WashU weekly Neuroscience publications: July 26, 2022

SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice
(2022) Nature Communications, 13 (1), art. no. 4112, . 

El Chehadeh, S.^a b c , Han, K.A.^d , Kim, D.^d , Jang, G.^d , Bakhtiari, S.^e f , Lim, D.^d , Kim, H.Y.^d , Kim, J.^d , Kim, H.^d , Wynn, J.^g , Chung, W.K.^g h , Vitiello, G.ⁱ , Cutcutache, I.^j , Page, M.^j , Gecz, J.^k l m , Harper, K.^k l , Han, A.-R.ⁿ , Kim, H.M.^n o , Wessels, M.^p , Bayat, A.^q r , Jaén, A.F.^s , Selicorni, A.^t , Maitz, S.^u , de Brouwer, A.P.M.^v , Silfhout, A.V.-V.^v w , Armstrong, M.^x , Symonds, J.^y , Küry, S.^z aa , Isidor, B.^z aa , Cogné, B.^z aa , Nizon, M.^z aa , Feger, C.^ab , Muller, J.^c ab , Torti, E.^ac , Grange, D.K.^ad , Willems, M.^ae , Kruer, M.C.^e f , Ko, J.^d , Piton, A.^b ab af , Um, J.W.^d

^a Service de Génétique Médicale, Institut de Génétique Médicale d’Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France
^b Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS-UMR7104, Université de Strasbourg, Illkirch-Graffenstaden, France
^c Laboratoire de Génétique Médicale, UMRS_1112, Institut de Génétique Médicale d’Alsace (IGMA), Université de Strasbourg et INSERM, Strasbourg, France
^d Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, South Korea
^e Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
^f Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, AZ, United States
^g Departments of Pediatrics, Columbia University Medical Center, New York, NY, United States
^h Department of Medicine, Columbia University, New York, NY 10032, United States
ⁱ Department of Molecular Medicine and Medical Biotechnologies, Federico II University Hospital, Via Pansini 5, Naples, 80131, Italy
^j Translational Medicine, UCB Pharma, Slough, United Kingdom
^k Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
^l Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
^m Women and Kids, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
ⁿ Center for Biomolecular and Cellular Structure, Institute for Basic Science, Daejeon, 34126, South Korea
^o Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea
^p Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
^q Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark
^r Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
^s Department of Pediatrics Neurology, Quirónsalud Hospital & Universidad Europea, Madrid, Spain
^t Department of Pediatrics, Center for Fragile Child, ASST Lariana Sant’Anna Hospital, San Fermo della Battaglia, Como, Italy
^u Fondazione MBBM, Monza, Italy
^v Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
^w Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
^x Translational Medicine, UCB Pharma, Braine-l’Alleud, Belgium
^y Paediatric Neurosciences Research Group, Royal Hospital for Children, Queen Elizabeth University Hospitals, Glasgow, United Kingdom
^z Service de Génétique Médicale, CHU Nantes, Nantes, France
^aa Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, F-44000, France
^ab Laboratoire de Diagnostic Génétique, Institut de Génétique Médicale d’Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France
^ac GeneDx, Gaithersburg, MD 20877, United States
^ad Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^ae Service de Génétique Médicale, Reference Centre AD SOOR, AnDDI-RARE, Inserm U1298, INM, Arnaud de Villeneuve Hospital and University of Montpellier, Montpellier, France
^af Institut Universitaire de France, Paris, France

Abstract
SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function. © 2022, The Author(s).

Funding details
National Institutes of HealthNIHNS106298
JPB FoundationJPBF
Simons Foundation Autism Research InitiativeSFARI
Ministry of Science, ICT and Future PlanningMSIP22-CoE-BT-01
National Research Foundation of KoreaNRF
Ministry of Science ICT and Future PlanningMSIP2019R1A2C1086048, 2020R1A4A1019009, 2021R1A2C1091863
Daegu Gyeongbuk Institute of Science and TechnologyDGIST
Institute for Basic ScienceIBSIBS-R030-C1

Document Type: Article
Publication Stage: Final
Source: Scopus

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes
(2022) Molecular Neurodegeneration, 17 (1), art. no. 48, . 

Bowles, K.R.^a b , Pugh, D.A.^a b , Liu, Y.^a b , Patel, T.^a b , Renton, A.E.^a b , Bandres-Ciga, S.^c , Gan-Or, Z.^d e f , Heutink, P.^g h , Siitonen, A.^i j , Bertelsen, S.^a b , Cherry, J.D.^k l m n , Karch, C.M.^o , Frucht, S.J.^p , Kopell, B.H.^q r , Peter, I.^s t , Park, Y.J.^q u , Charney, A.^a q s u , Raj, T.^a b s v , Crary, J.F.^a b w , Goate, A.M.^a b s v , International Parkinson’s Disease Genomics Consortium (IPDGC)^x

^a Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^b Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^c Laboratory of Neurogenetics, National Institute On Aging, National Institutes of Health, Bethesda, MD, United States
^d Department of Human Genetics, McGill University, Montréal, QC, Canada
^e The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada
^f Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
^g Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
^h German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
ⁱ Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland
^j Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland
^k Alzheimer’s Disease and CTE Center, Boston University, Boston University School of Medicine, Boston, MA, United States
^l Department of Neurology, Boston University School of Medicine, Boston, MA, United States
^m VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA, United States
ⁿ Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, United States
^o Department of Psychiatry, Washington University in St Louis, St. Louis, MO, United States
^p Department of Neurology, Fresco Institute for Parkinson’s and Movement Disorders, New York University Langone, New York, NY, United States
^q Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^r Center for Neuromodulation, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^s Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^t Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^u Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^v Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^w Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^x IPDGC Authors and Affiliations in Supplementary Material 2, New York, NY, United States

Abstract
Background: Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. Methods: To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. Results: We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. Conclusion: These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types. © 2022, The Author(s).

Author Keywords
17q21.31;  Astrocytes;  Copy number variation;  LRRC37A;  Parkinson’s disease

Funding details
National Institutes of HealthNIHP01 AG026276
U.S. Department of Health and Human ServicesHHS1ZIA-NS003154, Z01-AG000949-02, Z01-ES101986
National Institute on AgingNIA1ZIAAG000935, 1ZIANS003154
National Institute of Neurological Disorders and StrokeNINDS
National Institute of Environmental Health SciencesNIEHS
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
New York Stem Cell FoundationNYSCF
Association for Frontotemporal DegenerationAFTD
GlaxoSmithKlineGSK
BrightFocus FoundationBFF
CurePSP
McGill UniversityMGU
Consortium canadien en neurodégénérescence associée au vieillissementCCNA
Rainwater Charitable FoundationRCF
Verily Life Sciences
Fonds de Recherche du Québec – SantéFRQS
School of Medicine, CHA University
Parkinson Canada
Canada First Research Excellence FundCFREF

Document Type: Article
Publication Stage: Final
Source: Scopus

Anesthetic modulations dissociate neuroelectric characteristics between sensory-evoked and spontaneous activities across bilateral rat somatosensory cortical laminae
(2022) Scientific Reports, 12 (1), art. no. 11661, . 

Baek, K.^a , Park, C.R.^b , Jang, S.^c , Shim, W.H.^b d , Kim, Y.R.^e f

^a School of Biomedical Convergence Engineering, Pusan National University, Busan, South Korea
^b Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
^c Washington University in St. Louis, St. Louis, MO, United States
^d Department of Radiology, Asan Medical Center, College of Medicine, University of Ulsan, Ulsan, South Korea
^e Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
^f Department of Radiology, Harvard Medical School, Boston, MA, United States

Abstract
Spontaneous neural activity has been widely adopted to construct functional connectivity (FC) amongst distant brain regions. Although informative, the functional role and signaling mechanism of the resting state FC are not intuitive as those in stimulus/task-evoked activity. In order to bridge the gap, we investigated anesthetic modulation of both resting-state and sensory-evoked activities. We used two well-studied GABAergic anesthetics of varying dose (isoflurane: 0.5–2.0% and α-chloralose: 30 and 60 mg/kg∙h) and recorded changes in electrophysiology using a pair of laminar electrode arrays that encompass the entire depth of the bilateral somatosensory cortices (S1fl) in rats. Specifically, the study focused to describe how varying anesthesia conditions affect the resting state activities and resultant FC between bilateral hemispheres in comparison to those obtained by evoked responses. As results, isoflurane decreased the amplitude of evoked responses in a dose-dependent manner mostly due to the habituation of repetitive responses. However, α-chloralose rather intensified the amplitude without exhibiting habituation. No such diverging trend was observed for the spontaneous activity, in which both anesthetics increased the signal power. For α-chloralose, overall FC was similar to that obtained with the lowest dose of isoflurane at 0.5% while higher doses of isoflurane displayed increased FC. Interestingly, only α-chloralose elicited relatively much greater increases in the ipsi-stimulus evoked response (i.e., in S1fl ipsilateral to the stimulated forelimb) than those associated with the contra-stimulus response, suggesting enhanced neuronal excitability. Taken together, the findings demonstrate modulation of the FC profiles by anesthesia is highly non-linear, possibly with a distinct underlying mechanism that affects either resting state or evoked activities differently. Further, the current study warrants thorough investigation of the basal neuronal states prior to the interpretation of resting state FC and evoked activities for accurate understanding of neural signal processing and circuitry. © 2022, The Author(s).

