“Automated sleep state classification of wide-field calcium imaging data via multiplex visibility graphs and deep learning” (2022) Journal of Neuroscience Methods
Automated sleep state classification of wide-field calcium imaging data via multiplex visibility graphs and deep learning(2022) Journal of Neuroscience Methods, 366, art. no. 109421, .
Zhang, X.a , Landsness, E.C.b , Chen, W.b , Miao, H.b , Tang, M.b , Brier, L.M.c , Culver, J.P.c d e f , Lee, J.-M.b c d , Anastasio, M.A.a
a Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, United Statesb Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United Statesc Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United Statesd Department of Biomedical Engineering, Washington University School of Engineering, St. Louis, MO 63130, United Statese Department of Electrical and Systems Engineering, Washington University School of Engineering, St. Louis, MO 63130, United Statesf Department of Physics, Washington University School of Arts and Science, St. Louis, MO 63130, United States
AbstractBackground: Wide-field calcium imaging (WFCI) allows for monitoring of cortex-wide neural dynamics in mice. When applied to the study of sleep, WFCI data are manually scored into the sleep states of wakefulness, non-REM (NREM) and REM by use of adjunct EEG and EMG recordings. However, this process is time-consuming and often suffers from low inter- and intra-rater reliability and invasiveness. Therefore, an automated sleep state classification method that operates on WFCI data alone is needed. New method: A hybrid, two-step method is proposed. In the first step, spatial-temporal WFCI data is mapped to multiplex visibility graphs (MVGs). Subsequently, a two-dimensional convolutional neural network (2D CNN) is employed on the MVGs to be classified as wakefulness, NREM and REM. Results: Sleep states were classified with an accuracy of 84% and Cohen’s κ of 0.67. The method was also effectively applied on a binary classification of wakefulness/sleep (accuracy=0.82, κ = 0.62) and a four-class wakefulness/sleep/anesthesia/movement classification (accuracy=0.74, κ = 0.66). Gradient-weighted class activation maps revealed that the CNN focused on short- and long-term temporal connections of MVGs in a sleep state-specific manner. Sleep state classification performance when using individual brain regions was highest for the posterior area of the cortex and when cortex-wide activity was considered. Comparison with existing method: On a 3-hour WFCI recording, the MVG-CNN achieved a κ of 0.65, comparable to a κ of 0.60 corresponding to the human EEG/EMG-based scoring. Conclusions: The hybrid MVG-CNN method accurately classifies sleep states from WFCI data and will enable future sleep-focused studies with WFCI. © 2021 The Authors
Author Keywords2D CNN; Automated sleep state classification; Deep learning; Local sleep; Multiplex visibility graph; Wide-field calcium imaging
Funding detailsNational Institute on AgingNIAF30AG061932National Institute of Neurological Disorders and StrokeNINDSK08NS109292-01A1, R01NS094692, R01NS099429, R37NS110699American Heart AssociationAHA20CDA35310607American Academy of Sleep Medicine FoundationAASMF201-BS-19
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Sonobiopsy for minimally invasive, spatiotemporally-controlled, and sensitive detection of glioblastoma-derived circulating tumor DNA” (2022) Theranostics
Sonobiopsy for minimally invasive, spatiotemporally-controlled, and sensitive detection of glioblastoma-derived circulating tumor DNA(2022) Theranostics, 27 (1), pp. 362-378.
Pacia, C.P.a , Yuan, J.a , Yue, Y.a , Xu, L.a , Nazeri, A.b , Desai, R.c d , Gach, H.M.a b e , Wang, X.f g , Talcott, M.R.h , Chaudhuri, A.A.e i j k , Dunn, G.P.c d , Leuthardt, E.C.a c l m , Chen, H.a e
a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United Statesb Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United Statesc Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United Statesd Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, United Statese Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United Statesf Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL 60612, United Statesg University of Illinois Cancer Center, Chicago, IL 60612, United Statesh Division of Comparative Medicine, Washington University School of Medicine, Saint Louis, MO 63110, United Statesi Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United Statesj Department of Computer Science and Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United Statesk Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, United Statesl Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United Statesm Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, Saint Louis, MO 63110, United States
AbstractThough surgical biopsies provide direct access to tissue for genomic characterization of brain cancer, they are invasive and pose significant clinical risks. Brain cancer management via blood-based liquid biopsies is a minimally invasive alternative; however, the blood-brain barrier (BBB) restricts the release of brain tumor-derived molecular biomarkers necessary for sensitive diagnosis. Methods: A mouse glioblastoma multiforme (GBM) model was used to demonstrate the capability of focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) to improve the diagnostic sensitivity of brain tumor-specific genetic mutations compared with conventional blood-based liquid biopsy. Furthermore, a pig GBM model was developed to characterize the translational implications of sonobiopsy in humans. Magnetic resonance imaging (MRI)-guided FUS sonication was performed in mice and pigs to locally enhance the BBB permeability of the GBM tumor. Contrast-enhanced T1-weighted MR images were acquired to evaluate the BBB permeability change. Blood was collected immediately after FUS sonication. Droplet digital PCR was used to quantify the levels of brain tumor-specific genetic mutations in the circulating tumor DNA (ctDNA). Histological staining was performed to evaluate the potential for off-target tissue damage by sonobiopsy. Results: Sonobiopsy improved the detection sensitivity of EGFRvIII from 7.14% to 64.71% and TERT C228T from 14.29% to 45.83% in the mouse GBM model. It also improved the diagnostic sensitivity of EGFRvIII from 28.57% to 100% and TERT C228T from 42.86% to 71.43% in the porcine GBM model. Conclusion: Sonobiopsy disrupts the BBB at the spatially-targeted brain location, releases tumor-derived DNA into the blood circulation, and enables timely collection of ctDNA. Converging evidence from both mouse and pig GBM models strongly supports the clinical translation of sonobiopsy for the minimally invasive, spatiotemporally-controlled, and sensitive molecular characterization of brain cancer. © The author(s).
