WashU weekly Neuroscience publications: April 16, 2023

BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy
(2023) The Journal of General Physiology, 155 (5), . 

Geng, Y.^a , Li, P.^b , Butler, A.^b , Wang, B.^b , Salkoff, L.^b c , Magleby, K.L.^a

^a Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, United States
^b Department of Neuroscience, Washington University St. Louis, St. Louis, MO, United States
^c Department of Genetics, Washington University St. Louis, St. Louis, MO, United States

Abstract
The molecular basis of a severe developmental and neurological disorder associated with a de novo G375R variant of the tetrameric BK channel is unknown. Here, we address this question by recording from single BK channels expressed to mimic a G375R mutation heterozygous with a WT allele. Five different types of functional BK channels were expressed: 3% were consistent with WT, 12% with homotetrameric mutant, and 85% with three different types of hybrid (heterotetrameric) channels assembled from both mutant and WT subunits. All channel types except WT showed a marked gain-of-function in voltage activation and a smaller decrease-of-function in single-channel conductance, with both changes in function becoming more pronounced as the number of mutant subunits per tetrameric channel increased. The net cellular response from the five different types of channels comprising the molecular phenotype was a shift of -120 mV in the voltage required to activate half of the maximal current through BK channels, giving a net gain-of-function. The WT and homotetrameric mutant channels in the molecular phenotype were consistent with genetic codominance as each displayed properties of a channel arising from only one of the two alleles. The three types of hybrid channels in the molecular phenotype were consistent with partial dominance as their properties were intermediate between those of mutant and WT channels. A model in which BK channels randomly assemble from mutant and WT subunits, with each subunit contributing increments of activation and conductance, approximated the molecular phenotype of the heterozygous G375R mutation. © 2023 Geng et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

Quantitative MRI identifies lesional and non-lesional abnormalities in MOGAD
(2023) Multiple Sclerosis and Related Disorders, 73, art. no. 104659, . 

Brier, M.R.^a , Xiang, B.^b , Ciotti, J.R.^a c , Chahin, S.^a , Wu, G.F.^a , Naismith, R.T.^a , Yablonskiy, D.^b , Cross, A.H.^a

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Neurology, University of South Florida, Tampa, FL, United States

Abstract
Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct central nervous system (CNS) disorder that shares features with multiple sclerosis (MS) and may be misdiagnosed as MS. MOGAD and MS share a frequently relapsing clinical course and lesions with inflammatory demyelinating pathology. One key feature of MS pathology is tissue damage in normal-appearing white matter (NAWM) outside of discrete lesions, whereas the extent to which similar non-lesional damage occurs in MOGAD is not known and could be assessed using qGRE. The goal of this study was to examine the brains of people with MOGAD using quantitative gradient-recalled echo (qGRE) magnetic resonance imaging and to compare tissue damage with MS patients matched for disability. Methods: MOGAD and MS patients were recruited to match in terms of age and disability. Similarly aged healthy control (HC) data were drawn from existing studies. qGRE brain imaging of HC (N = 15), MOGAD (N = 17), and MS (N = 15) patients was used to examine the severity and extent of tissue damage within and outside of discrete lesions. The qGRE metric R2t* is sensitive to changes in tissue microstructure and was measured in white matter lesions (WMLs), NAWM, cortical (CGM) and deep gray matter (DGM). Statistical inference was performed with linear models. Results: R2t* was reduced in CGM (p = 0.00047), DGM (p = 0.0055) and NAWM (p = 0.0019) in MOGAD and MS compared to similar regions in age-matched HCs. However, the degree of R2t* reduction in all these regions was less in the MOGAD patients compared with MS. WMLs in MOGAD demonstrated reduced R2t* compared to NAWM but this reduction was modest compared to changes associated with WMLs in MS (p = 0.026). Conclusion: These results demonstrate abnormalities in lesional and non-lesional CNS tissues in MOGAD that are not detectable on standard MRI. The abnormalities seen in NAWM, CGM, and DGM were less severe in MOGAD compared to MS. MOGAD-related WMLs showed reduced R2t*, but were less abnormal than WMLs in MS. These data reveal damage to non-lesional tissues in two different demyelinating diseases, suggesting that damage outside of WMLs may be a common feature of demyelinating diseases. The lesser degree of R2t* abnormality in MOGAD tissues compared to MS suggests less underlying tissue damage and may underlie the greater propensity for recovery in MOGAD. © 2023 Elsevier B.V.

Author Keywords
Multiple sclerosis;  Myelin oligodendrocyte glycoprotein antibody-associated disease;  qGRE;  Quantitative gradient recalled echo imaging

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD2R25NS090978-06, W81XWH-19-1-0820
National Institute of Neurological Disorders and StrokeNINDSR03 NS121960-01
National Multiple Sclerosis SocietyNMSSFG-1908-34882, FP-1907-34282, R01AG054513, RF1AG077658
Conrad N. Hilton FoundationCNHF
National Center for Advancing Translational SciencesNCATSKL2 TR002346
Foundation for Barnes-Jewish HospitalFBJH

Document Type: Article
Publication Stage: Final
Source: Scopus

Chemogenetic inhibition of amygdala excitatory neurons impairs rhEPO-enhanced contextual fear memory after TBI
(2023) Neuroscience Letters, 804, art. no. 137216, . 

Celorrio, M., Friess, S.H.

One Children’s Place, Department of Pediatrics, Washington University in St. Louis School of Medicine, Campus Box 8208, St. Louis, MO 63110, United States

Abstract
Erythropoietin (EPO) is a hypoxia-responsive cytokine that induces neuroprotective effect in hypoxic-ischaemic, traumatic, excitotoxic and inflammatory injuries. Recently, utilizing a clinically relevant murine model of TBI and delayed hypoxemia, we have found that ongoing recombinant human EPO (rhEPO) administration influenced neurogenesis, neuroprotection, synaptic density and, behavioral outcomes early after TBI, and the impact on long-lasting outcomes 6 months after injury. We also demonstrated that the 1-month behavioral improvement was associated with mitogen-activated protein kinase (MAPK)/cAMP response element-binding protein (CREB) signaling activation and increased of excitatory synaptic density in the amygdala. However, we did not uncover which type of cells were involved in fear memory response enhancement after rhEPO treatment in the setting of TBI with delayed hypoxemia. In this report, using chemogenetic tools in our controlled cortical impact (CCI) model, we were able to inactivate excitatory neurons and eliminate rhEPO-induced fear memory recall enhancement. In summary, these data demonstrate that rhEPO treatment initiated after TBI enhances contextual fear memory in the injured brain via activation of excitatory neurons in the amygdala. © 2023 Elsevier B.V.

Author Keywords
Designer receptors exclusively activated by designer drugs (DREADDs);  Erythropoietin;  Fear memory;  Hypoxemia;  Traumatic brain injury

Funding details
National Institutes of HealthNIHR01NS097721
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813

Document Type: Article
Publication Stage: Final
Source: Scopus

Liver pathology in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: vasculopathic disease beyond nodular regenerative hyperplasia
(2023) Human Pathology, 135, pp. 22-34. 

Khonde, P.^a , Chatterjee, D.^b , Bogacki, M.^c , Liszewski, M.K.^c , Ford, A.L.^d , Miner, J.J.^e , Atkinson, J.P.^c , Brunt, E.M.^a

^a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030, United States
^c Department of Medicine/Rheumatology Division, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, PA 19104, United States

Abstract
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare autosomal dominant disease resulting from a frame-shift mutation in TREX1, an intracellular 3′–5′ exonuclease 1. Hepatic findings include an elevated alkaline phosphatase (ALP) and nodular regenerative hyperplasia (NRH). Affected individuals typically succumb to brain lesions before clinically apparent hepatic manifestations; thus, little else is known about the hepatic pathology. Autopsy reports and a liver section from each (n = 11) of three unrelated kindreds with the most common mutation in TREX1 (V235Gfs∗6) were studied with standard and immunohistochemical stains. Cases were compared with “normal liver” controls from similar autopsy years. Cases consisted of six men and five women who died at a median age of 50 yr (range, 41–60 yr.). Seven had elevated ALP. Two had liver atrophy. Foci of NRH were variably detected in all. Inhomogeneous distribution of other findings included patternless parenchymal fibrous bands, approximation of vascular structures, and commonly, architectural changes of vascular structures. Only bile duct epithelia were unaffected. In addition, small trichrome-positive nodules were found along vein walls or isolated in the parenchyma. Rare foci of non-NRH hepatocytic nodules were noted in 3. Increased CD34 and altered α-SMA IHC expression were variably noted. Periportal ductules and perivenular K7 IHC expression were increased to unpredictable degrees. The extensive but inhomogeneous histopathologic findings in livers of autopsied patients with RVCL-S appear to involve hepatic vascular structures. These findings validate inclusion of vascular liver involvement beyond NRH in this complex hereditary disorder. © 2023 Elsevier Inc.

