WashU weekly Neuroscience publications

Fronto-cerebellar connectivity mediating cognitive processing speed
(2021) NeuroImage, 226, art. no. 117556, .

Wong, C.H.Y.^a b c , Liu, J.^d e f l , Lee, T.M.C.^b c j k , Tao, J.^d e l , Wong, A.W.K.^g h , Chau, B.K.H.^a i , Chen, L.^d e l , Chan, C.C.H.^a i

^a Applied Cognitive Neuroscience Laboratory, Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong
^b Laboratory of Neuropsychology and Human Neuroscience, Department of Psychology, The University of Hong Kong, Hong Kong
^c The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, Hong Kong
^d College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, 1 Huatuo Road, Minhou Shangjie, Fuzhou, Fujian 350122, China
^e National-Local Joint Engineering Research Center of Rehabilitation Medicine Technology, Fujian University of Traditional Chinese Medicine, Fuzhou, China
^f Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, United States
^g Program in Occupational Therapy, Washington University School of Medicine, St. Louis, United States
^h Department of Neurology, Washington University School of Medicine, St. Louis, United States
ⁱ University Research Facility in Behavioral and Systems Neuroscience, The Hong Kong Polytechnic University, Hong Kong
^j The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
^k Center for Brain Science and Brain-Inspired Intelligence, Guangdong–Hong Kong–Macao Greater Bay Area, Guangzhou, China
^l Key Laboratory of Orthopedics & Traumatology of Traditional Chinese Medicine and Rehabilitation (Fujian University of Traditional Chinese Medicine), Ministry of Education

Abstract
Processing speed is an important construct in understanding cognition. This study was aimed to control task specificity for understanding the neural mechanisms underlying cognitive processing speed. Forty young adult subjects performed attention tasks of two modalities (auditory and visual) and two levels of task rules (compatible and incompatible). Block-design fMRI captured BOLD signals during the tasks. Thirteen regions of interest were defined with reference to publicly available activation maps for processing speed tasks. Cognitive speed was derived from task reaction times, which yielded six sets of connectivity measures. Mixed-effect LASSO regression revealed six significant paths suggestive of a cerebello-frontal network predicting the cognitive speed. Among them, three are long range (two fronto-cerebellar, one cerebello-frontal), and three are short range (fronto-frontal, cerebello-cerebellar, and cerebello-thalamic). The long-range connections are likely to relate to cognitive control, and the short-range connections relate to rule-based stimulus-response processes. The revealed neural network suggests that automaticity, acting on the task rules and interplaying with effortful top–down attentional control, accounts for cognitive speed. © 2020

Author Keywords
Cerebellum;  Connectivity;  Individual differences;  Medial frontal cortex;  Processing speed

Funding details
Science and Technology Planning Project of Guangdong Province2018B030334001
Ministry of Science and Technology of the People’s Republic of ChinaMOST2013BAI10B01

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Alterations in gray matter volumes and intrinsic activity in the prefrontal cortex are associated with suicide attempts in patients with bipolar disorder
(2021) Psychiatry Research – Neuroimaging, 307, art. no. 111229, .

Zhao, Y.^a b c , Wang, L.^a c , Edmiston, E.K.^d , Womer, F.Y.^e , Jiang, X.^c f , Wu, F.^b , Kong, L.^b , Zhou, Y.^b g , Wang, F.^b c f , Tang, Y.^b g , Wei, S.^c f

^a Department of Psychiatry, China Medical University, Shenyang, Liaoning, China
^b Department of Psychiatry, First Affiliated Hospital, China Medical University, 155 Nanjing North St., Shenyang, Liaoning 110001, China
^c Brain Function Research Section, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
^d Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Radiology, First Affiliated Hospital, China Medical University, 155 Nanjing North St., Shenyang, Liaoning 110001, China
^g Department of Geriatric Medicine, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China

Abstract
Bipolar disorder (BD) is associated with increased suicidal behavior. Understanding the neural features of suicide attempts (SA) in patients with BD is critical to preventing suicidal behavior. The prefrontal cortex (PFC) is a key region related to SA. In this study, forty BD patients with a history of SA (BD+SA), 70 BD patients without a history of SA (BD-SA), and 110 individuals in a healthy control (HC) group underwent structural magnetic resonance imaging (MRI) and resting-state functional MRI. We used voxel-based morphometry (VBM) and amplitude of low frequency fluctuations (ALFF) techniques to examine the gray matter volumes (GMVs) and ALFF values in the PFC. Compared with the HC group, both the BD+SA and BD-SA groups had lower GMVs and higher ALFF values in the medial PFC (MPFC), ventral PFC (VPFC), and dorsolateral PFC (DLPFC). The ALFF values in the MPFC, VPFC, and DLPFC in the BD+SA group were significantly higher than those in the BD-SA group. These findings suggest that BD patients with SA have intrinsic activity abnormalities in PFC regions. This provides potentially identifiable neuroimaging markers in BD patients with SA that could be used to increase our understanding of suicidal behavior. © 2020

Author Keywords
Amplitude of low frequency fluctuations;  Bipolar disorder;  Gray matter volume;  Prefrontal cortex;  Suicide attempts

Funding details
L2015591
2015AA020513, 2016YFC1306900
National Natural Science Foundation of ChinaNSFC81571311, 81725005, 81571331, 81271499, 81701336
2016YFC0904300

Document Type: Article
Publication Stage: Final
Source: Scopus

Function of mammalian M-cones depends on the level of CRALBP in Müller cells
(2021) The Journal of General Physiology, 153 (1), .

Kolesnikov, A.V.^a , Kiser, P.D.^b c d , Palczewski, K.^b c e , Kefalov, V.J.^a

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO
^b Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, CA
^c Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translation Vision Research, School of Medicine, University of California, Irvine, Irvine, CA
^d Research Service, VA Long Beach Healthcare System, Long Beach, CA, Italy
^e Department of Chemistry, School of Medicine, University of California, Irvine, Irvine, CA

Abstract
Cone photoreceptors mediate daytime vision in vertebrates. The rapid and efficient regeneration of their visual pigments following photoactivation is critical for the cones to remain photoresponsive in bright and rapidly changing light conditions. Cone pigment regeneration depends on the recycling of visual chromophore, which takes place via the canonical visual cycle in the retinal pigment epithelium (RPE) and the Müller cell-driven intraretinal visual cycle. The molecular mechanisms that enable the neural retina to regenerate visual chromophore for cones have not been fully elucidated. However, one known component of the two visual cycles is the cellular retinaldehyde-binding protein (CRALBP), which is expressed both in the RPE and in Müller cells. To understand the significance of CRALBP in cone pigment regeneration, we examined the function of cones in mice heterozygous for Rlbp1, the gene encoding CRALBP. We found that CRALBP expression was reduced by ∼50% in both the RPE and retina of Rlbp1+/- mice. Electroretinography (ERG) showed that the dark adaptation of rods and cones is unaltered in Rlbp1+/- mice, indicating a normal RPE visual cycle. However, pharmacologic blockade of the RPE visual cycle revealed suppressed cone dark adaptation in Rlbp1+/- mice in comparison with controls. We conclude that the expression level of CRALPB specifically in the Müller cells modulates the efficiency of the retina visual cycle. Finally, blocking the RPE visual cycle also suppressed further cone dark adaptation in Rlbp1-/- mice, revealing a shunt in the classical RPE visual cycle that bypasses CRALBP and allows partial but unexpectedly rapid cone dark adaptation. © 2020 Kolesnikov et al.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Generation of Human Neurons by microRNA-Mediated Direct Conversion of Dermal Fibroblasts
(2021) Methods in Molecular Biology, 2239, pp. 77-100.

Church, V.A., Cates, K., Capano, L., Aryal, S., Kim, W.K., Yoo, A.S.

Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
MicroRNAs (miRNAs), miR-9/9*, and miR-124 (miR-9/9*-124) display fate-reprogramming activities when ectopically expressed in human fibroblasts by erasing the fibroblast identity and evoking a pan-neuronal state. In contrast to induced pluripotent stem cell-derived neurons, miRNA-induced neurons (miNs) retain the biological age of the starting fibroblasts through direct fate conversion and thus provide a human neuron-based platform to study cellular properties inherent in aged neurons and model adult-onset neurodegenerative disorders using patient-derived cells. Furthermore, expression of neuronal subtype-specific transcription factors in conjunction with miR-9/9*-124 guides the miNs to distinct neuronal fates, a feature critical for modeling disorders that affect specific neuronal subtypes. Here, we describe the miR-9/9*-124-based neuronal reprogramming protocols for the generation of several disease-relevant neuronal subtypes: striatal medium spiny neurons, cortical neurons, and spinal cord motor neurons. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Aging;  Cortical neuron;  Human neuron;  Medium spiny neuron;  miN;  miRNA-mediated direct conversion;  Motor neuron;  Neurogenesis;  Neuronal cell-fate;  Neuronal reprogramming

Funding details
National Institutes of HealthNIHRF1AG056296, R01NS107488
CHDI FoundationCHDI

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

Nonliteral language processing across the lifespan
(2021) Acta Psychologica, 212, art. no. 103213, .

Rothermich, K.^a , Giorio, C.^b , Falkins, S.^c , Leonard, L.^a , Roberts, A.^d

^a Department of Communication Sciences and Disorders, East Carolina University, Greenville, NC, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychology, East Carolina University, Greenville, NC, United States
^d Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, United States

Abstract
Studies investigating the effects of aging on nonliteral language processing have mainly focused on one sensory modality, for example written vignettes. In the current study, we used a video-based task to examine the effect of healthy aging on social communication perception using a novel database called RISC (Relation Inference in Social Communication). By means of an online recruitment platform, we asked young, middle-aged, and older adults between the ages of 18 and 76 (N = 100) to evaluate videos of actors using different forms of literal and nonliteral language, such as sarcasm or teasing. The participants’ task was to infer the speakers’ belief and the speakers’ intention. Older participants demonstrated lower accuracy in discriminating nonliteral from literal interactions compared to younger and middle-aged groups. When evaluating speaker intentions, older adults judged sarcasm as friendlier compared to literal negative utterances. We also found that the older the participant, the more difficulty they have identifying teasing as insincere. Our results expand on age-related similarities and differences in evaluating speaker intentions and demonstrate the practicality of the RISC database for studying nonliteral language across the lifespan. © 2020 The Authors

Author Keywords
Aging;  Irony;  Nonliteral language;  Pragmatics;  Social cognition

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

IL-10 based immunomodulation initiated at birth extends lifespan in a familial mouse model of amyotrophic lateral sclerosis
(2020) Scientific Reports, 10 (1), art. no. 20862, .

Strickland, M.R.^a d , Ibanez, K.R.^a , Yaroshenko, M.^a , Diaz, C.C.^a , Borchelt, D.R.^a b c , Chakrabarty, P.^a b c

^a Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, United States
^b Department of Neuroscience, University of Florida, Gainesville, FL 32610, United States
^c McKnight Brain Institute, University of Florida, Gainesville, FL 32610, United States
^d Department of Neuroscience, Washington University, St. Louis, MN, United States

Abstract
Inflammatory signaling is thought to modulate the neurodegenerative cascade in amyotrophic lateral sclerosis (ALS). We have previously shown that expression of Interleukin-10 (IL-10), a classical anti-inflammatory cytokine, extends lifespan in the SOD1-G93A mouse model of familial ALS. Here we test whether co-expression of the decoy chemokine receptor M3, that can scavenge inflammatory chemokines, augments the efficacy of IL-10. We found that recombinant adeno-associated virus (AAV)-mediated expression of IL-10, alone, or in combination with M3, resulted in modest extension of lifespan relative to control SOD1-G93A cohort. Interestingly neither AAV-M3 alone nor AAV-IL-10 + AAV-M3 extend survival beyond that of the AAV-IL-10 alone cohort. Focused transcriptomic analysis revealed induction of innate immunity and phagocytotic pathways in presymptomatic SOD1-G93A mice expressing IL-10 + M3 or IL-10 alone. Further, while IL-10 expression increased microglial burden, the IL-10 + M3 group showed lower microglial burden, suggesting that M3 can successfully lower microgliosis before disease onset. Our data demonstrates that over-expression of an anti-inflammatory cytokine and a decoy chemokine receptor can modulate inflammatory processes in SOD1-G93A mice, modestly delaying the age to paralysis. This suggests that multiple inflammatory pathways can be targeted simultaneously in neurodegenerative disease and supports consideration of adapting these approaches to treatment of ALS and related disorders. © 2020, The Author(s).

Funding details
National Institutes of HealthNIHR01NS092788
Amyotrophic Lateral Sclerosis AssociationALSA

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Reduced expression of cerebral metabotropic glutamate receptor subtype 5 in men with fragile x syndrome
(2020) Brain Sciences, 10 (12), art. no. 899, pp. 1-17.

Brašić, J.R.^a , Nandi, A.^a , Russell, D.S.^b c , Jennings, D.^b c d , Barret, O.^b , Mathur, A.^a , Slifer, K.^e f , Sedlak, T.^a g , Martin, S.D.^a h , Brinson, Z.^a , Vyas, P.^a , Seibyl, J.P.^b c , Berry-Kravis, E.M.ⁱ , Wong, D.F.^a j , Budimirovic, D.B.^e k

^a Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan, Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
^b Clinical Research, Institute for Neurodegenerative Disorders, New Haven, CT 06510, United States
^c Research Clinic, Invicro LLC, New Haven, CT 06510, United States
^d Denali Therapeutics, Inc, South San Francisco, CA 94080, United States
^e Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^f Department of Behavioral Psychology, Kennedy Krieger Institute, Baltimore, MD 21205, United States
^g Department of Psychiatry and Behavioral Sciences-General Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^h Department of Neuroscience, Zanvyl Krieger School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, United States
ⁱ Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL 60612, United States
^j Precision Radio-Theranostics Translational Laboratories, Mallinckrodt Institute of Radiology, School of Medicine, Washington University, Saint Louis, MO 63110, United States
^k Departments of Psychiatry and Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, United States

Abstract
Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) in fmr1 knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR5 expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR5 density as a proxy of mGluR5 expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluR5s. The density and the distribution of mGluR5 were measured in two independent samples of men with FXS (N = 9) and typical development (TD) (N = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR5 expression showed that mGluR5 expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB);  Binding potential;  Caudate nucleus;  FMR1 gene;  Fragile X Mental Retardation Protein (FMRP);  Genetic mutation;  Magnetic resonance imaging (MRI);  Mosaicism;  Neuropsychological testing;  Positron emission tomography (PET)

Funding details
Centers for Disease Control and PreventionCDC
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATS
School of Medicine, Johns Hopkins UniversitySOM, JHU
Institute for Clinical and Translational Research, University of Wisconsin, MadisonUW ICTRUL1 TR003098
Intellectual and Developmental Disabilities Research CenterIDDRCU54 HD079123
Centers for Disease Control and PreventionCDC

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration
(2020) Nature Communications, 11 (1), art. no. 5990, .

Choi, Y.S.^a b c , Hsueh, Y.-Y.^d e f , Koo, J.^a b g h , Yang, Q.^b i , Avila, R.ⁱ , Hu, B.^d j , Xie, Z.^k l m , Lee, G.^a b , Ning, Z.ⁿ , Liu, C.^b o , Xu, Y.^b c , Lee, Y.J.^b , Zhao, W.^d j , Fang, J.^d j , Deng, Y.^i p , Lee, S.M.^a b , Vázquez-Guardado, A.^a b c , Stepien, I.^q , Yan, Y.^r , Song, J.W.^o , Haney, C.^s , Oh, Y.S.^a b , Liu, W.^d , Yun, H.-J.^b t , Banks, A.^a b , MacEwan, M.R.^r , Ameer, G.A.^o u v , Ray, W.Z.^r , Huang, Y.^a c i w , Xie, T.ⁿ , Franz, C.K.^x y z , Li, S.^d j , Rogers, J.A.^{a b c i o aa}

^a Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL 60208, United States
^b Querrey Simpson Institute for Biotechnology, Northwestern University, Evanston, IL 60208, United States
^c Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, United States
^d Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, United States
^e Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70456, Taiwan
^f International Research Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, 70456, Taiwan
^g School of Biomedical Engineering, Korea University, Seoul, 02841, South Korea
^h Interdisciplinary Program in Precision Public Health, Korea University, Seoul, 02841, South Korea
ⁱ Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, United States
^j Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States
^k State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian, University of Technology, Dalian, 116024, China
^l Department of Engineering Mechanics, Dalian University of Technology, Dalian, 116024, China
^m International Research Center for Computational Mechanics, Dalian University of Technology, Dalian, 116024, China
ⁿ State Key Laboratory of Chemical Engineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China
^o Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, United States
^p State Key Laboratory of Mechanical System and Vibration, Shanghai Jiao Tong University, Shanghai, 200240, China
^q Center for Developmental Therapeutics, Chemistry Life Processes Institute, Northwestern University, Evanston, IL 60208, United States
^r Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
^s Center for Advanced Molecular Imaging, Northwestern University, Evanston, IL 60208, United States
^t School of Advanced Materials Science and Engineering, Sungkyunkwan University (SKKU), Suwon, 16419, South Korea
^u Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL 60208, United States
^v Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
^w Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, United States
^x Regenerative Neurorehabilitation Laboratory, Biologics, Shirley Ryan AbilityLab, Chicago, IL 60611, United States
^y Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
^z The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
^aa Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States

Abstract
Bioresorbable electronic stimulators are of rapidly growing interest as unusual therapeutic platforms, i.e., bioelectronic medicines, for treating disease states, accelerating wound healing processes and eliminating infections. Here, we present advanced materials that support operation in these systems over clinically relevant timeframes, ultimately bioresorbing harmlessly to benign products without residues, to eliminate the need for surgical extraction. Our findings overcome key challenges of bioresorbable electronic devices by realizing lifetimes that match clinical needs. The devices exploit a bioresorbable dynamic covalent polymer that facilitates tight bonding to itself and other surfaces, as a soft, elastic substrate and encapsulation coating for wireless electronic components. We describe the underlying features and chemical design considerations for this polymer, and the biocompatibility of its constituent materials. In devices with optimized, wireless designs, these polymers enable stable, long-lived operation as distal stimulators in a rat model of peripheral nerve injuries, thereby demonstrating the potential of programmable long-term electrical stimulation for maintaining muscle receptivity and enhancing functional recovery. © 2020, The Author(s).