Author KeywordsBlood-based liquid biopsy; Blood-brain barrier; Droplet digital PCR; Glioblastoma mutation; Image-guided focused ultrasound
Funding detailsNational Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981, T32NS115672Washington University in St. LouisWUSTL
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Acute ischemic stroke interventions in the United States and racial, socioeconomic, and geographic disparities” (2021) Neurology
Acute ischemic stroke interventions in the United States and racial, socioeconomic, and geographic disparities(2021) Neurology, 97 (23), pp. E2292-E2303.
De Havenon, A.a , Sheth, K.b , Johnston, K.C.c , Delic, A.a , Stulberg, E.a , Majersik, J.a , Anadani, M.d , Yaghi, S.e , Tirschwell, D.f , Ney, J.g
a University of Utah, Salt Lake City, United Statesb Yale University, New Haven, CT, United Statesc University of Virginia, Charlottesville, United Statesd Washington University, St. Louis, MO, United Statese Brown University, Providence, RI, United Statesf University of Washington, Seattle, United Statesg Boston UniversityMA, United States
AbstractBackground and Objectives In patients with ischemic stroke (IS), IV alteplase (tissue plasminogen activator [tPA]) and endovascular thrombectomy (EVT) reduce long-term disability, but their utilization has not been fully optimized. Prior research has also demonstrated disparities in the use of tPA and EVT specific to sex, race/ethnicity, socioeconomic status, and geographic location. We sought to determine the utilization of tPA and EVT in the United States from 2016-2018 and if disparities in utilization persist. Methods This is a retrospective, longitudinal analysis of the 2016-2018 National Inpatient Sample. We included adult patients who had a primary discharge diagnosis of IS. The primary study outcomes were the proportions who received tPA or EVT. We fit a multivariate logistic regression model to our outcomes in the full cohort and also in the subset of patients who had an available baseline National Institutes of Health Stroke Scale (NIHSS) score. Results The full cohort after weighting included 1, 439, 295 patients with IS. The proportion who received tPA increased from 8.8% in 2016 to 10.2% in 2018 (p < 0.001) and who had EVT from 2.8% in 2016 to 4.9% in 2018 (p < 0.001). Comparing Black to White patients, the odds ratio (OR) of receiving tPA was 0.82 (95% confidence interval [CI] 0.79-0.86) and for having EVT was 0.75 (95% CI 0.70-0.81). Comparing patients with a median income in their zip code of ≤$37, 999 to >$64, 000, the OR of receiving tPA was 0.81 (95% CI 0.78-0.85) and for having EVT was 0.84 (95% CI 0.77-0.91). Comparing patients living in a rural area to a large metro area, the OR of receiving tPA was 0.48 (95% CI 0.44-0.52) and for having EVT was 0.92 (95% CI 0.81-1.05). These associations were largely maintained after adjustment for NIHSS, although the effect size changed for many of them. Contrary to prior reports with older datasets, sex was not consistently associated with tPA or EVT. Discussion Utilization of tPA and EVT for IS in the United States increased from 2016 to 2018. There are racial, socioeconomic, and geographic disparities in the accessibility of tPA and EVT for patients with IS, with important public health implications that require further study. Copyright © 2021 American Academy of Neurology.
Funding detailsK23NS105924, R01NR018335, R01NS11072, R03NS112859, U01NS106513, U24NS107136, U24NS107215National Institutes of HealthNIHNational Institute of Neurological Disorders and StrokeNINDSU24NS107228American Heart AssociationAHA17CSA33550004NovartisBiogen
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Quantitative MRI Differences Between Early versus Late Onset Alzheimer’s Disease” (2021) American Journal of Alzheimer’s Disease and other Dementias
Quantitative MRI Differences Between Early versus Late Onset Alzheimer’s Disease(2021) American Journal of Alzheimer’s Disease and other Dementias, 36, .