Author Keywords
Fibrosis;  Liver pathology;  Microvasculopathy;  Nodular regenerative hyperplasia;  RVCL-S;  TREX1 mutations

Document Type: Article
Publication Stage: Final
Source: Scopus

Transcriptomic cell type structures in vivo neuronal activity across multiple timescales
(2023) Cell Reports, 42 (4), art. no. 112318, . 

Schneider, A.^a , Azabou, M.^b , McDougall-Vigier, L.^a , Parks, D.F.^c , Ensley, S.^a , Bhaskaran-Nair, K.^a , Nowakowski, T.^d , Dyer, E.L.^b e , Hengen, K.B.^a

^a Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
^b School of Electrical & Computer Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States
^c Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, United States
^d Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, United States
^e Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States

Abstract
Cell type is hypothesized to be a key determinant of a neuron’s role within a circuit. Here, we examine whether a neuron’s transcriptomic type influences the timing of its activity. We develop a deep-learning architecture that learns features of interevent intervals across timescales (ms to >30 min). We show that transcriptomic cell-class information is embedded in the timing of single neuron activity in the intact brain of behaving animals (calcium imaging and extracellular electrophysiology) as well as in a bio-realistic model of the visual cortex. Further, a subset of excitatory cell types are distinguishable but can be classified with higher accuracy when considering cortical layer and projection class. Finally, we show that computational fingerprints of cell types may be universalizable across structured stimuli and naturalistic movies. Our results indicate that transcriptomic class and type may be imprinted in the timing of single neuron activity across diverse stimuli. © 2023 The Author(s)

Author Keywords
cell types;  CP: Neuroscience;  deep learning;  electrophysiology;  multihead attention;  optophysiology;  transcriptomics;  visual cortex

Funding details
National Science FoundationNSFIIS-2039741
National Institutes of HealthNIH1R01EB029852, 1R01NS118442
Alfred P. Sloan FoundationAPSF
McKnight Foundation
Washington University in St. LouisWUSTL

Document Type: Article
Publication Stage: Final
Source: Scopus

Plasma proteomics of SARS-CoV-2 infection and severity reveals impact on Alzheimer’s and coronary disease pathways
(2023) iScience, 26 (4), art. no. 106408, . 

Wang, L.^a b , Western, D.^a b , Timsina, J.^a b , Repaci, C.^a b , Song, W.-M.^c , Norton, J.^a b , Kohlfeld, P.^a b , Budde, J.^a b , Climer, S.^d , Butt, O.H.^e , Jacobson, D.^f , Garvin, M.^f , Templeton, A.R.^g , Campagna, S.^h , O’Halloran, J.ⁱ , Presti, R.ⁱ , Goss, C.W.^j , Mudd, P.A.^k , Ances, B.M.^e , Zhang, B.^c , Sung, Y.J.^a b j , Cruchaga, C.^a b l

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, United States
^c Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Department of Computer Science, University of Missouri-St. Louis, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^f Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States
^g Department of Biology, Washington University School of Medicine, St Louis, MO, United States
^h Department of Chemistry, University of Tennessee, Knoxville, TN, United States
ⁱ Division of Infectious Diseases, Washington University School of Medicine, St Louis, MO, United States
^j Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^k Department of Emergency Medicine, Washington University School of Medicine, St Louis, MO, United States
^l The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States

Abstract
Identification of proteins dysregulated by COVID-19 infection is critically important for better understanding of its pathophysiology, building prognostic models, and identifying new targets. Plasma proteomic profiling of 4,301 proteins was performed in two independent datasets and tested for the association for three COVID-19 outcomes (infection, ventilation, and death). We identified 1,449 proteins consistently associated in both datasets with any of these three outcomes. We subsequently created highly accurate models that distinctively predict infection, ventilation, and death. These proteins were enriched in specific biological processes including cytokine signaling, Alzheimer’s disease, and coronary artery disease. Mendelian randomization and gene network analyses identified eight causal proteins and 141 highly connected hub proteins including 35 with known drug targets. Our findings provide distinctive prognostic biomarkers for two severe COVID-19 outcomes, reveal their relationship to Alzheimer’s disease and coronary artery disease, and identify potential therapeutic targets for COVID-19 outcomes. © 2023 The Author(s)

Author Keywords
Biochemistry;  Biological sciences;  Disease;  Protein

Funding details
UL1TR002345
National Institutes of HealthNIHP01AG026276, P01AG03991, P30AG066444, R01AG044546, RF1AG053303, RF1AG058501, RF1AG074007, U01AG058922
National Cancer InstituteNCI
Alzheimer’s AssociationAA925002
GlaxoSmithKlineGSK
Biogen
National Center for Advancing Translational SciencesNCATS
Foundation for Barnes-Jewish HospitalFBJH
Washington University School of Medicine in St. LouisWUSM
Alvin J. Siteman Cancer CenterP30 CA091842
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZIZEN-22-848604

Document Type: Article
Publication Stage: Final
Source: Scopus

Neuronal birthdate reveals topography in a vestibular brainstem circuit for gaze stabilization
(2023) Current Biology, 33 (7), pp. 1265-1281.e7. 

Goldblatt, D.^a b , Huang, S.^a b , Greaney, M.R.^a c , Hamling, K.R.^a , Voleti, V.^d , Perez-Campos, C.^d , Patel, K.B.^d , Li, W.^d , Hillman, E.M.C.^d , Bagnall, M.W.^e , Schoppik, D.^a

^a Departments of Otolaryngology, Neuroscience & Physiology, and, the Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, United States
^b Center for Neural Science, New York University, New York, NY 10004, United States
^c University of Chicago, Chicago, IL 60637, United States
^d Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, United States
^e Department of Neuroscience, Washington University, St. Louis, MO 63130, United States

Abstract
Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Finally, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. Collectively, we find that development reveals previously hidden organization to the input, processing, and output layers of a highly conserved vertebrate sensorimotor circuit. The spatial and temporal attributes we uncover constrain the developmental mechanisms that may specify the fate, function, and organization of vestibulo-ocular reflex neurons. More broadly, our data suggest that, like invertebrates, temporal mechanisms may assemble vertebrate sensorimotor architecture. © 2023 The Author(s)

Author Keywords
circuit assembly;  development;  topography;  vestibular;  zebrafish

Funding details
National Institutes of HealthNIHF31DC019554, R00DC012775, R01DC017489, R56DC016316
National Institute on Deafness and Other Communication DisordersNIDCD
National Institute of Neurological Disorders and StrokeNINDSF99NS129179, T32NS086750, U01NS094296, UF1NS108213

Document Type: Article
Publication Stage: Final
Source: Scopus

Sphingomyelin 16:0 is a therapeutic target for neuronal death in acid sphingomyelinase deficiency
(2023) Cell Death & Disease, 14 (4), p. 248. 

Gaudioso, Á.^a , Jiang, X.^b , Casas, J.^c , Schuchman, E.H.^d , Ledesma, M.D.^a

^a Centro Biologia Molecular Severo Ochoa (CSIC-UAM)Madrid 28049, Spain
^b Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Barcelona, 08034, Spain
^d Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Abstract
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the SMPD1 gene encoding for the acid sphingomyelinase (ASM). While intravenous infusion of recombinant ASM is an effective treatment for the peripheral disease, the neurological complications of ASMD remain unaddressed. It has been shown that aberrantly high level of total brain sphingomyelin (SM) is a key pathological event leading to neurodegeneration. Using mice lacking ASM (ASMko), which mimic the disease, we here demonstrate that among the SM species, SM16:0 shows the highest accumulation and toxicity in ASMko neurons. By targeting lysosomes, SM16:0 causes permeabilization and exocytosis of these organelles and induces oxidative stress and cell death. We also show that genetic silencing of Ceramide Synthase 5, which is involved in SM16:0 synthesis and overexpressed in the ASMko brain, prevents disease phenotypes in ASMko cultured neurons and mice. The levels of SM16:0 in plasma also show a strong correlation with those in brain that is higher than in liver, even at early stages of the disease. These results identify SM16:0 both as a novel therapeutic target and potential biomarker of brain pathology in ASMD. © 2023. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Chronic brain damage in HIV-infected individuals under antiretroviral therapy is associated with viral reservoirs, sulfatide release, and compromised cell-to-cell communication
(2023) Cellular and Molecular Life Sciences: CMLS, 80 (4), p. 116. 