Funding details
Kementerian Pendidikan MalaysiaKPM
National Science FoundationNSF1842165
W. M. Keck Foundation
National Institutes of HealthNIHHL121450
Materials Research Science and Engineering Center, University of NebraskaMRSECNSF DMR-1720139
National Cheng Kung UniversityNCKU
ECCS-1542205
Fundamental Research Funds for the Central UniversitiesDUT20RC(3)032, CMMI1635443
Ford Foundation
Ministry of Science and TechnologyMOST106-2918-I-006 −006, 108-2628-B-006 −017
National Research Foundation of KoreaNRFNRF-2020R1F1A1068083
National Cheng Kung UniversityNCKU
National Natural Science Foundation of ChinaNSFC12072057

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1
(2020) Human Molecular Genetics, 29 (19), pp. 3249-3265. Cited 1 time.

Chopra, R.^a b c , Bushart, D.D.^b d e , Cooper, J.P.^b f , Yellajoshyula, D.^b , Morrison, L.M.^b , Huang, H.^b , Handler, H.P.^g , Man, L.J.^b , Dansithong, W.^h , Scoles, D.R.^h , Pulst, S.M.^h , Orr, H.T.^g , Shakkottai, V.G.^b d

^a Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109, United States
^b Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
^c Department of Neurology, Washington University in St. Louis, MO, Saint Louis 63110, United States
^d Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, United States
^e Ohio State University College of Medicine, Columbus, OH 43210, USA
^f Department of Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, United States
^g Department of Laboratory Medicine and Pathology, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, United States
^h Department of Neurology, University of Utah, Salt Lake City, UT 84132, United States

Abstract
Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Aging and the encoding of changes in events: The role of neural activity pattern reinstatement
(2020) Proceedings of the National Academy of Sciences of the United States of America, 117 (47), pp. 29346-29353. Cited 1 time.

Stawarczyk, D.^a b , Wahlheim, C.N.^c , Etzel, J.A.^a , Snyder, A.Z.^d e , Zacks, J.M.^a d

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63105, United States
^b Department of Psychology, Psychology, Neuroscience of Cognition Research Unit, University of Liège, Liège, 4000, Belgium
^c Department of Psychology, University of North Carolina at Greensboro, Greensboro, NC 27412, United States
^d Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
^e Department of Neurology, Washington University in St. Louis, St. Louis, MO 63105, United States

Abstract
When encountering unexpected event changes, memories of relevant past experiences must be updated to form new representations. Current models of memory updating propose that people must first generate memory-based predictions to detect and register that features of the environment have changed, then encode the new event features and integrate them with relevant memories of past experiences to form configural memory representations. Each of these steps may be impaired in older adults. Using functional MRI, we investigated these mechanisms in healthy young and older adults. In the scanner, participants first watched a movie depicting everyday activities in a day of an actor’s life. They next watched a second nearly identical movie in which some scenes ended differently. Crucially, before watching the last part of each activity, the second movie stopped, and participants were asked to mentally replay how the activity previously ended. Three days later, participants were asked to recall the activities. Neural activity pattern reinstatement in medial temporal lobe (MTL) during the replay phase of the second movie was associated with detecting changes and with better memory for the original activity features. Reinstatements in posterior medial cortex (PMC) additionally predicted better memory for changed features. Compared to young adults, older adults showed a reduced ability to detect and remember changes and weaker associations between reinstatement and memory performance. These findings suggest that PMC and MTL contribute to change processing by reinstating previous event features, and that older adults are less able to use reinstatement to update memory for changed features. © 2020 National Academy of Sciences. All rights reserved.

Author Keywords
Change comprehension;  Cognitive aging;  Episodic memory;  Event cognition;  Representational similarity analysis

Funding details
1P30NS098577
National Institutes of HealthNIHR37MH066078
National Institutes of HealthNIHR21AG05231401
Horizon 2020 Framework ProgrammeH2020798109

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

DNMT3A Haploinsufficiency Results in Behavioral Deficits and Global Epigenomic Dysregulation Shared across Neurodevelopmental Disorders
(2020) Cell Reports, 33 (8), p. 108416.

Christian, D.L.^a , Wu, D.Y.^a , Martin, J.R.^a , Moore, J.R.^a , Liu, Y.R.^a , Clemens, A.W.^a , Nettles, S.A.^a , Kirkland, N.M.^b , Papouin, T.^a , Hill, C.A.^b , Wozniak, D.F.^c , Dougherty, J.D.^d , Gabel, H.W.^a

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110-1093, USA
^b Department of Pathology and Anatomical Science, University of Missouri School of Medicine, Columbia, MO 65212, USA
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110-1093, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110-1093, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110-1093, USA
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110-1093, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110-1093, USA

Abstract
Mutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here, we define the effects of DNMT3A mutations associated with neurodevelopmental disease. We show that diverse mutations affect different aspects of protein activity but lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice, we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define the effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Author Keywords
Autism;  cerebral cortex;  DNA methylation;  DNMT3A;  enhancer;  intellectual disability;  MeCP2;  non-CG methylation;  Rett Syndrome;  TBRS

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Proteomic biomarkers of sleep apnea
(2020) Sleep, 43 (11), .

Ambati, A.^a , Ju, Y.-E.^b , Lin, L.^a , Olesen, A.N.^a , Koch, H.^a , Hedou, J.J.^a , Leary, E.B.^a , Sempere, V.P.^a , Mignot, E.^a , Taheri, S.^c

^a Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO
^c Department of Medicine and Clinical Research Core, Weill Cornell Medicine-Qatar, Qatar Foundation-Education City, Doha, Qatar

Abstract
STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is characterized by recurrent partial to complete upper airway obstructions during sleep, leading to repetitive arousals and oxygen desaturations. Although many OSA biomarkers have been reported individually, only a small subset have been validated through both cross-sectional and intervention studies. We sought to profile serum protein biomarkers in OSA in unbiased high throughput assay. METHODS: A highly multiplexed aptamer array (SomaScan) was used to profile 1300 proteins in serum samples from 713 individuals in the Stanford Sleep Cohort, a patient-based registry. Outcome measures derived from overnight polysomnography included Obstructive Apnea Hypopnea Index (OAHI), Central Apnea Index (CAI), 2% Oxygen Desaturation index, mean and minimum oxygen saturation indices during sleep. Additionally, a separate intervention-based cohort of 16 individuals was used to assess proteomic profiles pre- and post-intervention with positive airway pressure. RESULTS: OAHI was associated with 65 proteins, predominantly pathways of complement, coagulation, cytokine signaling, and hemostasis which were upregulated. CAI was associated with two proteins including Roundabout homolog 3 (ROBO3), a protein involved in bilateral synchronization of the pre-Bötzinger complex and cystatin F. Analysis of pre- and post intervention samples revealed IGFBP-3 protein to be increased while LEAP1 (Hepicidin) to be decreased with intervention. An OAHI machine learning classifier (OAHI >=15 vs OAHI<15) trained on SomaScan protein measures alone performed robustly, achieving 76% accuracy in a validation dataset. CONCLUSIONS: Multiplex protein assays offer diagnostic potential and provide new insights into the biological basis of sleep disordered breathing. © Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Author Keywords
apnea;  biomarkers;  oxygen saturation;  polysomnography;  proteomics;  serum;  sleep-disordered breathing

Document Type: Article
Publication Stage: Final
Source: Scopus

Exploring Differences in the Role of Hospitalization on Weight Gain Based on Treatment Type From Randomized Clinical Trials for Adolescent Anorexia Nervosa
(2020) Frontiers in Psychiatry, 11, art. no. 609675, .

Datta, N.^a , Matheson, B.E.^a , Le Grange, D.^b c , Brandt, H.A.^d e , Woodside, B.^f g , Halmi, K.A.^h , Wilfley, D.E.ⁱ , Lock, J.D.^a

^a Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^b Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, United States
^c Department of Psychiatry and Behavioral Neurosciences, The University of Chicago, Chicago, IL, United States
^d St. Joseph Medical Center, University of Maryland, Towson, MD, United States
^e Eastern Region Eating Recovery Center, Towson, MD, United States
^f Program for Eating Disorders, Toronto General Hospital, Toronto, ON, Canada
^g Department of Psychiatry, University of Toronto, Toronto, ON, Canada
^h Department of Psychiatry, Weill Cornell Medical College, New York, NY, United States
ⁱ Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: This study explores the impact of weight gain during medical stabilization hospitalization on weight outcomes between three outpatient treatments for adolescent anorexia nervosa (AN): Adolescent Focused Therapy (AFT), Systemic Family Therapy (SyFT), and Family Based Treatment (FBT). Methods: A secondary analysis of weight gain data (N = 215) of adolescents (12–18 years) meeting DSM-IV criteria for AN (exclusive of amenorrhea criteria) who participated in two randomized clinical trials (RCTs) was conducted. Main outcomes examined were changes in weight restoration (≥95% expected body weight or EBW) and differences in weight change attributable to hospital weight gain. Results: Weight gain resulting from hospitalizations did not substantially change weight recovery rates. Hospital weight gain contributed most to overall treatment weight gain in AFT compared to FBT and SyFT. Conclusion: Brief medical stabilization weight gain does not contribute substantially to weight recovery in adolescents with AN who participated in RCTs. © Copyright © 2020 Datta, Matheson, Le Grange, Brandt, Woodside, Halmi, Wilfley and Lock.

Author Keywords
adolescent;  anorexia;  hospitalization;  inpatient;  treatment outcome;  weight gain

Funding details
Foundation for the National Institutes of HealthFNIHR01-MH-070620, R01-MH-070621
National Institute of Mental HealthNIMHMH 076254, 1UO1 MH076290, MH 076250, MH 076252, MH 076251, MH 076255

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Diverse coactive neurons encode stimulus-driven and stimulus-independent variables
(2020) Journal of Neurophysiology, 124 (5), pp. 1505-1517.

Xia, J.^a , Marks, T.D.^b , Goard, M.J.^b c d , Wessel, R.^a

^a Department of Physics, Washington University in St. Louis, St. Louis, MO, United States
^b Neuroscience Research Institute, University of California, Santa Barbara, California
^c Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California
^d Department of Psychological & Brain Sciences, University of California, Santa Barbara, California

Abstract
Both experimenter-controlled stimuli and stimulus-independent variables impact cortical neural activity. A major hurdle to understanding neural representation is distinguishing between qualitatively different causes of the fluctuating population activity. We applied an unsupervised low-rank tensor decomposition analysis to the recorded population activity in the visual cortex of awake mice in response to repeated presentations of naturalistic visual stimuli. We found that neurons covaried largely independently of individual neuron stimulus response reliability and thus encoded both stimulus-driven and stimulus-independent variables. Importantly, a neuron’s response reliability and the neuronal coactivation patterns substantially reorganized for different external visual inputs. Analysis of recurrent balanced neural network models revealed that both the stimulus specificity and the mixed encoding of qualitatively different variables can arise from clustered external inputs. These results establish that coactive neurons with diverse response reliability mediate a mixed representation of stimulus-driven and stimulus-independent variables in the visual cortex.NEW & NOTEWORTHY V1 neurons covary largely independently of individual neuron’s response reliability. A single neuron’s response reliability imposes only a weak constraint on its encoding capabilities. Visual stimulus instructs a neuron’s reliability and coactivation pattern. Network models revealed using clustered external inputs.

Author Keywords
neural encoding;  neural ensemble;  neuronal coactivation

Document Type: Article
Publication Stage: Final
Source: Scopus

The association of opioid use duration and new depression episode among patients with and without insomnia
(2020) Journal of Opioid Management, 16 (5), pp. 317-328.

Salas, J.^a , Miller, M.B.^b , Scherrer, J.F.^a , Moore, R.^c , McCrae, C.S.^b , Sullivan, M.D.^d , Bucholz, K.K.^e , Copeland, L.A.^f , Ahmedani, B.K.^g , Schneider, F.D.^h , Lustman, P.J.ⁱ

^a Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, Missouri; Harry S. Truman Memorial Veterans’ Administration Medical Center, Columbia, Missouri
^b Department of Psychiatry, University of Missouri School of Medicine, Columbia, MO, United States
^c Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States
^d Department of Psychiatry and Behavioral Health, University of Washington School of Medicine, Seattle, WA, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f VA Central Western Massachusetts Healthcare System, Leeds, Massachusetts; Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts
^g Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan; School of Social Work, Michigan State University, East Lansing, Michigan
^h Department of Family and Community Medicine, University of Texas Southwestern, Dallas, TX, United States
ⁱ Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri; The Bell Street Clinic, VA St. Louis Health Care System-John Cochran Division, St. Louis, Missouri

Abstract
OBJECTIVE: Insomnia commonly co-occurs with depression, chronic pain, and opioid use. Both insomnia and chronic opioid analgesic use (OAU) are independent risk factors for a new depression episode (NDE). This study determined if the association between longer OAU duration and NDE was stronger in those with versus without insomnia. DESIGN: Retrospective cohort. SETTING: Veterans Health Administration electronic medical records (2000-2012). PARTICIPANTS: New opioid users in follow-up (2002-2012), free of depression for two years prior to follow-up, and aged 18-80 (n = 70,997). METHODS: NDE was ≥ 2 ICD-9 codes in a 12-month period. Insomnia before OAU initiation was ≥1 ICD-9 code. Cox proportional hazard models stratified on insomnia assessed the relationship between initiating a 1-30, 31-90, or > 90 day period of OAU and NDE while controlling for confounders using inverse probability of treatment-weighted propensity scores (PS). RESULTS: Compared to 1-30 day OAU, 31-90 day was associated with NDE in those without (HR = 1.20; 95 percent CI: 1.12-1.28) but not with insomnia (HR = 1.06; 95 percent CI: 0.86-1.32). Results showed a stronger effect of chronic (>90) OAU in those with insomnia (HR = 1.59; 95 percent CI: 1.27-1.98) compared to those without (HR = 1.31; 95 percent CI: 1.21-1.42). However, all stratum-specific effects were not significantly different (p = 0.136). CONCLUSIONS: Although stratum-specific risks were statistically similar, there was evidence for a trend that chronic OAU is a stronger risk factor for NDE in those with versus without insomnia. Providers are encouraged to monitor sleep impairment among patients on opioid therapy, as sleep may be associated with greater risk for NDE in patients with chronic OAU.

Document Type: Article
Publication Stage: Final
Source: Scopus

Biphasic cortical macro- and microstructural changes in autosomal dominant Alzheimer’s disease
(2020) Alzheimer’s and Dementia, .