Funding details
National Institutes of HealthNIH1R21EY02637901, 2021R1A1C2007251, 5R01MH111438-03, HI18C2383
Pusan National UniversityPNU
Ministry of EducationMOE2018R1A6A3A01013571
Ministry of Science, ICT and Future PlanningMSIP
National Research Foundation of KoreaNRF2021H1D3A2A01099707
Institute for Information and Communications Technology PromotionIITP2020-0-01450

Document Type: Article
Publication Stage: Final
Source: Scopus

Children show adult-like hippocampal pattern similarity for familiar but not novel events
(2022) Brain Research, 1791, art. no. 147991, . 

Benear, S.L.^a , Horwath, E.A.^a , Cowan, E.^a , Camacho, M.C.^b , Ngo, C.T.^c , Newcombe, N.S.^a , Olson, I.R.^a , Perlman, S.B.^b , Murty, V.P.^a

^a Department of Psychology, Temple University, Philadelphia, United States
^b Department of Psychiatry, Washington University of St. Louis, St. Louis, United States
^c Max Planck Institute for Human Development, Berlin, Germany

Abstract
The ability to detect differences among similar events in our lives is a crucial aspect of successful episodic memory performance, which develops across early childhood. The neural substrate of this ability is supported by operations in the medial temporal lobe (MTL). Here, we used representational similarity analysis (RSA) to measure neural pattern similarity in hippocampus, perirhinal cortex, and parahippocampal cortex for 4- to 10-year-old children and adults during naturalistic viewing of clips from the same compared to different movies. Further, we assessed the role of prior exposure to individual movie clips on pattern similarity in the MTL. In both age groups, neural pattern similarity in hippocampus was lower for clips drawn from the same movies compared to those drawn from different movies, suggesting that related content activates processes focused on keeping representations with shared content distinct. However, children showed this only for movies with which they had prior exposures, whereas adults showed the effect regardless of any prior exposures to the movies. These findings suggest that children require repeated exposure to stimuli to show adult-like MTL functioning in distinguishing among similar events. © 2022

Author Keywords
Cognitive development;  Episodic memory;  Hippocampus;  Representational similarity analysis

Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHK01 MH094467, K01 MH111991, R01 HD099165, R01 MH091113, R01 MH107540, R21 DA043568, R21 HD098509

Document Type: Article
Publication Stage: Final
Source: Scopus

Mild hypothermia fails to protect infant macaques from brain injury caused by prolonged exposure to Antiseizure drugs
(2022) Neurobiology of Disease, 171, art. no. 105814, . 

Ikonomidou, C.^a , Wang, S.H.^b , Fuhler, N.A.^b , Larson, S.^c , Capuano, S., III^c , Brunner, K.R.^c , Crosno, K.^c , Simmons, H.A.^c , Mejia, A.F.^c , Noguchi, K.K.^b

^a Department of Neurology, University of Wisconsin, School of Medicine, Madison, WI, United States
^b Department of Psychiatry, Washington University, School of Medicine, St Louis, United States
^c Wisconsin National Primate Research Center, Madison, WI, United States

Abstract
Barbiturates and benzodiazepines are GABAA-receptor agonists and potent antiseizure medications. We reported that exposure of neonatal macaques to combination of phenobarbital and midazolam (Pb/M) for 24 h, at clinically relevant doses and plasma levels, causes widespread apoptosis affecting neurons and oligodendrocytes. Notably, the extent of injury was markedly more severe compared to shorter (8 h) exposure to these drugs. We also reported that, in the infant macaque, mild hypothermia ameliorates the apoptosis response to the anesthetic sevoflurane. These findings prompted us explore whether mild hypothermia might protect infant nonhuman primates from neuro- and gliotoxicity of Pb/M. Since human infants with seizures may receive combinations of benzodiazepines and barbiturates for days, we opted for 24 h treatment with Pb/M. Neonatal rhesus monkeys received phenobarbital intravenously, followed by midazolam infusion over 24 h under normothermia (T > 36.5 °C-37.5 °C; n = 4) or mild hypothermia (T = 35 °C-36.5 °C; n = 5). Medication doses and blood levels measured were comparable to those in human infants. Animals were euthanized at 36 h and brains examined immunohistochemically and stereologically. Treatment was well tolerated. Extensive degeneration of neurons and oligodendrocytes was seen at 36 h in both groups within neocortex, basal ganglia, hippocampus and brainstem. Mild hypothermia over 36 h (maintained until terminal perfusion) conferred no protection against the neurotoxic and gliotoxic effects of Pb/M. This is in marked contrast to our previous findings that mild hypothermia is protective in the context of a 5 h-long exposure to sevoflurane in infant macaques. These findings demonstrate that brain injury caused by prolonged exposure to Pb/M in the neonatal primate cannot be ameliorated by mild hypothermia. © 2022

Author Keywords
Antiseizure;  Apoptosis;  Barbiturate;  Benzodiazepine;  Brain injury;  Development;  Sedative

Funding details
National Institutes of HealthNIH
Office of the DirectorODHD052664, P51OD011106, U54-HD087011
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR01HD083001-01A1

Document Type: Article
Publication Stage: Final
Source: Scopus

The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021
(2022) Multiple Sclerosis Journal, 28 (9), pp. 1424-1456. 

Tur, C.^a , Dubessy, A.-L.^b at , Otero-Romero, S.^a , Amato, M.P.^c au , Derfuss, T.^d , Di Pauli, F.^e , Iacobaeus, E.^f , Mycko, M.^g , Abboud, H.^h , Achiron, A.ⁱ , Bellinvia, A.^j , Boyko, A.^k ar , Casanova, J.-L.^l , Clifford, D.^m , Dobson, R.^n aq , Farez, M.F.^o , Filippi, M.^p ay , Fitzgerald, K.C.^q , Fonderico, M.^j , Gouider, R.^r , Hacohen, Y.^s , Hellwig, K.^t , Hemmer, B.^u ap , Kappos, L.^v , Ladeira, F.^w , Lebrun-Frénay, C.^x , Louapre, C.^y as , Magyari, M.^z , Mehling, M.^d , Oreja-Guevara, C.^aa , Pandit, L.^ab , Papeix, C.^y as , Piehl, F.^f , Portaccio, E.^j , Ruiz-Camps, I.^ac , Selmaj, K.^ad ax , Simpson-Yap, S.^ae , Siva, A.^af , Sorensen, P.S.^ag , Sormani, M.P.^ah , Trojano, M.^ai , Vaknin-Dembinsky, A.^aj , Vukusic, S.^ak av aw , Weinshenker, B.^al , Wiendl, H.^am , Winkelmann, A.^an , Zuluaga Rodas, M.I.^ao , Tintoré, M.^a , Stankoff, B.^b at