Meysami, S.a , Raji, C.A.b , Merrill, D.A.c d , Porter, V.R.a d , Mendez, M.F.a c e
a Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, United Statesb Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St Louis, St Louis, MO, United Statesc Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at, University of California, Los Angeles, CA, United Statesd Providence and St Johns Health Center, Pacific Neuroscience Institute, Santa Monica, CA, United Statese V.A. Greater Los Angeles Healthcare System, Los Angeles, CA, United States
AbstractInvestigators report greater parietal tau deposition and alternate frontoparietal network involvement in early onset Alzheimer’s Disease (EOAD) with onset <65 years as compared with typical late onset AD (LOAD). To determine whether clinical brain MRI volumes reflect these differences in EOAD compared with LOAD. This study investigated the clinical MRI scans of 45 persons with Clinically Probable AD with onset <65 years, and compared them to 32 with Clinically Probable AD with onset ≥65 years. Brain volumes on their T1 MRI scans were quantified with a volumetric program. Receiver operating curve analyses were performed. Persons with EOAD had significantly smaller parietal lobes (volumetric percentiles) than LOAD. Late onset Alzheimer’s Disease had a smaller left putamen and hippocampus. Area Under the Curve was 96.5% with brain region delineation of EOAD compared to LOAD. This study indicates parietal atrophy less than 30% of normal on clinical MRI scans is suggestive of EOAD compared to LOAD. © The Author(s) 2021.
Author KeywordsAlzheimer’s; early onset; late onset; MRI; volumetric quantification
Funding details1RF1AG050967KL2 TR000450Radiological Society of North AmericaRSNA
Document Type: ArticlePublication Stage: FinalSource: Scopus
“TMS-EEG Biomarkers of Amnestic Mild Cognitive Impairment Due to Alzheimer’s Disease: A Proof-of-Concept Six Years Prospective Study” (2021) Frontiers in Aging Neuroscience
TMS-EEG Biomarkers of Amnestic Mild Cognitive Impairment Due to Alzheimer’s Disease: A Proof-of-Concept Six Years Prospective Study(2021) Frontiers in Aging Neuroscience, 13, art. no. 737281, .
Ferreri, F.a b , Guerra, A.c , Vollero, L.d , Ponzo, D.a b , Määtta, S.b , Könönen, M.e , Vecchio, F.f g , Pasqualetti, P.h , Miraglia, F.f , Simonelli, I.h , Corbetta, M.a i j , Rossini, P.M.f
a Unit of Neurology, Unit of Clinical Neurophysiology and Study Center of Neurodegeneration (CESNE), Department of Neuroscience, University of Padua, Padua, Italyb Department of Clinical Neurophysiology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finlandc IRCCS Neuromed, Pozzilli, Italyd Department of Computer Science and Computer Engineering, Campus Bio-Medico University of Rome, Rome, Italye Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finlandf Brain Connectivity Laboratory, Department of Neuroscience and Neurorehabilitation, IRCCS San Raffaele Roma, Rome, Italyg eCampus University, Novedrate, Como, Italyh Servizio di Statistica Medica ed Information Technology, Associazione Fatebenefratelli per la Ricerca (AFaR), Rome, Italyi Department of Neuroscience, Neurology, Radiology and Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United Statesj Padua Neuroscience Center, University of Padua, Padua, Italy
AbstractBackground: Early and affordable identification of subjects with amnestic mild cognitive impairment (aMCI) who will convert to Alzheimer’s disease (AD) is a major scientific challenge. Objective: To investigate the neurophysiological hallmarks of sensorimotor cortex function in aMCI under the hypothesis that some may represent the plastic rearrangements induced by neurodegeneration, hence predictors of future conversion to AD. We sought to determine (1) whether the sensorimotor network shows peculiar alterations in patients with aMCI and (2) if sensorimotor network alterations predict long-term disease progression at the individual level. Methods: We studied several transcranial magnetic stimulation (TMS)-electroencephalogram (EEG) parameters of the sensorimotor cortex in a group of patients with aMCI and followed them for 6 years. We then identified aMCI who clinically converted to AD [prodromal to AD-MCI (pAD-MCI)] and those who remained cognitively stable [non-prodromal to AD-MCI (npAD-MCI)]. Results: Patients with aMCI showed reduced motor cortex (M1) excitability and disrupted EEG synchronization [decreased intertrial coherence (ITC)] in alpha, beta and gamma frequency bands compared to the control subjects. The degree of alteration in M1 excitability and alpha ITC was comparable between pAD-MCI and npAD-MCI. Importantly, beta and gamma ITC impairment in the stimulated M1 was greater in pAD-MCI than npAD-MCI. Furthermore, an additional parameter related to the waveform shape of scalp signals, reflecting time-specific alterations in global TMS-induced activity [stability of the dipolar activity (sDA)], discriminated npAD-MCI from MCI who will convert to AD. Discussion: The above mentioned specific cortical changes, reflecting deficit of synchronization within the cortico-basal ganglia-thalamo-cortical loop in aMCI, may reflect the pathological processes underlying AD. These changes could be tested in larger cohorts as neurophysiological biomarkers of AD. Copyright © 2021 Ferreri, Guerra, Vollero, Ponzo, Määtta, Könönen, Vecchio, Pasqualetti, Miraglia, Simonelli, Corbetta and Rossini.