Montal, V.^a v , Vilaplana, E.^a v , Pegueroles, J.^a v , Bejanin, A.^a v , Alcolea, D.^a v , Carmona-Iragui, M.^a b v , Clarimón, J.^a v , Levin, J.^c d e , Cruchaga, C.^f g h i , Graff-Radford, N.R.^j , Noble, J.M.^k , Lee, J.-H.^l , Allegri, R.^m , Karch, C.M.ⁿ , Laske, C.^o p , Schofield, P.R.^q r , Salloway, S.^s , Ances, B.^f g i t , Benzinger, T.^i t , McDale, E.^f i , Bateman, R.^f g i , Blesa, R.^a v , Sánchez-Valle, R.^u , Lleó, A.^a v , Fortea, J.^a b v , for the Dominantly Inherited Alzheimer Network (DIAN)^v

^a Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
^b Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain
^c Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^d German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^e Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g The Hope Center for Neurological Disorders, St. Louis, MO, United States
^h NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^k Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, United States
^l Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
^m Department of Cognitive Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina
ⁿ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^o German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^p Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
^q Neuroscience Research Australia, Sydney, Australia
^r School of Medical Sciences, University of New South Wales, Sydney, Australia
^s Neurology and the Memory and Aging Program, Butler Hospital, Providence, RI, United States
^t Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^u Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic, Fundació Clínic per a la Recerca Biomèdica, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
^v Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

Abstract
INTRODUCTION: A biphasic model for brain structural changes in preclinical Alzheimer’s disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials. METHODS: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity—a novel marker of cortical microstructure—changes in 389 participants from the Dominantly Inherited Alzheimer Network. RESULTS: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations. DISCUSSION: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials. © 2020 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  autosomal-dominant Alzheimer’s disease;  biphasic cortical changes;  cortical diffusivity;  magnetic resonance imaging;  preclinical Alzheimer’s disease

Funding details
Generalitat de CatalunyaSLT006/17/00125, SLT006/17/95, SLT006/17/00119
National Institute on AgingNIA
Fleni
Fundació la Marató de TV3044412, 20141210, FI18/00275
Instituto de Salud Carlos IIIISCIIIPI17/01896, PI18/00435, PI18/00335, PI14/1561, PI14/01126, PI16/01825, PI13/01532, PI17/01019, PI16/0235, INT19/00016
IJCI‐2017‐32609
European Regional Development FundFEDER
National Institutes of HealthNIH1R01AG056850 ‐ 01A1, R21AG056974, R01AG061566
Japan Agency for Medical Research and DevelopmentAMED
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Japan Agency for Medical Research and DevelopmentAMED
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Korea Health Industry Development InstituteKHIDI
Institut Català de la SalutICSSLT002/16/00408

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

Is Levodopa Response a Valid Indicator of Parkinson’s Disease?
(2020) Movement Disorders, .

Martin, W.R.W.^a , Miles, M.^b , Zhong, Q.^c , Hartlein, J.^b , Racette, B.A.^b d , Norris, S.A.^b e , Ushe, M.^b , Maiti, B.^b , Criswell, S.^b , Davis, A.A.^b , Kotzbauer, P.T.^b , Cairns, N.J.^f , Perrin, R.J.^b g , Perlmutter, J.S.^b e h

^a Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Medicine, Mayo Clinic, Rochester, MO, United States
^d Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, Parktown, South Africa
^e Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^f College of Medicine and Health, University of Exeter, Exeter, United Kingdom
^g Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
^h Departments of Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: The clinical diagnosis of Parkinson’s disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. Methods: We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. Results: There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. Conclusion: A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society. © 2020 International Parkinson and Movement Disorder Society

Author Keywords
diagnostic specificity;  levodopa;  Parkinson’s disease;  parkinsonism

Funding details
National Institutes of HealthNIHNS097799, NS07532, U10NS077384
American Parkinson Disease AssociationAPDA
National Institutes of HealthNIHNS097437, NS097799, NS075321
National Institute of Environmental Health SciencesNIEHSR01ES026891‐S1, R01ES025991‐02S1, R01ES026891, R01ES025991
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Hope Center for Neurological Disorders
Cure Alzheimer’s FundCAFROH01166, R01ES029524, R01ES030937‐S1
American Parkinson Disease AssociationAPDA
Dystonia Medical Research Foundation CanadaDMRFC
National Institutes of HealthNIHR01 NS107281, TR00145609, RO1 NS103957
American Academy of NeurologyAAN
American Brain FoundationABF
National Center for Advancing Translational SciencesNCATS
KL2 TR002346
St. Louis American Parkinson Disease Association
National Institutes of HealthNIHR01 OH011661, R01 ES026891, R01 ES029524
Mary E. Groff Surgical and Medical Research and Education Charitable Trust
BrightFocus FoundationBFF
National Institutes of HealthNIHNS101118
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
National Institutes of HealthNIHU01 NS110436, R01 NS097437, R01 NS075321, R01 AG050263, R01 NS097799, R21 NS109831
Amyotrophic Lateral Sclerosis AssociationALSA
National Institutes of HealthNIHRF1 AG053550, U19 AG032438, AG003991, AG005681, R01 NS075321, R01 AG054513, R01 NS092865, R01 NS097799, R01 AG054567, AG024904, UF1 AG032438, R01 AG052550
Janssen Biotech
BrightFocus FoundationBFFA2014296S
American Parkinson Disease AssociationAPDA
CHDI FoundationCHDINS065701, NS116025
National Institute of Neurological Disorders and StrokeNINDSTR 001456
National Institute of Neurological Disorders and StrokeNINDS
American Parkinson Disease AssociationAPDA
National Institutes of HealthNIHNS097799, U54NS116025, NS107281, ES029524, NS109487, AG050263, R61 AT010753, U10NS077384, NS075321, NS097437, NS075527, AG‐64937, NS103957, NS092865, U19 NS110456
National Center for Advancing Translational SciencesNCATS
National Institute on AgingNIA
U.S. Department of DefenseDODDOD W81XWH‐217‐1‐0393
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Huntington’s Disease Society of AmericaHDSA
National Center for Advancing Translational SciencesNCATS
National Institute of Neurological Disorders and StrokeNINDS

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

Smartphone data during the COVID-19 pandemic can quantify behavioral changes in people with ALS
(2020) Muscle and Nerve, .

Beukenhorst, A.L.^a , Collins, E.^b , Burke, K.M.^b , Rahman, S.M.^b , Clapp, M.^c , Konanki, S.C.^a , Paganoni, S.^b d , Miller, T.M.^c , Chan, J.^e , Onnela, J.-P.^a , Berry, J.D.^b

^a Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^b Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA, United States
^c Department of Neurology, Washington University, St. Louis, MO, United States
^d Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United States
^e Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

Abstract
Introduction: Passive data from smartphone sensors may be useful for health-care research. Our aim was to use the coronavirus disease-2019 (COVID-19) pandemic as a positive control to assess the ability to quantify behavioral changes in people with amyotrophic lateral sclerosis (ALS) from smartphone data. Methods: Eight participants used the Beiwe smartphone application, which passively measured their location during the COVID-19 outbreak. We used an interrupted time series to quantify the effect of the US state of emergency declaration on daily home time and daily distance traveled. Results: After the state of emergency declaration, median daily home time increased from 19.4 (interquartile range [IQR], 15.4-22.0) hours to 23.7 (IQR, 22.2-24.0) hours and median distance traveled decreased from 42 (IQR, 13-83) km to 3.7 (IQR, 1.5-10.3) km. The participant with the lowest functional ability changed behavior earlier. This participant stayed at home more and traveled less than the participant with highest functional ability, both before and after the state of emergency. Discussion: We provide evidence that smartphone-based digital phenotyping can quantify the behavior of people with ALS. Although participants spent large amounts of time at home at baseline, the COVID-19 state of emergency declaration reduced their mobility further. Given participants’ high level of daily home time, it is possible that their exposure to COVID-19 could be less than that of the general population. © 2020 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.

Author Keywords
ALS, COVID-19, digital phenotyping, mobile health, smartphones

Funding details
American Academy of NeurologyAAN
Boehringer Ingelheim
National Institutes of HealthNIH
Spastic Paraplegia FoundationSPF
Amyotrophic Lateral Sclerosis AssociationALSA
Otsuka America PharmaceuticalOAPI

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

Student engagement with school and personality: a biopsychosocial and person-centred approach
(2020) British Journal of Educational Psychology, .

Moreira, P.A.S.^a b , Inman, R.A.^b , Cloninger, K.^c , Cloninger, C.R.^d

^a Instituto de Psicologia e de Ciências da Educação [Institute of Psychology and Education], Universidade Lusíada-Norte, Porto, Portugal
^b Centro de Investigação em Psicologia para o Desenvolvimento (CIPD) [The Psychology for Positive Development Research Center], Porto, Portugal
^c Anthropedia Foundation, Washington, DC, United States
^d Washington University School of Medicine, St. Louis, WA, United States

Abstract
Background: Engagement with school is a key predictor of students’ academic outcomes, yet little is known about its association with personality. No research has considered this association using Cloninger’s biopsychosocial model of personality. This model may be particularly informative because it posits the structure of human personality corresponds to three systems of human learning and memory that regulate associative conditioning, intentionality, and self-awareness, all of which are relevant for understanding engagement. Aims: To test for defined personality phenotypes and describe how they relate to student engagement. Sample: 469 adolescents (54.2% female) attending the eighth (Mage = 13.2, SD =.57) or 11th (Mage = 16.5, SD =.84) grades. Methods: Students completed self-report measures of personality and engagement. We used mixture models to identify latent classes defined by common (1) temperament profiles, (2) character profiles, and (3) joint temperament–character networks, and then tested how these classes differed in engagement. Results: Latent class analysis revealed three distinct joint temperament–character networks: Emotional-Unreliable (emotionally reactive, low self-control, and low creativity), Organized-Reliable (self-control but not creative), and Creative-Reliable (highly creative and prosocial). These networks differed significantly in engagement, with the emotional-unreliable network linked to lower engagement. However, the magnitudes of these differences across engagement dimensions did not appear to be uniform. Conclusions: Different integrated configurations of the biopsychosocial systems for associative conditioning, intentionality, and self-awareness (differences in personality) underlie student engagement. Our results offer a fine-grained understanding of engagement dimensions in terms of their underlying personality networks, with implications for educational policies and practices. © 2020 The British Psychological Society

Author Keywords
character;  person-centred;  personality;  student engagement with school;  temperament

Funding details
Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e NeuroproteçãoINCT-EN
Fundação para a Ciência e a TecnologiaFCT
Fundação para a Ciência e a TecnologiaFCTPTDC/MHC‐CED/2224/2014, PTDC/CPE‐CED/122257/2010

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

Comparing eating disorder characteristics and treatment in self-identified competitive athletes and non-athletes from the National Eating Disorders Association online screening tool
(2020) International Journal of Eating Disorders, .

Flatt, R.E.^a b , Thornton, L.M.^b , Fitzsimmons-Craft, E.E.^c , Balantekin, K.N.^d , Smolar, L.^e , Mysko, C.^e , Wilfley, D.E.^c , Taylor, C.B.^f g , DeFreese, J.D.^h , Bardone-Cone, A.M.^a , Bulik, C.M.^b i j

^a Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^b Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, NY, United States
^e National Eating Disorders Association, New York City, NY, United States
^f Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^g Center for m2Health, Palo Alto University, Palo Alto, CA, United States
^h Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
ⁱ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
^j Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Objective: We compared eating disorder (ED) characteristics and treatment seeking behaviors between self-identified competitive athletes and non-athletes in a large, community-based sample. Method: During the 2018 National Eating Disorders Awareness Week, 23,920 respondents, 14.7% of whom identified as competitive athletes, completed the National Eating Disorders Association online screen. Data were collected on demographics, disordered eating behaviors, probable ED diagnosis/risk, treatment history, and intent to seek treatment. Results: The sample was predominantly White (81.8%), female (90.3%), and between 13 and 24 years (82.6%). Over 86% met criteria for an ED/subthreshold ED, and of those, only 2.5% were in treatment. Suicidal ideation was reported in over half of the sample. Athletes reported a significantly greater likelihood of engaging in and more frequent excessive exercise episodes than non-athletes. Athletes also reported a significantly lower likelihood of engaging in and less frequent binge-eating episodes compared with non-athletes. Athletes were more likely to screen positive for an ED/subthreshold ED than non-athletes, but percentages across all probable ED diagnoses were similar. No significant differences between athletes and non-athletes emerged on treatment history or intention to seek treatment post-screen (less than 30%). Discussion: Although the distribution of probable ED diagnoses was similar in athletes and non-athletes, symptom profiles related to disordered eating behavior engagement and frequency may differ. Athletes may be less likely to seek treatment due to stigma, accessibility, and sport-specific barriers. Future work should directly connect survey respondents to tailored treatment tools and increase motivation to seek treatment. © 2020 Wiley Periodicals LLC

Author Keywords
athletes;  disordered eating behaviors;  eating disorders;  online screen;  treatment seeking

Funding details
National Science FoundationNSFDGE‐1650116
National Institutes of HealthNIHR01 MH100455, K08 MH120341, R01 MH120170, R01 MH119084
VetenskapsrådetVR
National Science FoundationNSFDGE‐1650116
VetenskapsrådetVR
National Institutes of HealthNIHK01 DK120778, R01 MH100455, K08 MH120341, R01 MH120170, R01 MH119084
VetenskapsrådetVR538‐2013‐8864

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

Brain volumetric deficits in MAPT mutation carriers: a multisite study
(2020) Annals of Clinical and Translational Neurology, .

Chu, S.A.^a , Flagan, T.M.^a , Staffaroni, A.M.^a , Jiskoot, L.C.^b c , Deng, J.^a , Spina, S.^a , Zhang, L.^a , Sturm, V.E.^a , Yokoyama, J.S.^a , Seeley, W.W.^a , Papma, J.M.^b , Geschwind, D.H.^d , Rosen, H.J.^a , Boeve, B.F.^e , Boxer, A.L.^a , Heuer, H.W.^a , Forsberg, L.K.^e , Brushaber, D.E.^e , Grossman, M.^f , Coppola, G.^d , Dickerson, B.C.^g , Bordelon, Y.M.^d , Faber, K.^h , Feldman, H.H.ⁱ , Fields, J.A.^e , Fong, J.C.^a , Foroud, T.^h , Gavrilova, R.H.^e , Ghoshal, N.^j , Graff-Radford, N.R.^k , Hsiung, G.-Y.R.^l , Huey, E.D.^m , Irwin, D.J.^d , Kantarci, K.^f , Kaufer, D.I.ⁿ , Karydas, A.M.^a , Knopman, D.S.^e , Kornak, J.^o , Kramer, J.H.^a , Kukull, W.A.^p , Lapid, M.I.^e , Litvan, I.ⁱ , Mackenzie, I.R.A.^l , Mendez, M.F.^d , Miller, B.L.^a , Onyike, C.U.^q , Pantelyat, A.Y.^q , Rademakers, R.^k , Marisa Ramos, E.^d , Roberson, E.D.^r , Carmela Tartaglia, M.^s , Tatton, N.A.^t , Toga, A.W.^u , Vetor, A.^h , Weintraub, S.^v , Wong, B.^g , Wszolek, Z.K.^k , Van Swieten, J.C.^b , Lee, S.E.^a , the ARTFL/LEFFTDS Consortium^w

^a Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
^b Erasmus Medical Center, Rotterdam, Netherlands
^c Dementia Research Center, University College London, London, United Kingdom
^d University of California, Los Angeles, Los Angeles, CA, United States
^e Mayo Clinic, Rochester, MN, United States
^f Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^g Massachusetts General Hospital, Boston, MA, United States
^h School of Medicine, Indiana University, Indianapolis, IN, United States
ⁱ University of California, San Diego, La Jolla, CA, United States
^j Washington University School of Medicine, St. Louis, MO, United States
^k Mayo Clinic, Jacksonville, FL, United States
^l University of British Columbia, Vancouver, BC, Canada
^m Departments of Psychiatry and Neurology, Columbia University, New York, NY, United States
ⁿ University of North Carolina, Chapel Hill, NC, United States
^o Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
^p National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, United States
^q Johns Hopkins University School of Medicine, Baltimore, MD, United States
^r University of Alabama at Birmingham, Birmingham, AL, United States
^s Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
^t The Association for Frontotemporal Degeneration, Radnor, PA, United States
^u USC Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, United States
^v Northwestern Feinberg School of Medicine, Chicago, IL, United States

Abstract
Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

Funding details
Mayo Clinic
AbbVie
Alzheimer’s Drug Discovery FoundationADDF
Canadian Institutes of Health ResearchCIHR
University of Southern CaliforniaUSC
National Institutes of HealthNIH
Alzheimer Society of B.C.
Eli Lilly and Company
Biogen
BrightFocus FoundationBFF
Biogen
Sol Goldman Charitable Trust
Alzheimer’s AssociationAA
Canadian Institutes of Health ResearchCIHR
Parkinsonfonden
Avid Radiopharmaceuticals
Parkinson Study GroupPSG

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

Practical approaches to sedation and analgesia in the newborn
(2020) Journal of Perinatology, .

McPherson, C.^a b , Ortinau, C.M.^a , Vesoulis, Z.^a

^a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pharmacy, St. Louis Children’s Hospital, St. Louis, MO, United States

Abstract
The prevention, assessment, and treatment of neonatal pain and agitation continues to challenge clinicians and researchers. Substantial progress has been made in the past three decades, but numerous outstanding questions remain. In this setting, clinicians must establish safe and compassionate standardized practices that consider available efficacy data, long-term outcomes, and research gaps. Novel approaches with limited data must be carefully considered against historic standards of care with robust data suggesting limited benefit and clear adverse effects. This review summarizes available evidence while suggesting practical clinical approaches to pain assessment and avoidance, procedural analgesia, postoperative analgesia, sedation during mechanical ventilation and therapeutic hypothermia, and the issues of tolerance and withdrawal. Further research in all areas represents an urgent priority for optimal neonatal care. In the meantime, synthesis of available data offers clinicians challenging choices as they balance benefit and risk in vulnerable critically ill neonates. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institute of Neurological Disorders and StrokeNINDSK23 NS111086
National Heart, Lung, and Blood InstituteNHLBIK23 HL141602

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

Cerebral oxygen extraction fraction (OEF): Comparison of challenge-free gradient echo QSM+qBOLD (QQ) with 15O PET in healthy adults
(2020) Journal of Cerebral Blood Flow and Metabolism, .