^a Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d’Hebron, Barcelona Hospital Campus, Barcelona, Spain
^b Sorbonne Université, Inserm, CNRS, UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), Paris, France
^c Department of NEUROFARBA, University of Florence, Florence, Italy
^d Neurology Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedicine and Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland
^e Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
^f Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
^g Department of Neurology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
^h Multiple Sclerosis and Neuroimmunology Program, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland Medical Center, Cleveland, OH, United States
ⁱ Sheba Medical Center at Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
^j Department of NEUROFARBA, University of Florence, Florence, Italy
^k Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, Moscow, Russian Federation
^l Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States
^m Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
ⁿ Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom
^o Center for Research on Neuroimmunological Diseases, FLENI, Buenos Aires, Argentina
^p Neurology Unit, Neurorehabilitation Unit and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
^q Department of Neurology and Epidemiology, Johns Hopkins University, Baltimore, MD, United States
^r Department of Neurology, Razi Hospital, Tunis, Tunisia
^s Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, United Kingdom
^t Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany
^u Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
^v Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland
^w Neurology Department, Hospital Santo António dos Capuchos, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal
^x CRCSEP Côte d’Azur, CHU de Nice Pasteur 2, UR2CA-URRIS, Université Nice Côte d’Azur, Nice, France
^y Sorbonne Université, Inserm, CNRS, UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), Paris, France
^z Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Copenhagen, Denmark
^aa Department of Neurology, Hospital Clínico San Carlos, Idissc, Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
^ab Center for Advanced Neurological Research, KS Hegde Medical Academy, Nitte, (Deemed to be University), Mangalore, India
^ac Servicio de Enfermedades Infecciosas, Hospital Universitari Vall d’Hebron, Barcelona, Spain
^ad Department of Neurology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
^ae Clinical Outcomes Research Unit, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia
^af Department of Neurology, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
^ag Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
^ah Department of Health Sciences, University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy
^ai Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro, Bari, Italy
^aj Hadassah-Hebrew University Medical Center, Department of Neurology, The Agnes-Ginges Center for Neurogenetics Jerusalem, Jerusalem, Israel
^ak Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France
^al Department of Neurology, Mayo Clinic, Rochester, MN, United States
^am Department of Neurology with Institute of Translational Neurology, University of Muenster, Münster, Germany
^an Department of Neurology, University of Rostock, Rostock, Germany
^ao MS Clinic, Instituto Neurológico de Colombia and Medicarte, Medellin, Colombia
^ap Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^aq Department of Neurology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
^ar Institute of Clinical Neurology and Department of Neuroimmunology, Federal Center of Brain Research and Neurotechnologies, Moscow, Russian Federation
^as Sorbonne University, Paris Brain Institute—ICM, Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, CIC Neurosciences, Paris, France
^at Department of Neurology, Saint Antoine Hospital, AP-HP, Paris, France
^au IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
^av Centre des Neurosciences de Lyon, Observatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, Lyon, France
^aw Université Claude Bernard Lyon 1, Faculté de médecine Lyon Est, Lyon, France
^ax Center of Neurology, Lodz, Poland
^ay Vita-Salute San Raffaele University, Milan, Italy

Abstract
Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research. © The Author(s), 2022.

Author Keywords
coronavirus disease 2019;  COVID-19;  disease-modifying treatment;  DMT-associated infections;  Multiple sclerosis;  neuromyelitis optica spectrum disorder;  progressive multifocal leukoencephalopathy;  risk mitigation strategies;  SARS-CoV-2

Funding details
Bayer
Genzyme
Merck
Novartis
Sanofi
EMD Serono
Biogen
Alexion Pharmaceuticals
Celgene
“la Caixa” Foundation100010434
UCB
Sanofi Genzyme
GlaxoSmithKline EspañaGSK
Roche España
European CommissionEC
Deutsche ForschungsgemeinschaftDFG
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF
Bundesministerium für Bildung und ForschungBMBF
Istanbul Üniversitesi
Else Kröner-Fresenius-StiftungEKFS
Narodowe Centrum NaukiNCN2020/01/0/NZ6/00072
Schweizerische Multiple Sklerose Gesellschaft
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum WürzburgIZKF Würzburg

Document Type: Article
Publication Stage: Final
Source: Scopus

Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation
(2022) Molecular Genetics and Metabolism, 136 (4), pp. 260-267. 

Wongkittichote, P.^a , Magistrati, M.^b , Shimony, J.S.^c , Smyser, C.D.^c d , Fatemi, S.A.^e , Fine, A.S.^e , Bellacchio, E.^f , Dallabona, C.^b , Shinawi, M.^a

^a Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
^d Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^e Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, United States
^f Genetics and Rare Diseases Research Area, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

Abstract
Biallelic pathogenic variants in the nuclear gene DARS2 (MIM# 610956), encoding the mitochondrial enzyme aspartyl-tRNA synthetase (MT-ASPRS) cause leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL) (MIM# 611105), a neurometabolic disorder characterized by progressive ataxia, spasticity, developmental arrest or regression and characteristic brain MRI findings. Most patients exhibit a slowly progressive disease course with motor deterirartion that begins in childhood or adolescence, but can also occasionaly occur in adulthood. More severe LBSL presentations with atypical brain MRI findings have been recently described. Baker’s yeast orthologue of DARS2, MSD1, is required for growth on oxidative carbon sources. A yeast with MSD1 knockout (msd1Δ) demonstrated a complete lack of oxidative growth which could be rescued by wild-type MSD1 but not MSD1 with pathogenic variants. Here we reported two siblings who exhibited developmental regression and ataxia with different age of onset and phenotypic severity. Exome sequencing revealed 2 compound heterozygous missense variants in DARS2: c.473A>T (p.Glu158Val) and c.829G>A (p.Glu277Lys); this variant combination has not been previously reported. The msd1Δ yeast transformed with plasmids expressing p.Glu259Lys, equivalent to human p.Glu277Lys, showed complete loss of oxidative growth and oxygen consumption, while the strain carrying p.Gln137Val, equivalent to human p.Glu158Val, showed a significant reduction of oxidative growth, but a residual ability to grow was retained. Structural analysis indicated that p.Glu158Val may interfere with protein binding of tRNAAsp, while p.Glu277Lys may impact both homodimerization and catalysis of MT-ASPRS. Our data illustrate the utility of yeast model and in silico analysis to determine pathogenicity of DARS2 variants, expand the genotypic spectrum and suggest intrafamilial variability in LBSL. © 2022 Elsevier Inc.

Author Keywords
Aspartyl-tRNA synthetase;  DARS2;  Leukodystrophy;  Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation;  Mitochondrial disorder

Funding details
National Institutes of HealthNIHP50 HD103525
University of WashingtonUWU54NS115052, US4HD079123
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Ministero dell’Istruzione, dell’Università e della RicercaMIUR

Document Type: Article
Publication Stage: Final
Source: Scopus

Proteinopathy and Longitudinal Cognitive Decline in Parkinson Disease
(2022) Neurology, 99 (1), pp. E66-E76. 

Myers, P.S.^a , O’Donnell, J.L.^a , Jackson, J.J.^h , Lessov-Schlaggar, C.N.^b , Miller, R.L.^a , Foster, E.R.^a b c , Cruchaga, C.^a b d , Benitez, B.A.^b , Kotzbauer, P.T.^a , Perlmutter, J.S.^c e f g , Campbell, M.C.^a

^a Department of Neurology, Washington University, St. Louis, MO, United States
^b Department of Psychiatry, Washington University, St. Louis, MO, United States
^c Program in Occupational Therapy, Washington University, St. Louis, MO, United States
^d Department of Genetics, Washington University, St. Louis, MO, United States
^e Department of Radiology, Washington University, St. Louis, MO, United States
^f Department of Neuroscience, Washington University, St. Louis, MO, United States
^g Program in Physical Therapy, Washington University, School of Medicine, St. Louis, MO, United States
^h Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
Background and ObjectivesPeople with Parkinson disease (PD) commonly experience cognitive decline, which may relate to increased α-synuclein, tau, and β-amyloid accumulation. This study examines whether the different proteins predict longitudinal cognitive decline in PD.MethodsAll participants (PD n = 152, controls n = 52) were part of a longitudinal study and completed a lumbar puncture for CSF protein analysis (α-synuclein, total tau [tau], and β-amyloid42 [β-amyloid]), a β-amyloid PET scan, and/or provided a blood sample for APOE genotype (ϵ4+, ϵ4-), which is a risk factor for β-amyloid accumulation. Participants also had comprehensive, longitudinal clinical assessments of overall cognitive function and dementia status, as well as cognitive testing of attention, language, memory, and visuospatial and executive function. We used hierarchical linear growth models to examine whether the different protein metrics predict cognitive change and multivariate Cox proportional hazard models to predict time to dementia conversion. Akaike information criterion was used to compare models for best fit.ResultsBaseline measures of CSF β-amyloid predicted decline for memory (p = 0.04) and overall cognitive function (p = 0.01). APOE genotypes showed a significant group (ϵ4+, ϵ4-) effect such that ϵ4+ individuals declined faster than ϵ4- individuals in visuospatial function (p = 0.03). Baseline β-amyloid PET significantly predicted decline in all cognitive measures (all p ≤ 0.004). Neither baseline CSF α-synuclein nor tau predicted cognitive decline. All 3 β-amyloid – related metrics (CSF, PET, APOE) also predicted time to dementia. Models with β-amyloid PET as a predictor fit the data the best.DiscussionPresence or risk of β-amyloid accumulation consistently predicted cognitive decline and time to dementia in PD. This suggests that β-amyloid has high potential as a prognostic indicator and biomarker for cognitive changes in PD. © 2022 American Academy of Neurology.

Funding details
National Institute of Neurological Disorders and StrokeNINDSF32NS105365, NS058714, NS075321, NS097437, NS097799, NS118146, NS41509, NS48924, P30 NS048056
National Center for Research ResourcesNCRRUL1RR024992
American Parkinson Disease AssociationAPDA
Foundation for Barnes-Jewish HospitalFBJH

Document Type: Article
Publication Stage: Final
Source: Scopus

Multi-Task Learning for Randomized Controlled Trials: A case study on predicting depression with wearable data
(2022) Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies, 6 (2), art. no. 50, . 