Author KeywordsAlzheimer’s disease (AD); electroencephalography (EEG); mild cognitive impairment (MCI); navigated transcranial magnetic stimulation (nTMS); TMS-EEG coregistration
Funding detailsGR-2016-02361802
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Pharmacological and Biophysical Characteristics of Picrotoxin-Resistant, δSubunit-Containing GABAA Receptors” (2021) Frontiers in Synaptic Neuroscience
Pharmacological and Biophysical Characteristics of Picrotoxin-Resistant, δSubunit-Containing GABAA Receptors(2021) Frontiers in Synaptic Neuroscience, 13, art. no. 763411, .
Shu, H.-J.a , Lu, X.a , Bracamontes, J.b , Steinbach, J.H.b c , Zorumski, C.F.a c d , Mennerick, S.a c d
a Department of Psychiatry, Washington University in St. Louis, School of Medicine, St. Louis, MO, United Statesb Department of Anesthesiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United Statesc Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, St. Louis, MO, United Statesd Department of Neuroscience, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
AbstractGABAA receptors (GABAARs) play a crucial role in inhibition in the central nervous system. GABAARs containing the δ subunit mediate tonic inhibition, have distinctive pharmacological properties and are associated with disorders of the nervous system. To explore this receptor sub-class, we recently developed mice with δ-containing receptors rendered resistant to the common non-competitive antagonist picrotoxin (PTX). Resistance was achieved with a knock-in point mutation (T269Y; T6’Y) in the mouse genome. Here we characterize pharmacological and biophysical features of GABAARs containing the mutated subunit to contextualize results from the KI mice. Recombinant receptors containing δ T6’Y plus WT α4 and WT β2 subunits exhibited 3-fold lower EC50 values for GABA but not THIP. GABA EC50 values in native receptors containing the mutated subunit were in the low micromolar range, in contrast with some published results that have suggested nM sensitivity of recombinant receptors. Rectification properties of δ-containing GABAARs were similar to γ2-containing receptors. Receptors containing δ T6’Y had marginally weaker sensitivity to positive allosteric modulators, likely a secondary consequence of differing GABA sensitivity. Overexpression of δT6’Y in neurons resulted in robust PTX-insensitive IPSCs, suggesting that δ-containing receptors are readily recruited by synaptically released GABA. Overall, our results give context to the use of δ receptors with the T6’Y mutation to explore the roles of δ-containing receptors in inhibition. Copyright © 2021 Shu, Lu, Bracamontes, Steinbach, Zorumski and Mennerick.
Author Keywordsantidepressant; dentate gyrus; ethanol; GABA allosteric modulators; inhibition; neurosteroid
Funding detailsNational Institutes of HealthNIHAA026753, MH111461, MH114866, MH122379, MH123748Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion” (2021) Frontiers in Immunology
Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion(2021) Frontiers in Immunology, 12, art. no. 785519, .
Huuskonen, M.T.a , Liu, Q.a , Lamorie-Foote, K.a , Shkirkova, K.a , Connor, M.b , Patel, A.c , Montagne, A.a , Baertsch, H.a , Sioutas, C.d , Morgan, T.E.e , Finch, C.E.e , Zlokovic, B.V.a , Mack, W.J.a f
a Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United Statesb Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United Statesc Department of Neurological Surgery, University of California San Francisco School of Medicine, San Francisco, CA, United Statesd Department of Civil and Environmental Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, United Statese Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United Statesf Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
AbstractCerebrovascular pathologies are commonly associated with dementia. Because air pollution increases arterial disease in humans and rodent models, we hypothesized that air pollution would also contribute to brain vascular dysfunction. We examined the effects of exposing mice to nanoparticulate matter (nPM; aerodynamic diameter ≤200 nm) from urban traffic and interactions with cerebral hypoperfusion. C57BL/6 mice were exposed to filtered air or nPM with and without bilateral carotid artery stenosis (BCAS) and analyzed by multiparametric MRI and histochemistry. Exposure to nPM alone did not alter regional cerebral blood flow (CBF) or blood brain barrier (BBB) integrity. However, nPM worsened the white matter hypoperfusion (decreased CBF on DSC-MRI) and exacerbated the BBB permeability (extravascular IgG deposits) resulting from BCAS. White matter MRI diffusion metrics were abnormal in mice subjected to cerebral hypoperfusion and worsened by combined nPM+BCAS. Axonal density was reduced equally in the BCAS cohorts regardless of nPM status, whereas nPM exposure caused demyelination in the white matter with or without cerebral hypoperfusion. In summary, air pollution nPM exacerbates cerebrovascular pathology and demyelination in the setting of cerebral hypoperfusion, suggesting that air pollution exposure can augment underlying cerebrovascular contributions to cognitive loss and dementia in susceptible elderly populations. Copyright © 2021 Huuskonen, Liu, Lamorie-Foote, Shkirkova, Connor, Patel, Montagne, Baertsch, Sioutas, Morgan, Finch, Zlokovic and Mack.
