WashU weekly Neuroscience publications: March 24, 2024 | Office of Neuroscience Research

“CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods” (2024) Genome Biology

CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods
(2024) Genome Biology, 25 (1), art. no. 53, .

Jain, S.^a , Bakolitsa, C.^b , Brenner, S.E.^b , Radivojac, P.^a ^c , Moult, J.^d , Repo, S.^b , Hoskins, R.A.^b , Andreoletti, G.^b , Barsky, D.^b , Chellapan, A.^e , Chu, H.^a ^f ^g , Dabbiru, N.^e , Kollipara, N.K.^e , Ly, M.^b , Neumann, A.J.^b , Pal, L.R.^d , Odell, E.^b , Pandey, G.^b ^h , Peters-Petrulewicz, R.C.^b , Srinivasan, R.^e , Yee, S.F.^b , Yeleswarapu, S.J.^e , Zuhl, M.^d ⁱ , Adebali, O.^j ^k , Patra, A.^l ^m , Beer, M.A.^l , Hosur, R.ⁿ ^o , Peng, J.ⁿ , Bernard, B.M.^p ^q , Berry, M.^j , Dong, S.^r , Boyle, A.P.^r , Adhikari, A.^b ^s , Chen, J.^b ^t , Hu, Z.^b , Wang, R.^b ^u , Wang, Y.^b ^t , Miller, M.^v , Wang, Y.^v ^w , Bromberg, Y.^v , Turina, P.^x , Capriotti, E.^x , Han, J.J.^y , Ozturk, K.^y , Carter, H.^y , Babbi, G.^x , Bovo, S.^x , Di Lena, P.^x , Martelli, P.L.^x , Savojardo, C.^x , Casadio, R.^x , Cline, M.S.^z , De Baets, G.^aa , Bonache, S.^ab ^ac , Díez, O.^ab ^ad , Gutiérrez-Enríquez, S.^ab , Fernández, A.^ab ^ad , Montalban, G.^ab ^ae , Ootes, L.^ab , Özkan, S.^ab , Padilla, N.^ab , Riera, C.^ab , De la Cruz, X.^ab , Diekhans, M.^z , Huwe, P.J.^af ^ag , Wei, Q.^af ^ah , Xu, Q.^af , Dunbrack, R.L.^af , Gotea, V.^ai , Elnitski, L.^ai , Margolin, G.^ai , Fariselli, P.^aj ^ak , Kulakovskiy, I.V.^al ^am , Makeev, V.J.^al , Penzar, D.D.^al ^an , Vorontsov, I.E.^al ^am , Favorov, A.V.^l ^al , Forman, J.R.^ao ^ap , Hasenahuer, M.^aq ^ar , Fornasari, M.S.^aq , Parisi, G.^aq , Avsec, Z.^as , Çelik, M.H.^as ^at , Nguyen, T.Y.D.^as , Gagneur, J.^as , Shi, F.-Y.^au , Edwards, M.D.ⁿ ^av , Guo, Y.ⁿ ^aw , Tian, K.ⁿ ^ax , Zeng, H.ⁿ ^ay , Gifford, D.K.ⁿ , Göke, J.^az , Zaucha, J.^ba ^bb , Gough, J.^bc , Ritchie, G.R.S.^ar ^bd , Frankish, A.^ar ^be , Mudge, J.M.^ar ^be , Harrow, J.^be ^bf , Young, E.L.^bg , Yu, Y.^bh , Huff, C.D.^bh , Murakami, K.^bi ^bj , Nagai, Y.^bi ^bk , Imanishi, T.^bi ^bl , Mungall, C.J.^bm , Jacobsen, J.O.B.^be ^bn , Kim, D.^bo , Jeong, C.-S.^bo ^bp , Jones, D.T.^bq , Li, M.J.^br ^bs , Guthrie, V.B.^l ^bb , Bhattacharya, R.^l ^bt , Chen, Y.-C.^l ^bu , Douville, C.^l , Fan, J.^l , Kim, D.^g ^l , Masica, D.^l , Niknafs, N.^l , Sengupta, S.^l ^bv , Tokheim, C.^f ^l ^bw , Turner, T.N.^l ^bx , Yeo, H.T.G.^l ^az , Karchin, R.^l , Shin, S.^by , Welch, R.^bz , Keles, S.^bz , Li, Y.ⁿ ^ca , Kellis, M.^g ⁿ , Corbi-Verge, C.^cb ^cc , Strokach, A.V.^cb , Kim, P.M.^cb , Klein, T.E.^ax , Mohan, R.^cd ^ce , Sinnott-Armstrong, N.A.^ax , Wainberg, M.^cd ^cf , Kundaje, A.^ax , Gonzaludo, N.^cg ^ch , Mak, A.C.Y.^cg ^ci , Chhibber, A.^cj ^ck , Lam, H.Y.K.^cj ^cl , Dahary, D.^cm , Fishilevich, S.^cn , Lancet, D.^cn , Lee, I.^co , Bachman, B.^cp , Katsonis, P.^cp , Lua, R.C.^cp , Wilson, S.J.^cp ^cq , Lichtarge, O.^cp , Bhat, R.R.^cr , Sundaram, L.^ax , Viswanath, V.^cr , Bellazzi, R.^cs , Nicora, G.^cs ^ct , Rizzo, E.^ct , Limongelli, I.^ct , Mezlini, A.M.^cb , Chang, R.^cu , Kim, S.^cu , Lai, C.^cu , O’Connor, R.^cu ^cv , Topper, S.^cu , van den Akker, J.^cu , Zhou, A.Y.^cu , Zimmer, A.D.^cu , Mishne, G.