Dai, R.^a , Kannampallil, T.^b , Zhang, J.^a , Lv, N.^c , Ma, J.^c , Lu, C.^a

^a Washington University in St. Louis, Department of Computer Science and Engineering, St. Louis, MO, United States
^b Washington University in St. Louis, Department of Anesthesiology, Department of Computer Science and Engineering, St. Louis, MO, United States
^c University of Illinois Chicago, Department of Medicine, Chicago, IL, United States

Abstract
A randomized controlled trial (RCT) is used to study the safety and efficacy of new treatments, by comparing patient outcomes of an intervention group with a control group. Traditionally, RCTs rely on statistical analyses to assess the differences between the treatment and control groups. However, such statistical analyses are generally not designed to assess the impact of the intervention at an individual level. In this paper, we explore machine learning models in conjunction with an RCT for personalized predictions of a depression treatment intervention, where patients were longitudinally monitored with wearable devices. We formulate individual-level predictions in the intervention and control groups from an RCT as a multi-Task learning (MTL) problem, and propose a novel MTL model specifically designed for RCTs. Instead of training separate models for the intervention and control groups, the proposed MTL model is trained on both groups, effectively enlarging the training dataset. We develop a hierarchical model architecture to aggregate data from different sources and different longitudinal stages of the trial, which allows the MTL model to exploit the commonalities and capture the differences between the two groups. We evaluated the MTL approach in an RCT involving 106 patients with depression, who were randomized to receive an integrated intervention treatment. Our proposed MTL model outperforms both single-Task models and the traditional multi-Task model in predictive performance, representing a promising step in utilizing data collected in RCTs to develop predictive models for precision medicine. © 2022 Owner/Author.

Author Keywords
Depression;  Multi-Task Learning;  Randomized Controlled Trial;  Wearables

Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIUH2HL132368
Fullgraf Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Individualized Functional Subnetworks Connect Human Striatum and Frontal Cortex
(2022) Cerebral Cortex, 32 (13), pp. 2868-2884. 

Gordon, E.M.^a , Laumann, T.O.^b , Marek, S.^b , Newbold, D.J.^c , Hampton, J.M.^b , Seider, N.A.^c , Montez, D.F.^c , Nielsen, A.M.^d , Van, A.N.^e , Zheng, A.^c , Miller, R.^b c , Siegel, J.S.^b , Kay, B.P.^c , Snyder, A.Z.^a c , Greene, D.J.^f , Schlaggar, B.L.^g h i , Petersen, S.E.^a c j k , Nelson, S.M.^l m , Dosenbach, N.U.F.^{a c g n o}

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Institute for Innovations in Developmental Sciences, Northwestern University, Chicago, IL 60611, United States
^e Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Cognitive Science, University of California San Diego, La JollaCA 92093, United States
^g Kennedy Krieger Institute, Baltimore, MD 21205, United States
^h Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
ⁱ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^j Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^k Department of Psychological & Brain Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
^l Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, United States
^m Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN 55454, United States
ⁿ Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
^o Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
The striatum and cerebral cortex are interconnected via multiple recurrent loops that play a major role in many neuropsychiatric conditions. Primate corticostriatal connections can be precisely mapped using invasive tract-tracing. However, noninvasive human research has not mapped these connections with anatomical precision, limited in part by the practice of averaging neuroimaging data across individuals. Here we utilized highly sampled resting-state functional connectivity MRI for individual-specific precision functional mapping (PFM) of corticostriatal connections. We identified ten individual-specific subnetworks linking cortex – predominately frontal cortex – to striatum, most of which converged with nonhuman primate tract-tracing work. These included separable connections between nucleus accumbens core/shell and orbitofrontal/medial frontal gyrus; between anterior striatum and dorsomedial prefrontal cortex; between dorsal caudate and lateral prefrontal cortex; and between middle/posterior putamen and supplementary motor/primary motor cortex. Two subnetworks that did not converge with nonhuman primates were connected to cortical regions associated with human language function. Thus, precision subnetworks identify detailed, individual-specific, neurobiologically plausible corticostriatal connectivity that includes human-specific language networks. © 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved.

Author Keywords
brain networks;  fMRI;  functional connectivity;  individual variability;  striatum

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of Molecular Senescence Markers in Late-Life Depression with Clinical Characteristics and Treatment Outcome
(2022) JAMA Network Open, 5 (6), p. E2219678. 

Diniz, B.S.^a b , Mulsant, B.H.^c d , Reynolds, C.F., Iii^e , Blumberger, D.M.^c d , Karp, J.F.^f , Butters, M.A.^e , Mendes-Silva, A.P.^d , Vieira, E.L.^c d , Tseng, G.^g , Lenze, E.J.^h

^a UConn Center on Aging, University of Connecticut, Farmington, United States
^b Department of Psychiatry, University of Connecticut, School of Medicine, Farmington, United States
^c Centre for Addiction and Mental Health, Toronto, ON, Canada
^d Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
^e Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States
^f Department of Psychiatry, The University of Arizona, College of Medicine, Tucson, United States
^g Department of Biostatistics, University of Pittsburgh, School of Public Health, Pittsburgh, PA, United States
^h Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States

Abstract
Importance: Many older adults with depression do not experience remission with antidepressant treatment, and markers of cellular senescence in late-life depression (LLD) are associated with greater severity of depression, greater executive dysfunction, and higher medical illness burden. Since these clinical characteristics are associated with remission in LLD, molecular and cellular senescence abnormalities could be a possible biological mechanism underlying poor treatment response in this population. Objective: To examine whether the senescence-associated secretory phenotype (SASP) index was associated with the likelihood of remission from a depressive episode in older adults. Design, Setting, and Participants: A nonrandomized, open-label clinical trial was conducted between August 2009 and August 2014 in Pittsburgh, Pennsylvania; St Louis, Missouri; and Toronto, Ontario, Canada, with older adults in a current major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnostic criteria. Data from biomarker analyses were reported according to the clinical trial archived plasma samples run in March 2021. Data were analyzed from June to November 2021. Exposure: Venlafaxine extended release (dose ranging from 37.5 mg to 300 mg daily) for up to 12 weeks. Main Outcomes and Measures: The association between a composite biomarker-based index (SASP index) and treatment remission in older adults with major depression was measured using clinical data and blood samples. Results: There were 416 participants with a mean (SD) age of 60.02 (7.13) years; 64% (265 participants) were self-reported female, and the mean (SD) Montgomery-Asberg Depression Rating Scale score was 26.6 (5.7). Higher SASP index scores were independently associated with higher rates of nonremission, with an increase of 1 unit in the SASP index score increasing the odds of nonremission by 19% (adjusted odds ratio, 1.19; 95% CI, 1.05-1.35; P =.006). In contrast, no individual SASP factors were associated with remission in LLD. Conclusions and Relevance: Using clinical data and blood samples from a nonrandomized clinical trial, the results of this study suggest that molecular and cellular senescence, as measured with the SASP index, is associated with worse treatment outcomes in LLD. Combining this index score reflecting interrelated biological processes with other molecular, clinical, and neuroimaging markers may be useful in evaluating antidepressant treatment outcomes. These findings inform a path forward for geroscience-guided interventions targeting senescence to improve remission rates in LLD. Trial Registration: ClinicalTrials.gov Identifier: NCT00892047. © 2022 American Medical Association. All rights reserved.

Funding details
National Institutes of HealthNIHR01 MH083660, R01MH118311
National Institute of Mental HealthNIMH
Patient-Centered Outcomes Research InstitutePCORI
University of Pittsburgh
Fondation Brain Canada
Centre for Addiction and Mental HealthCAMH
Centre for Addiction and Mental Health FoundationCAMH
Canadian Institutes of Health ResearchIRSC

Document Type: Article
Publication Stage: Final
Source: Scopus

Automated Measurement of Net Water Uptake From Baseline and Follow-Up CTs in Patients With Large Vessel Occlusion Stroke
(2022) Frontiers in Neurology, 13, art. no. 898728, . 