Author Keywordsair pollution; blood brain barrier; carotid artery stenosis; hypoperfusion; MRI
Funding detailsNational Institutes of HealthNIH5P01AG055367, 5R01ES024936-05, 5R01NS100459-03
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Cortical feedback and gating in odor discrimination and generalization” (2021) PLoS Computational Biologyon
Cortical feedback and gating in odor discrimination and generalization(2021) PLoS Computational Biology, 17 (10), p. e1009479.
Tavoni, G.a b c , Kersen, D.E.C.a d , Balasubramanian, V.a b d e
a Computational Neuroscience Initiative, University of Pennsylvania, Philadelphia, PA, United Statesb Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA, United Statesc Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United Statesd Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United Statese Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, United States
AbstractA central question in neuroscience is how context changes perception. In the olfactory system, for example, experiments show that task demands can drive divergence and convergence of cortical odor responses, likely underpinning olfactory discrimination and generalization. Here, we propose a simple statistical mechanism for this effect based on unstructured feedback from the central brain to the olfactory bulb, which represents the context associated with an odor, and sufficiently selective cortical gating of sensory inputs. Strikingly, the model predicts that both convergence and divergence of cortical odor patterns should increase when odors are initially more similar, an effect reported in recent experiments. The theory in turn predicts reversals of these trends following experimental manipulations and in neurological conditions that increase cortical excitability.
Document Type: ArticlePublication Stage: FinalSource: Scopus
“PTPN4 germline variants result in aberrant neurodevelopment and growth” (2021) Human Genetics and Genomics Advances
PTPN4 germline variants result in aberrant neurodevelopment and growth(2021) Human Genetics and Genomics Advances, 2 (3), art. no. 100033, .
Chmielewska, J.J.a b , Burkardt, D.c , Granadillo, J.L.d , Slaugh, R.d , Morgan, S.e , Rotenberg, J.e , Keren, B.f , Mignot, C.f g , Escobar, L.h , Turnpenny, P.i , Zuteck, M.j , Seaver, L.H.j k , Ploski, R.l , Dziembowska, M.b , Wynshaw-Boris, A.c , Adegbola, A.c m
a Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Polandb Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Polandc Center for Human Genetics and Department of Genetics and Genome Sciences, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, United Statesd Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United Statese Houston Specialty Clinic, Houston, TX, United Statesf Département de Génétique, APHP, Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière, Paris, Franceg Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, Franceh Medical Genetics and Neurodevelopmental Center, Peyton Manning Children’s Hospital, Indianapolis, IN, United Statesi University of Exeter Medical School and Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdomj Medical Genetics and Genomics, Spectrum Health/Helen Devos Children’s Hospital, Grand Rapids, MI, United Statesk Department of Pediatrics and Human Development, Michigan State College of Human Medicine, Grand Rapids, MI, United Statesl Department of Medical Genetics, Warsaw Medical University, Warsaw, Polandm Department of Psychiatry, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, United States
AbstractProtein-tyrosine phosphatases (PTPs) are pleomorphic regulators of eukaryotic cellular responses to extracellular signals that function by modulating the phosphotyrosine of specific proteins. A handful of PTPs have been implicated in germline and somatic human disease. Using exome sequencing, we identified missense and truncating variants in PTPN4 in six unrelated individuals with varying degrees of intellectual disability or developmental delay. The variants occurred de novo in all five subjects in whom segregation analysis was possible. Recurring features include postnatal growth deficiency or excess, seizures, and, less commonly, structural CNS, heart, or skeletal anomalies. PTPN4 is a widely expressed protein tyrosine phosphatase that regulates neuronal cell homeostasis by protecting neurons against apoptosis. We suggest that pathogenic variants in PTPN4 confer risk for growth and cognitive abnormalities in humans. © 2021 The Authors
Author KeywordsDevelopmental Delay; Intellectual Disability; Macrocephaly; Neurodevelopment; Protein tyrosine phosphatase; PTPN4; Somatic growth anomaly
Funding detailsHICF-1009-003National Institutes of HealthNIHR01MH113106National Center for Advancing Translational SciencesNCATSCenter for Advanced Systems and Engineering, Syracuse UniversityCASEWellcome TrustWT25533962Narodowe Centrum NaukiNCN2014/14/E/NZ3/00375, 2017/27/N/NZ1/01381
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Exploring the genetic overlap of suicide-related behaviors and substance use disorders” (2021) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Exploring the genetic overlap of suicide-related behaviors and substance use disorders(2021) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, .
