatry

Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci
(2022) Molecular Psychiatry, . Cited 1 time.

Deak, J.D.a b , Zhou, H.a b , Galimberti, M.a b , Levey, D.F.a b , Wendt, F.R.a b , Sanchez-Roige, S.c d , Hatoum, A.S.e , Johnson, E.C.e , Nunez, Y.Z.a b , Demontis, D.f g h , Børglum, A.D.f g h , Rajagopal, V.M.f g h , Jennings, M.V.c , Kember, R.L.i j , Justice, A.C.a b , Edenberg, H.J.k , Agrawal, A.e , Polimanti, R.a b , Kranzler, H.R.i j , Gelernter, J.a b

a Yale School of Medicine, New Haven, CT, United States
b VA Connecticut Healthcare Center, West Haven, CT, United States
c University of California San Diego, La Jolla, CA, United States
d Vanderbilt University Medical Center, Nashville, TN, United States
e Washington University St. Louis Medical School, St. Louis, MO, United States
f Biomedicine, Aarhus University, Aarhus, Denmark
g Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
h Center for Genomics and Personalized Medicine, Aarhus, Denmark
i University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
j Crescenz VA Medical Center, Philadelphia, PA, United States
k Indiana University School of Medicine, Indianapolis, IN, United States

Abstract
Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10−8) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10−10) and two OPRM1 variants (rs1799971, p = 4.92 × 10−09; rs79704991, p = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10−47) and AUD (rg = 0.77; p = 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs. © 2022, The Author(s).

Funding details
T29KT0526
I01 CX001734, I01BX003342, I01BX004820, I01CX001849
575B
National Institutes of HealthNIHDP1 DA054394, F32 MH122058, K01 AA028292, K02 DA032573, R01 AA026364, R01 DA051906, R01DA054869, R33 DA047527, T32 AA028259, U01 AA020790, U10 AA013566, U24 AA020794, U24 AA022001
Brain and Behavior Research FoundationBBRF
Office of Research and DevelopmentORD
Health Services Research and DevelopmentHSR&DMVP004, MVP025
Aarhus UniversitetAU
Society for the Study of ReproductionSSR
LundbeckfondenR102-A9118, R155-2014-1724, R248-2017-2003, U01 MH109514-01
Novo Nordisk FondenNNF

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

Theta-gamma coupling as a cortical biomarker of brain-computer interface-mediated motor recovery in chronic stroke” (2022) Brain Communications

Theta-gamma coupling as a cortical biomarker of brain-computer interface-mediated motor recovery in chronic stroke
(2022) Brain Communications, 4 (3), art. no. fcac136, . 

Rustamov, N.a b , Humphries, J.c , Carter, A.d , Leuthardt, E.C.a b c e f

a Department of Neurological Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, United States
b Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, United States
d Department of Neurology, Washington University in St Louis, St Louis, MO, United States
e Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
f Department of Mechanical Engineering and Materials Science, Washington University in St Louis, St Louis, MO, United States

Abstract
Chronic stroke patients with upper-limb motor disabilities are now beginning to see treatment options that were not previously available. To date, the two options recently approved by the United States Food and Drug Administration include vagus nerve stimulation and brain-computer interface therapy. While the mechanisms for vagus nerve stimulation have been well defined, the mechanisms underlying brain-computer interface-driven motor rehabilitation are largely unknown. Given that cross-frequency coupling has been associated with a wide variety of higher-order functions involved in learning and memory, we hypothesized this rhythm-specific mechanism would correlate with the functional improvements effected by a brain-computer interface. This study investigated whether the motor improvements in chronic stroke patients induced with a brain-computer interface therapy are associated with alterations in phase-Amplitude coupling, a type of cross-frequency coupling. Seventeen chronic hemiparetic stroke patients used a robotic hand orthosis controlled with contralesional motor cortical signals measured with EEG. Patients regularly performed a therapeutic brain-computer interface task for 12 weeks. Resting-state EEG recordings and motor function data were acquired before initiating brain-computer interface therapy and once every 4 weeks after the therapy. Changes in phase-Amplitude coupling values were assessed and correlated with motor function improvements. To establish whether coupling between two different frequency bands was more functionally important than either of those rhythms alone, we calculated power spectra as well. We found that theta-gamma coupling was enhanced bilaterally at the motor areas and showed significant correlations across brain-computer interface therapy sessions. Importantly, an increase in theta-gamma coupling positively correlated with motor recovery over the course of rehabilitation. The sources of theta-gamma coupling increase following brain-computer interface therapy were mostly located in the hand regions of the primary motor cortex on the left and right cerebral hemispheres. Beta-gamma coupling decreased bilaterally at the frontal areas following the therapy, but these effects did not correlate with motor recovery. Alpha-gamma coupling was not altered by brain-computer interface therapy. Power spectra did not change significantly over the course of the brain-computer interface therapy. The significant functional improvement in chronic stroke patients induced by brain-computer interface therapy was strongly correlated with increased theta-gamma coupling in bihemispheric motor regions. These findings support the notion that specific cross-frequency coupling dynamics in the brain likely play a mechanistic role in mediating motor recovery in the chronic phase of stroke recovery. © 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
brain-computer interface;  chronic stroke rehabilitation;  theta-gamma coupling

Document Type: Article
Publication Stage: Final
Source: Scopus

Differentiating amyloid beta spread in autosomal dominant and sporadic Alzheimer’s disease” (2022) Brain Communications

Differentiating amyloid beta spread in autosomal dominant and sporadic Alzheimer’s disease
(2022) Brain Communications, 4 (3), art. no. fcac085, . 