Kumar, A.^a , Chen, Y.^a , Corbin, A.^b , Hamzehloo, A.^a , Abedini, A.^c , Vardar, Z.^d , Carey, G.^a , Bhatia, K.^a , Heitsch, L.^e , Derakhshan, J.J.^c , Lee, J.-M.^a , Dhar, R.^a

^a Department of Neurology, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States
^b Saint Louis University School of Medicine, Saint Louis, MO, United States
^c Department of Radiology, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States
^d Department of Radiology, University of Massachusetts Medical School, Worcester, MA, United States
^e Department of Emergency Medicine, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States

Abstract
Quantifying the extent and evolution of cerebral edema developing after stroke is an important but challenging goal. Lesional net water uptake (NWU) is a promising CT-based biomarker of edema, but its measurement requires manually delineating infarcted tissue and mirrored regions in the contralateral hemisphere. We implement an imaging pipeline capable of automatically segmenting the infarct region and calculating NWU from both baseline and follow-up CTs of large-vessel occlusion (LVO) patients. Infarct core is extracted from CT perfusion images using a deconvolution algorithm while infarcts on follow-up CTs were segmented from non-contrast CT (NCCT) using a deep-learning algorithm. These infarct masks were flipped along the brain midline to generate mirrored regions in the contralateral hemisphere of NCCT; NWU was calculated as one minus the ratio of densities between regions, removing voxels segmented as CSF and with HU outside thresholds of 20–80 (normal hemisphere and baseline CT) and 0–40 (infarct region on follow-up). Automated results were compared with those obtained using manually-drawn infarcts and an ASPECTS region-of-interest based method that samples densities within the infarct and normal hemisphere, using intraclass correlation coefficient (ρ). This was tested on serial CTs from 55 patients with anterior circulation LVO (including 66 follow-up CTs). Baseline NWU using automated core was 4.3% (IQR 2.6–7.3) and correlated with manual measurement (ρ = 0.80, p < 0.0001) and ASPECTS (r = −0.60, p = 0.0001). Automatically segmented infarct volumes (median 110-ml) correlated to manually-drawn volumes (ρ = 0.96, p < 0.0001) with median Dice similarity coefficient of 0.83 (IQR 0.72–0.90). Automated NWU was 24.6% (IQR 20–27) and highly correlated to NWU from manually-drawn infarcts (ρ = 0.98) and the sampling-based method (ρ = 0.68, both p < 0.0001). We conclude that this automated imaging pipeline is able to accurately quantify region of infarction and NWU from serial CTs and could be leveraged to study the evolution and impact of edema in large cohorts of stroke patients. Copyright © 2022 Kumar, Chen, Corbin, Hamzehloo, Abedini, Vardar, Carey, Bhatia, Heitsch, Derakhshan, Lee and Dhar.

Author Keywords
cerebral edema area;  computed tomography;  image segmentation;  machine learning;  stroke

Funding details
National Institutes of HealthNIHRR1817, U24NS107230
National Institute of Neurological Disorders and StrokeNINDSK23NS099440, K23NS099487, R01NS085419
Foundation of the American Society of NeuroradiologyFASNR

Document Type: Article
Publication Stage: Final
Source: Scopus

The Longitudinal Impact of Maternal Depression and Neighborhood Social Context on Adolescent Mental Health
(2022) Frontiers in Pediatrics, 10, art. no. 854418, . 

Lew, D.^a b , Xian, H.^c , Loux, T.^c , Shacham, E.^d , Scharff, D.^d

^a Division of Biostatistics, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States
^b Center for Population Health Informatics, Institute for Informatics, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States
^c Department of Epidemiology and Biostatistics, College for Public Health and Social Justice, Saint Louis University, Saint Louis, MO, United States
^d Department of Behavioral Science and Health Education, College for Public Health and Social Justice, Saint Louis University, Saint Louis, MO, United States

Abstract
Purpose: Maternal depression and neighborhood characteristics are known to be associated both with each other and with adolescent mental health outcomes. These exposures are also subject to change throughout the life of a child. This study sought to identify multi-trajectories of maternal depression (MD) and self-reported neighborhood collective efficacy (NCE) over a 12-year period and determine whether these trajectories are differentially associated with adolescent mental health. Methods: Data from the Fragile Families and Child Wellbeing study, a longitudinal cohort study of new parents and their children, were used. Maternal depression (MD) and self-reported NCE when the child was 3, 5, 9, and 15 years of age were the primary exposures of interest. Adolescent depression and anxiety symptomology when the child was 15 years of age were the primary outcomes. Primary analyses were conducted using multi-trajectory modeling and linear regressions. Results: Five multi-trajectories were identified, two of which were characterized by no MD but either high or low NCE, and three of which were characterized by similarly moderate levels of NCE but either increasing, decreasing, or consistently high MD. Children of mothers with increasing or consistently high depressive symptomology and moderate NCE had significantly higher depression and anxiety scores compared to children of mothers with no depressive symptomology and high NCE. Conclusion: Adolescents with consistent and proximal exposure to MD are most likely to suffer from adverse mental health and should be provided with appropriate support systems to mitigate these outcomes. Copyright © 2022 Lew, Xian, Loux, Shacham and Scharff.

Author Keywords
anxiety;  collective efficacy;  depression;  longitudinal studies;  maternal-child health;  mental health;  neighborhoods

Document Type: Article
Publication Stage: Final
Source: Scopus

Avoid or Embrace? Practice Effects in Alzheimer’s Disease Prevention Trials
(2022) Frontiers in Aging Neuroscience, 14, art. no. 883131, . 

Aschenbrenner, A.J.^a , Hassenstab, J.^a , Wang, G.^a , Li, Y.^a , Xiong, C.^a , McDade, E.^a , Clifford, D.B.^a , Salloway, S.^b , Farlow, M.^c , Yaari, R.^d , Cheng, E.Y.J.^d , Holdridge, K.C.^d , Mummery, C.J.^e , Masters, C.L.^f , Hsiung, G.-Y.^g , Surti, G.^h , Day, G.S.ⁱ , Weintraub, S.^j , Honig, L.S.^k , Galvin, J.E.^l , Ringman, J.M.^m , Brooks, W.S.ⁿ , Fox, N.C.^o , Snyder, P.J.^h , Suzuki, K.^p , Shimada, H.^q , Gräber, S.^r , Bateman, R.J.^a , the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU)^s

^a Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Warren Alpert Medical School of Brown University, Providence, RI, United States
^c Indiana University School of Medicine, Indianapolis, IN, United States
^d Eli Lilly and Company, Indianapolis, IN, United States
^e University College London, London, United Kingdom
^f University of Melbourne, Melbourne, VIC, Australia
^g The University of British Columbia, Vancouver, BC, Canada
^h The University of Rhode Island, Kingston, RI, United States
ⁱ Mayo Clinic, Jacksonville, FL, United States
^j Feiniberg School of Medicine, Northwestern University, Chicago, IL, United States
^k Columbia University Irving Medical Center, New York, NY, United States
^l Miller School of Medicine, University of Miami, Miami, FL, United States
^m University of Southern California, Los Angeles, CA, United States
ⁿ Neuroscience Research Australia, University of New South Wales Medicine, Randwick, NSW, Australia
^o Dementia Research Center, University College London, London, United Kingdom
^p The University of Tokyo, Tokyo, Japan
^q Osaka City University, Osaka, Japan
^r German Center for Neurodegenerative Disease (DZNE), Tübingen, Germany

Abstract
Demonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer’s disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed “practice effects”). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies. Copyright © 2022 Aschenbrenner, Hassenstab, Wang, Li, Xiong, McDade, Clifford, Salloway, Farlow, Yaari, Cheng, Holdridge, Mummery, Masters, Hsiung, Surti, Day, Weintraub, Honig, Galvin, Ringman, Brooks, Fox, Snyder, Suzuki, Shimada, Gräber and Bateman.

Author Keywords
alternative forms;  Alzheimer’s disease;  assessment frequency;  clinical trials;  learning;  practice effects

Funding details
K23AG064029
National Institutes of HealthNIHU01AG042791
Foundation for the National Institutes of HealthFNIHDIAN-TU-001, R01AG053267-S1, R1AG046179
National Institute on AgingNIA
Alzheimer’s AssociationAA
Amgen
Bristol-Myers SquibbBMS
Eli Lilly and Company
Roche
Biogen
AbbVie
F. Hoffmann-La Roche
Janssen Pharmaceuticals
American Neurological AssociationANA
GHR FoundationGHR
Canadian Institutes of Health ResearchIRSC
Alzheimer Society
Eisai
Alzheimer Society of B.C.

Document Type: Article
Publication Stage: Final
Source: Scopus

Pilot feasibility study of a simple regenerative peripheral nerve interface designed to diminish cutaneous dysesthesia after supraclavicular operations
(2022) Journal of Vascular Surgery Cases, Innovations and Techniques, 8 (2), pp. 287-292. 