Colbert, S.M.C.a , Hatoum, A.S.a , Shabalin, A.b , Li, Q.S.c , Coon, H.b , Nelson, E.C.a , Agrawal, A.a , Docherty, A.R.b , Johnson, E.C.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United Statesb Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United Statesc Neuroscience and JRD Data Science, Janssen Research & Development, LLC, Titusville, NJ, United States
AbstractSuicide-related behaviors are heterogeneous and transdiagnostic, and may demonstrate varying levels of genetic overlap with different substance use disorders (SUDs). We used linkage disequilibrium score regression, genomic structural equation models, and Mendelian randomization to examine the genetic relationships between several SUDs and suicide-related behaviors. Our analyses incorporated summary statistics from the largest genome-wide association studies (GWAS) of problematic alcohol use, the Fagerström test for nicotine dependence, cannabis use disorder, and opioid use disorder (Ns ranging from 46,213–435,563) and GWAS of ever self-harmed, suicide attempt, and suicide death (Ns ranging from 18,223–117,733). We also accounted for genetic liability to depression (N = 500,199) and risk tolerance (N = 315,894). Suicide-related behaviors were significantly genetically correlated with each other and each SUD, but there was little evidence of causal relationships between the traits. Simultaneously correlating a common SUD factor with each specific suicide indicator while controlling for depression and risk tolerance revealed significant, positive genetic correlations between the SUD factor and suicide-related behaviors (rg = 0.26–0.45, SE = 0.08–0.09). In the model, depression’s association with suicide death (β = 0.42, SE = 0.06) was weaker compared to ever-self harmed and suicide attempt (β = 0.58, SE = 0.05 and β = 0.50, SE = 0.06, respectively). We identify a general level of genetic overlap between SUDs and suicide-related behaviors, which is independent of depression and risk tolerance. Additionally, our findings suggest that genetic and behavioral contributions to suicide death may somewhat differ from nonlethal suicide-related behaviors. © 2021 Wiley Periodicals LLC.
Author Keywordsgenetic overlap; genome-wide association studies; genomic structural equation models; substance use disorders; suicide
Funding detailsNational Institute of Mental HealthNIMHR01 MH122412, R01 MH123489, R01 MH123619National Institute on Drug AbuseNIDADA007261‐17, K02DA032573U.S. Department of Veterans AffairsVAMH109532Brain and Behavior Research FoundationBBRFSimons FoundationSFAmerican Foundation for Suicide PreventionAFSPYIG‐0‐064‐18Office of Research and DevelopmentORDHealth Services Research and DevelopmentHSR&D
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Intrinsic functional connectivity in the default mode network predicts mnemonic discrimination: A connectome-based modeling approach” (2021) Hippocampus
Intrinsic functional connectivity in the default mode network predicts mnemonic discrimination: A connectome-based modeling approach(2021) Hippocampus, .
Wahlheim, C.N.a , Christensen, A.P.b , Reagh, Z.M.c , Cassidy, B.S.a
a Department of Psychology, University of North Carolina at Greensboro, Greensboro, NC, United Statesb Department of Neurology, University of Pennsylvania, Philadelphia, PA, United Statesc Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
AbstractThe ability to distinguish existing memories from similar perceptual experiences is a core feature of episodic memory. This ability is often examined using the mnemonic similarity task in which people discriminate memories of studied objects from perceptually similar lures. Studies of the neural basis of such mnemonic discrimination have mostly focused on hippocampal function and connectivity. However, default mode network (DMN) connectivity may also support such discrimination, given that the DMN includes the hippocampus, and its connectivity supports many aspects of episodic memory. Here, we used connectome-based predictive modeling to identify associations between intrinsic DMN connectivity and mnemonic discrimination. We leveraged a wide range of abilities across healthy younger and older adults to facilitate this predictive approach. Resting-state functional connectivity in the DMN predicted mnemonic discrimination outside the MRI scanner, especially among prefrontal and temporal regions and including several hippocampal regions. This predictive relationship was stronger for younger than older adults, primarily for temporal–prefrontal connectivity. The novel associations established here are consistent with mounting evidence that broader cortical networks including the hippocampus support mnemonic discrimination. They also suggest that age-related network disruptions undermine the extent that the DMN supports this ability. This study provides the first indication of how intrinsic functional properties of the DMN support mnemonic discrimination. © 2021 Wiley Periodicals LLC
Author Keywordsconnectomics; default mode network; functional connectivity; hippocampus; mnemonic discrimination
Funding detailsNational Institute on AgingNIAR24‐AG054355
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine” (2021) Human Brain Mapping
Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine(2021) Human Brain Mapping, .