^cu , Bergquist, T.R.^cw ^cx , Breese, M.R.^cg ^cy , Guerrero, R.F.^c ^cz , Jiang, Y.^c , Kiga, N.^cw , Li, B.^cy ^da , Mort, M.^cy ^db , Pagel, K.A.^c , Pejaver, V.^h ^cw , Stamboulian, M.H.^c , Thusberg, J.^cy , Mooney, S.D.^cw , Teerakulkittipong, N.^d ^dc , Cao, C.^d ^dd , Kundu, K.^d ^de , Yin, Y.^d , Yu, C.-H.^d , Kleyman, M.^d ^df , Lin, C.-F.^u ^dg , Stackpole, M.^d ^dh , Mount, S.M.^d , Eraslan, G.^g ^di , Mueller, N.S.^di , Naito, T.^dj , Rao, A.R.^ae , Azaria, J.R.^dk ^dl , Brodie, A.^dk , Ofran, Y.^dk , Garg, A.^dm , Pal, D.^dm , Hawkins-Hooker, A.^ao ^bq , Kenlay, H.^ao ^dn , Reid, J.^ao ^do , Mucaki, E.J.^dp , Rogan, P.K.^dp , Schwarz, J.M.^dq , Searls, D.B.^dr , Lee, G.R.^cw ^ds , Seok, C.^ds , Krämer, A.^dt , Shah, S.^dt ^du , Huang, C.V.^b ^dv , Kirsch, J.F.^b , Shatsky, M.^bm , Cao, Y.^dw , Chen, H.^dw ^dx , Karimi, M.^dv ^dw , Moronfoye, O.^dw , Sun, Y.^dw , Shen, Y.^dw , Shigeta, R.^dy ^dz , Ford, C.T.^ea , Nodzak, C.^ea , Uppal, A.^ea ^eb , Shi, X.^ea ^ec , Joseph, T.^e , Kotte, S.^e , Rana, S.^e , Rao, A.^e , Saipradeep, V.G.^e , Sivadasan, N.^e , Sunderam, U.^e , Stanke, M.^ed , Su, A.^ee , Adzhubey, I.^ef ^eg , Jordan, D.M.^h ^eh , Sunyaev, S.^eh , Rousseau, F.^aa , Schymkowitz, J.^aa , Van Durme, J.^aa , Tavtigian, S.V.^bg , Carraro, M.^aj , Giollo, M.^aj ^dv , Tosatto, S.C.E.^aj , Adato, O.^dk , Carmel, L.^ei , Cohen, N.E.^ei ^ej , Fenesh, T.^dk , Holtzer, T.^dk , Juven-Gershon, T.^dk , Unger, R.^dk , Niroula, A.^ek , Olatubosun, A.^el , Väliaho, J.^el , Yang, Y.^em , Vihinen, M.^ek ^el , Wahl, M.E.^ah ^eh , Chang, B.^en , Chong, K.C.^en , Hu, I.^eo ^ep , Sun, R.^en ^eq , Wu, W.K.K.^en , Xia, X.^en , Zee, B.C.^en , Wang, M.H.^en , Wang, M.^au , Wu, C.^ee , Lu, Y.^eq , Chen, K.^eq , Yang, Y.^er ^et , Yates, C.M.^eu ^ev , Kreimer, A.^b ^v , Yan, Z.^b ⁿ , Yosef, N.^b , Zhao, H.^et , Wei, Z.^ew , Yao, Z.^ex , Zhou, F.^ew , Folkman, L.^es ^ey , Zhou, Y.^es ^ez , Daneshjou, R.^ax , Altman, R.B.^ax , Inoue, F.^cg ^fa , Ahituv, N.^cg , Arkin, A.P.^b , Lovisa, F.^aj ^fb , Bonvini, P.^aj ^fb , Bowdin, S.^fc , Gianni, S.^fd , Mantuano, E.^fe , Minicozzi, V.^ff , Novak, L.^fd , Pasquo, A.^fg , Pastore, A.^fh , Petrosino, M.^fi ^fj , Puglisi, R.^ap , Toto, A.^fd , Veneziano, L.^fe , Chiaraluce, R.^fi , Ball, M.P.^eh ^fk , Bobe, J.R.^eh ^fl , Church, G.M.^eh , Consalvi, V.^fd , Cooper, D.N.^db , Buckley, B.A.^du , Sheridan, M.B.^fm , Cutting, G.R.^fm , Scaini, M.C.^fn , Cygan, K.J.^de ^fo , Fredericks, A.M.^fo , Glidden, D.T.^fo , Neil, C.^fo ^fp , Rhine, C.L.^fo ^fp , Fairbrother, W.G.^fo , Alontaga, A.Y.^fq , Fenton, A.W.^fq , Matreyek, K.A.^cw ^fr , Starita, L.M.^cw , Fowler, D.M.^cw , Löscher, B.-S.^fs , Franke, A.^ft , Adamson, S.I.^fu , Graveley, B.R.^fu , Gray, J.W.^fv , Malloy, M.J.^cg , Kane, J.P.^cg , Kousi, M.^fw , Katsanis, N.^fx ^fy , Schubach, M.^dq , Kircher, M.^dq , Mak, A.C.Y.^cg ^ci , Tang, P.L.F.^cg ^fz , Kwok, P.-Y.^cg , Lathrop, R.H.^at , Clark, W.T.^ga , Yu, G.K.^ga ^gb , LeBowitz, J.H.^ga , Benedicenti, F.^gc , Bettella, E.^aj , Bigoni, S.^gd , Cesca, F.^aj , Mammi, I.^ge , Marino-Buslje, C.^gf , Milani, D.^gg , Peron, A.^gh ^gi , Polli, R.^aj , Sartori, S.^aj ^fb , Stanzial, F.^gc , Toldo, I.^aj , Turolla, L.^gj , Aspromonte, M.C.^aj , Bellini, M.