Cho, J.^a , Lee, J.^b , An, H.^b , Goyal, M.S.^b , Su, Y.^c , Wang, Y.^a d

^a Department of Radiology, Weill Cornell Medical CollegeNY, United States
^b Mallinkckrodt Institute of Radiology, Washington University School of Medicine, St Louis, United States
^c Computational Image Analysis, Banner Alzheimer’s Institute, Phoenix, United States
^d Department of Biomedical Engineering, Cornell University, Ithaca, United States

Abstract
We aimed to validate oxygen extraction fraction (OEF) estimations by quantitative susceptibility mapping plus quantitative blood oxygen-level dependence (QSM+qBOLD, or QQ) using 15O-PET. In ten healthy adult brains, PET and MRI were acquired simultaneously on a PET/MR scanner. PET was acquired using C[15O], O[15O], and H2[15O]. Image-derived arterial input functions and standard models of oxygen metabolism provided quantification of PET. MRI included T1-weighted imaging, time-of-flight angiography, and multi-echo gradient-echo imaging that was processed for QQ. Region of interest (ROI) analyses compared PET OEF and QQ OEF. In ROI analyses, the averaged OEF differences between PET and QQ were generally small and statistically insignificant. For whole brains, the average and standard deviation of OEF was 32.8 ± 6.7% for PET; OEF was 34.2 ± 2.6% for QQ. Bland-Altman plots quantified agreement between PET OEF and QQ OEF. The interval between the 95% limits of agreement was 16.9 ± 4.0% for whole brains. Our validation study suggests that respiratory challenge-free QQ-OEF mapping may be useful for non-invasive clinical assessment of regional OEF impairment. © The Author(s) 2020.

Author Keywords
Oxygen extraction fraction;  positron emission tomography;  QSM+qBOLD;  quantitative blood oxygenation level-dependent imaging;  quantitative susceptibility mapping

Funding details
National Institutes of HealthNIHS10OD021782, R01NS095562, R01NS090464, R01AG057536, R21EB024366, 1R01NS082561, R01NS105144, 1P30NS098577

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

Comparison of hyperpolarized 13C and non-hyperpolarized deuterium MRI approaches for imaging cerebral glucose metabolism at 4.7 T
(2020) Magnetic Resonance in Medicine, .

von Morze, C.^a , Engelbach, J.A.^a , Blazey, T.^a , Quirk, J.D.^a , Reed, G.D.^b , Ippolito, J.E.^a , Garbow, J.R.^a

^a Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
^b GE Healthcare, Dallas, TX, United States

Abstract
Purpose: The purpose of this study was to directly compare two isotopic metabolic imaging approaches, hyperpolarized (HP) 13C MRI and deuterium metabolic imaging (DMI), for imaging specific closely related segments of cerebral glucose metabolism at 4.7 T. Methods: Comparative HP-13C and DMI neuroimaging experiments were conducted consecutively in normal rats during the same scanning session. Localized conversions of [1-13C]pyruvate and [6,6-2H2]glucose to their respective downstream metabolic products were measured by spectroscopic imaging, using an identical 2D-CSI sequence with parameters optimized for the respective experiments. To facilitate direct comparison, a pair of substantially equivalent 2.5-cm double-tuned X/1H RF surface coils was developed. For improved results, multidimensional low-rank reconstruction was applied to denoise the raw DMI data. Results: Localized conversion of HP [1-13C]pyruvate to [1-13C]lactate, and [6,6-2H2]glucose to [3,3-2H2]lactate and Glx-d (glutamate and glutamine), was detected in rat brain by spectroscopic imaging at 4.7 T. The SNR and spatial resolution of HP-13C MRI was superior to DMI but limited to a short time window, whereas the lengthy DMI acquisition yielded maps of not only lactate, but also Glx production, albeit with relatively poor spectral discrimination between metabolites at this field strength. Across the individual rats, there was an apparent inverse correlation between cerebral production of HP [1-13C]lactate and Glx-d, along with a trend toward increased [3,3-2H2]lactate. Conclusion: The HP-13C MRI and DMI methods are both feasible at 4.7 T and have significant potential for metabolic imaging of specific segments of glucose metabolism. © 2020 International Society for Magnetic Resonance in Medicine

Author Keywords
brain;  dynamic nuclear polarization;  imaging;  stable isotopes

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

Transdiagnostic time-varying dysconnectivity across major psychiatric disorders
(2020) Human Brain Mapping, .

Li, C.^a b , Dong, M.^a b , Womer, F.Y.^c , Han, S.^d , Yin, Y.^e , Jiang, X.^a b f , Wei, Y.^b f , Duan, J.^b f , Feng, R.^a b , Zhang, L.^b f , Zhang, X.^g h , Wang, F.^a b f i , Tang, Y.^b f , Xu, K.^a b

^a Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, China
^b Brain Function Research Section, The First Affiliated Hospital of China Medical University, Shenyang, China
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of MRI, The First Affiliated Hospital of ZhengZhou University, ZhengZhou, China
^e Guangdong Second Provincial General Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
^f Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China
^g School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
^h Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
ⁱ Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States

Abstract
Dynamic functional connectivity (DFC) analysis can capture time-varying properties of connectivity. However, studies on large samples using DFC to investigate transdiagnostic dysconnectivity across schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are rare. In this study, we used resting-state functional magnetic resonance imaging and a sliding-window method to study DFC in a total of 610 individuals (150 with SZ, 100 with BD, 150 with MDD, and 210 healthy controls [HC]) at a single site. Using k-means clustering, DFCs were clustered into three functional connectivity states: one was a more frequent state with moderate positive and negative connectivity (State 1), and the other two were less frequent states with stronger positive and negative connectivity (State 2 and State 3). Significant 4-group differences (SZ, BD, MDD, and HC groups; q <.05, false-discovery rate [FDR]-corrected) in DFC were nearly only in State 1. Post hoc analyses (q <.05, FDR-corrected) in State 1 showed that transdiagnostic dysconnectivity patterns among SZ, BD and MDD featured consistently decreased connectivity within most networks (the visual, somatomotor, salience and frontoparietal networks), which was most obvious in both range and extent for SZ. Our findings suggest that there is more common dysconnectivity across SZ, BD and MDD than we previously expected and that such dysconnectivity is state-dependent, which provides new insights into the pathophysiological mechanism of major psychiatric disorders. © 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Author Keywords
bipolar disorder;  dynamic functional connectivity;  major depressive disorder;  schizophrenia;  transdiagnostic study

Funding details
China Medical UniversityCMU3110117059, 3110118055
2018YFC1311600, 2016YFC1306900
Liaoning Revitalization Talents ProgramXLYC1808036
LT2017007
National Science Fund for Distinguished Young Scholars81725005
3110117059, 3110118055
2018YFC1311600, 2016YFC1306900
LT2017007
Liaoning Revitalization Talents ProgramXLYC1808036
2015225018
National Science Fund for Distinguished Young Scholars81725005

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

Current and future nonstimulants in the treatment of pediatric ADHD: Monoamine reuptake inhibitors, receptor modulators, and multimodal agents
(2020) CNS Spectrums, .

Cutler, A.J.^a , Mattingly, G.W.^b , Jain, R.^c , O’Neal, W.^d

^a Neuroscience Education Institute, SUNY Upstate Medical University, Sarasota, FL, United States
^b Washington University School of Medicine, Washington University, St. Louis, MO and Midwest Research Group, St. Charles, MO, United States
^c Department of Psychiatry, Texas Tech Health Sciences Center School of Medicine – Permian Basin, Midland, TX, United States
^d Supernus Pharmaceuticals, Inc., Rockville, MD, United States

Abstract
Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the FDA, all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these “pipeline” ADHD medications have a unique chemical structure and differ in their pharmacologic profiles in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents has been accepted for review by the FDA with a target action date in late 2020. © 2020 Georg Thieme Verlag. All rights reserved.

Author Keywords
ADHD;  Atomoxetine;  Centanafadine;  Clonidine;  Dasotraline;  Guanfacine;  Mazindol;  Nonstimulants;  Viloxazine;  Vortioxetine

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

Regional Brain Growth Trajectories in Fetuses with Congenital Heart Disease
(2020) Annals of Neurology, .

Rollins, C.K.^a b , Ortinau, C.M.^c , Stopp, C.^d , Friedman, K.G.^d e f , Tworetzky, W.^d e f , Gagoski, B.^g h , Velasco-Annis, C.^g , Afacan, O.^g h , Vasung, L.^g h , Beaute, J.I.^a , Rofeberg, V.^d , Estroff, J.A.^c e g h , Grant, P.E.^g h , Soul, J.S.^a b e , Yang, E.^g h , Wypij, D.^d f i , Gholipour, A.^g h , Warfield, S.K.^g h , Newburger, J.W.^d f

^a Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^b Departments of Neurology, Harvard Medical School, Boston, MA, United States
^c Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Cardiology, Boston Children’s Hospital, Boston, MA, United States
^e Maternal Fetal Care Center, Boston Children’s Hospital, Boston, MA, United States
^f Department of Pediatrics, Harvard Medical School, Boston, MA, United States
^g Department of Radiology, Boston Children’s Hospital, Boston, MA, United States
^h Department of Radiology, Harvard Medical School, Boston, MA, United States
ⁱ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States

Abstract
Objective: Congenital heart disease (CHD) is associated with abnormal brain development in utero. We applied innovative fetal magnetic resonance imaging (MRI) techniques to determine whether reduced fetal cerebral substrate delivery impacts the brain globally, or in a region-specific pattern. Our novel design included two control groups, one with and the other without a family history of CHD, to explore the contribution of shared genes and/or fetal environment to brain development. Methods: From 2014 to 2018, we enrolled 179 pregnant women into 4 groups: “HLHS/TGA” fetuses with hypoplastic left heart syndrome (HLHS) or transposition of the great arteries (TGA), diagnoses with lowest fetal cerebral substrate delivery; “CHD-other,” with other CHD diagnoses; “CHD-related,” healthy with a CHD family history; and “optimal control,” healthy without a family history. Two MRIs were obtained between 18 and 40 weeks gestation. Random effect regression models assessed group differences in brain volumes and relationships to hemodynamic variables. Results: HLHS/TGA (n = 24), CHD-other (50), and CHD-related (34) groups each had generally smaller brain volumes than the optimal controls (71). Compared with CHD-related, the HLHS/TGA group had smaller subplate (−13.3% [standard error = 4.3%], p < 0.01) and intermediate (−13.7% [4.3%], p < 0.01) zones, with a similar trend in ventricular zone (−7.1% [1.9%], p = 0.07). These volumetric reductions were associated with lower cerebral substrate delivery. Interpretation: Fetuses with CHD, especially those with lowest cerebral substrate delivery, show a region-specific pattern of small brain volumes and impaired brain growth before 32 weeks gestation. The brains of fetuses with CHD were more similar to those of CHD-related than optimal controls, suggesting genetic or environmental factors also contribute. ANN NEUROL 2020. © 2020 American Neurological Association

Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIK23HL141602
National Institute of Biomedical Imaging and BioengineeringNIBIBR01NS106030, R01EB013248, R01EB018988
Brain and Behavior Research FoundationBBRF
Mend a Heart Foundation
National Institute of Neurological Disorders and StrokeNINDSK23NS101120

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

Implantable Optofluidic Systems for Wireless In Vivo Photopharmacology
(2020) ChemPhotoChem, .

Qazi, R.^a b , Yeon Kim, C.^a , Kang, I.^a , Binazarov, D.^a , G. McCall, J.^c , Jeong, J.-W.^a

^a School of Electrical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
^b Department of Electrical, Computer and Energy Engineering, University of Colorado, Boulder, CO, United States
^c Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Photopharmacology, which uses chemical photoswitches for the optical manipulation of biological process, holds immense potential for neuroscience and clinical medicine due to its high specificity, fast response, and versatility. However, enabling photopharmacology in living subjects has been an arduous undertaking mainly because of limitations of the available tools. Conventional approaches to drug delivery and photostimulation involve the use of bulky, rigid, and tethered implants in the form of metal cannulas and optical fibers. These prevent highly precise, spatially matching stimulation with drugs and light, aggravates adverse tissue responses, and causes undue stress in the freely-moving subject. Recent advances in materials science and device engineering have led to the development of miniaturized, standalone multimodal implants referred to as “optofluidic” devices, which allow wireless delivery of both light and drugs. Herein, we review state-of-the-art wireless optofluidic systems, which can open up new horizons for in vivo photopharmacology, and discuss future directions for further technology developments. © 2020 Wiley-VCH GmbH

Author Keywords
implantable devices;  in vivo technology;  optofluidics;  photopharmacology;  wireless technology

Funding details
NRF‐2018025230, NRF‐2018R1 C1B6001706
National Research Foundation of KoreaNRF

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

In vivo gamma-aminobutyric acid -A/benzodiazepine receptor availability and genetic liability in asymptomatic individuals with high genetic loading of schizophrenia: A [11C]flumazenil positron emission tomography study
(2020) Human Psychopharmacology, .

Lee, J.^a , Yoon, Y.B.^b , Cho, K.I.K.^c , Seo, S.^d , Lee, J.S.^e , Jeong, J.M.^e , Kim, E.^a , Kim, M.^a , Lee, T.Y.^a , Kwon, J.S.^a f g

^a Department of Psychiatry, Seoul National University College of Medicine, Seoul, South Korea
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c Psychiatry Neuroimaging Laboratory, Harvard Medical School, Boston, MA, United States
^d Department of Neuroscience, Gachon University College of Medicine, Incheon, South Korea
^e Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
^f Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, South Korea
^g Institute of Human Behavioral Medicine, SNU-MRC, Seoul, South Korea

Abstract
Objectives: Whilst reduced signalling and gene expression related to gamma-aminobutyric acid (GABA) play a role in the presumed pathophysiology of schizophrenia, its origin is unclear. Studying asymptomatic individuals with high genetic liability to schizophrenia (AIs) would provide insights. Therefore, this study aimed to investigate the role of genetic liability in GABAergic dysfunction of schizophrenia by exploring in vivo GABA-A/benzodiazepine receptor (GABAR) availability in AIs. Methods: A total of 10 AIs with multiple relatives diagnosed as schizophrenia and 11 healthy controls underwent [11C]flumazenil positron emission tomography and neurocognitive function tests. Results: There was no significant difference in [11C]flumazenil availability based on the groups. GABAR availability in caudate nuclei had positive correlations with genetic liability of AIs. GABAR availability in caudate nuclei and verbal memory measures of AIs revealed positive correlations. Only the correlation between right caudate and short-term verbal memory survived multiple-comparison correction (p = 0.030). Conclusions: This study, for the first time, reports correlations between the genetic liability of schizophrenia and GABAR availability. Correlations between [11C]flumazenil binding in caudate of individuals with high genetic liability to schizophrenia suggests that the GABAergic dysfunction may arise from shared genetic factors and also that it may be responsible for cognitive impairment of AIs. © 2020 John Wiley & Sons Ltd.

Author Keywords
caudate nucleus;  flumazenil;  GABA;  genetic liability;  receptor;  schizophrenia

Funding details
National Research Foundation of KoreaNRF

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

Dominantly inherited Alzheimer’s disease in Latin America: Genetic heterogeneity and clinical phenotypes
(2020) Alzheimer’s and Dementia, .