D’Amico, D.^a b , Barone, R.^b , Di Felice, V.^b , Ances, B.^c , Prideaux, B.^d , Eugenin, E.A.^e

^a Department of Neurobiology, The University of Texas Medical Branch (UTMB), Research Building 17, Fifth Floor, 11Th Street, Galveston, TX, 77555, USA
^b Department of Biomedicine, Neuroscience, Advanced Diagnostics (BiND), University of Palermo, Palermo, Italy
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurobiology, The University of Texas Medical Branch (UTMB), Research Building 17, Fifth Floor, 11Th Street, Galveston, TX, 77555, USA. brpridea@utmb.edu
^e Department of Neurobiology, The University of Texas Medical Branch (UTMB), Research Building 17, Fifth Floor, 11Th Street, Galveston, TX, 77555, USA. eleugeni@utmb.edu

Abstract
HIV infection has become a chronic and manageable disease due to the effective use of antiretroviral therapies (ART); however, several chronic aging-related comorbidities, including cognitive impairment, remain a major public health issue. However, these mechanisms are unknown. Here, we identified that glial and myeloid viral reservoirs are associated with local myelin damage and the release of several myelin components, including the lipid sulfatide. Soluble sulfatide compromised gap junctional communication and calcium wave coordination, essential for proper cognition. We propose that soluble sulfatide could be a potential biomarker and contributor to white matter compromise observed in HIV-infected individuals even in the current ART era. © 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Author Keywords
Calcium waves;  Cure;  Gap junctions;  HAND;  Mass spectrometry imaging;  Reservoirs;  White matter

Document Type: Article
Publication Stage: Final
Source: Scopus

Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma
(2023) Nature Communications, 14 (1), p. 1839. 

Chen, Z.^a b c , Soni, N.^d , Pinero, G.^a , Giotti, B.^d , Eddins, D.J.^b e , Lindblad, K.E.^a f g h , Ross, J.L.ⁱ , Puigdelloses Vallcorba, M.^a , Joshi, T.^a , Angione, A.^a , Thomason, W.^a , Keane, A.^a , Tsankova, N.M.^j , Gutmann, D.H.^k , Lira, S.A.^l , Lujambio, A.^a f g h , Ghosn, E.E.B.^b e , Tsankov, A.M.^d , Hambardzumyan, D.^a b c m

^a Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
^b Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Children’s Healthcare of Atlanta and Winship Cancer Institute, Atlanta, GA 30322, United States
^c Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, United States
^d Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
^e Department of Medicine, Lowance Center for Human Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, United States
^f Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
^g The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
^h Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
ⁱ Emory University Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, GA 30322, United States
^j Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
^k Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^l Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
^m Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

Abstract
Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genome editing, we generate a mouse model that is deficient of all monocyte chemoattractant proteins. Using this strain, we effectively abolish monocyte infiltration in genetically engineered murine models of de novo glioblastoma (GBM) and hepatocellular carcinoma (HCC), which show differential enrichment patterns for monocytes and neutrophils. Eliminating monocyte chemoattraction in monocyte enriched PDGFB-driven GBM invokes a compensatory neutrophil influx, while having no effect on Nf1-silenced GBM model. Single-cell RNA sequencing reveals that intratumoral neutrophils promote proneural-to-mesenchymal transition and increase hypoxia in PDGFB-driven GBM. We further demonstrate neutrophil-derived TNF-a directly drives mesenchymal transition in PDGFB-driven primary GBM cells. Genetic or pharmacological inhibiting neutrophils in HCC or monocyte-deficient PDGFB-driven and Nf1-silenced GBM models extend the survival of tumor-bearing mice. Our findings demonstrate tumor-type and genotype dependent infiltration and function of monocytes and neutrophils and highlight the importance of targeting them simultaneously for cancer treatments. © 2023. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Using synthetic MR images for distortion correction
(2023) Developmental Cognitive Neuroscience, 60, art. no. 101234, . 

Montez, D.F.^a b , Van, A.N.^a d , Miller, R.L.^a b , Seider, N.A.^a , Marek, S.^b , Zheng, A.^a , Newbold, D.J.^a c , Scheidter, K.^a b , Feczko, E.^e f , Perrone, A.J.^e g , Miranda-Dominguez, O.^e f , Earl, E.A.^e g , Kay, B.P.^a , Jha, A.K.^d h , Sotiras, A.^h i , Laumann, T.O.^b , Greene, D.J.^j , Gordon, E.M.^h , Tisdall, M.D.^k , van der Kouwe, A.^l m , Fair, D.A.^e f n , Dosenbach, N.U.F.^a d h o

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neurology, New York University Langone Medical Center, New York, NY 10016, United States
^d Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Masonic Institute for the Developing Brain, University of Minnesota Medical School, Minneapolis, MN 55455, United States
^f Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, United States
^g Department of Psychiatry, Oregon Health and Science University, Portland, OR 97239, United States
^h Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁱ Institute for Informatics, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Department of Cognitive Science, University of California, San Diego, La JollaCA 92093, United States
^k Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^l Department of Radiology, Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA 02129, United States
^m Department of Radiology, Harvard Medical School, Boston, MA 02115, United States
ⁿ Institute of Child Development, University of Minnesota Medical School, Minneapolis, MN 55455, United States
^o Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Functional MRI (fMRI) data acquired using echo-planar imaging (EPI) are highly distorted by magnetic field inhomogeneities. Distortion and differences in image contrast between EPI and T1-weighted and T2-weighted (T1w/T2w) images makes their alignment a challenge. Typically, field map data are used to correct EPI distortions. Alignments achieved with field maps can vary greatly and depends on the quality of field map data. However, many public datasets lack field map data entirely. Additionally, reliable field map data is often difficult to acquire in high-motion pediatric or developmental cohorts. To address this, we developed Synth, a software package for distortion correction and cross-modal image registration that does not require field map data. Synth combines information from T1w and T2w anatomical images to construct an idealized undistorted synthetic image with similar contrast properties to EPI data. This synthetic image acts as an effective reference for individual-specific distortion correction. Using pediatric (ABCD: Adolescent Brain Cognitive Development) and adult (MSC: Midnight Scan Club; HCP: Human Connectome Project) data, we demonstrate that Synth performs comparably to field map distortion correction approaches, and often outperforms them. Field map-less distortion correction with Synth allows accurate and precise registration of fMRI data with missing or corrupted field map information. © 2023 The Author(s)

Author Keywords
Distortion correction;  EPI;  Field map;  fMRI;  Registration

Funding details
National Institutes of HealthNIH1U54MH091657, U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
National Institute of Mental HealthNIMH
NIH Blueprint for Neuroscience Research
Neurosciences Research FoundationNRF
McDonnell Center for Systems Neuroscience
Jacobs Foundation2016121703

Document Type: Article
Publication Stage: Final
Source: Scopus

Lurasidone and risk of metabolic syndrome: Results from short and long-term studies in patients with bipolar depression
(2023) CNS Spectrums, 64 (5), . 

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

^a Sunovion Pharmaceuticals Inc., Fort Lee, NJ, United States
^b Sunovion Pharmaceuticals Inc., Marlborough, MA, United States
^c Thriving Mind South Florida, Miami, FL, United States
^d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Objective The elevated prevalence of metabolic syndrome (MetS) in patients with depression has been associated with increased mortality. This post hoc analysis assessed the effect of treatment with lurasidone on risk of MetS in patients with bipolar depression. Methods Data used in the current analyses consisted of 3 double-blind (DB), placebo-controlled, 6-week studies in adults with bipolar I depression (N = 1192), consisting of 1 monotherapy, and 2 adjunctive trials (lithium or valproate). Also analyzed was a 6-month open-label (OL) extension study (monotherapy, N = 316; adjunctive therapy, N = 497); and a 5-month, OL, stabilization phase followed by randomization to a 28-week DB, placebo-controlled, adjunctive therapy study with lurasidone (N = 490). MetS was defined based on NCEP ATP III criteria (2005 revision). Results The proportion of patients with new-onset MetS was similar for lurasidone vs placebo in the short-term studies (monotherapy, 13.9% vs 15.3%; adjunctive therapy, 13.6% vs 11.0%); and remained stable during both the 6-month extension phase study (monotherapy, 15.2%; adjunctive therapy, 16.9%), and the 5-month stabilization study (adjunctive therapy, 12.2%). After 28 weeks of DB treatment (following 5-month treatment in the stabilization study), new onset MetS was observed at endpoint (OC) in 26.2% of the lurasidone group, and 30.8% of the placebo group. Conclusions This post hoc analysis found that both short and long-term treatment with lurasidone was associated with a relatively low risk for the development of MetS in patients with bipolar I disorder. These findings are consistent with similar analyses in patients with schizophrenia. © The Author(s), 2023. Published by Cambridge University Press.

Author Keywords
Atypical antipsychotic;  bipolar disorder;  depressive disorder;  lurasidone;  metabolic syndrome

Funding details
National Institutes of HealthNIH
Substance Abuse and Mental Health Services AdministrationSAMHSA
Sunovion

Document Type: Article
Publication Stage: Final
Source: Scopus

Transient disruption of functional connectivity and depression of neural fluctuations in a mouse model of acute septic encephalopathy
(2023) Cerebral Cortex (New York, N.Y. : 1991), 33 (7), pp. 3548-3561. 