Yang, A.^a b , Thompson, R.W.^a c

^a Center for Thoracic Outlet Syndrome, Department of Surgery, Washington University School of Medicine, St Louis, MO
^b Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO
^c Section of Vascular Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO

Abstract
Supraclavicular operations can be associated with postoperative cutaneous dysesthesia and hypersensitivity. Regenerative peripheral nerve interfaces, created by attaching the proximal end of a divided peripheral nerve into a viable muscle target, can promote neurite regrowth and neuromuscular connections to help suppress painful nerve hyperactivity. During 40 consecutive operations for neurogenic thoracic outlet syndrome, we demonstrated that division of at least one of the superficial supraclavicular cutaneous sensory nerve branches was necessary in 98% of cases. We subsequently developed a novel regenerative peripheral nerve interface for supraclavicular operations using the adjacent omohyoid muscle and have described the technical steps involved in this procedure. © 2022 The Author(s)

Author Keywords
Cutaneous dysesthesia;  Omohyoid muscle;  Regenerative peripheral nerve interface;  Supraclavicular nerve;  Surgical technique;  Thoracic outlet syndrome

Funding details
Foundation for Barnes-Jewish HospitalFBJH

Document Type: Article
Publication Stage: Final
Source: Scopus

Convergent mosaic brain evolution is associated with the evolution of novel electrosensory systems in teleost fishes.
(2022) eLife, 11, . 

Schumacher, E.L., Carlson, B.A.

Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Brain region size generally scales allometrically with brain size, but mosaic shifts in brain region size independent of brain size have been found in several lineages and may be related to the evolution of behavioral novelty. African weakly electric fishes (Mormyroidea) evolved a mosaically enlarged cerebellum and hindbrain, yet the relationship to their behaviorally novel electrosensory system remains unclear. We addressed this by studying South American weakly electric fishes (Gymnotiformes) and weakly electric catfishes (Synodontis spp.), which evolved varying aspects of electrosensory systems, independent of mormyroids. If the mormyroid mosaic increases are related to evolving an electrosensory system, we should find similar mosaic shifts in gymnotiforms and Synodontis. Using micro-computed tomography scans, we quantified brain region scaling for multiple electrogenic, electroreceptive, and non-electrosensing species. We found mosaic increases in cerebellum in all three electrogenic lineages relative to non-electric lineages and mosaic increases in torus semicircularis and hindbrain associated with the evolution of electrogenesis and electroreceptor type. These results show that evolving novel electrosensory systems is repeatedly and independently associated with changes in the sizes of individual major brain regions independent of brain size, suggesting that selection can impact structural brain composition to favor specific regions involved in novel behaviors. © 2022, eLife Sciences Publications Ltd. All rights reserved.

Author Keywords
behavioral novelty;  cerebellum;  communication;  electric organ discharge;  electrolocation;  Gymnotiformes;  key innovation;  Mormyroidea;  Weakly electric fish

Document Type: Article
Publication Stage: Final
Source: Scopus

Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke
(2022) eLife, 11, art. no. e68852, . 

Bice, A.R.^a , Xiao, Q.^b , Kong, J.^c , Yan, P.^b , Rosenthal, Z.P.^b , Kraft, A.W.^b , Smith, K.^b , Wieloch, T.^f , Lee, J.-M.^a b d , Culver, J.P.^a d e , Bauer, A.Q.^a d

^a Departments of Radiology, Washington University in St. Louis, United States
^b Departments of Neurology, Washington University in St. Louis, United States
^c Departments of Biology and Biomedical Sciences, Washington University in St. Louis, United States
^d Departments of Biomedical Engineering, Washington University in St. Louis, United States
^e Departments of Physics, Washington University in St. Louis, United States
^f Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, BMC A13, Lund, 22184, Sweden

Abstract
Understanding circuit-level manipulations that affect the brain’s capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems-and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging (OISI) to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally-distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for therapeutic intervention after focal ischemia. © 2022, eLife Sciences Publications Ltd. All rights reserved.

Author Keywords
functional recovery;  optogenetics;  Plasticity;  resting state functional connectivity;  stroke

Funding details
National Institutes of HealthNIHF31NS089135, F31NS103275, K25-NS083754, P01NS080675, R01-NS102870, R01NS078223, R01NS084028, R01NS094692, R01NS099429, R37NS110699
Alborada Trust
McDonnell Center for Systems Neuroscience
VetenskapsrådetVR

Document Type: Article
Publication Stage: Final
Source: Scopus

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment
(2022) Brain, 145 (6), pp. 1924-1938. Cited 5 times.

Levey, A.I.^a b , Qiu, D.^a c , Zhao, L.^a d , Hu, W.T.^a b , Duong, D.M.^e , Higginbotham, L.^a b , Dammer, E.B.^e , Seyfried, N.T.^a e , Wingo, T.S.^a b f , Hales, C.M.^a b , Tansey, M.G.^g , Goldstein, D.S.^h , Abrol, A.ⁱ , Calhoun, V.D.ⁱ , Goldstein, F.C.^a b , Hajjar, I.^a b , Fagan, A.M.^j , Galasko, D.^k , Edland, S.D.^k , Hanfelt, J.^a d , Lah, J.J.^a b , Weinshenker, D.^a f

^a Goizueta Alzheimer’s Disease Research Center, Emory University, Atlanta, GA 30322, United States
^b Department of Neurology, Emory University, Atlanta, GA 30322, United States
^c Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA 30322, United States
^d Department of Biostatistics, Emory University, Atlanta, GA 30322, United States
^e Department of Biochemistry, Emory University, Atlanta, GA 30322, United States
^f Department of Human Genetics, Emory University, Atlanta, GA 30322, United States
^g Department of Physiology, Emory University, Atlanta, GA 30322, United States
^h NINDS, NIH, Bethesda, MD 20892, United States
ⁱ Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, GA 30303, United States
^j Department of Neurology and Knight ADRC, Washington University, St. Louis, MO 630130, United States
^k Department of Neurosciences and ADRC, UCSD, San Diego, CA 92093, United States

Abstract
The locus coeruleus is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer’s pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer’s disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer’s disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-β42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-β42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer’s disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer’s disease progression. © The Author(s) 2022.

Author Keywords
Alzheimer’s disease;  atomoxetine;  locus coeruleus;  mild cognitive impairment;  norepinephrine

Document Type: Article
Publication Stage: Final
Source: Scopus

Detection of Brain Tau Pathology in Down Syndrome Using Plasma Biomarkers
(2022) JAMA Neurology, . 

Janelidze, S.^a , Christian, B.T.^b , Price, J.^c , Laymon, C.^d , Schupf, N.^e , Klunk, W.E.^d , Lott, I.^f , Silverman, W.^f , Rosas, H.D.^c g , Zaman, S.^h , Mapstone, M.ⁱ , Lai, F.^g , Ances, B.M.^j , Handen, B.L.^d , Hansson, O.^a k

^a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sölvegatan 19, BMC B11, Lund, 221 84, Sweden
^b Waisman Center, University of Wisconsin, Madison, United States
^c Harvard Medical School, Department of Radiology, Massachusetts General Hospital, Charlestown, United States
^d Department of Psychiatry, University of Pittsburgh, 3811 O’Hara St, Pittsburgh, PA 15213, United States
^e Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, United States
^f School of Medicine, Department of Pediatrics, University of California, Irvine, United States
^g Harvard Medical School, Department of Neurology, Massachusetts General Hospital, Charlestown, United States
^h School of Clinical Medicine, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
ⁱ Department of Neurology, University of California, Irvine, United States
^j Washington University, School of Medicine in St Louis, St Louis, MO, United States
^k Memory Clinic, Skåne University Hospital, Malmö, Sweden

Abstract
Importance: Novel plasma biomarkers, especially phosphorylated tau (p-tau), can detect brain tau aggregates in Alzheimer disease. Objective: To determine which plasma biomarker combinations can accurately detect tau pathological brain changes in Down syndrome (DS). Design, Setting, and Participants: The cross-sectional, multicenter Alzheimer’s Biomarker Consortium-Down Syndrome study included adults with DS and a control group of siblings without DS. All participants with plasma, positron emission tomography (PET), and cognitive measures available by the time of data freeze 1.0 were included. Participants were enrolled between 2016 and 2019, and data were analyzed from August 2021 to April 2022. Exposures: Plasma p-tau217, glial fibrillary acidic protein (GFAP), amyloid β42/40 (Aβ42/Aβ40), neurofilament light (NfL), and total tau (t-tau); tau positron emission tomography (tau-PET) and Aβ-PET. Main Outcomes and Measures: The primary outcome was tau-PET status. Secondary outcomes included Aβ-PET status and cognitive performance. Results: Among 300 participants with DS and a control group of 37 non-DS siblings, mean (SD) age was 45.0 (10.1) years, and 167 (49.6%) were men. Among participants with DS who all underwent plasma p-tau217 and GFAP analyses, 258 had other plasma biomarker data available and 119, 213, and 288 participants had tau-PET, Aβ-PET, and cognitive assessments, respectively. Plasma p-tau217 and t-tau were significantly increased in Aβ-PET-positive tau-PET-positive (A+T+) DS and A+T-DS compared with A-T-DS while GFAP was only increased in A+T+DS. Plasma p-tau217 levels were also significantly higher in A+T+DS than A+T-DS. In participants with DS, plasma p-tau217 and GFAP (but not other plasma biomarkers) were consistently associated with abnormal tau-PET and Aβ-PET status in models covaried for age (odds ratio range, 1.59 [95% CI, 1.05-2.40] to 2.32 [95% CI, 1.36-3.96]; P &lt;.03). A combination of p-tau217 and age performed best when detecting tau-PET abnormality in temporal and neocortical regions (area under the curve [AUC] range, 0.96-0.99). The most parsimonious model for Aβ-PET status included p-tau217, t-tau, and age (AUC range, 0.93-0.95). In multivariable models, higher p-tau217 levels but not other biomarkers were associated with worse performance on DS Mental Status Examination (β, -0.24, 95% CI, -0.36 to -0.12; P &lt;.001) and Cued Recall Test (β, -0.40; 95% CI, -0.53 to -0.26; P &lt;.001). Conclusions and Relevance: Plasma p-tau217 is a very accurate blood-based biomarker of both tau and Aβ pathological brain changes in DS that could help guide screening and enrichment strategies for inclusion of individuals with DS in future AD clinical trials, especially when it is combined with age as a covariate. © 2022 American Medical Association. All rights reserved.