Levitis, E.a , Vogel, J.W.a , Funck, T.a , Hachinski, V.b , Gauthier, S.c , Vöglein, J.d e f , Levin, J.d , Gordon, B.A.g , Benzinger, T.g , Iturria-Medina, Y.a , Evans, A.C.a

a Montreal Neurological Institute, McGill University, Montreal, QC, Canada
b Western University, London, ON, Canada
c McGill Centre for Studies in Aging, McGill University, Montreal, QC, Canada
d German Center for Neurodegenerative Diseases, Munich, Germany
e Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
f Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
g Department of Radiology, Washington University School of Medicine in Saint Louis, St Louis, MO, United States

Abstract
Amyloid-beta deposition is one of the hallmark pathologies in both sporadic Alzheimer’s disease and autosomal-dominant Alzheimer’s disease, the latter of which is caused by mutations in genes involved in amyloid-beta processing. Despite amyloid-beta deposition being a centrepiece to both sporadic Alzheimer’s disease and autosomal-dominant Alzheimer’s disease, some differences between these Alzheimer’s disease subtypes have been observed with respect to the spatial pattern of amyloid-beta. Previous work has shown that the spatial pattern of amyloid-beta in individuals spanning the sporadic Alzheimer’s disease spectrum can be reproduced with high accuracy using an epidemic spreading model which simulates the diffusion of amyloid-beta across neuronal connections and is constrained by individual rates of amyloid-beta production and clearance. However, it has not been investigated whether amyloid-beta deposition in the rarer autosomal-dominant Alzheimer’s disease can be modelled in the same way, and if so, how congruent the spreading patterns of amyloid-beta across sporadic Alzheimer’s disease and autosomal-dominant Alzheimer’s disease are. We leverage the epidemic spreading model as a data-driven approach to probe individual-level variation in the spreading patterns of amyloid-beta across three different large-scale imaging datasets (2 sporadic Alzheimer’s disease, 1 autosomal-dominant Alzheimer’s disease). We applied the epidemic spreading model separately to the Alzheimer’s Disease Neuroimaging initiative (n = 737), the Open Access Series of Imaging Studies (n = 510) and the Dominantly Inherited Alzheimer’s Network (n = 249), the latter two of which were processed using an identical pipeline. We assessed inter-and intra-individual model performance in each dataset separately and further identified the most likely subject-specific epicentre of amyloid-beta spread. Using epicentres defined in previous work in sporadic Alzheimer’s disease, the epidemic spreading model provided moderate prediction of the regional pattern of amyloid-beta deposition across all three datasets. We further find that, whilst the most likely epicentre for most amyloid-beta-positive subjects overlaps with the default mode network, 13% of autosomal-dominant Alzheimer’s disease individuals were best characterized by a striatal origin of amyloid-beta spread. These subjects were also distinguished by being younger than autosomal-dominant Alzheimer’s disease subjects with a default mode network amyloid-beta origin, despite having a similar estimated age of symptom onset. Together, our results suggest that most autosomal-dominant Alzheimer’s disease patients express amyloid-beta spreading patterns similar to those of sporadic Alzheimer’s disease, but that there may be a subset of autosomal-dominant Alzheimer’s disease patients with a separate, striatal phenotype. © 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
Alzheimer’s disease;  amyloid beta;  brain networks;  diffusion models

Document Type: Article
Publication Stage: Final
Source: Scopus

Detection of β-amyloid positivity in Alzheimer’s Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers” (2021) Brain Communications

Detection of β-amyloid positivity in Alzheimer’s Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers
(2021) Brain Communications, 3 (2), art. no. fcab008, . Cited 13 times.

Tosun, D.a b , Veitch, D.b , Aisen, P.c , Jack, C.R.d , Jagust, W.J.e , Petersen, R.C.f g , Saykin, A.J.h i j , Bollinger, J.k l , Ovod, V.k l , Mawuenyega, K.G.k l , Bateman, R.J.k l m , Shaw, L.M.n , Trojanowski, J.Q.o , Blennow, K.a p , Zetterberg, H.a p q r , Weiner, M.W.a b

a San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
b Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
c Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, United States
d Department of Radiology, Mayo Clinic, Rochester, MN, United States
e School of Public Health, Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States
f Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
g Department of Neurology, Mayo Clinic, Rochester, MN, United States
h Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, United States
i Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, United States
j Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
k Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
l Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
m Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
n Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
o Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
p Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
q Department of Neurodegenerative Disease, Ucl Institute of Neurology, London, United Kingdom
r Uk Dementia Research Institute at Ucl, London, United Kingdom

Abstract
In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer’s disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer’s disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer’s Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid42/β-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly APOE ϵ4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid42/β-amyloid40 may be improved by age and APOE genotype. © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
Alzheimer’s;  MRI;  PET;  plasma;  β-amyloid

Document Type: Article
Publication Stage: Final
Source: Scopus