Llibre-Guerra, J.J.^a , Li, Y.^a , Allegri, R.F.^b , Mendez, P.C.^b , Surace, E.I.^b , Llibre-Rodriguez, J.J.^c , Sosa, A.L.^d , Aláez-Verson, C.^e , Longoria, E.-M.^d , Tellez, A.^d , Carrillo-Sánchez, K.^e , Flores-Lagunes, L.L.^e , Sánchez, V.^f , Takada, L.T.^g , Nitrini, R.^g , Ferreira-Frota, N.A.^h , Benevides-Lima, J.^h , Lopera, F.ⁱ , Ramírez, L.ⁱ , Jiménez-Velázquez, I.^j , Schenk, C.^j , Acosta, D.^k , Behrens, M.I.^l , Doering, M.^m , Ziegemeier, E.^a , Morris, J.C.^a , McDade, E.^a , Bateman, R.J.^a

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Cognitive Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina
^c Universidad de Ciencias Medicas de la Habana, Havana, Cuba
^d Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico, Mexico City, Mexico
^e Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Ciudad de México, Mexico
^f Department of Neurology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil
^g General Hospital of Fortaleza, Fortaleza, Brazil
^h Grupo de Neurociencias de Antioquia, Medellín, Colombia
ⁱ University of Puerto Rico School of Medicine, San Juan, Puerto Rico, United States
^j Universidad Nacional Pedro Henríquez Ureña, Santo Domingo, Dominican Republic
^k Departamento de Neurología y Neurocirugía Hospital Clínico, Departamento de Neurociencias, Centro de Investigación Clínica Avanzada (CICA), Universidad de Chile & Clínica Alemana, Santiago, Chile
^l Becker Medical Library, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Introduction: A growing number of dominantly inherited Alzheimer’s disease (DIAD) cases have become known in Latin American (LatAm) in recent years. However, questions regarding mutation distribution and frequency by country remain open. Methods: A literature review was completed aimed to provide estimates for DIAD pathogenic variants in the LatAm population. The search strategies were established using a combination of standardized terms for DIAD and LatAm. Results: Twenty-four DIAD pathogenic variants have been reported in LatAm countries. Our combined dataset included 3583 individuals at risk; countries with highest DIAD frequencies were Colombia (n = 1905), Puerto Rico (n = 672), and Mexico (n = 463), usually attributable to founder effects. We found relatively few reports with extensive documentation on biomarker profiles and disease progression. Discussion: Future DIAD studies will be required in LatAm, albeit with a more systematic approach to include fluid biomarker and imaging studies. Regional efforts are under way to extend the DIAD observational studies and clinical trials to Latin America. © 2020 the Alzheimer’s Association

Funding details
National Institute on AgingNIA
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Japan Agency for Medical Research and DevelopmentAMED
Fleni
Japan Agency for Medical Research and DevelopmentAMED
Alzheimer’s AssociationAASG‐20‐690363
Korea Health Industry Development InstituteKHIDI
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Consejo Nacional de Investigaciones Científicas y TécnicasCONICETPICT 2015/2110

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

Neurobehaviour of very preterm infants at term equivalent age is related to early childhood outcomes
(2020) Acta Paediatrica, International Journal of Paediatrics, .

Meether, M.^a , Bush, C.N.^b c , Richter, M.^d , Pineda, R.^a d e

^a Washington University Program in Occupational Therapy, St. Louis, MO, United States
^b Synova Associates, LLC, Milwaukee, WI, United States
^c Tarry Medical Products, Danbury, CT, United States
^d Chan Division of Occupational Science and Occupational Therapy, University of Southern CA, Los Angeles, CA, United States
^e Department of Pediatrics, Keck School of Medicine, Los Angeles, CA, United States

Abstract
Aim: To describe neurodevelopmental outcomes during early childhood among infants born very preterm and define the relationships between neurobehaviour of very preterm infants and neurodevelopmental outcomes at 4 years. Methods: Forty-eight infants born ≤32 weeks gestation had neurobehaviour assessed at term equivalent age using the NICU Network Neurobehavioral Scale (NNNS). Outcomes at 4 years were assessed with the Ages and Stages Questionnaire (ASQ-3), the Sensory Profile-Short Form (SF) and the Behavior Rating Inventory of Executive Function-Preschool version (BRIEF-P). Results: At 4 years, 23 (48%) children had at least one below average score on the ASQ-3, 15 (31%) had a below average total score on the Sensory Profile-SF, and 3 (6%) had an abnormal total score on the BRIEF-P. Children with lower fine motor scores at 4 years had poorer orientation (P = 0.03) and self-regulation (P =0.03), hypertonia (P = 0.01), and more sub-optimal reflexes (P = 0.02) as neonates. Children with lower gross motor scores at 4 years of age had more sub-optimal reflexes (P = 0.03) and lethargy (P = 0.046) as neonates. Children with tactile sensitivity at 4 years of age had poorer orientation (P = 0.01) and tolerance of handling (P = 0.03) as neonates. Children with decreased responsiveness at 4 years of age had low arousal (P = 0.02) as neonates, and those with poor auditory filtering at age 4 years had hypotonia (P = 0.03) as neonates. Conclusion: Early neurobehaviour is related to neurodevelopmental outcome in early childhood. © 2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd

Author Keywords
development;  neonatal intensive care unit;  NICU Network Neurobehavioral Scale;  preterm birth

Funding details
Intellectual and Developmental Disabilities Research CenterIDDRC1P0HD062171, K12 HD055931

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

Functional ensemble survival tree: Dynamic prediction of Alzheimer’s disease progression accommodating multiple time-varying covariates
(2020) Journal of the Royal Statistical Society. Series C: Applied Statistics, .

Jiang, S.^a , Xie, Y.^b , Colditz, G.A.^a

^a Division of Public Health Sciences, Washington University School of Medicine in St. Louis, St. Louis, United States
^b Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, Canada

Abstract
With the exponential growth in data collection, multiple time-varying biomarkers are commonly encountered in clinical studies, along with a rich set of baseline covariates. This paper is motivated by addressing a critical issue in the field of Alzheimer’s disease (AD) in which we aim to predict the time for AD conversion in people with mild cognitive impairment to inform prevention and early treatment decisions. Conventional joint models of biomarker trajectory with time-to-event data rely heavily on model assumptions and may not be applicable when the number of covariates is large. This motivated us to consider a functional ensemble survival tree framework to characterize the joint effects of both functional and baseline covariates in predicting disease progression. The proposed framework incorporates multivariate functional principal component analysis to characterize the changing patterns of multiple time-varying neurocognitive biomarker trajectories and then nest these features within an ensemble survival tree in predicting the progression of AD. We provide a fast implementation of the algorithm that accommodates personalized dynamic prediction that can be updated as new observations are gathered to reflect the patient’s latest prognosis. The algorithm is empirically shown to perform well in simulation studies and is illustrated through the analysis of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (http://adni.loni.usc.edu/). We provide implementation of our proposed method in an R package funest. © 2020 Royal Statistical Society

Author Keywords
Dynamic prediction;  Functional principal component analysis;  Random survival forest;  Time-varying covariates

Funding details
P30 CA091842

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

Predictors of long-term opioid use and opioid use disorder among construction workers: Analysis of claims data
(2020) American Journal of Industrial Medicine, .

Dale, A.M., Buckner-Petty, S., Evanoff, B.A., Gage, B.F.

Division of General Medical Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Construction workers have high rates of work-related musculoskeletal disorders, which lead to frequent opioid use and opioid use disorder (OUD). This paper quantified the incidence of opioid use and OUD among construction workers with and without musculoskeletal disorders. Methods: We conducted a retrospective study using union health claims from January 2015 to June 2018 from 19,909 construction workers. Claims for diagnoses of chronic musculoskeletal disorders, acute musculoskeletal injuries, musculoskeletal surgery, and other conditions were linked to new opioid prescriptions. We examined the effects of high doses (≥50 morphine mg equivalents per day), large supply (more than 7 days per fill), long-term opioid use (60 or more days supplied within a calendar quarter), and musculoskeletal disorders, on the odds of a future OUD. Results: There were high rates (42.8% per year) of chronic musculoskeletal disorders among workers, of whom 24.1% received new opioid prescriptions and 6.3% received long-term opioid prescriptions per year. Workers receiving opioids for chronic musculoskeletal disorders had the highest odds of future OUD: 4.71 (95% confidence interval 3.09–7.37); workers prescribed long-term opioids in any calendar quarter had a nearly 10-fold odds of developing an OUD. Conclusions: Among construction workers, opioids initiated for musculoskeletal pain were strongly associated with incident long-term opioid use and OUD. Musculoskeletal pain from physically demanding work is likely one driver of the opioid epidemic in occupations like construction. Prevention of work injuries and alternative pain management are needed for workers at risk for musculoskeletal injuries. © 2020 Wiley Periodicals LLC

Author Keywords
blue collar worker;  musculoskeletal disorders;  opioid prescriptions;  pain treatment

Funding details
National Institutes of HealthNIHUL1 TR000448
National Center for Advancing Translational SciencesNCATS

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

Item response theory analysis of the Clinical Dementia Rating
(2020) Alzheimer’s and Dementia, .

Li, Y.^a b , Xiong, C.^b c , Aschenbrenner, A.J.^a c , Chang, C.-H.^d e f , Weiner, M.W.^g h , Nosheny, R.L.^g i , Mungas, D.^j , Bateman, R.J.^a c , Hassenstab, J.^a c , Moulder, K.L.^a c , Morris, J.C.^a c

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^c Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^d Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^e Institute for Informatics, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
^h San Francisco Veteran’s Administration Medical Center, San Francisco, CA, United States
ⁱ Department of Psychiatry, University of California, San Francisco, San Francisco, CA, United States
^j Department of Neurology, University of California, Davis, Davis, CA, United States

Abstract
Introduction: The Clinical Dementia Rating (CDR) is widely used in Alzheimer’s disease research studies and has well established reliability and validity. To facilitate the development of an online, electronic CDR (eCDR) for more efficient clinical applications, this study aims to produce a shortened version of the CDR, and to develop the statistical model for automatic scoring. Methods: Item response theory (IRT) was used for item evaluation and model development. An automatic scoring algorithm was validated using existing CDR global and domain box scores as the reference standard. Results: Most CDR items discriminate well at mild and very mild levels of cognitive impairment. The bi-factor IRT model fits best and the shortened CDR still demonstrates very high classification accuracy (81%∼92%). Discussion: The shortened version of the CDR and the automatic scoring algorithm has established a good foundation for developing an eCDR and will ultimately improve the efficiency of cognitive assessment. © 2020 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  bi-factor model;  Clinical Dementia Rating;  cognitive assessment;  dementia severity;  item response theory

Funding details
National Institute on AgingNIAP01AG03991, P50AG05681, P01AG026276
National Institutes of HealthNIH1RF1AG059009‐01
Eli Lilly and Company
GHR FoundationGHR
Biogen
BrightFocus FoundationBFF
Janssen Biotech
Cure Alzheimer’s FundCAF
Alzheimer’s AssociationAA
National Institutes of HealthNIH
Eisai Incorporated
Association for Frontotemporal DegenerationAFTD

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

Ante- and postmortem tau in autosomal dominant and late-onset Alzheimer’s disease
(2020) Annals of Clinical and Translational Neurology, .

Chen, C.D.^a , Holden, T.R.^b , Gordon, B.A.^a , Franklin, E.E.^c , Li, Y.^d , Coble, D.W.^e , Luo, H.^f , Bateman, R.J.^d , Ances, B.M.^d , Perrin, R.J.^c d , Benzinger, T.L.S.^a , Cairns, N.J.^g , Morris, J.C.^d , for the Dominantly Inherited Alzheimer Network (DIAN) and for the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU)^h

^a Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Medicine, Division of Geriatrics and Nutritional Science, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^e Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Neurology, Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, China
^g College of Medicine and Health, University of Exeter, Exeter, United Kingdom

Abstract
Antemortem tau positron emission tomography imaging suggests elevated tau pathology in autosomal dominant versus late-onset Alzheimer’s disease at equivalent clinical stages, but does not implicate the specific tau pathologies responsible. Here we made stereological measurements of tau neurofibrillary tangles, neuritic plaques, and neuropil threads and found compared to late-onset Alzheimer’s disease, autosomal dominant Alzheimer’s disease showed even greater tangle and thread burdens. Regional tau burden resembled that observed in tau imaging of a separate cohort at earlier clinical stages. Finally, our results suggest tau imaging measures total tau burden in Alzheimer’s disease, composed predominantly of tangle and thread pathology. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

Funding details
GHR FoundationGHR
P30NS098577
National Institutes of HealthNIHU01AG042791‐S1, P01AG03991, R01AG052550‐01A1, U01AG042791, R01AG53267‐S1, R01AG046179, U19AG032438, P50AG005681, P01AG026276
Alzheimer’s AssociationAA
National Science FoundationNSFDGE‐1745038, K01AG053474, UF1AG032438
GHR FoundationGHR
National Institutes of HealthNIHP01AG03991, U19AG032438, P50AG005681, P01AG026276
Roche DiagnosticsU01AG042791‐S1, U01AG042791
Eli Lilly and Company
Foundation for the National Institutes of HealthFNIHR01AG53267‐S1, R01AG046179
National Science FoundationNSFDGE‐1745038, K01AG053474, UF1AG032438

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

Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease
(2020) NeuroImage: Clinical, 28, art. no. 102491, .

Dincer, A.^a , Gordon, B.A.^a , Hari-Raj, A.^b , Keefe, S.J.^a , Flores, S.^a , McKay, N.S.^a , Paulick, A.M.^a , Shady Lewis, K.E.^y , Feldman, R.L.^a , Hornbeck, R.C.^a , Allegri, R.^c , Ances, B.M.^a , Berman, S.B.^d , Brickman, A.M.^e , Brooks, W.S.^f g , Cash, D.M.^h , Chhatwal, J.P.ⁱ , Farlow, M.R.^j , la Fougère, C.^k l , Fox, N.C.^h , Fulham, M.J.^m , Jack, C.R., Jr.ⁿ , Joseph-Mathurin, N.^a , Karch, C.M.^a , Lee, A.^o , Levin, J.^p q r , Masters, C.L.^s , McDade, E.M.^a , Oh, H.^o , Perrin, R.J.^a , Raji, C.^a , Salloway, S.P.^o , Schofield, P.R.^f t , Su, Y.^u , Villemagne, V.L.^v , Wang, Q.^a , Weiner, M.W.^w , Xiong, C.^a , Yakushev, I.^x , Morris, J.C.^a , Bateman, R.J.^a , L.S. Benzinger, T.^a , for the Dominantly Inherited Alzheimer Network DIAN^z

^a Department of Radiology, Department of Neurology, Department of Psychiatry, Department of Pathology and Immunology, Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, United States
^b The Ohio State University College of Medicine, Columbus, OH, United States
^c Department of Cognitive Neurology, Neuropsychology and Neuropsychiatry, FLENI, Buenos Aires, Argentina
^d Department of Neurology and Clinical & Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^e Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, United States
^f Neuroscience Research Australia, Sydney, NSW, Australia
^g Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
^h Dementia Research Centre and UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom
ⁱ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^j Department of Neurology, Department of Radiology and Imaging Science, Indiana University School of Medicine, Indianapolis, IN, United States
^k German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^l Department of Nuclear Medicine and Clinical Molecular Imaging, University Hospital of Tübingen, Tübingen, Germany
^m Department of Molecular Imaging, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW, Australia
ⁿ Department of Radiology, Mayo Clinic, Rochester, MN, United States
^o Department of Psychiatry and Human Behavior, Department of Neurology, Butler Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States
^p German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
^q Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^r Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^s The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
^t School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
^u Banner Alzheimer’s Institute, Phoenix, AZ, United States
^v Department of Molecular Imaging and Therapy, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia
^w Department of Radiology and Biomedical Imaging, School of Medicine, University of California San Francisco, San Francisco, CA, United States
^x Department of Nuclear Medicine, Technical University of Munich, Munich, Germany
^y Sanders Brown Center on Aging & Alzheimer’s, University of Kentucky College of Medicine, Lexington, KY, United States

Abstract
Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD. © 2020 The Authors

Author Keywords
Alzheimer disease;  Amyloid;  Autosomal dominant Alzheimer disease;  Cortical signature;  Cortical thickness;  Preclinical

Funding details
Foundation for Barnes-Jewish Hospital
P30NS098577
AARG-17-532945
Fleni
AARFD-20-681815
R01EB009352
Arizona Alzheimer’s ConsortiumAAC
National Institutes of HealthNIHK01AG053474, P01AG003991, U19AG03243808, P01AG005681, P30AG019610, P01AG026276, R01AG03158
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Japan Agency for Medical Research and DevelopmentAMED
Japan Agency for Medical Research and DevelopmentAMED
Center for High Performance ComputingCHPC1S10OD018091-0, ADHS14-052688, 1S10RR022984-01A1, CTR040636
BrightFocus FoundationBFFADR A2017272S
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Korea Health Industry Development InstituteKHIDI
Mayo Clinic
Arizona Department of Health ServicesADHS
Bundesministerium für Bildung und ForschungBMBF
Foundation for Barnes-Jewish Hospital
Association for Frontotemporal DegenerationAFTD
Deutsche ForschungsgemeinschaftDFG
Consejo Nacional de Investigaciones Científicas y TécnicasCONICET
GHR FoundationGHR
Arizona Alzheimer’s ConsortiumAAC
National Institutes of HealthNIH
F. Hoffmann-La Roche
National Institutes of HealthNIH
Eli Lilly and Company
National Institute on AgingNIA
BrightFocus FoundationBFF
Janssen Biotech
Alzheimer’s AssociationAA
Department of Human ServicesDHS
Eli Lilly and Company

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Measuring implicit intergroup biases
(2020) Social and Personality Psychology Compass, .

Lai, C.K., Wilson, M.E.

Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Implicit intergroup biases are automatically activated prejudices and stereotypes that may influence judgments of others on the basis of group membership. We review evidence on the measurement of implicit intergroup biases, finding: implicit intergroup biases reflect the personal and the cultural, implicit measures vary in reliability and validity, and implicit measures vary greatly in their prediction of explicit and behavioral outcomes due to theoretical and methodological moderators. We then discuss three challenges to the application of implicit intergroup biases to real-world problems: (1) a lack of research on social groups of scientific and public interest, (2) developing implicit measures with diagnostic capabilities, and (3) resolving ongoing ambiguities in the relationship between implicit bias and behavior. Making progress on these issues will clarify the role of implicit intergroup biases in perpetuating inequality. © 2020 John Wiley & Sons Ltd.

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

Resting-State Functional Connectivity Predicts STN DBS Clinical Response
(2020) Movement Disorders, .

Younce, J.R.^a , Campbell, M.C.^a b , Hershey, T.^b c , Tanenbaum, A.B.^a , Milchenko, M.^b , Ushe, M.^a , Karimi, M.^a , Tabbal, S.D.^d , Kim, A.E.^a , Snyder, A.Z.^a b , Perlmutter, J.S.^{a b c e f g} , Norris, S.A.^a b

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Neurology, American University of Beirut, Beirut, Lebanon
^e Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^f Program in Physical Therapy, Washington University in St. Louis, St. Louis, MO, United States
^g Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson’s disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. Methods: We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15O H2O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. Results: Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = −0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. Discussion: Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society. © 2020 International Parkinson and Movement Disorder Society

Author Keywords
DBS;  functional connectivity;  Parkinson’s disease

Funding details
UL1TR000448
Brain and Behavior Research FoundationBBRF
American Parkinson Disease AssociationAPDA
National Institutes of HealthNIHNS097799, R01 NS41509, U54NS116025, NS107281, P30NS98577, NS41248, NS109487, CO6 RR020092, NS075321, U19NS110456, NS097437, NS58797, R01 AG050263, T32 EB021955, NS075527, F31 NS071639, 1U10NS077384, NS103957, NS092865
National Alliance for Research on Schizophrenia and DepressionNARSAD
International Parkinson and Movement Disorder SocietyMDS
National Institutes of HealthNIHT32 EB021955
Alzheimer’s AssociationAA
Parkinsonfonden
National Institutes of HealthNIHR21 AG063974, R01 NS097437, R01 NS075321, R01 NS097799, R61 AT010753
McDonnell Center for Systems Neuroscience
American Brain Tumor AssociationABTA
Massachusetts General HospitalMGH
CHDI FoundationCHDI
Dystonia CoalitionNS065701, NS116025, TR001456
American Parkinson Disease AssociationAPDA
Dystonia Medical Research FoundationDMRF
American Parkinson’s Disease FoundationAPDA
National Institutes of HealthNIHNS097799, U54NS116025, NS107281, ES029524, NS109487, AG050263, R61 AT010753, U10NS077384, NS075321, NS097437, NS075527, AG‐64937, NS103957, NS092865, U19 NS110456
U.S. Department of DefenseDODDOD W81XWH‐217‐1‐0393
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Dystonia Medical Research FoundationDMRF
National Institutes of HealthNIHR01 NS103957, TR00145609

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

Assessment of Chronic Pain Management in the Treatment of Opioid Use Disorder: Gaps in Care and Implications for Treatment Outcomes
(2020) Journal of Pain, .

Ellis, M.S., Kasper, Z., Cicero, T.

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

Abstract
Chronic pain is a significant comorbid condition among individuals with opioid use disorder (OUD). However, due to conflicting perceptions of responsibility, structural barriers, and a lack of widely applied standards of care, it is unclear what the landscape of chronic pain management looks like in addiction medicine. Using a national opioid surveillance system, we analyzed survey data from new entrants (n = 14,449) to 225 OUD treatment centers from 2013 to 2018, as well as an online survey among a subset of respondents (n = 309). While chronic pain was reported by 33.4% of the sample, two-thirds of the chronic pain group (66.0%) reported their pain was not managed through their OUD treatment program, with 47% reporting worsening pain. Pain that was managed was primarily done so through pharmaceuticals (75.2%), notably as a secondary effect of medication-assisted treatment. In addition, 43.2% reported chronic pain as a primary factor in their opioid relapse. These data suggest that chronic pain is commonly reported, yet not managed by many OUD treatment programs, increasing the likelihood of opioid relapse. In order to improve poor outcomes among OUD patients, interdisciplinary collaboration/care, along with evidence-based policies or processes for quality pain management in addiction care need to be prioritized. Perspective: This article suggests chronic pain is commonly reported, yet not managed by many OUD treatment programs, increasing the likelihood of opioid relapse. In order to improve low retention and success rates among OUD patients, interdisciplinary collaboration, evidence-based policies or processes (eg, referral) for quality pain management in addiction care need to be prioritized. © 2020 United States Association for the Study of Pain, Inc.

Author Keywords
Addiction medicine;  Buprenorphine;  Chronic pain;  Methadone;  Opioid use disorder

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

Neurological Complications and Recovery Rates of Patients With Adult Cervical Deformity Surgeries
(2020) Global Spine Journal, .

Kim, H.J.^a , Yao, Y.-C.^a b , Shaffrey, C.I.^c , Smith, J.S.^d , Kelly, M.P.^e , Gupta, M.^e , Albert, T.J.^a , Protopsaltis, T.S.^f , Mundis, G.M., Jr.^g , Passias, P.^f , Klineberg, E.^h , Bess, S.ⁱ , Lafage, V.^a , Ames, C.P.^j , International Spine Study Group (ISSG)^k

^a Spine Service, Hospital for Special Surgery, New York, NY, United States
^b Department of Orthopedics and Traumatology, Taipei Veterans General Hospital, Beitou District, Taipei, Taiwan
^c Department of Orthopaedic Surgery, Duke University, Raleigh, NC, United States
^d Department of Neurosurgery, University of Virginia Health Sciences Center, Charlottesville, VA, United States
^e Department of Orthopaedic Surgery, Washington University in St. LouisMO, United States
^f Department of Orthopaedics, NYU Langone Medical Center-Orthopaedic Hospital, New York, NY, United States
^g San Diego Center for Spinal Disorders, La Jolla, CA, United States
^h Department of Orthopaedic Surgery, University of California, Sacramento, Davis, CA, United States
ⁱ Paediatric and Adult Spine Surgery, Rocky Mountain Hospital for Children, Presbyterian St Luke’s Medical Center, Denver, CO, United States
^j Department of Neurological Surgery, University of California, San Francisco, CA, United States

Abstract
Study Design: Retrospective cohort study. Objective: This study aims to report the incidence, risk factors, and recovery rate of neurological complications (NC) in patients with adult cervical deformity (ACD) who underwent corrective surgery. Methods: ACD patients undergoing surgery from 2013 to 2015 were enrolled in a prospective, multicenter database. Patients were separated into 2 groups according to the presence of neurological complications (NC vs no-NC groups). The types, timing, recovery patterns, and interventions for NC were recorded. Patients’ demographics, surgical details, radiographic parameters, and health-related quality of life (HRQOL) scores were compared. Results: 106 patients were prospectively included. Average age was 60.8 years with a mean of 18.2 months follow-up. The overall incidence of NC was 18.9%; of these, 68.1% were major complications. Nerve root motor deficit was the most common complication, followed by radiculopathy, sensory deficit, and spinal cord injury. The proportion of complications occurring within 30 days of surgery was 54.5%. The recovery rate from neurological complication was high (90.9%), with most of the recoveries occurring within 6 months and continuing even after 12 months. Only 2 patients (1.9%) had continuous neurological complication. No demographic or preoperative radiographic risk factors could be identified, and anterior corpectomy and posterior foraminotomy were found to be performed less in the NC group. The final HRQOL outcome was not significantly different between the 2 groups. Conclusions: Our data is valuable to surgeons and patients to better understand the neurological complications before performing or undergoing complex cervical deformity surgery. © The Author(s) 2020.

Author Keywords
cervical;  deformity;  fusion;  lordosis;  neurological complication;  neurology;  sagittal alignment;  scoliosis

Funding details
Taipei Veterans General Hospital108-V-A-010

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

Synthesis and Pharmacology of a Novel μ-δOpioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template
(2020) Journal of Medicinal Chemistry, .

Faouzi, A.^a d , Uprety, R.^b , Gomes, I.^c , Massaly, N.^d , Keresztes, A.I.^e , Le Rouzic, V.^b , Gupta, A.^c , Zhang, T.^b , Yoon, H.J.^d , Ansonoff, M.^f , Allaoa, A.^b , Pan, Y.X.^b , Pintar, J.^f , Morón, J.A.^d g , Streicher, J.M.^e , Devi, L.A.^c , Majumdar, S.^a d

^a Center for Clinical Pharmacology, St Louis College of Pharmacy, Washington University, School of Medicine, St. Louis, MO 63110, United States
^b Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
^c Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AR 85724, United States
^f Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States
^g Department of Neuroscience and Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
In this work, we studied a series of carfentanyl amide-based opioid derivatives targeting the mu opioid receptor (μOR) and the delta opioid receptor (δOR) heteromer as a credible novel target in pain management therapy. We identified a lead compound named MP135 that exhibits high G-protein activity at μ-δheteromers compared to the homomeric δOR or μOR and low β-arrestin2 recruitment activity at all three. Furthermore, MP135 exhibits distinct signaling profile, as compared to the previously identified agonist targeting μ-δheteromers, CYM51010. Pharmacological characterization of MP135 supports the utility of this compound as a molecule that could be developed as an antinociceptive agent similar to morphine in rodents. In vivo characterization reveals that MP135 maintains untoward side effects such as respiratory depression and reward behavior; together, these results suggest that optimization of MP135 is necessary for the development of therapeutics that suppress the classical side effects associated with conventional clinical opioids. © 2020 American Chemical Society.

Funding details
National Institutes of HealthNIHW81XWH-17-1-0256, DA045884, DA046487, AA026949
National Institute on Drug AbuseNIDADA041781, DA042888, DA007242, DA046714, DA042499, DA008863, DA045463, DA006241, UG3DA047717, R21DA044509, DA026880
P30 CA008748
Office of the Assistant Secretary for HealthOASH

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

Novel Alzheimer Disease risk loci and pathways in african American individuals using the african genome resources panel a meta-analysis
(2020) JAMA Neurology, . Cited 1 time.

Kunkle, B.W.^a b , Schmidt, M.^a b , Klein, H.-U.^c d e , Naj, A.C.^f g , Hamilton-Nelson, K.L.^a , Larson, E.B.^h i , Evans, D.A.^j k , de Jager, P.L.^c d e , Crane, P.K.^g , Buxbaum, J.D.^l m n o , Ertekin-Taner, N.^p q , Barnes, L.L.^r s t , Daniele Fallin, M.^u , Manly, J.J.^c d e , Go, R.C.P.^v , Obisesan, T.O.^w , Ilyas Kamboh, M.^x y , Bennett, D.A.^z aa , Hall, K.S.^ab , Goate, A.M.^m n o ac , Foroud, T.M.^ad , Martin, E.R.^a b , Wang, L.-S.^g , Byrd, G.S.^ae , Farrer, L.A.^{af ag ah ai aj} , Haines, J.L.^ak , Schellenberg, G.D.^g , Mayeux, R.^{c d e al am} , Pericak-Vance, M.A.^a b , Reitz, C.^c d e am , Graff-Radford, N.R.^p q , Martinez, I.^d , Ayodele, T.^d , Logue, M.W.^af an ao , Cantwell, L.B.^g , Jean-Francois, M.^a , Kuzma, A.B.^g , Adams, L.D.^a , Vance, J.M.^a b , Cuccaro, M.L.^a b , Chung, J.^af , Mez, J.^ag , Lunetta, K.L.^ah , Jun, G.R.^ag ah ai , Lopez, O.L.^y , Hendrie, H.C.^ab , Reiman, E.M.^ap , Kowall, N.W.^aq , Leverenz, J.B.^ar , Small, S.A.^as , Levey, A.I.^at , Golde, T.E.^au , Saykin, A.J.^ad av aw , Starks, T.D.^ae , Albert, M.S.^ax , Hyman, B.T.^ay , Petersen, R.C.^az , Sano, M.^l , Wisniewski, T.^ba , Vassar, R.^bb , Kaye, J.A.^bc , Henderson, V.W.^bd be , DeCarli, C.^bf , LaFerla, F.M.^bg , Brewer, J.B.^bh , Miller, B.L.^bi , Swerdlow, R.H.^bj , van Eldik, L.J.^bk , Paulson, H.L.^bl , Trojanowski, J.Q.^bm , Chui, H.C.^bn , Rosenberg, R.N.^bo , Craft, S.^bp , Grabowski, T.J.^bq br , Asthana, S.^bs , Morris, J.C.^bt , Strittmatter, S.M.^bu , Kukull, W.A.^bv bw , Writing Group for the Alzheimer’s Disease Genetics Consortium (ADGC)^bx

^a John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, United States
^b Dr. John T. MacDonald Foundation, Department of Human Genetics, University of Miami, Miami, FL, United States
^c Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, United States
^d Gertrude H. Sergievsky Center, Columbia University, New York, NY, United States
^e Department of Neurology, Columbia University, New York, NY, United States
^f Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman, School of Medicine, Philadelphia, United States
^g Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman, School of Medicine, Philadelphia, United States
^h Department of Medicine, University of Washington, Seattle, United States
ⁱ Group Health Research Institute, Group Health, Seattle, WA, United States
^j Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL, United States
^k Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
^l Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States
^m Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, NY, United States
ⁿ Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, United States
^o Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, United States
^p Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
^q Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^r Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
^s Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, United States
^t Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^u Department of Epidemiology, Johns Hopkins University, School of Public Health, Baltimore, MD, United States
^v Department of Epidemiology, University of Alabama at Birmingham, Birmingham, United States
^w Howard University, Howard University Hospital, Washington, DC, United States
^x Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
^y Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh, PA, United States
^z Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
^aa Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^ab Department of Psychiatry, Indiana University, School of Medicine, Indianapolis, United States
^ac Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^ad Department of Medical and Molecular Genetics, Indiana University, Indianapolis, United States
^ae Maya Angelou Center for Health Equity, Wake Forest School of Medicine, Winston-Salem, NC, United States
^af Department of Medicine (Biomedical Genetics), Boston University, School of Medicine, Boston, MA, United States
^ag Department of Neurology, Boston University, School of Medicine, Boston, MA, United States
^ah Department of Biostatistics, Boston University, School of Public Health, Boston, MA, United States
^ai Department of Ophthalmology, Boston University, School of Medicine, Boston, MA, United States
^aj Department of Epidemiology, Boston University, School of Public Health, Boston, MA, United States
^ak Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States
^al Department of Psychiatry, Columbia University, New York, NY, United States
^am Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY, United States
^an National Center for PTSD, VA Boston Healthcare System, Boston, MA, United States
^ao Department of Psychiatry, Boston University, School of Medicine, Boston, MA, United States
^ap Arizona Alzheimer’s Center, Banner Alzheimer’s Institute, Phoenix, United States
^aq Boston University, Boston VA Medical Center, Jamaica Plain, MA, United States
^ar Cleveland Clinic, Cleveland, OH, United States
^as Columbia University Alzheimer’s Disease Research Center, New York, NY, United States
^at Department of Neurology, Emory University, Atlanta, GA, United States
^au Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, United States
^av Indiana Alzheimer Disease Center, Indiana University, School of Medicine, Indianapolis, United States
^aw Department of Radiology and Imaging Sciences, Indiana University, School of Medicine, Indianapolis, United States
^ax Johns Hopkins University, School of Medicine, Baltimore, MD, United States
^ay Massachusetts Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital, Charlestown, United States
^az Department of Neurology, Mayo Clinic, Rochester, MN, United States
^ba Center for Cognitive Neurology, New York University, New York, United States
^bb Department of Neurology, Northwestern University, Chicago, IL, United States
^bc Aging and Alzheimer Disease Center, Oregon Health and Science University, Portland, United States
^bd Department of Epidemiology and Population Health, Stanford University, Stanford, CA, United States
^be Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
^bf University of California Davis at Medical Center, Sacramento, United States
^bg University of California Irvine, Irvine, United States
^bh Shiley-Marcos Alzheimer’s Disease Center, UC San Diego, San Diego, CA, United States
^bi University of California San Francisco, San Francisco, United States
^bj Alzheimer’s Disease Research Center, University of Kansas, Kansas City, United States
^bk Sanders-Brown Center on Aging, University of Kentucky, Lexington, United States
^bl Alzheimer Disease Center, University of Michigan, Ann Arbor, United States
^bm Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States
^bn University of Southern California, Los Angeles, United States
^bo University of Texas Southwestern Medical Center, Dallas, United States
^bp Wake Forest School of Medicine, Winston-Salem, NC, United States
^bq Department of Radiology, University of Washington, Seattle, United States
^br Department of Neurology, University of Washington, Seattle, United States
^bs University of Wisconsin, Madison, United States
^bt Department of Neurology, Washington University, School of Medicine, St Louis, MO, United States
^bu Department of Neurology, Yale University, School of Medicine, New Haven, CT, United States
^bv National Alzheimer’s Coordinating Center, University of Washington, Seattle, United States
^bw Department of Epidemiology, University of Washington, Seattle, United States

Abstract
IMPORTANCE Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. OBJECTIVE To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. MAIN OUTCOMES AND MEASURES Diagnosis of Alzheimer disease. RESULTS A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. CONCLUSIONS AND RELEVANCE While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ. © 2020 American Medical Association. All rights reserved.