Brier, L.M.^a , Chen, S.^a , Sherafati, A.^b , Bice, A.R.^a , Lee, J.M.^c , Culver, J.P.^a b d e

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Physics, Washington University School of Arts and Science, St. Louis, MO 63110, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Biomedical Engineering, Washington University School of Engineering, St. Louis, MO 63110, United States
^e Department of Electrical and Systems Engineering, Washington University School of Engineering, St. Louis, MO 63110, United States

Abstract
Septic encephalopathy leads to major and costly burdens for a large percentage of admitted hospital patients. Elderly patients are at an increased risk, especially those with dementia. Current treatments are aimed at sedation to combat mental status changes and are not aimed at the underlying cause of encephalopathy. Indeed, the underlying pathology linking together peripheral infection and altered neural function has not been established, largely because good, acutely accessible readouts of encephalopathy in animal models do not exist. Behavioral testing in animals lasts multiple days, outlasting the time frame of acute encephalopathy. Here, we propose optical fluorescent imaging of neural functional connectivity (FC) as a readout of encephalopathy in a mouse model of acute sepsis. Imaging and basic behavioral assessment were performed at baseline, Hr8, Hr24, and Hr72 following injection of either lipopolysaccharide or phosphate buffered saline. Neural FC strength decreased at Hr8 and returned to baseline by Hr72 in motor, somatosensory, parietal, and visual cortical regions. Additionally, neural fluctuations transiently declined at Hr8 and returned to baseline by Hr72. Both FC strength and fluctuation tone correlated with neuroscore indicating this imaging methodology is a sensitive and acute readout of encephalopathy. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
acute septic encephalopathy;  calcium neuroimaging;  functional connectivity;  mouse models

Document Type: Article
Publication Stage: Final
Source: Scopus

Using Wearable Sensors to Assess Freezing of Gait in the Real World
(2023) Bioengineering, 10 (3), art. no. 289, . 

May, D.S.^a , Tueth, L.E.^a , Earhart, G.M.^a b c , Mazzoni, P.^b

^a Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63108, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Freezing of gait (FOG) is a debilitating symptom of Parkinson’s disease (PD) that remains difficult to assess. Wearable movement sensors and associated algorithms can be used to quantify FOG in laboratory settings, but the utility of such methods for real world use is unclear. We aimed to determine the suitability of our wearable sensor-based FOG assessment method for real world use by assessing its performance during in-clinic simulated real world activities. Accuracy of the sensor-based method during simulated real-world tasks was calculated using expert rated video as the gold standard. To determine feasibility for unsupervised home use, we also determined correlations between the percent of active time spent freezing (%ATSF) during unsupervised home use and in-clinic activities. Nineteen people with PD and FOG participated in this study. Results from our sensor-based method demonstrated an accuracy above 90% compared to gold-standard expert review during simulated real-world tasks. Additionally, %ATSF from our sensor-based method during unsupervised home use correlated strongly with %ATSF from our sensor-based method during in-clinic simulated real-world activities (ρ = 0.73). Accuracy values and correlation patterns suggest our method may be useful for FOG assessment in the real world. © 2023 by the authors.

Author Keywords
freezing of gait;  gait;  home environment;  Parkinson’s disease;  sensors for rehabilitation;  wearable sensors

Document Type: Article
Publication Stage: Final
Source: Scopus

Multi-omics cannot replace sample size in genome-wide association studies
(2023) Genes, Brain and Behavior, . 

Baranger, D.A.A.^a , Hatoum, A.S.^b , Polimanti, R.^c d , Gelernter, J.^c d e f , Edenberg, H.J.^g h , Bogdan, R.^a , Agrawal, A.^b

^a Department of Psychological & Brain Sciences, Washington University in St. Louis Medical School, Saint Louis, MO, United States
^b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Psychiatry, Division of Human Genetics, Yale School of Medicine, New Haven, CT, United States
^d Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
^e Department of Genetics, Yale School of Medicine, New Haven, CT, United States
^f Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
^g Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
^h Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract
The integration of multi-omics information (e.g., epigenetics and transcriptomics) can be useful for interpreting findings from genome-wide association studies (GWAS). It has been suggested that multi-omics could circumvent or greatly reduce the need to increase GWAS sample sizes for novel variant discovery. We tested whether incorporating multi-omics information in earlier and smaller-sized GWAS boosts true-positive discovery of genes that were later revealed by larger GWAS of the same/similar traits. We applied 10 different analytic approaches to integrating multi-omics data from 12 sources (e.g., Genotype-Tissue Expression project) to test whether earlier and smaller GWAS of 4 brain-related traits (alcohol use disorder/problematic alcohol use, major depression/depression, schizophrenia, and intracranial volume/brain volume) could detect genes that were revealed by a later and larger GWAS. Multi-omics data did not reliably identify novel genes in earlier less-powered GWAS (PPV <0.2; 80% false-positive associations). Machine learning predictions marginally increased the number of identified novel genes, correctly identifying 1–8 additional genes, but only for well-powered early GWAS of highly heritable traits (i.e., intracranial volume and schizophrenia). Although multi-omics, particularly positional mapping (i.e., fastBAT, MAGMA, and H-MAGMA), can help to prioritize genes within genome-wide significant loci (PPVs = 0.5–1.0) and translate them into information about disease biology, it does not reliably increase novel gene discovery in brain-related GWAS. To increase power for discovery of novel genes and loci, increasing sample size is required. © 2023 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Author Keywords
genetics;  GWAS;  human;  multi-omics;  sample size;  transcriptomics

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

Developmental trajectories of behavioral inhibition from infancy to age seven: The role of genetic and environmental risk for psychopathology
(2023) Child Development, . 

Anaya, B.^a b , Neiderhiser, J.M.^a , Pérez-Edgar, K.^a , Leve, L.D.^c , Ganiban, J.M.^d , Reiss, D.^e , Natsuaki, M.N.^f , Shaw, D.S.^g

^a The Pennsylvania State University, State College, PA, United States
^b Washington University in St. Louis, St. Louis, MO, United States
^c University of Oregon, Eugene, OR, United States
^d George Washington University, Washington, DC, United States
^e Yale Child Study Center, Yale University School of Medicine, New Haven, CT, United States
^f University of California Riverside, Riverside, CA, United States
^g University of Pittsburgh, Pittsburgh, PA, United States

Abstract
The present study leveraged data from a longitudinal adoption study of 361 families recruited between 2003 and 2010 in the United States. We investigated how psychopathology symptoms in birth parents (BP; Mage = 24.1 years; 50.5–62.9% completed high school) and adoptive parents (AP; Mage = 37.8 years; 80.9% completed college; 94% mother–father couples) influenced children’s behavioral inhibition (BI) trajectories. We used latent growth models of observed BI at 18 and 27 months, and 4.5 and 7 years in a sample of adopted children (Female = 42%, White = 57%, Black = 11%, Multi-racial = 21%, Latinx = 9%). BI generally decreased over time, yet there was substantial variability in these trajectories. Neither BP nor AP psychopathology symptoms independently predicted systematic differences in BI trajectories. Instead, we found that AP internalizing symptoms moderated the effects of BP psychopathology on trajectories of BI, indicating a gene by environment interaction. © 2023 The Authors. Child Development published by Wiley Periodicals LLC on behalf of Society for Research in Child Development.

Funding details
R01DA020585
National Institutes of HealthNIH
National Institute of Mental HealthNIMHR01 DA045108, R01 MH092118, UH3 OD023389
National Institute on Drug AbuseNIDA
National Institute of Neurological Disorders and StrokeNINDSR01 MH094633
National Institute of Child Health and Human DevelopmentNICHD
Office of Behavioral and Social Sciences ResearchOBSSR
Office of the DirectorODF99NS120411

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

Quantitative determination of SLC2A1 variant functional effects in GLUT1 deficiency syndrome
(2023) Annals of Clinical and Translational Neurology, . 

Tayebi, N.^a , Leon-Ricardo, B.^a , McCall, K.^a , Mehinovic, E.^b , Engelstad, K.^c , Huynh, V.^c , Turner, T.N.^b , Weisenberg, J.^a , Thio, L.L.^a , Hruz, P.^d , Williams, R.S.B.^e , De Vivo, D.C.^c , Petit, V.^f , Haller, G.^a b g , Gurnett, C.A.^a

^a Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^b Department of Genetics, Washington University in St Louis, St Louis, MO, United States
^c Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^d Department of Pediatrics, Washington University in St Louis, St Louis, MO, United States
^e Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom
^f Metafora Biosystems, Paris, France
^g Department of Neurological Surgery, Washington University in St Louis, St Louis, MO, United States