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

Comparative analytical performance of multiple plasma Aβ42 and Aβ40 assays and their ability to predict positron emission tomography amyloid positivity
(2022) Alzheimer’s and Dementia, . 

Zicha, S.^a , Bateman, R.J.^b , Shaw, L.M.^c , Zetterberg, H.^d e f g , Bannon, A.W.^h , Horton, W.A.ⁱ , Baratta, M.^a , Kolb, H.C.^j , Dobler, I.^a , Mordashova, Y.^k , Saad, Z.S.^j , Raunig, D.L.^a , Spanakis, E.^k , Li, Y.^b , Schindler, S.E.^b , Ferber, K.^l , Rubel, C.E.^l , Martone, R.L.^l , Weber, C.J.^m , Edelmayer, R.M.^m , Meyers, E.A.^m , Bollinger, J.G.^b , Rosenbaugh, E.G.ⁱ , Potter, W.Z.ⁿ , Alzheimer’s Disease Neuroimaging Initiative (ADNI)^o , Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Plasma Abeta as a Predictor of Amyloid Positivity in Alzheimer’s Disease Project Team^o

^a Takeda, Pharmaceutical Company Ltd., Cambridge, MA, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^d Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
^e Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^f UK Dementia Research Institute Fluid Biomarkers Laboratory, UK DRI at UCL, London, United Kingdom
^g Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
^h AbbVie, North Chicago, IL, United States
ⁱ The Foundation for the National Institutes of Health, North Bethesda, MD, United States
^j Neuroscience Biomarkers, Janssen Research and Development LLC, La Jolla, CA, United States
^k AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany
^l Biogen, Cambridge, MA, United States
^m Alzheimer’s Association, Chicago, IL, United States

Abstract
Introduction: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. Methods: Alzheimer’s Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aβ assays. Statistical tests were performed to determine whether the plasma Aβ measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. Results: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P <.05, uncorrected for multiple comparisons). Discussion: Measurement of Aβ in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. Highlights: The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aβ) assays using Alzheimer’s Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aβ42/40 predicted amyloid positron emission tomography status better than Aβ42 or Aβ40 alone. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  Alzheimer’s Disease Neuroimaging Initiative;  amyloid;  amyloid beta 40;  amyloid beta 42;  amyloid positron emission tomography;  amyloid prediction;  biomarkers;  plasma

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
Foundation for the National Institutes of HealthFNIH
National Institute on AgingNIAP30 AG010124, U19 AG024904
National Institute of Biomedical Imaging and BioengineeringNIBIB
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAA
Biogen
AbbVie
Alzheimer’s Disease Neuroimaging InitiativeADNI
Takeda Pharmaceuticals U.S.A.TPUSA
BioClinica

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

Progressive White Matter Injury in Preclinical Dutch Cerebral Amyloid Angiopathy
(2022) Annals of Neurology, . 

Shirzadi, Z.^a , Yau, W.-Y.W.^a , Schultz, S.A.^a , Schultz, A.P.^a , Scott, M.R.^a , Goubran, M.^b , Mojiri-Forooshani, P.^b , Joseph-Mathurin, N.^c , Kantarci, K.^d , Preboske, G.^d , Wermer, M.J.H.^e , Jack, C.^d , Benzinger, T.^c , Taddei, K.^f , Sohrabi, H.R.^g , Sperling, R.A.^a , Johnson, K.A.^a , Bateman, R.J.^c , Martins, R.N.^f , Greenberg, S.M.^a , Chhatwal, J.P.^a , DIAN Investigators^h

^a Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^b Physical Sciences Platform and Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Radiology, Mayo Clinic, Rochester, MN, United States
^e Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands
^f Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
^g Centre for Healthy Ageing, Health Future Institute, Murdoch University, Murdoch, WA, Australia

Abstract
Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage. These results indicate that white matter disruption measures may be valuable cross-sectional and longitudinal biomarkers of D-CAA progression. ANN NEUROL 2022. © 2022 American Neurological Association.

Funding details
National Institutes of HealthNIHP41EB015896, S10RR021110, S10RR023043, S10RR023401
National Institute on AgingNIAK23AG049087, P01AG036694, UF1AG032438
National Institute of Neurological Disorders and StrokeNINDSR01NS070834
National Institute of Biomedical Imaging and BioengineeringNIBIB
Massachusetts General HospitalMGH
Alzheimer Society
National Health and Medical Research CouncilNHMRCAPP1129627

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

Carotid Intima-Media Thickness and Amyloid-β Deposition: The ARIC-PET Study
(2022) Journal of Alzheimer’s Disease, 88 (1), pp. 17-22. 

Wang, W.^a , Gottesman, R.F.^b , Meyer, M.L.^c , Hughes, T.M.^d , Sullivan, K.J.^e , Wong, D.F.^f g h i , Lakshminarayan, K.^a j , Lutsey, P.L.^a

^a Division of Epidemiology and Community Health, University of Minnesota, 1300 S 2nd Street, Minneapolis, MN 55454, United States
^b Stroke Branch, National Institute of Neurological Disorders and Stroke Intramural Research Program, Bethesda, MD, United States
^c Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^d Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
^e Department of Medicine: the Mind Center, University of Mississippi Medical Center, Jackson, MS, United States
^f Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^j Department of Neurology, University of Minnesota, Minneapolis, MN, United States

Abstract
We assessed whether carotid intima-media thickness (cIMT) is prospectively associated with amyloid-β (Aβ). 332 nondemented Atherosclerosis Risk in Communities Study participants with carotid ultrasounds (1990-1992) and PET scans (2012-2014) were studied. Participants in the highest (versus lowest) cIMT tertile had 2.17 times the odds of elevated Aβ (95% CI: 1.15-4.11), after demographic and APOE ϵ4 adjustments. An interaction with APOE ϵ4 was observed (p = 0.02). Greater cIMT was associated with elevated Aβ independent of vascular risk factors among those with ≥1 APOE ϵ4 allele, but not in noncarriers. In this cohort, higher cIMT was associated with Aβ deposition 22 years later, particularly among APOE ϵ4 carriers. © 2022-IOS Press. All rights reserved.

Author Keywords
Alzheimer’s disease;  amyloid-β;  carotid intima-media thickness;  carotid ultrasound;  florbetapir PET

Funding details
National Institute on AgingNIAR01AG040282
National Heart, Lung, and Blood InstituteNHLBIR01-HL70825
National Institute of General Medical SciencesNIGMSK24HL159246, T32GM132063

Document Type: Article
Publication Stage: Final
Source: Scopus

Progression to Loss of Ambulation Among Patients with Autosomal Recessive Limb-girdle Muscular Dystrophy: A Systematic Review
(2022) Journal of Neuromuscular Diseases, 9 (4), pp. 477-492. 