Shokri-Kojori, E.a , Naganawa, M.b , Ramchandani, V.A.c , Wong, D.F.d e , Wang, G.-J.a , Volkow, N.D.a
a Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United Statesb Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, United Statesc Human Psychopharmacology Laboratory, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United Statesd Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, United Statese Mallinckrodt Institute of Radiology, Washington University in St Louis Missouri, St Louis, MO, United States
AbstractOpioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain-wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = −0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = −0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL- and MRP-DA release patterns (ΔR2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL- and MRP-induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern-based characterization of drug-induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release. © 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Author Keywordsdopamine; k-means; morphine; naloxone; opioid receptors; positron emission tomography (PET); striatum
Funding detailsNational Institute on Alcohol Abuse and AlcoholismNIAAAY1AA3009
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related to Alzheimer’s Disease” (2021) Journal of Proteome Research
Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related to Alzheimer’s Disease(2021) Journal of Proteome Research, .
Hubbard, E.E.a , Heil, L.R.b , Merrihew, G.E.b , Chhatwal, J.P.c , Farlow, M.R.d , Mclean, C.A.e , Ghetti, B.f , Newell, K.L.f , Frosch, M.P.g , Bateman, R.J.h , Larson, E.B.i , Keene, C.D.j , Perrin, R.J.l , Montine, T.J.k , Maccoss, M.J.b , Julian, R.R.a
a Department of Chemistry, University of California, Riverside, CA 92521, United Statesb Department of Genome Sciences, University of Washington, Seattle, WA 98195, United Statesc Massachusetts General Hospital, Department of Neurology, Harvard Medical School, 15 Parkman St, Suite 835, Boston, MA 02114, United Statesd Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, United Statese Department of Anatomical Pathology, Alfred Health, Melbourne, VIC 3004, Australiaf Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United Statesg C.S. Kubik Laboratory for Neuropathology, Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Boston, MA 02114, United Statesh Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, Missouri 63110, United Statesi Kaiser Permanente Washington Health Research Institute, Department of Medicine, University of Washington, Seattle, WA 98195, United Statesj Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, United Statesk Department of Pathology, Stanford University, Stanford, CA 94305, United Statesl Department of Pathology and Immunology, Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri 63110, United States
AbstractOne of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer’s disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples. To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains. This study illustrates that DIA data may contain unforeseen results of interest and may be particularly useful for pilot studies investigating new research directions. In this case, a promising target for future investigations into the therapy and prevention of AD has been identified. © 2021 The Authors. Published by American Chemical Society.
Author Keywordsage-related neurodegenerative disease; amyloid; amyloid-beta; aspartic acid; hippocampus; lysosome; neurofibrillary tangle; post-translational modification; proteomics; proteostasis
Funding detailsP30 AG062421, U19 AG032438, UF1AG032438National Institutes of HealthNIHP30 AG066509, R01 AG066626, RF1 AG053959, U01 AG006781National Institute on AgingNIAAlzheimer’s Disease Research Center, Emory UniversityADRCNancy and Buster Alvord EndowmentJapan Agency for Medical Research and DevelopmentAMEDKorea Health Industry Development InstituteKHIDIDeutsches Zentrum für Neurodegenerative ErkrankungenDZNEFleni
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Different rates of cognitive decline in autosomal dominant and late-onset Alzheimer disease” (2021) Alzheimer’s and Dementia
Different rates of cognitive decline in autosomal dominant and late-onset Alzheimer disease(2021) Alzheimer’s and Dementia, .