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

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
(2020) Genetics in Medicine, .

Ferdinandusse, S.^a , McWalter, K.^b , te Brinke, H.^a , IJlst, L.^a , Mooijer, P.M.^a , Ruiter, J.P.N.^a , van Lint, A.E.M.^a , Pras-Raves, M.^a c d , Wever, E.^a c d , Millan, F.^b , Guillen Sacoto, M.J.^b , Begtrup, A.^b , Tarnopolsky, M.^e , Brady, L.^e , Ladda, R.L.^f , Sell, S.L.^f , Nowak, C.B.^g , Douglas, J.^g , Tian, C.^h , Ulm, E.ⁱ , Perlman, S.^j , Drack, A.V.^k , Chong, K.^l , Martin, N.^l , Brault, J.^m , Brokamp, E.^m , Toro, C.ⁿ , Gahl, W.A.ⁿ , Macnamara, E.F.ⁿ , Wolfe, L.ⁿ , Alejandro, M.E.^v , Azamian, M.S.^v , Bacino, C.A.^v , Balasubramanyam, A.^v , Burrage, L.C.^v , Chao, H.-T.^v , Clark, G.D.^v , Craigen, W.J.^v , Dai, H.^v , Dhar, S.U.^v , Emrick, L.T.^v , Goldman, A.M.^v , Hanchard, N.A.^v , Jamal, F.^v , Karaviti, L.^v , Lalani, S.R.^v , Lee, B.H.^v , Lewis, R.A.^v , Marom, R.^v , Moretti, P.M.^v , Murdock, D.R.^v , Nicholas, S.K.^v , Orengo, J.P.^v , Posey, J.E.^v , Potocki, L.^v , Rosenfeld, J.A.^v , Samson, S.L.^v , Scott, D.A.^v , Tran, A.A.^v , Vogel, T.P.^v , Wangler, M.F.^w , Yamamoto, S.^w , Eng, C.M.^x , Liu, P.^x , Ward, P.A.^x , Behrens, E.^y , Deardorff, M.^y , Falk, M.^y , Hassey, K.^y , Sullivan, K.^y , Vanderver, A.^y , Goldstein, D.B.^z , Cope, H.^aa , McConkie-Rosell, A.^aa , Schoch, K.^aa , Shashi, V.^aa , Smith, E.C.^aa , Spillmann, R.C.^aa , Sullivan, J.A.^aa , Tan, Q.K.-G.^aa , Walley, N.M.^aa , Agrawal, P.B.^ab , Beggs, A.H.^ab , Berry, G.T.^ab , Briere, L.C.^ab , Cobban, L.A.^ab , Coggins, M.^ab , Cooper, C.M.^ab , Fieg, E.L.^ab , High, F.^ab , Holm, I.A.^ab , Korrick, S.^ab , Krier, J.B.^ab , Lincoln, S.A.^ab , Loscalzo, J.^ab , Maas, R.L.^ab , MacRae, C.A.^ab , Pallais, J.C.^ab , Rao, D.A.^ab , Rodan, L.H.^ab , Silverman, E.K.^ab , Stoler, J.M.^ab , Sweetser, D.A.^ab , Walker, M.^ab , Walsh, C.A.^ab , Esteves, C.^ac , Kelley, E.G.^ac , Kohane, I.S.^ac , LeBlanc, K.^ac , McCray, A.T.^ac , Nagy, A.^ac , Dasari, S.^ad , Lanpher, B.C.^ad , Lanza, I.R.^ad , Morava, E.^ad , Oglesbee, D.^ad , Bademci, G.^ae , Barbouth, D.^ae , Bivona, S.^ae , Carrasquillo, O.^ae , Chang, T.C.P.^ae , Forghani, I.^ae , Grajewski, A.^ae , Isasi, R.^ae , Lam, B.^ae , Levitt, R.^ae , Liu, X.Z.^ae , McCauley, J.^ae , Sacco, R.^ae , Saporta, M.^ae , Schaechter, J.^ae , Tekin, M.^ae , Telischi, F.^ae , Thorson, W.^ae , Zuchner, S.^ae , Colley, H.A.^af , Dayal, J.G.^af , Eckstein, D.J.^af , Findley, L.C.^af , Krasnewich, D.M.^af , Mamounas, L.A.^af , Manolio, T.A.^af , Mulvihill, J.J.^af , LaMoure, G.L.^af , Goldrich, M.P.^af , Urv, T.K.^af , Doss, A.L.^af , Acosta, M.T.^ag , Bonnenmann, C.^ag , D’Souza, P.^ag , Draper, D.D.^ag , Ferreira, C.^ag , Godfrey, R.A.^ag , Groden, C.A.^ag , Macnamara, E.F.^ag , Maduro, V.V.^ag , Markello, T.C.^ag , Nath, A.^ag , Novacic, D.^ag , Pusey, B.N.^ag , Toro, C.^ag , Wahl, C.E.^ag , Baker, E.^ah , Burke, E.A.^ai , Adams, D.R.^ai , Gahl, W.A.^ai , Malicdan, M.C.V.^ai , Tifft, C.J.^ai , Wolfe, L.A.^ai , Yang, J.^ai , Power, B.^ai , Gochuico, B.^ai , Huryn, L.^ai , Latham, L.^ai , Davis, J.^ai , Mosbrook-Davis, D.^ai , Rossignol, F.^ai , Solomon, B.^ai , MacDowall, J.^ai , Thurm, A.^ai , Zein, W.^ai , Yousef, M.^ai , Adam, M.^aj , Amendola, L.^aj , Bamshad, M.^aj , Beck, A.^aj , Bennett, J.^aj , Berg-Rood, B.^aj , Blue, E.^aj , Boyd, B.^aj , Byers, P.^aj , Chanprasert, S.^aj , Cunningham, M.^aj , Dipple, K.^aj , Doherty, D.^aj , Earl, D.^aj , Glass, I.^aj , Golden-Grant, K.^aj , Hahn, S.^aj , Hing, A.^aj , Hisama, F.M.^aj , Horike-Pyne, M.^aj , Jarvik, G.P.^aj , Jarvik, J.^aj , Jayadev, S.^aj , Lam, C.^aj , Maravilla, K.^aj , Mefford, H.^aj , Merritt, J.L.^aj , Mirzaa, G.^aj , Nickerson, D.^aj , Raskind, W.^aj , Rosenwasser, N.^aj , Scott, C.R.^aj , Sun, A.^aj , Sybert, V.^aj , Wallace, S.^aj , Wener, M.^aj , Wenger, T.^aj , Ashley, E.A.^ak , Bejerano, G.^ak , Bernstein, J.A.^ak , Bonner, D.^ak , Coakley, T.R.^ak , Fernandez, L.^ak , Fisher, P.G.^ak , Fresard, L.^ak , Hom, J.^ak , Huang, Y.^ak , Kohler, J.N.^ak , Kravets, E.^ak , Majcherska, M.M.^ak , Martin, B.A.^ak , Marwaha, S.^ak , McCormack, C.E.^ak , Raja, A.N.^ak , Reuter, C.M.^ak , Ruzhnikov, M.^ak , Sampson, J.B.^ak , Smith, K.S.^ak , Sutton, S.^ak , Tabor, H.K.^ak , Tucker, B.M.^ak , Wheeler, M.T.^ak , Zastrow, D.B.^ak , Zhao, C.^ak , Byrd, W.E.^al , Crouse, A.B.^al , Might, M.^al , Nakano-Okuno, M.^al , Whitlock, J.^al , Brown, G.^am , Butte, M.J.^am , Dell’Angelica, E.C.^am , Dorrani, N.^am , Douine, E.D.^am , Fogel, B.L.^am , Gutierrez, I.^am , Huang, A.^am , Krakow, D.^am , Lee, H.^am , Loo, S.K.^am , Mak, B.C.^am , Martin, M.G.^am , Martínez-Agosto, J.A.^am , McGee, E.^am , Nelson, S.F.^am , Nieves-Rodriguez, S.^am , Palmer, C.G.S.^am , Papp, J.C.^am , Parker, N.H.^am , Renteria, G.^am , Signer, R.H.^am , Sinsheimer, J.S.^am , Wan, J.^am , Wang, L.-K.^am , Perry, K.W.^am , Woods, J.D.^am , Alvey, J.^an , Andrews, A.^an , Bale, J.^an , Bohnsack, J.^an , Botto, L.^an , Carey, J.^an , Pace, L.^an , Longo, N.^an , Marth, G.^an , Moretti, P.^an , Quinlan, A.^an , Velinder, M.^an , Viskochil, D.^an , Bayrak-Toydemir, P.^ao , Mao, R.^ao , Westerfield, M.^ap , Bican, A.^aq , Brokamp, E.^aq , Duncan, L.^aq , Hamid, R.^aq , Kennedy, J.^aq , Kozuira, M.^aq , Newman, J.H.^aq , Phillips, J.A., III^aq , Rives, L.^aq , Robertson, A.K.^aq , Solem, E.^aq , Cogan, J.D.^ar , Cole, F.S.^as , Hayes, N.^as , Kiley, D.^as , Sisco, K.^as , Wambach, J.^as , Wegner, D.^as , Baldridge, D.^at , Pak, S.^au , Schedl, T.^au , Shin, J.^au , Solnica-Krezel, L.^au , Waisfisz, Q.^o , Zwijnenburg, P.J.G.^o , Ziegler, A.^p , Barth, M.^p , Smith, R.^q , Ellingwood, S.^q , Gaebler-Spira, D.^r , Bakhtiari, S.^s , Kruer, M.C.^s , van Kampen, A.H.C.^d t , Wanders, R.J.A.^a , Waterham, H.R.^a , Cassiman, D.^u , Vaz, F.M.^a , Undiagnosed Diseases Network^av

^a Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands
^b GeneDx, Gaithersburg, MD, United States
^c Core Facility Metabolomics, Amsterdam UMC, Amsterdam, Netherlands
^d Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
^e Department of Pediatrics, McMaster University Children’s Hospital, Hamilton, ON, Canada
^f Department of Pediatrics, Penn State Children’s Hospital, Hershey, PA, United States
^g The Feingold Center for Children, Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
^h Division of Neurology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
ⁱ Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^j Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
^k Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, United States
^l Mount Sinai Hospital, Department of Obstetrics and Gynecology, Prenatal Diagnosis and Medical Genetics Program, Toronto, ON, Canada
^m Vanderbilt University Medical Center, Department of Pediatrics, Nashville, TN, United States
ⁿ NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, United States
^o Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^p Genetic department, University Hospital Angers, Angers, France
^q Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, ME, United States
^r Feinberg Northwestern University School of Medicine, Shirley Ryan Ability Lab, Chicago, IL, United States
^s Barrow Neurological Institute, Phoenix Children’s Hospital and University of Arizona College of Medicine, Phoenix, AZ, United States
^t Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
^u Department of Gastroenterology-Hepatology, Metabolic Center, University Hospitals Leuven, Leuven, Belgium
^v BCM Clinical, Houston, TX, United States
^w BCM MOSC, Houston, TX, United States
^x BCM Sequencing, Houston, TX, United States
^y CHOP, Philadelphia, PA, United States
^z Columbia, New York, NY, United States
^aa Duke, Durham, NC, United States
^ab Harvard, Boston, MA, United States
^ac Harvard CC, Boston, MA, United States
^ad Mayo Clinic, Rochester, MN, United States
^ae Miami, Miami, FL, United States
^af NIH, Bethesda, MD, United States
^ag NIH UDP, Bethesda, MD, United States
^ah NIH UDP, DRM, Bethesda, MD, United States
^ai NIH UDP, NHGRI, Bethesda, MD, United States
^aj PNW, Seattle, WA, United States
^ak Stanford, Stanford, CA, United States
^al UAB CC, Birmingham, AL, United States
^am UCLA, Los Angeles, CA, United States
^an University of Utah, Salt Lake City, UT, United States
^ao University of Utah/ARUP, Salt Lake City, UT, United States
^ap UO MOSC, Eugene, OR, United States
^aq Vanderbilt, Nashville, TN, United States
^ar Vanderbilt, Nashville, TN, United States
^as Washington University Clinical, St. Louis, MO, United States
^at Washington University Clinical and MOSC, St. Louis, MO, United States
^au Washington University MOSC, St. Louis, MO, United States

Abstract
Purpose: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). Methods: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients’ fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. Results: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients’ fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. Conclusion: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts. © 2020, The Author(s).

Funding details
Common Fund for CommoditiesCFC
National Human Genome Research InstituteNHGRI1R01 NS106298
Office of the DirectorOD
National Institutes of HealthNIH

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

Advances in the Treatment of Chronic Pain by Targeting GPCRs
(2020) Biochemistry, .

Che, T.^a b

^a Department of Anesthesiology, Washington University in St. Louis School of Medicine, St. Louis, MI 63110, United States
^b Center for Clinical Pharmacology, St. Louis College of Pharmacology and Washington University in St. Louis, St. Louis, MI 63110, United States

Abstract
Pain is an essential protective mechanism that the body uses to alert or prevent further damage. Pain sensation is a complex event involving perception, transmission, processing, and response. Neurons at different levels (peripheral, spinal cord, and brain) are responsible for these pro- or antinociceptive activities to ensure an appropriate response to external stimuli. The terminals of these neurons, both in the peripheral endings and in the synapses, are equipped with G protein-coupled receptors (GPCRs), voltage- and ligand-gated ion channels that sense structurally diverse stimuli and inhibitors of neuronal activity. This review will focus on the largest class of sensory proteins, the GPCRs, as they are distributed throughout ascending and descending neurons and regulate activity at each step during pain transmission. GPCR activation also directly or indirectly controls the function of co-localized ion channels. The levels and types of some GPCRs are significantly altered in different pain models, especially chronic pain states, emphasizing that these molecules could be new targets for therapeutic intervention in chronic pain. © 2020 American Chemical Society.

Funding details
Washington University School of Medicine in St. Louis

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

Association of initial β-amyloid levels with subsequent flortaucipir positron emission tomography changes in persons without cognitive impairment
(2020) JAMA Neurology, .