Abstract
Objective: The goal of this study is to demonstrate the utility of a growth assay to quantify the functional impact of single nucleotide variants (SNVs) in SLC2A1, the gene responsible for Glut1DS. Methods: The functional impact of 40 SNVs in SLC2A1 was quantitatively determined in HAP1 cells in which SLC2A1 is required for growth. Donor libraries were introduced into the endogenous SLC2A1 gene in HAP1-Lig4KO cells using CRISPR/Cas9. Cell populations were harvested and sequenced to quantify the effect of variants on growth and generate a functional score. Quantitative functional scores were compared to 3-OMG uptake, SLC2A1 cell surface expression, CADD score, and clinical data, including CSF/blood glucose ratio. Results: Nonsense variants (N = 3) were reduced in cell culture over time resulting in negative scores (mean score: −1.15 ± 0.17), whereas synonymous variants (N = 10) were not depleted (mean score: 0.25 ± 0.12) (P < 2e-16). Missense variants (N = 27) yielded a range of functional scores including slightly negative scores, supporting a partial function and intermediate phenotype. Several variants with normal results on either cell surface expression (p.N34S and p.W65R) or 3-OMG uptake (p.W65R) had negative functional scores. There is a moderate but significant correlation between our functional scores and CADD scores. Interpretation: Cell growth is useful to quantitatively determine the functional effects of SLC2A1 variants. Nonsense variants were reliably distinguished from benign variants in this in vitro functional assay. For facilitating early diagnosis and therapeutic intervention, future work is needed to determine the functional effect of every possible variant in SLC2A1. © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Funding details
National Institutes of HealthNIHP50 HD103525
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSR01AR067715
National Center for Advancing Translational SciencesNCATS
Washington University in St. LouisWUSTL
University of WashingtonUW
Institute of Clinical and Translational SciencesICTSUL1TR002345
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Glut1 Deficiency FoundationG1D
Orphan Disease Center, Perelman School of Medicine, University of PennsylvaniaODC
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis

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

Rest-Activity Rhythm Characteristics Associated With Depression Symptoms in Stroke Survivors
(2023) Archives of Physical Medicine and Rehabilitation, . 

Stahl, S.T.^a , Skidmore, E.^b , Kringle, E.^c , Shih, M.^b , Baum, C.^d , Hammel, J.^e , Krafty, R.^f , Covassin, N.^g , Li, J.^g h , Smagula, S.F.^a i

^a Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
^b Department of Occupational Therapy, School of Health and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States
^c Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
^d Program in Occupational Therapy, School of Medicine, Washington University, St. Louis, MO, United States
^e Department of Occupational Therapy, College of Allied Health Sciences, University of Illinois at Chicago, Chicago, IL, United States
^f Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, United States
^g Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States
^h Department of Cardiovascular Medicine, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
ⁱ Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Objective: To examine which 24-hour rest-activity rhythm (RAR) characteristics are associated with depression symptoms in stroke survivors. Design: Cross-sectional observational study examining associations of RAR characteristics with the presence of depression symptoms adjusting for age, sex, race, and medical comorbidity. Setting: Community setting. Participants: Stroke survivors: (1) recruited locally (N women=35, N men=28) and (2) a nationally representative probability sample (the National Health and Nutrition Examination Survey [NHANES]; N women=156, N men=124). Interventions: None. Measurements: Objective RAR characteristics derived from accelerometer recordings including activity onset/offset times and non-parametric measures of RAR strength (relative amplitude), stability (interdaily stability), and fragmentation (intradaily variability). The presence of depression symptoms was categorized using Patient Health Questionnaire scores. Results: In both samples, the only RAR characteristic associated with depression symptoms was intradaily variability (fragmentation): local sample, odds ratio=1.96 [95% confidence interval=1.05-3.63]; NHANES sample, odds ratio=1.34, [95% confidence interval=1.01-1.78]). In the NHANES sample, which included both mild and moderate/severe depression, the association between 24-hour sleep-wake fragmentation and depression symptoms was driven by moderate-to-severe cases. Conclusions: Stroke survivors with higher levels of RAR fragmentation were more likely to have depression symptoms in both samples. These findings have implications, given prior studies in general samples linking RAR fragmentation with future depression and dementia risk. Research is needed to establish the potential consequences, mechanisms, and modifiability of RAR fragmentation in stroke survivors. © 2023 American Congress of Rehabilitation Medicine

Author Keywords
Actigraphy;  Depression;  Rehabilitation;  Sleep;  Stroke

Funding details
National Institutes of HealthNIHR41AG069596, UL1TR001857
Pittsburgh FoundationPF
School of Health and Rehabilitation Sciences, University of PittsburghSHRS

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

Predictive Utility of Irritability “In Context”: Proof-of-Principle for an Early Childhood Mental Health Risk Calculator
(2023) Journal of Clinical Child and Adolescent Psychology, . 

Wakschlag, L.S.^a b , MacNeill, L.A.^a b , Pool, L.R.^c , Smith, J.D.^d , Adam, H.^a , Barch, D.M.^e f g , Norton, E.S.^a b h , Rogers, C.E.^f i , Ahuvia, I.^j , Smyser, C.D.^g i k , Luby, J.L.^f , Allen, N.B.^b c

^a Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, United States
^b Institute for Innovations in Developmental Sciences, Northwestern University, United States
^c Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, United States
^d Department of Population Health Sciences, Spencer Fox Eccles School of Medicine at University of Utah, United States
^e Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
^f Department of Psychiatry, Washington University School of Medicine, United States
^g Mallinckrodt Institute of Radiology, Washington University School of Medicine, United States
^h Department of Communication Sciences and Disorders, Northwestern University, United States
ⁱ Department of Pediatrics, Washington University School of Medicine, United States
^j Department of Clinical Psychology, Stony Brook University, United States
^k Department of Neurology, Washington University School of Medicine, United States

Abstract
Objective: We provide proof-of-principle for a mental health risk calculator advancing clinical utility of the irritability construct for identification of young children at high risk for common, early onsetting syndromes. Method: Data were harmonized from two longitudinal early childhood subsamples (total N = 403; 50.1% Male; 66.7% Nonwhite; Mage = 4.3 years). The independent subsamples were clinically enriched via disruptive behavior and violence (Subsample 1) and depression (Subsample 2). In longitudinal models, epidemiologic risk prediction methods for risk calculators were applied to test the utility of the transdiagnostic indicator, early childhood irritability, in the context of other developmental and social-ecological indicators to predict risk of internalizing/externalizing disorders at preadolescence (Mage = 9.9 years). Predictors were retained when they improved model discrimination (area under the receiver operating characteristic curve [AUC] and integrated discrimination index [IDI]) beyond the base demographic model. Results: Compared to the base model, the addition of early childhood irritability and adverse childhood experiences significantly improved the AUC (0.765) and IDI slope (0.192). Overall, 23% of preschoolers went on to develop a preadolescent internalizing/externalizing disorder. For preschoolers with both elevated irritability and adverse childhood experiences, the likelihood of an internalizing/externalizing disorder was 39–66%. Conclusions: Predictive analytic tools enable personalized prediction of psychopathological risk for irritable young children, holding transformative potential for clinical translation. © 2023 Society of Clinical Child and Adolescent Psychology, Division 53, American Psychological Association. All Rights Reserved.

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

Julia for biologists
(2023) Nature Methods, . 

Roesch, E.^a b , Greener, J.G.^c , MacLean, A.L.^d , Nassar, H.^e , Rackauckas, C.^f g h , Holy, T.E.ⁱ , Stumpf, M.P.H.^a b j k

^a School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, Australia
^b Melbourne Integrative Genomics, University of Melbourne, Melbourne, VIC, Australia
^c Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
^d Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, United States
^e RelationalAI, Berkeley, CA, United States
^f Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, United States
^g Julia Computing, Somerville, MA, United States
^h Pumas-AI, Centreville, VA, United States
ⁱ Departments of Neuroscience and Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^j School of BioSciences, The University of Melbourne, Melbourne, VIC, Australia
^k ARC Centre of Excellence for the Mathematical Analysis of Cellular Systems, Melbourne, VIC, Australia

Abstract
Major computational challenges exist in relation to the collection, curation, processing and analysis of large genomic and imaging datasets, as well as the simulation of larger and more realistic models in systems biology. Here we discuss how a relative newcomer among programming languages—Julia—is poised to meet the current and emerging demands in the computational biosciences and beyond. Speed, flexibility, a thriving package ecosystem and readability are major factors that make high-performance computing and data analysis available to an unprecedented degree. We highlight how Julia’s design is already enabling new ways of analyzing biological data and systems, and we provide a list of resources that can facilitate the transition into Julian computing. © 2023, Springer Nature America, Inc.

Funding details
National Science FoundationNSFDMS 2045327
National Institutes of HealthNIH1UF1NS108176
Advanced Research Projects Agency – EnergyARPA-EDE-AR0001211, DE-AR0001222, IIP-1938400
Australian Research CouncilARC
Volkswagen Foundation93063
University of MelbourneUNIMELB

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

A practitioner’s guide to geospatial analysis in a neuroimaging context
(2023) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 15 (1), art. no. e12413, . 