Buckles, V.D.a , Xiong, C.b , Bateman, R.J.a , Hassenstab, J.a , Allegri, R.c , Berman, S.B.d , Chhatwal, J.P.e , Danek, A.f , Fagan, A.M.a , Ghetti, B.g , Goate, A.h , Graff-Radford, N.i , Jucker, M.j , Levin, J.k , Marcus, D.S.l , Masters, C.L.m , McCue, L.b , McDade, E.a , Mori, H.n , Moulder, K.L.a , Noble, J.M.o , Paumier, K.a , Preische, O.p , Ringman, J.M.q , Fox, N.C.r , Salloway, S.s , Schofield, P.R.t , Martins, R.u , Vöglein, J.v , Morris, J.C.a , for the Dominantly Inherited Alzheimer’s Networkw
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United Statesb Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United Statesc Institute for Neurological Research (FLENI), Buenos Aires, Argentinad Department of Neurology and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, PA, United Statese Department of Neurology, Massachusetts General Hospital, Boston, MA, United Statesf Neurologische Klinik und Poliklinik, Klinikum der Universität München, Munich, Germanyg Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United Statesh Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United Statesi Department of Neurology, Mayo Clinic, Jacksonville, FL, United Statesj DZNE Tuebingen & Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germanyk DZNE Munich, Munich Cluster of Systems Neurology (SyNergy) & Ludwig-Maximilians-Universität, Munich, Germanyl Department of Radiology, Washington University School of Medicine, St. Louis, MO, United Statesm Florey Institute, University of Melbourne, Melbourne, Australian Department of Neuroscience, Osaka City University Medical School, Osaka City, Japano Department of Neurology, Taub Institute for Research on Aging Brain, Columbia University Irving Medical Center, New York, NY, United Statesp DZNE Tuebingen & University of Tuebingen, Tuebingen, Germanyq Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United Statesr Department of Neurodegenerative Disease & UK Dementia Research Institute, Institute of Neurology, London, United Kingdoms Department of Neurology, Butler Hospital & Alpert Medical School of Brown University, Providence, RI, United Statest Neuroscience Research Australia & School of Medical Sciences, University of New South Wales, Sydney, NSW, Australiau Sir James McCusker Alzheimer’s Disease Research Unit, Edith Cowan University, Nedlands, WA, Australiav German Center for Neurodegenerative Diseases (DZNE) and Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany
AbstractAs prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and “sporadic” late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy-confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences. © 2021 the Alzheimer’s Association
Author KeywordsAlzheimer disease; autosomal dominant Alzheimer disease; cognitive; comorbidities; late-onset Alzheimer disease
Funding detailsNational Institutes of HealthNIHU24 AG072122National Institute on AgingNIADoris Duke Charitable FoundationDDCFJPB FoundationJapan Agency for Medical Research and DevelopmentAMEDRainwater Charitable FoundationRCFMedical Research CouncilMRCMR/009076/1, MR/L023784/1National Health and Medical Research CouncilNHMRCDeutsches Zentrum für Neurodegenerative ErkrankungenDZNEUCLH Biomedical Research CentreNIHR BRCFleni
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Long-term retinal vasculature abnormalities following intravitreal bevacizumab for retinopathy of prematurity” (2021) Graefe’s Archive for Clinical and Experimental Ophthalmology
Long-term retinal vasculature abnormalities following intravitreal bevacizumab for retinopathy of prematurity(2021) Graefe’s Archive for Clinical and Experimental Ophthalmology, .
Sternfeld, A.a b , Rahmani, S.c d , Rossen, J.L.c d , Zhang, D.L.c , Li, Y.D.c e f , Quan, V.L.c e g , Huang, R.d , Yoon, H.H.c d
a Ophthalmology Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, Israelb Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israelc Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago, Box 70, Chicago, IL 60611, United Statesd Department of Ophthalmology, Northwestern Feinberg School of Medicine, Chicago, IL, United Statese Northwestern University Feinberg School of Medicine, Chicago, IL, United Statesf Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United Statesg Department of Dermatology, Northwestern Feinberg School of Medicine, Chicago, IL, United States
AbstractPurpose: To report long-term fluorescein angiography (FA) findings in consecutive patients with type 1 retinopathy of prematurity (ROP) treated with intravitreal bevacizumab (IVB), whose ROP seemed to have resolved clinically. Methods: Data were retrospectively collected for all patients with IVB-treated type 1 ROP who underwent an exam under anesthesia (EUA) and FA at 60 weeks post-gestational age (PGA) or older at a tertiary medical center between 2011 and 2020. FA results were reviewed for pathological vascular findings. Results: Twenty-nine eyes of 16 patients were included. Mean gestational age and birth weight were 25.3 ± 1.5 weeks and 762.2 ± 189.8 g, respectively. The mean age at the time of EUA and FA was 23.4 ± 15.8 months. All eyes had a peripheral avascular zone and irregular peripheral branching. Vascular loops were seen in 27 eyes (93.1%) and vascular bulbs and anastomoses in 16 eyes each (55.2%). Additional abnormal findings included leakage (10 eyes, 34.5%), vessels crossing the fovea (5 eyes, 17.2%), tortuous arteries and veins (9 eyes, 31%, and 5 eyes, 17.2%, respectively), and neovascularization (2 eyes, 6.9%). When comparing patients who were less than or greater than 70 weeks PGA at follow-up, FA findings in the group with shorter follow-up were significant for more anastomoses and vascular bulbs (p = 0.002 and p = 0.024, respectively) and trended towards more leakage (45.5% vs. 27.8%, p = 0.331). Conclusion: The vast majority of IVB-treated type 1 ROP eyes suffered from vascular pathologies long after treatment. There may be long-term progression in the vascularization process of the retina in some cases. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Author KeywordsBevacizumab; Fluorescein angiography; Retinopathy of prematurity; Vasculature
Document Type: ArticlePublication Stage: Article in PressSource: Scopus