Audhya, I.F.^a , Cheung, A.^b , Szabo, S.M.^b , Flint, E.^b , Weihl, C.C.^c , Gooch, K.L.^a

^a Sarepta Therapeutics Inc, Cambridge, MA, United States
^b Broadstreet Heor, Vancouver, BC V6A 1A4, Canada
^c Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background The impact of age at autosomal recessive limb girdle muscular dystrophy (LGMDR) onset on progression to loss of ambulation (LOA) has not been well established, particularly by subtype. Objectives: To describe the characteristics of patients with adult-, late childhood-, and early childhood-onset LGMDR by subtype and characterize the frequency and timing of LOA. Methods: A systematic review was conducted in MEDLINE, Embase and the Cochrane library. Frequency and timing of LOA in patients with LGMDR1, LGMDR2/Miyoshi myopathy (MM), LGMDR3-6, LGMDR9, and LGMDR12 were synthesized from published data. Results: In 195 studies, 695 (43.4%) patients had adult-, 532 (33.2%) had late childhood-, and 376 (23.5%) had early childhood-onset of disease across subtypes among those with a reported age at onset (n = 1,603); distribution of age at onset varied between subtypes. Among patients with LOA (n = 228), adult-onset disease was uncommon in LGMDR3-6 (14%) and frequent in LGMDR2/MM (42%); LGMDR3-6 cases with LOA primarily had early childhood-onset (74%). Mean (standard deviation [SD]) time to LOA varied between subtypes and was shortest for patients with early childhood-onset LGMDR9 (12.0 [4.9] years, n = 19) and LGMDR3-6 (12.3 [10.7], n = 56) and longest for those with late childhood-onset LGMDR2/MM (21.4 [11.5], n = 36). Conclusions: This review illustrated that patients with early childhood-onset disease tend to have faster progression to LOA than those with late childhood-or adult-onset disease, particularly in LGMDR9. These findings provide a greater understanding of progression to LOA by LGMDR subtype, which may help inform clinical trial design and provide a basis for natural history studies. © 2022-The authors. Published by IOS Press.

Author Keywords
age of onset;  disease progression;  limb-girdle;  Muscular dystrophies;  systematic review;  walking

Funding details
Sarepta TherapeuticsSRPT

Document Type: Review
Publication Stage: Final
Source: Scopus

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy
(2022) Journal of Neuromuscular Diseases, 9 (4), pp. 493-501. 

Clemens, P.R.^a b , Rao, V.K.^c , Connolly, A.M.^d , Harper, A.D.^e , Mah, J.K.^f , McDonald, C.M.^g , Smith, E.C.^h , Zaidman, C.M.ⁱ , Nakagawa, T.^j , Hoffman, E.P.^k

^a Department of Neurology, University of Pittsburgh School of Medicine, 3550 Terrace St, Pittsburgh, PA 15261, United States
^b Department of Veterans Affairs Medical Center, Pittsburgh, PA, United States
^c Division of Neurology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
^d Division of Neurology, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
^e Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA, United States
^f Department of Pediatrics, University of Calgary, Calgary, AB, Canada
^g Department of Physical Medicine and Rehabilitation, Department of Pediatrics, Uc Davis Health, University of California, Davis, CA, United States
^h Duke University Medical Center, Durham, NC, United States
ⁱ Department of Neurology, Washington University at St Louis, St Louis, MO, United States
^j Ns Pharma, Inc, Paramus, NJ, United States
^k Department of Pharmaceutical Sciences, State University of New York at Binghamton, Binghamton, NY, United States

Abstract
Background: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group. Objective: To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy. Methods: This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety. Results: Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations. Conclusions: Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping. © 2022-The authors. Published by IOS Press.

Author Keywords
clinical efficacy;  Duchenne muscular dystrophy;  dystrophin;  exon skipping;  viltepso;  viltolarsen

Funding details
U.S. Department of DefenseDODR01AR061875
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS
U.S. Department of EducationED
Pfizer
Astellas Pharma USAPUS
Novartis
Roche
Biogen
Parent Project Muscular DystrophyPPMD
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRRW81XWH-12-1-0417
Washington University School of Medicine in St. LouisWUSM
PTC TherapeuticsPTC
AveXis
Sarepta TherapeuticsSRPT
Alberta Children’s Hospital Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Early childhood income instability, food insecurity, and adolescents’ behavioral health
(2022) Family Relations, .

Zhang, L.^a , Shimizu, R.^b , Zhang, Y.^c , Simmel, C.^d

^a Brown School, Washington University in St. Louis, St. Louis, MO, United States
^b School of Social Work, University of Alaska Anchorage, Anchorage, AK, United States
^c Grace Abbott School of Social Work, University of Nebraska Omaha, Omaha, NE, United States
^d School of Social Work, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States

Abstract
Objective: This research examines the associations of early childhood income instability with subsequent behavioral outcomes in adolescence, paying attention to the mediating role of food insecurity. Background: Existing research has documented the rise in income instability in recent decades. Yet, few studies have addressed how income instability during early childhood may shape subsequent behavioral health outcomes in adolescence, beyond the effect of income levels. Furthermore, the mechanism underlying the longitudinal link remains unexplored. Method: Structural equation modeling (SEM) was conducted with the Fragile Families and Child Well-being Study, a longitudinal data set following families with children in 20 large cities in the United States (N = 3,422). Results: Independent from average income levels, both incidence and frequency of negative income changes were significantly indirectly associated with higher levels of internalizing and externalizing behaviors in adolescence. Food insecurity operated as a mediator of the association. Conclusion: The results suggest cumulative associations between income instability and children’s behavioral outcomes and the substantial role of food insecurity in linking the two. Implications: Policies and programs need to promote economic stability during early childhood and to ensure food security in nurturing children’s short- and long-term well-being. © 2022 National Council on Family Relations.

Author Keywords
early childhood;  food insecurity;  income instability;  internalizing and externalizing behavior

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

The contribution of behavioral features to caregiver burden in FTLD spectrum disorders
(2021) Alzheimer’s and Dementia, . 

Silverman, H.E.^a , Ake, J.M.^a , Manoochehri, M.^a , Appleby, B.S.^b , Brushaber, D.^c , Devick, K.L.^c , Dickerson, B.C.^d , Fields, J.A.^e , Forsberg, L.K.^f , Ghoshal, N.^g , Graff-Radford, N.R.^h , Grossman, M.ⁱ , Heuer, H.W.^j , Kornak, J.^k , Lapid, M.I.^e , Litvan, I.^l , Mackenzie, I.R.^m , Mendez, M.F.^n o , Onyike, C.U.^p , Pascual, B.^q , Tartaglia, M.C.^r , Boeve, B.F.^f , Boxer, A.L.^j , Rosen, H.J.^j , Cosentino, S.^a , Huey, E.D.^a s , Barker, M.S.^a , Goldman, J.S.^a , the ALLFTD consortium^t

^a Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^b Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
^c Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
^d Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^e Division of Neurocognitive Disorders, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
^f Department of Neurology, Mayo Clinic, Rochester, MN, United States
^g Department of Neurology, Washington University, St. Louis, MO, United States
^h Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
ⁱ Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^j Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
^k Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
^l Department of Neuroscience, University of California, San Diego, San Diego, CA, United States
^m Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
ⁿ Department of Neurology, University of California, Los Angeles, CA, United States
^o Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, United States
^p Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States
^q Stanley H. Appel Department of Neurology, Houston Methodist Hospital, Weill Cornell Medicine, Houston Methodist Neurological and Research Institute, Houston, TX, United States
^r Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
^s Department of Psychiatry and New York Psychiatric Institute, Columbia University Medical Center, New York, United States

Abstract
Introduction: Caregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders. Methods: In a sample of 558 participants with FTLD spectrum disorders, we performed multiple-variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease. Results: Apathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician-rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross-sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia. Discussion: Caregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden. © 2021 the Alzheimer’s Association

Author Keywords
apathy;  behavioral symptoms;  caregiver burden;  dementia;  disinhibition;  frontotemporal dementia;  frontotemporal lobar degeneration;  neurodegeneration

Funding details
National Institutes of HealthNIH1R21NS114764‐01A1, 2R01AG007370, 2R01AG038791‐06A, 5P50AG008702, AG0066597, AG052943, AG054519, AG066418, P20GM109025, R01 AG054131‐Institution U19 AG063911‐Institution R01 AG068260‐Institution, R01 AG054525, R01 MH120794, R01 NS086736, R01AG058918, R01AG064614, R25AG059557, R25NS098999, U01NS090259, U01NS100610, U01NS80818, U19 AG063893, U19 AG063911‐1, U24AG056270
Centers for Disease Control and PreventionCDC
National Institute on AgingNIAU54AG 44170‐8
National Institute of Neurological Disorders and StrokeNINDSR01AG 68128‐1, R43AG 65088‐1, R44AG 65088‐2, RF1AG 57547‐4, U01AG 45390‐5, U01NS 100620‐4, U19AG 63911‐2, U54 NS092089, UH3NS 95495‐4
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAA
National Ataxia FoundationNAF
Association for Frontotemporal DegenerationAFTD
Roche
New York State Department of HealthNYSDOHRFA #1510130358
Biogen
National Center for Advancing Translational SciencesNCATSU01 AG045390
AbbVie
Wyncote Foundation
Parkinson’s FoundationPF
Huntington’s Disease Society of AmericaHDSA
Rainwater Charitable FoundationRCF

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