Wisch, J.K.^a , Babulal, G.M.^a b c , Petersen, K.^a , Millar, P.R.^a , Shacham, E.^d , Scroggins, S.^d , Boerwinkle, A.H.^a , Flores, S.^e , Keefe, S.^e , Gordon, B.A.^e f g , Morris, J.C.^a f , Ances, B.M.^a e f g

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
^c Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
^d Taylor Geospatial Institute, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO, United States
^e Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^f Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
^g Center for Clinical Studies, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Introduction: Health disparities arise from biological-environmental interactions. Neuroimaging cohorts are reaching sufficiently large sample sizes such that analyses could evaluate how the environment affects the brain. We present a practical guide for applying geospatial methods to a neuroimaging cohort. Methods: We estimated brain age gap (BAG) from structural magnetic resonance imaging (MRI) from 239 city-dwelling participants in St. Louis, Missouri. We compared these participants to population-level estimates from the American Community Survey (ACS). We used geospatial analysis to identify neighborhoods associated with patterns of altered brain structure. We also evaluated the relationship between Area Deprivation Index (ADI) and BAG. Results: We identify areas in St. Louis, Missouri that were significantly associated with higher BAG from a spatially representative cohort. We provide replication code. Conclusion: We observe a relationship between neighborhoods and brain health, which suggests that neighborhood-based interventions could be appropriate. We encourage other studies to geocode participant information to evaluate biological-environmental interaction. © 2023 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer’s Association.

Author Keywords
brain imaging;  epidemiologic methods;  magnetic resonance imaging

Funding details
National Institutes of HealthNIHF32MH129151, K01 AG053474, P01AG003991, P01AG026276, P30 AG066444, R01DA054009, R01MH118031, R01NR012657, R01NR012907, R01NR014449, U19 AG024904, U19 AG032438
Institute of Clinical and Translational SciencesICTSUL1 TR000448
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZI

Document Type: Article
Publication Stage: Final
Source: Scopus

Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-β monoclonal antibodies in dominantly inherited Alzheimer’s disease
(2023) European Journal of Nuclear Medicine and Molecular Imaging, . 

Chen, C.D.^a b , McCullough, A.^a , Gordon, B.^a , Joseph-Mathurin, N.^a , Flores, S.^a , McKay, N.S.^a , Hobbs, D.A.^a , Hornbeck, R.^a , Fagan, A.M.^c , Cruchaga, C.^d , Goate, A.M.^e , Perrin, R.J.^c f , Wang, G.^g , Li, Y.^c , Shi, X.^c , Xiong, C.^g , Pontecorvo, M.J.^h i , Klein, G.^j , Su, Y.^k l , Klunk, W.E.^m , Jack, C.ⁿ , Koeppe, R.^o , Snider, B.J.^c , Berman, S.B.^p , Roberson, E.D.^q , Brosch, J.^r , Surti, G.^s , Jiménez-Velázquez, I.Z.^t , Galasko, D.^u , Honig, L.S.^v , Brooks, W.S.^w , Clarnette, R.^x , Wallon, D.^y , Dubois, B.^z aa ab , Pariente, J.^ac ad , Pasquier, F.^ae af , Sanchez-Valle, R.^ag , Shcherbinin, S.ⁱ , Higgins, I.ⁱ , Tunali, I.ⁱ , Masters, C.L.^ah , van Dyck, C.H.^ai , Masellis, M.^aj , Hsiung, R.^ak , Gauthier, S.^al , Salloway, S.^am , Clifford, D.B.^c , Mills, S.^c , Supnet-Bell, C.^c , McDade, E.^c , Bateman, R.J.^c , Benzinger, T.L.S.^a , for the DIAN-TU Study Team^an

^a Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^b Washington University School of Medicine, 660 South Euclid, Campus Box 8225, St. Louis, MO 63110, United States
^c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Genetics and Genomic Sciences, Ichan School of Medicine at Mount Sinai, New York, NY, United States
^f Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^h Avid Radiopharmaceuticals, Philadelphia, PA, United States
ⁱ Eli Lilly and Company, Indianapolis, IN, United States
^j F. Hoffmann-La Roche Ltd., Basel, Switzerland
^k Banner Alzheimer’s Institute, Banner Health, Phoenix, AZ, United States
^l Arizona Alzheimer’s Consortium, Phoenix, AZ, United States
^m Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
ⁿ Department of Radiology, Mayo Clinic, Rochester, MN, United States
^o Department of Radiology, University of Michigan, Ann Arbor, MI, United States
^p Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
^q Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
^r Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
^s Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, United States
^t Department of Medicine, University of Puerto Rico School of Medicine, San Juan, PR, United States
^u Department of Neurology, University of California San Diego, San Diego, CA, United States
^v Department of Neurology, Columbia University, New York, NY, United States
^w Prince of Wales Medical Research Institute, University of New South Wales, Sydney, NSW, Australia
^x Department of Internal Medicine, University of Western Australia, Crawley, WA, Australia
^y Department of Neurology and CNR-MAJ, Normandie Univ, UNIROUEN, INSERM U1245, CHU Rouen, Rouen, F-76000, France
^z Sorbonne Université, AP-HP, GRC No. 21, APM, Hôpital de La Pitié-Salpêtrière, Paris, France
^aa Institut du Cerveau Et de La Moelle Épinière, INSERM U1127, CNRS UMR 7225, Paris, France
^ab Institut de La Mémoire Et de La Maladie d’Alzheimer, Département de Neurologie, Hôpital de La Pitié-Salpêtrière, Paris, France
^ac Department of Neurology, Hôpital Pierre-Paul Riquet, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
^ad Toulouse NeuroImaging Centre, Université de Toulouse, INSERM, UPS, Toulouse, France
^ae Univ. Lille, INSERM, CHU Lille, Lille, 59000, France
^af CNR-MAJ, Labex DISTALZ, LiCEND, Lille, 59000, France
^ag Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital ClínicInstitut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Fundació Clínic Per a La Recerca Biomèdica, University of Barcelona, Barcelona, Spain
^ah The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
^ai Yale School of Medicine, New Haven, CT, United States
^aj Sunnybrook Research Institute, Toronto, ON, Canada
^ak Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
^al Douglas Mental Health University Institute, Montreal, QC, Canada
^am Alpert Medical School of Brown University, Providence, RI, United States

Abstract
Purpose: Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-β (Aβ) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer’s disease (AD) clinical trials to evaluate the efficacy of anti-Aβ monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aβ radiotracers were used. To study the consequences of using different Aβ radiotracers to measure Aβ clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aβ monoclonal antibodies. Methods: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aβ PET imaging. Results: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aβ radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aβ radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aβ radiotracers were used versus trials where only one Aβ radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. Conclusion: Gantenerumab treatment induces longitudinal changes in Aβ PET, and the absolute rates of these longitudinal changes differ significantly between Aβ radiotracers. These differences were not seen in the placebo arm, suggesting that Aβ-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aβ radiotracers. Our results suggest converting Aβ PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aβ PET biomarker data and, if feasible, use a single radiotracer for the best results. Trial registration: ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
18F-florbetapir;  Dominantly inherited Alzheimer’s disease;  Gantenerumab;  Pittsburgh compound B

Funding details
R01AG046179, R01AG53267-S1, U01AG042791, U01AG042791-S1
P30NS098577
National Science FoundationNSFDGE-1745038, DGE-2139839
National Institutes of HealthNIHR01AG052550-01A1, U19AG032438
Alzheimer’s AssociationAAAARF-21–722022, AARFD-20–681815
Roche
BrightFocus FoundationBFFA2022013F
Avid Radiopharmaceuticals
GHR FoundationGHR
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. LouisKGAD5T32AG058518-04

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

Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving reldesemtiv or placebo in FORTITUDE-ALS
(2023) Journal of Medical Economics, 26 (1), pp. 488-493. 

Gebrehiwet, P.^a , Meng, L.^a , Rudnicki, S.A.^a , Sarocco, P.^a , Wei, J.^a , Wolff, A.A.^a , Butzner, M.^a , Chiò, A.^b , Andrews, J.A.^c , Genge, A.^d , Hughes, D.A.^e , Jackson, C.E.^f , Lechtzin, N.^g , Miller, T.M.^h , Shefner, J.M.^i j

^a Cytokinetics, Incorporated, South San Francisco, CA, United States
^b ‘Rita Levi Montalcini’ Department of Neuroscience, University of Turin, Turin, Italy
^c The Neurological Institute of New York, Columbia University Irving Medical Center, New York, NY, USA
^d Clinical Research Unit, Montreal Neurological Institute-Hospital, Montreal, QC, Canada
^e Centre for Health Economics & Medicines Evaluation, School of Medical and Health Sciences, Bangor University, Bangor, United Kingdom
^f Department of Neurology, University of Texas Health Science Center at San AntonioTX, United States
^g Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^h Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Barrow Neurological Institute, University of Arizona, Phoenix, AZ, United States
^j Department of Neurology, Creighton University, Phoenix, AZ, United States

Abstract
AIMS: To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving reldesemtiv versus placebo in FORTITUDE-ALS. MATERIALS AND METHODS: We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated reldesemtiv in patients with ALS. Health utilities from the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) were estimated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores collected during the trial. QALYs were estimated using the area under the curve method. RESULTS: The full analysis set consisted of 456 patients (reldesemtiv n = 342, placebo n = 114), who received at least one dose of the double-blind study drug, and had ALSFRS-R assessed at baseline and at least one post-baseline assessment. The difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% confidence interval [CI]: 0.01, 0.05; p = .0008). The incremental QALY of reldesemtiv versus placebo adjusted for baseline utility values showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058). CONCLUSIONS: This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings. CLINICALTRIALS.GOV IDENTIFIER: NCT03160898.