^aj , Leonardi, E.^aj , Liu, X.^gk ^gl , Marshall, C.^cb , McCombie, W.R.^gm , Elefanti, L.^fn , Menin, C.^fn , Meyn, M.S.^bz ^gn , Murgia, A.^aj , Nadeau, K.C.Y.^ax , Neuhausen, S.L.^go , Nussbaum, R.L.^du , Pirooznia, M.^bu ^gp , Potash, J.B.^fm , Dimster-Denk, D.F.^b , Rine, J.D.^b , Sanford, J.R.^z , Snyder, M.^ax , Cote, A.G.^cb ^gq , Sun, S.^cb ^gq , Verby, M.W.^cb ^gq , Weile, J.^cb ^gq , Roth, F.P.^cb ^gq , Tewhey, R.^gr , Sabeti, P.C.^g , Campagna, J.^cg , Refaat, M.M.^cg ^gs , Wojciak, J.^cg , Grubb, S.^gt , Schmitt, N.^gt , Shendure, J.^cw , Spurdle, A.B.^gu , Stavropoulos, D.J.^cb , Walton, N.A.^gv ^gw , Zandi, P.P.^fm , Ziv, E.^cg , Burke, W.^cw , Chen, F.^cg ^eh , Carr, L.R.^dr , Martinez, S.^dr , Paik, J.^dr , Harris-Wai, J.^cg , Yarborough, M.^gx , Fullerton, S.M.^gy , Koenig, B.A.^cg , McInnes, G.^ax ^gz , Shigaki, D.^l , Chandonia, J.-M.^b ^bm , Furutsuki, M.^b , Kasak, L.^b ^ha , Yu, C.^b ^hb , Chen, R.^ax ^cj , Friedberg, I.^hc , Getz, G.A.^g ^eg ^hd , Cong, Q.^he , Kinch, L.N.^he , Zhang, J.^he , Grishin, N.V.^he , Voskanian, A.^hf , Kann, M.G.^hf , Tran, E.^cd , Ioannidis, N.M.^b , Hunter, J.M.^bz ^hg , Udani, R.^bz ^hh , Cai, B.^cw , Morgan, A.A.^ax ^hi , Sokolov, A.^z ^eg , Stuart, J.M.^z , Minervini, G.^aj , Monzon, A.M.^aj , Batzoglou, S.^s ^hj , Butte, A.J.^cg , Greenblatt, M.S.^hk , Hart, R.K.^hl , Hernandez, R.^ca ^cg , Hubbard, T.J.P.^ap , Kahn, S.^s ^hm , O’Donnell-Luria, A.^g , Ng, P.C.^az , Shon, J.^s ^hn , Veltman, J.^ho , Zook, J.M.^hp , The Critical Assessment of Genome Interpretation Consortium^hq

^a Northeastern University, Boston, MA, United States
^b University of California, Berkeley, CA, United States
^c Indiana University, Bloomington, IN, United States
^d University of Maryland, College Park, MD, United States
^e Tata Consultancy Services, Hyderabad, India
^f Dana-Farber Cancer Institute, Boston, MA, United States
^g Broad Institute of MIT and Harvard, Cambridge, MA, United States
^h Icahn School of Medicine at Mount Sinai, New York City, NY, United States
ⁱ ICF International, Cambridge, MA, United States
^j University of Tennessee, Knoxville, TN, United States
^k Sabanci University, Tuzla, Turkey
^l Johns Hopkins University, Baltimore, MD, United States
^m Intel Corporation, Santa Clara, CA, United States
ⁿ Massachusetts Institute of Technology, Cambridge, MA, United States
^o Encoded Genomics, South San Francisco, CA, United States
^p Institute for Systems Biology, Seattle, WA, United States
^q Earle A. Chiles Research Institute, Providence Health & Services, Portland, OR, United States
^r University of Michigan, Ann Arbor, MI, United States
^s Illumina, San Diego, CA, United States
^t Fudan University, Shanghai, China
^u University of Pennsylvania, Philadelphia, PA, United States
^v Rutgers University, New Brunswick, NJ, United States
^w Genentech, South San Francisco, CA, United States
^x University of Bologna, Bologna, Italy
^y University of California at San Diego, San Diego, CA, United States
^z University of California at Santa Cruz, Bologna, CA, United States
^aa Katholieke Universiteit Leuven, Leuven, Belgium
^ab Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
^ac Germans Trias i Pujol Hospital, Badalona, Spain