Knopman, D.S.^a g , Lundt, E.S.^b , Therneau, T.M.^b , Albertson, S.M.^b , Gunter, J.L.^c g , Senjem, M.L.^c g , Schwarz, C.G.^c , Mielke, M.M.^b , Machulda, M.M.^d , Boeve, B.F.^a , Jones, D.T.^a g , Graff-Radford, J.^a , Vemuri, P.^c g , Kantarci, K.^c g , Lowe, V.J.^c , Petersen, R.C.^a b g , Jack, C.R., Jr.^c g , Weiner, M.W.^e , Aisen, P.^f , Jagust, W.^e h , Trojanowki, J.Q.^i ah ci , Toga, A.W.^f , Beckett, L.^j , Green, R.C.^k , Saykin, A.J.^l , Morris, J.^m , Shaw, L.M.^i ah ci , Khachaturian, Z.^cm , Sorensen, G.ⁿ , Carrillo, M.^o , Kuller, L.^p , Raichle, M.^m , Paul, S.^q , Davies, P.^r , Fillit, H.^s , Hefti, F.^t , Holtzman, D.^m , Marcel Mesulam, M.^u , Potter, W.^v , Snyder, P.^w , Lilly, E.^cm , Logovinsky, V.^cm , Montine, T.^x ck , Jimenez, G.^f , Donohue, M.^f z , Gessert, D.^f , Harless, K.^f , Salazar, J.^f , Cabrera, Y.^f , Walter, S.^f , Hergesheimer, L.^f , Harvey, D.^j , Bernstein, M.^g , Fox, N.^aa , Thompson, P.^ab , Schuff, N.^ac , DeCArli, C.^j , Borowski, B.^g , Ward, C.^g , Koeppe, R.A.^ad , Foster, N.^ae , Reiman, E.M.^af , Chen, K.^af , Mathis, C.^p , Landau, S.^e h , Cairns, N.J.^m , Franklin, E.^m , Taylor-Reinwald, L.^ag , Lee, V.^ah ci , Korecka, M.^ah ci , Figurski, M.^ah ci , Crawford, K.^f , Neu, S.^f , Foroud, T.M.^l , Potkin, S.^ai , Shen, L.^l , Faber, K.^l , Kim, S.^l , Nho, K.^l , Thal, L.^z , Buckholtz, N.^aj , Albert, M.^ak , Frank, R.^al , Hsiao, J.^aj , Quinn, J.^am , Silbert, L.C.^am , Lind, B.^am , Kaye, J.A.^am , Carter, R.^cm , Dolen, S.^cm , Schneider, L.S.^f , Pawluczyk, S.^f , Becerra, M.^f , Teodoro, L.^cm , Spann, B.M.^cm , Brewer, J.^e , Vanderswag, H.^e , Fleisher, A.^e bu , Ziolkowski, J.^ad , Heidebrink, J.L.^ad , Lord, J.L.^ad , Mason, S.S.^g , Albers, C.S.^g , Johnson, K.^g , Villanueva-Meyer, J.^an , Pavlik, V.^an , Pacini, N.^an , Lamb, A.^an , Kass, J.S.^an , Doody, R.S.^an , Shibley, V.^cm , Chowdhury, M.^cm , Rountree, S.^cm , Dang, M.^cm , Stern, Y.^ao , Honig, L.S.^ao , Bell, K.L.^ao , Yeh, R.^ao , Ances, B.^m , Winkfield, D.^m , Carroll, M.^m , Oliver, A.^m , Creech, M.L.^m , Mintun, M.A.^m , Schneider, S.^m , Marson, D.^ap , Geldmacher, D.^ap , Love, M.N.^ap , Griffith, R.^ap , Clark, D.^ap , Brockington, J.^ap , Sinai, M.^ap , Grossman, H.^aq , Mitsis, E.^aq , Shah, R.C.^ar , Lamar, M.^ar , Samuels, P.^ar , Duara, R.^as , Greig-Custo, M.T.^as , Rodriguez, R.^as , Onyike, C.^ak , D’Agostino, D., II^ak , Kielb, S.^ak , Sadowski, M.^at , Sheikh, M.O.^cm , Singleton-Garvin, J.^cm , Ulysse, A.^cm , Gaikwad, M.^cm , Murali Doraiswamy, P.^au , Petrella, J.R.^au , James, O.^au , Borges-Neto, S.^au , Wong, T.Z.^au , Coleman, E.^au , Karlawish, J.H.ⁱ , Wolk, D.A.ⁱ , Vaishnavi, S.ⁱ , Clark, C.M.ⁱ , Arnold, S.E.ⁱ , Smith, C.D.^av , Jicha, G.^av , Hardy, P.^av , El Khouli, R.^av , Oates, E.^av , Conrad, G.^av , Lopez, O.L.^p , Oakley, M.A.^p , Porsteinsson, A.P.^aw , Martin, K.^aw , Kowalksi, N.^aw , Keltz, M.^aw , Goldstein, B.S.^aw , Makino, K.M.^aw , Saleem Ismail, M.^aw , Brand, C.^aw , Thai, G.^ax , Pierce, A.^ax , Yanez, B.^ax , Sosa, E.^ax , Witbracht, M.^ax , Womack, K.^ay , Mathews, D.^ay , Quiceno, M.^ay , Levey, A.I.^az , Lah, J.J.^az , Cellar, J.S.^az , Burns, J.M.^ba , Swerdlow, R.H.^ba , Brooks, W.M.^ba , Woo, E.^bb , Silverman, D.H.S.^bb , Teng, E.^bb , Kremen, S.^bb , Apostolova, L.^bb , Tingus, K.^bb , Lu, P.H.^bb , Bartzokis, G.^bb , Graff-Radford, N.R.^bc , Parfitt, F.^bc , Poki-Walker, K.^bc , Farlow, M.R.^l , Hake, A.M.^l , Matthews, B.R.^l , Brosch, J.R.^l , Herring, S.^l , van Dyck, C.H.^bd , Carson, R.E.^bd , Varma, P.^bd , Chertkow, H.^be , Bergman, H.^be , Hosein, C.^be , Black, S.^bf , Stefanovic, B.^bf , Heyn, C.^bf , Hsiung, G.-Y.R.^bg , Mudge, B.^bg , Sossi, V.^bg , Feldman, H.^bg , Assaly, M.^bg , Finger, E.^bh ce , Pasternack, S.^bh , Pavlosky, W.^bh , Rachinsky, I.^bh ce , Drost, D.^bh ce , Kertesz, A.^bh ce , Bernick, C.^bi , Munic, D.^bi , Rogalski, E.^u , Lipowski, K.^u , Weintraub, S.^u , Bonakdarpour, B.^u , Kerwin, D.^u , Wu, C.K.^u , Johnson, N.^u , Sadowsky, C.^bj , Villena, T.^bj , Turner, R.S.^bk , Johnson, K.^bk , Reynolds, B.^bk , Sperling, R.A.^bl , Johnson, K.A.^bl , Marshall, G.A.^bl , Yesavage, J.^bm , Taylor, J.L.^bm , Chao, S.^bm , Lane, B.^bm , Rosen, A.^bm , Tinklenberg, J.^bm , Zamrini, E.^bk , Belden, C.M.^bk , Sirrel, S.A.^bn , Kowall, N.^bo , Killiany, R.^bo , Budson, A.E.^bo , Norbash, A.^bo , Johnson, P.L.^bo , Obisesan, T.O.^bp , Oyonumo, N.E.^bp , Allard, J.^bp , Ogunlana, O.^bp , Lerner, A.^bq , Ogrocki, P.^bq , Tatsuoka, C.^bq , Fatica, P.^bq , Fletcher, E.^j , Maillard, P.^j , Olichney, J.^j , Carmichael, O.^j , Kittur, S.^br , Borrie, M.^bs , Lee, T.-Y.^bs , Bartha, R.^bs , Johnson, S.^bt , Asthana, S.^bt , Carlsson, C.M.^bt , Tariot, P.^bu , Burke, A.^bu , Hetelle, J.^bu , DeMarco, K.^bu , Trncic, N.^bu , Reeder, S.^bu , Bates, V.^bv , Capote, H.^bv , Rainka, M.^bv , Scharre, D.W.^bw , Kataki, M.^bw , Tarawneh, R.^bw , Zimmerman, E.A.^bx , Celmins, D.^bx , Hart, D.^bx , Pearlson, G.D.^by , Blank, K.^by , Anderson, K.^by , Flashman, L.A.^bz , Seltzer, M.^bz , Hynes, M.L.^bz , Santulli, R.B.^bz , Sink, K.M.^ca , Yang, M.^ca , Mintz, A.^ca , Ott, B.R.^cb , Tremont, G.^cb , Daiello, L.A.^cb , Bodge, C.^cc , Salloway, S.^cc , Malloy, P.^cc , Correia, S.^cc , Lee, A.^cc , Rosen, H.J.^e , Miller, B.L.^e , Perry, D.^e , Mintzer, J.^cd , Spicer, K.^cd , Bachman, D.^cd , Pasternak, S.^ce , Rogers, J.^ce , Pomara, N.^cf , Hernando, R.^cf , Sarrael, A.^cf , Miller, D.D.^cg , Smith, K.E.^cg , Koleva, H.^cg , Nam, K.^cg , Shim, H.^cg , Schultz, S.K.^cg , Relkin, N.^q , Chiang, G.^q , Lin, M.^q , Ravdin, L.^q , Smith, A.^ch , Leach, C.^ch , Raj, B.A.^ch , Fargher, K.^ch , Neylan, T.^e y , Grafman, J.^cj , Hergesheimen, L.^f , Hayes, J.^e y , Finley, S.^e y , Householder, E.^m , Friedl, K.^cl , Fleischman, D.^ar , Arfanakis, K.^ar , Varon, D.^as , Greig, M.T.^as , Goldstein, B.^aw , Martin, K.S.^aw , Potkin, S.G.^ai , Preda, A.^ai , Nguyen, D.^ai , Massoglia, D.^cd , Brawman-Mintzer, O.^cd , Martinez, W.^bj , Rosen, H.^e , Behan, K.^bk , Marshall, G.^bl , Sabbagh, M.N.^bn , Jacobson, S.A.^bn , Wolday, S.^bp , Johnson, S.C.^bt , Jay Fruehling, J.^bt , Harding, S.^bt , Peskind, E.R.^x , Petrie, E.C.^x , Li, G.^x , Yesavage, J.A.^bm , Furst, A.J.^bm , Mackin, S.^e , Raman, R.^f , Drake, E.^k , Shaffer, E.^f , Nelson, C.^e , Bickford, D.^e , Butters, M.^p , Zmuda, M.^p , Reyes, D.^g , Faber, K.M.^l , Nudelman, K.N.^l , Au, Y.H.^e , Scherer, K.^e , Catalinotto, D.^e , Stark, S.^e , Ong, E.^e , Fernandez, D.^e , Simpson, D.M.^p , Alzheimer’s Disease Neuroimaging Initiative^cm

^a Department of Neurology, Mayo Clinic, Rochester, MN, United States
^b Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
^c Department of Radiology, Mayo Clinic, Rochester, MN, United States
^d Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
^e University of California San Francisco, San Francisco, United States
^f University of Southern California, Los Angeles, United States
^g Mayo Clinic, Rochester, MN, United States
^h University of California Berkeley, Berkeley, United States
ⁱ University of Pennsylvania, Philadelphia, United States
^j University of California Davis, Sacramento, United States
^k Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^l Indiana University, Bloomington, United States
^m Washington University, St. Louis, MO, United States
ⁿ Siemens, United States
^o Alzheimer’s Association
^p University of Pittsburgh, Pittsburgh, PA, United States
^q Cornell University, Ithaca, NY, United States
^r Albert Einstein College of Medicine, Yeshiva University, New York, NY, United States
^s AD Drug Discovery Foundation
^t Acumen Pharmaceuticals
^u Northwestern University, Chicago, IL, United States
^v National Institute of Mental Health, Bethesda, MD, United States
^w Brown University, Providence, RI, United States
^x University of Washington, Seattle, United States
^y San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
^z University of California San Diego, San Diego, United States
^aa University of London, London, United Kingdom
^ab UCLA, School of Medicine, Los Angeles, United States
^ac University of California San Francisco Magnetic Resonance Imaging, San Francisco, United States
^ad University of Michigan, Ann Arbor, United States
^ae University of Utah, Salt Lake City, United States
^af Banner Alzheimer’s Institute, Phoenix, AZ, United States
^ag Washington University, St. Louis, MN, United States
^ah University of Pennsylvania, School of Medicine, Philadelphia, United States
^ai University of California Irvine, Irvine, United States
^aj National Institute on Aging, Baltimore, MD, United States
^ak Johns Hopkins University, Baltimore, MD, United States
^al Richard Frank Consulting, New York, NY, United States
^am Oregon Health and Science University, Portland, United States
^an Baylor College of Medicine, Houston, TX, United States
^ao Columbia University Medical Center, New York, NY, United States
^ap University of Alabama-Birmingham, Birmingham, United States
^aq School of Medicine, New York, NY, United States
^ar Rush University Medical Center, Chicago, IL, United States
^as Wien Center, Miami Beach, FL, United States
^at New York University, New York, United States
^au Duke University Medical Center, Durham, NC, United States
^av University of Kentucky, Lexington, United States
^aw University of Rochester Medical Center, Rochester, NY, United States
^ax University of California Irvine, IMIND, Irvine, United States
^ay University of Texas Southwestern, Medical School, Dallas, United States
^az Emory University, Atlanta, GA, United States
^ba University of Kansas Medical Center, Kansas City, United States
^bb University of California, Los Angeles, Los Angeles, United States
^bc Mayo Clinic, Jacksonville, FL, United States
^bd Yale University, School of Medicine, New Haven, CT, United States
^be McGill University Montreal-Jewish General Hospital, Montreal, QC, Canada
^bf Sunnybrook Health Sciences, Toronto, ON, Canada
^bg UBC Clinic for Alzheimer Disease and Related Disorders, Vancouver, BC, Canada
^bh Cognitive Neurology St. Joseph’s, London, ON, Canada
^bi Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland, OH, United States
^bj Premiere Research Institute (Palm Beach Neurology), West Palm Beach, FL, United States
^bk Georgetown University Medical Center, Washington, DC, United States
^bl Brigham and Women’s Hospital, Boston, MA, United States
^bm Stanford University, Palo Alto, CA, United States
^bn Banner Sun Health Research Institute, Phoenix, AZ, United States
^bo Boston University, Boston, MA, United States
^bp Howard University, Washington, DC, United States
^bq Case Western Reserve University, Cleveland, OH, United States
^br Neurological Care of CNY, Syracuse, United States
^bs Parkwood Institute, London, ON, Canada
^bt University of Wisconsin, Madison, United States
^bu Banner Alzheimer’s Institute, Phoenix, AZ, United States
^bv Dent Neurologic Institute, Amherst, NY, United States
^bw Ohio State University, Columbus, United States
^bx Albany Medical College, Albany, NY, United States
^by Hartford Hospital, Olin Neuropsychiatry Research Center, Hartford, CT, United States
^bz Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
^ca Wake Forest University Health Sciences, Winston-Salem, NC, United States
^cb Rhode Island Hospital, Providence, United States
^cc Butler Hospital, Providence, RI, United States
^cd Medical University of South Carolina, Charleston, United States
^ce St. Joseph’s Health Care, London, ON, Canada
^cf Nathan Kline Institute, Orangeburg, NY, United States
^cg University of Iowa, College of Medicine, Iowa City, United States
^ch University of South Florida USF, Health Byrd Alzheimer’s Institute, Miami, United States
^ci Perelman School of Medicine, University Pennsylvania, Philadelphia, United States
^cj Rehabilitation Institute of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^ck University of Washington, St Louis, MO, United States
^cl Department of Defense

Abstract
IMPORTANCE Tau accumulation in Alzheimer disease (AD) is closely associated with cognitive impairment. Quantitating tau accumulation by positron emission tomography (PET) will be a useful outcome measure for future clinical trials in the AD spectrum. OBJECTIVE To investigate the association of β -amyloid (Aβ) on PET with subsequent tau accumulation on PET in persons who were cognitively unimpaired (CU) to gain insight into temporal associations between Aβ and tau accumulation and inform clinical trial design. DESIGN, SETTING, AND PARTICIPANTS This cohort study included individuals aged 65 to 85 years who were CU and had participated in the Mayo Clinic Study of Aging, with serial cognitive assessments, serial magnetic resonance imaging, 11C-Pittsburgh compound B (Aβ) PET scans, and 18F-flortaucipir PET scans, collected from May 2015 to March 2020. Persons were excluded if they lacked follow-up PET scans. A similarly evaluated CU group from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were also studied. These data were collected from September 2015 to March 2020. EXPOSURES Participants were stratified by index Aβ levels on PET into low Aβ (≤8 centiloid [CL]), subthreshold Aβ (9-21 CL), suprathreshold Aβ (22-67 CL), and high Aβ (≥68 CL). MAIN OUTCOMES AND MEASURES Changes over a mean of 2.7 (range, 1.1-4.1) years in flortaucipir PET in entorhinal, inferior temporal, and lateral parietal regions of interest and an AD meta-region of interest (ROI). RESULTS A total of 167 peoplewere included (mean age, 74 [range, 65-85] years; 75women [44.9%]); 101 individualswere excluded lacking follow-up, and 114 individuals from the ADNI were also studied (mean [SD] age, 74.14 [5.29] years; 64women [56.1%]). In the Mayo Clinic Study of Aging, longitudinal flortaucipir accumulation rates in the high Aβ groupwere greater than the suprathreshold, subthreshold, and low Aβ groups in the entorhinal ROI (suprathreshold, 0.025 [95%CI, 0.013-0.037] standardized uptake value ratio [SUVR] units; subthreshold, 0.026 [95%CI, 0.014-0.037] SUVR units; low Aβ, 0.034 [95%CI, 0.02-0.049] SUVR units), inferior temporal ROI (suprathreshold,0.025 [95%CI,0.014-0.035] SUVR units; subthreshold,0.027 [95%CI,0.017-0.037] SUVR units; low Aβ,0.035 [95%CI,0.022-0.047] SUVR units), and the AD meta-ROI (suprathreshold,0.023 [95%CI,0.013-0.032] SUVR units; subthreshold,0.025 [95% CI,0.016-0.034] SUVR units; low Aβ,0.032 [95%CI,0.021-0.043] SUVR units) (all P &lt;.001). Flortaucipir accumulation rates in the subthreshold and suprathreshold Aβ groups in temporal Regions were non significantly elevated compared with the low Aβ group. In the ADNI cohort, the Variance was larger than in the Mayo Clinic Study of Aging but point estimates for annualized flortaucipir accumulation in the inferior temporal ROI were very similar. An estimated 216 participants who were C Uper group with PET Aβ of 68 CL or more would be needed to detect a 25% annualized reduction in flortaucipir accumulation rate in the AD meta-ROI with80%power. CONCLUSIONS AND RELEVANCE Substantial flortaucipir accumulation in temporal regions is greatest in persons aged 65 to 85 years who were CU and had high initial Aβ PET levels, compared with those with lower Aβ levels. Recruiting persons who were CU and exhibiting Aβ of 68 CL or more on an index Aβ PET is a feasible strategy to recruit for clinical trials in which a change in tau PET signal is an outcome measure. © 2020 American Medical Association. All rights reserved.

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