Author Keywords
ALS;  amyotrophic lateral sclerosis;  EQ-5D-5L;  health utilities;  I;  I1;  I10;  I19;  Randomized clinical trial;  reldesemtiv

Document Type: Article
Publication Stage: Final
Source: Scopus

Meditation Practice, Mindfulness, and Pain-Related Outcomes in Mindfulness-Based Treatment for Episodic Migraine
(2023) Mindfulness, . 

Hunt, C.A.^a b , Letzen, J.E.^a , Krimmel, S.R.^c , Burrowes, S.A.B.^d e , Haythornthwaite, J.A.^a , Keaser, M.^e f , Reid, M.^a , Finan, P.H.^a b , Seminowicz, D.A.^e f

^a Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Department of Anesthesiology, University of Virginia, Charlottesville, VA, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, MA 02218, United States
^e Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD 21201, United States
^f Center to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, MD 21201, United States

Abstract
Objectives: Mindfulness-based interventions (MBIs) have emerged as promising prophylactic episodic migraine treatments. The present study investigated biopsychosocial predictors and outcomes associated with formal, daily-life meditation practice in migraine patients undergoing MBI, and whether augmented mindfulness mechanistically underlies change. Methods: Secondary analyses of clinical trial data comparing a 12-week enhanced mindfulness-based stress reduction course (MBSR + ; n = 50) to stress management for headache (SMH; n = 48) were conducted. Results: Pre-treatment mesocorticolimbic system functioning (i.e., greater resting state ventromedial prefrontal cortex-right nucleus accumbens [vmPFC-rNAC] functional connectivity) predicted greater meditation practice duration over MBSR + (r = 0.58, p = 0.001), as well as the change in headache frequency from pre- to post-treatment (B = − 12.60, p = 0.02) such that MBSR + participants with greater vmPFC-rNAC connectivity showed greater reductions in headache frequency. MBSR + participants who meditated more showed greater increases in mindfulness (B = 0.52, p = 0.02) and reductions in the helplessness facet of pain catastrophizing (B = − 0.13, p = 0.01), but not headache frequency, severity, or impact. Augmented mindfulness mediated reductions in headache impact resulting from MBSR + , but not headache frequency. Conclusions: Mesocorticolimbic system function is implicated in motivated behavior, and thus, motivation-enhancing interventions might be delivered alongside mindfulness-based training to enhance meditation practice engagement. Formal, daily-life meditation practice duration appears to benefit pain-related cognitions, but not clinical pain, while mindfulness emerges as a mechanism of MBIs on headache impact, but not frequency. Further research is needed to investigate the day-to-day effects of formal, daily-life meditation practice on pain, and continue to characterize the specific mechanisms of MBIs on headache outcomes. Preregistration: This study is not preregistered. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Headache;  Home practice;  Meditation practice;  Mindfulness;  Motivation

Funding details
National Institutes of HealthNIHR01AT007176, T32NS070201

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

Chromatin access regulates the formation of Müller glia-derived progenitor cells in the retina
(2023) GLIA, . 

Campbell, W.A.^a , El-Hodiri, H.M.^a , Torres, D.^a , Hawthorn, E.C.^a , Kelly, L.E.^a , Volkov, L.^b , Akanonu, D.^c , Fischer, A.J.^a

^a Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^c Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States

Abstract
Chromatin access and epigenetic control over gene expression play important roles in regulating developmental processes. However, little is known about how chromatin access and epigenetic gene silencing influence mature glial cells and retinal regeneration. Herein, we investigate the expression and functions of S-adenosylhomocysteine hydrolase (SAHH; AHCY) and histone methyltransferases (HMTs) during the formation of Müller glia (MG)-derived progenitor cells (MGPCs) in the chick and mouse retinas. In chick, AHCY, AHCYL1 and AHCYL2, and many different HMTs are dynamically expressed by MG and MGPCs in damaged retinas. Inhibition of SAHH reduced levels of H3K27me3 and potently blocks the formation of proliferating MGPCs. By using a combination of single cell RNA-seq and single cell ATAC-seq, we find significant changes in gene expression and chromatin access in MG with SAHH inhibition and NMDA-treatment; many of these genes are associated with glial and neuronal differentiation. A strong correlation across gene expression, chromatin access, and transcription factor motif access in MG was observed for transcription factors known to convey glial identity and promote retinal development. By comparison, in the mouse retina, inhibition of SAHH has no influence on the differentiation of neuron-like cells from Ascl1-overexpressing MG. We conclude that in the chick the activity of SAHH and HMTs are required for the reprogramming of MG into MGPCs by regulating chromatin access to transcription factors associated with glial differentiation and retinal development. © 2023 The Authors. GLIA published by Wiley Periodicals LLC.

Funding details
National Institutes of HealthNIHRO1 EY022030‐10

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

Exercise Training to Improve Brain Health in Older People Living With HIV: Study Protocol for a Randomized Controlled Trial
(2023) JMIR Research Protocols, 12, art. no. e41421, . 

Cooley, S.^a , Nelson, B.M.^a , Rosenow, A.^a , Westerhaus, E.^a , Cade, W.T.^b , Reeds, D.N.^c , Vaida, F.^d , Yarasheski, K.E.^e , Paul, R.H.^f , Ances, B.M.^a g

^a Department of Neurology, School of Medicine, Washington University in St. Louis, Saint Louis, MO, United States
^b Physical Therapy Division, Duke University, School of Medicine, Durham, NC, United States
^c Department of Medicine, The Center for Human Nutrition, Washington University in St. Louis, Saint Louis, MO, United States
^d Division of Biostatistics and Bioinformatics, School of Public Health, University of California San Diego, San Diego, CA, United States
^e Division of Endocrinology, School of Medicine, Washington University in Saint Louis, Saint Louis, MO, United States
^f Department of Psychology, University of Missouri St. Louis, Saint Louis, MO, United States
^g Department of Radiology, School of Medicine, Washington University in St. Louis, Saint Louis, MO, United States

Abstract
Background: With the advent of antiretrovirals, people living with HIV are living near-normal lifespans. However, people living with HIV are at greater risk of experiencing cognitive impairment and reduced brain integrity despite well-controlled viremia. A robust literature supports exercise interventions as a method of improving cognition and structural brain integrity in older individuals without HIV. The effects of exercise on cardiometabolic, neurocognitive, and neural structures in middle-aged to older people living with HIV are less well known, with few prospective studies examining these measures. Objective: This prospective randomized clinical trial will examine the effects of a 6-month exercise training intervention compared to a 6-month stretching intervention (control) on cardiorespiratory fitness, physical function and strength, cognition, and neuroimaging measures of brain volumes and cerebral blood flow in people living with HIV. Methods: Sedentary middle-aged to older people living with HIV (ages≥40; n=150) with undetectable HIV viral load (<20 copies/mL) will be enrolled in the study. At the baseline and final visit, fasting plasma lipid, insulin, glucose, and brain neurotrophic factor concentrations; cardiorespiratory fitness; cognitive performance; brain volumes; and cerebral blood flow via a magnetic resonance imaging scan will be measured. Participants will be randomized in a 2:1 ratio to either the exercise or control stretching intervention. All participants will complete their assigned programs at a community fitness center 3 times a week for 6 months. A professional fitness trainer will provide personal training guidance at all sessions for individuals enrolled in both arms. Individuals randomized to the exercise intervention will perform endurance and strength training exercises, while those randomized to the control intervention will perform stretches to increase flexibility. A midpoint visit (at 3 months) will assess cognitive performance, and at the end point visit, subjects will undergo cardiorespiratory fitness and cognition testing, and a magnetic resonance imaging scan. Physical activity throughout the duration of the trial will be recorded using an actigraph. Results: Recruitment and data collection are complete as of December 2020. Data processing, cleaning, and organization are complete as of December 2021. Data analysis began in January 2022, with the publication of study results for primary aims 1 and 2 expected by early 2023. Conclusions: This study will investigate the effects of a 6-month aerobic and resistance exercise training intervention to improve cardiometabolic risk factors, cognitive performance, cerebral structure, and blood flow in sedentary people living with HIV. Results will inform clinicians and patients of the potential benefits of a structured aerobic exercise training program on the cognitive, functional, and cardiometabolic health status of older people living with HIV. Assessment of compliance will inform the development and implementation of future exercise programs for people living with HIV. © Sarah Cooley, Brittany M Nelson, Alexander Rosenow, Elizabeth Westerhaus, W Todd Cade, Dominic N Reeds, Florin Vaida, Kevin E Yarasheski, Robert H Paul, Beau M Ances.