^ad University Hospital of Vall d’Hebron, Barcelona, Spain
^ae Université Laval, Québec, QC, Canada
^af Fox Chase Cancer Center, Philadelphia, PA, United States
^ag Belmont University, Nashville, TN, United States
^ah Microsoft, Redmond, WA, United States
^ai National Human Genome Research Institute, Bethesda, MD, United States
^aj University of Padova, Padova, Italy
^ak University of Turin, Turin, Italy
^al Vavilov Institute of General Genetics, Moscow, Russian Federation
^am Institute of Protein Research, Pushchino, Russian Federation
^an Lomonosov Moscow State University, Moscow, Russian Federation
^ao University of Cambridge, Cambridge, United Kingdom
^ap King’s College, London, United Kingdom
^aq Universidad Nacional de Quilmes, Bernal, Argentina
^ar European Molecular Biology Laboratory—European Bioinformatics Institute, Hinxton, United Kingdom
^as Technical University of Munich, Munich, Germany
^at University of California at Irvine, Irvine, CA, United States
^au Peking University, Beijing, China
^av Verily Life Sciences, South San Francisco, CA, United States
^aw CAMP4 Therapeutics, Cambridge, MA, United States
^ax Stanford University, Stanford, CA, United States
^ay Insitro, South San Francisco, CA, United States
^az Genome Institute of Singapore, Singapore
^ba University of Bristol, Bristol, United Kingdom
^bb AstraZeneca, Cambridge, United Kingdom
^bc MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
^bd Amazon Web Services, Seattle, WA, United States
^be Wellcome Sanger Institute, Hinxton, United Kingdom
^bf ELIXIR, Hinxton, United Kingdom
^bg University of Utah, Salt Lake City, UT, United States
^bh University of Texas MD Anderson Cancer Center, Houston, TX, United States
^bi National Institute of Advanced Industrial Science and Technology, Tokyo, Japan
^bj Fujitsu Ltd., Tokyo, Japan
^bk Varinos Inc., Tokyo, Japan
^bl Tokai University School of Medicine, Tokyo, Japan
^bm Lawrence Berkeley National Laboratory, Berkeley, CA, United States
^bn Queen Mary University, London, United Kingdom
^bo Korea Advanced Institute of Science and Technology, Daejeon, South Korea
^bp Korea Institute of Science and Technology Information, Daejeon, South Korea
^bq University College, London, United Kingdom
^br University of Hong Kong, Hong Kong
^bs Tianjin Medical University, Tianjin, China
^bt Williams College, Williamstown, MA, United States
^bu Johnson & Johnson, New Brunswick, NJ, United States
^bv PierianDx, Creve Coeur, MO, United States
^bw Harvard T. H. Chan School of Public Health, Boston, MA, United States
^bx Washington University School of Medicine, St. Louis, MO, United States
^by Pohang University of Science and Technology, Pohang, South Korea
^bz University of Wisconsin-Madison, Madison, WI, United States
^ca McGill University, Montreal, Canada
^cb University of Toronto, Toronto, ON, Canada
^cc Cyclica Inc., Toronto, ON, Canada
^cd Stanford University School of Medicine, Stanford, CA, United States
^ce Dashworks, Boston, MA, United States
^cf Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada
^cg University of California at San Francisco, San Francisco, CA, United States
^ch Pacific Biosciences, Menlo Park, CA, United States
^ci CytomX Therapeutics, South San Francisco, CA, United States