Author Keywords
cardiorespiratory fitness;  cognition;  exercise;  HIV;  magnetic resonance imaging;  resistance training

Funding details
National Institute of Nursing ResearchNINRR01NR015738

Document Type: Article
Publication Stage: Final
Source: Scopus

A Dynamic Systems Analysis of Dyadic Flexibility and Shared Affect in Preschoolers with and Without Major Depressive Disorder
(2023) Research on Child and Adolescent Psychopathology, . 

Quiñones-Camacho, L.E.^a , Whalen, D.J.^b , Luby, J.L.^b , Gilbert, K.E.^b

^a Department of Educational Psychology, University of Texas at Austin, 1912 Speedway STE 5.708 Mail Stop D5800, Austin, TX 78712, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Preschool onset Major Depressive Disorder (PO-MDD) is a severe disorder often leading to chronic impairment and poor outcomes across development. Recent work suggests that the caregiver-child relationship may contribute to PO-MDD symptoms partially through disrupted caregiver-child interactions. The current study uses a dynamic systems approach to investigate whether co-regulation patterns in a dyad with a child experiencing PO-MDD differ from dyads with a child without the disorder. Preschoolers between the ages of 3–7 years-old (N = 215; M(SD) = 5.22(1.06); 35% girls; 77% white) were recruited for a randomized controlled trial of an adapted version of parent-child interaction therapy. An additional sample (N = 50; M(SD) = 5.17(.84)’ 34% girls; 76% white) was recruited as a control group. Dyads completed two interactive tasks and affect was coded throughout the interaction. State Space Grids (SSG) were used to derive measures of dyadic affective flexibility (i.e., affective variability in dyadic interactions) and shared affect. PO-MDD dyads did not differ from controls in dyadic affective flexibility. However, there were significant differences in shared positive and neutral affect. PO-MDD dyads spent less time and had fewer instances of shared positive affect and spent more time and had more instances of shared neutral affect than the community control group. These comparisons survived multiple comparisons correction. There were no differences for shared negative affect. Findings suggest that children experiencing PO-MDD have differing dyadic affective experiences with their caregivers than healthy developing children, which may be a mechanism through which depressive states are reinforced and could be targeted for treatment. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Caregiver-child interactions;  Depression;  SSG;  State Space Grids

Funding details
National Institute of Mental HealthNIMH5R01MH098454-04, K23MH115074-01, K23MH22325028202-01

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

Independent study demonstrates amyloid probability score accurately indicates amyloid pathology
(2023) Annals of Clinical and Translational Neurology, . 

Fogelman, I.^a , West, T.^a , Braunstein, J.B.^a , Verghese, P.B.^a , Kirmess, K.M.^a , Meyer, M.R.^a , Contois, J.H.^a , Shobin, E.^b , Ferber, K.L.^b , Gagnon, J.^b , Rubel, C.E.^b , Graham, D.^b , Bateman, R.J.^c , Holtzman, D.M.^c , Huang, S.^d , Yu, J.^d , Yang, S.^d , Yarasheski, K.E.^a

^a C2N Diagnostics, St. Louis, MO, United States
^b Biogen, Cambridge, MA, United States
^c Dept. of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Tracey Family SILQ Center, Washington University School of Medicine, St. Louis, MO, United States
^d Stat4ward, Pittsburgh, PA, United States

Abstract
Background: The amyloid probability score (APS) is the model read-out of the analytically validated mass spectrometry-based PrecivityAD® blood test that incorporates the plasma Aβ42/40 ratio, ApoE proteotype, and age to identify the likelihood of brain amyloid plaques among cognitively impaired individuals being evaluated for Alzheimer’s disease. Purpose: This study aimed to provide additional independent evidence that the pre-established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals. Methods: The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker &amp; Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available. Results: In a subset of the dataset aligned with the Intended Use population (patients aged 60 and older with CDR ≥0.5), the pre-established APS algorithm predicted amyloid PET with a sensitivity of 84.9% (CI: 72.9–92.1%) and specificity of 96% (CI: 80.5–99.3%), exclusive of 13 individuals for whom the test was inconclusive. Interpretation: The study shows individuals with a high APS are more likely than those with a low APS to have abnormal amounts of amyloid plaques and be on an amyloid accumulation trajectory, a dynamic and evolving process characteristic of progressive AD pathology. Exploratory data suggest APS retains its diagnostic performance in healthy individuals, supporting further screening studies in the cognitively unimpaired. © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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

Persistent Brain Connectivity Changes in Healthy Volunteers Following Nitrous Oxide Inhalation
(2023) Biological Psychiatry Global Open Science, . 

Palanca, B.J.A.^{a b c d e f} , Conway, C.R.^b e , Zeffiro, T.^g , Gott, B.M.^b e , Nguyen, T.^a , Janski, A.^b , Jain, N.^h , Komen, H.^a , Burke, B.A.ⁱ , Zorumski, C.F.^b , Nagele, P.^h

^a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States
^b Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, United States
^d Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States
^e Neuroimaging Labs Research Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States
^f Center on Biological Rhythms and Sleep, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States
^g Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
^h Department of Anesthesia and Critical Care, University of Chicago Medicine, Chicago, Illinois, United States
ⁱ Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado, United States

Abstract
Background: Nitrous oxide holds promise in the treatment of major depressive disorder. Its psychotropic effects and NMDA receptor antagonism have led to comparisons with ketamine. Despite longstanding use, persistent effects of nitrous oxide on the brain have not been characterized. Methods: Sixteen healthy volunteers were recruited in a double-blind crossover study. In randomized order, individuals underwent a 1-hour inhalation of either 50% nitrous oxide/oxygen or air/oxygen mixtures. At least two 7.5-minute echo-planar resting-state functional magnetic resonance imaging scans were obtained before and at 2 and 24 hours after each inhalation (average 130 min/participant). Using the time series of preprocessed, motion artifact–scrubbed, and nuisance covariate–regressed imaging data, interregional signal correlations were measured and converted to T scores. Hierarchical clustering and linear mixed-effects models were employed. Results: Nitrous oxide inhalation produced changes in global brain connectivity that persisted in the occipital cortex at 2 and 24 hours postinhalation (p < .05, false discovery rate–corrected). Analysis of resting-state networks demonstrated robust strengthening of connectivity between regions of the visual network and those of the dorsal attention network, across 2 and 24 hours after inhalation (p < .05, false discovery rate–corrected). Weaker changes in connectivity were found between the visual cortex and regions of the frontoparietal and default mode networks. Parallel analyses following air/oxygen inhalation yielded no significant changes in functional connectivity. Conclusions: Nitrous oxide inhalation in healthy volunteers revealed persistent increases in global connectivity between regions of primary visual cortex and dorsal attention network. These findings suggest that nitrous oxide inhalation induces neurophysiological cortical changes that persist for at least 24 hours. © 2023 The Authors

Author Keywords
Depression;  Functional connectivity;  Functional magnetic resonance imaging;  Ketamine;  Nitrous oxide;  NMDA receptor

Funding details
P50 MH122351
National Institute of Mental HealthNIMHP50MH122379, R21MH108901
American Foundation for Suicide PreventionAFSP
RocheUS20170071975A1
University of Chicago
Washington University in St. LouisWUSTL
University of WashingtonUW
McDonnell Center for Systems Neuroscience
American Society of AnesthesiologistsASA
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis1U01MH12848 3
Sage Therapeutics

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

GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models
(2023) Diabetologia, . 

Gorgogietas, V.^a , Rajaei, B.^a , Heeyoung, C.^b , Santacreu, B.J.^a , Marín-Cañas, S.^a , Salpea, P.^a , Sawatani, T.^a , Musuaya, A.^a , Arroyo, M.N.^a , Moreno-Castro, C.^a , Benabdallah, K.^a , Demarez, C.^a , Toivonen, S.^a , Cosentino, C.^a , Pachera, N.^a , Lytrivi, M.^a c , Cai, Y.^a , Carnel, L.^d , Brown, C.^e , Urano, F.^e , Marchetti, P.^f , Gilon, P.^b , Eizirik, D.L.^a , Cnop, M.^a c , Igoillo-Esteve, M.^a

^a ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
^b Institut de Recherche Expérimental et Clinique, Pôle d’Endocrinologie, Diabète et Nutrition, Université Catholique de Louvain, Bruxelles, Belgium
^c Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
^d Eye Hope Foundation, Damme, Belgium
^e Department of Medicine, Washington University School of Medicine in St Louis, St Louis, MO, United States
^f Department of Clinical and Experimental Medicine, AOUP Cisanello University Hospital, University of Pisa, Pisa, Italy

Abstract
Aims/hypothesis: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. Methods: The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. Results: Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. Conclusions/interpretation: Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome. Graphical abstract: [Figure not available: see fulltext.]. © 2023, The Author(s).

Author Keywords
GLP-1R agonists;  Human pancreatic beta cells;  iPSC-derived beta cells;  iPSC-derived neurons;  Wolfram syndrome

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