^cj Roche, Basel, Switzerland
^ck Bristol Myers Squibb, Redwood City, CA, United States
^cl HypaHub, Sunnyvale, CA, United States
^cm LifeMap Sciences Inc., Alameda, CA, United States
^cn Weizmann Institute, Rehovot, Israel
^co Yonsei University, Seoul, South Korea
^cp Baylor College of Medicine, Houston, TX, United States
^cq Calm, San Francisco, CA, United States
^cr University of Florida, Gainesville, FL, United States
^cs University of Pavia, Pavia, Italy
^ct enGenome, Pavia, Italy
^cu Color Genomics, Burlingame, CA, United States
^cv Syapse, San Francisco, CA, United States
^cw University of Washington, Seattle, WA, United States
^cx Sage Bionetworks, Seattle, WA, United States
^cy Buck Institute for Research on Aging, Novato, CA, United States
^cz North Carolina State University, Raleigh, NC, United States
^da Gilead, Foster City, CA, United States
^db Institute of Medical Genetics, Cardiff University, Cardiff, United Kingdom
^dc Burapha University, Chonburi, Thailand
^dd Google LLC, Mountain View, CA, United States
^de Regeneron, Tarrytown, NY, United States
^df Moderna, Cambridge, MA, United States
^dg DNANexus, Mountain View, CA, United States
^dh EarlyDiagnostics, Los Angeles, CA, United States
^di Helmholtz Zentrum Muenchen, Neuherberg, Germany
^dj University of Tokyo, Tokyo, Japan
^dk Bar-Ilan University, Ramat-Gan, Israel
^dl Imperva, San Mateo, CA, United States
^dm Indian Institute of Science, Bengaluru, India
^dn University of Oxford, Oxford, United Kingdom
^do Blue Prism, Warrington, United Kingdom
^dp University of Western Ontario, London, ON, Canada
^dq Charité—Universitätsmedizin Berlin, Berlin, Germany
^ds Seoul National University, Seoul, South Korea
^dt Qiagen, Germantown, MD, United States
^du Invitae, San Francisco, CA, United States
^dv Amazon, Seattle, WA, United States
^dw Texas A&M University, College Station, TX, United States
^dx Carnegie Mellon University, Pittsburgh, PA, United States
^dy IndieBio, San Francisco, CA, United States
^dz iAccelerate, North Wollongong, Australia
^ea University of North Carolina at Charlotte, Charlotte, NC, United States
^eb Vindara, Orlando, FL, United States
^ec Temple University, Philadelphia, PA, United States
^ed University of Greifswald, Greifswald, Germany
^ee Scripps Research Institute, San Diego, CA, United States
^ef Brigham and Women’s Hospital, Boston, MA, United States
^eg Harvard Medical School, Boston, MA, United States
^eh Harvard University, Cambridge, MA, United States
^ei Hebrew University of Jerusalem, Jerusalem, Israel
^ej School of Software Engineering and Computer Science, Azrieli College of Engineering, Jerusalem, Israel
^ek Lund University, Lund, Sweden
^el University of Tampere, Tampere, Finland
^em Soochow University, Suzhou, China
^en Chinese University of Hong Kong, Hong Kong
^eo Hong Kong University of Science and Technology, Hong Kong
^ep George Mason UniversityVA, United States
^eq Sun Yat-sen University, Guangzhou, China
^er Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States
^es Griffith UniversityQLD, Australia
^et Sun Yat-sen Memorial Hospital, Guangzhou, China
^eu Imperial College, London, United Kingdom
^ev Vertex Pharmaceuticals, Boston, MA, United States
^ew Jilin University, Changchun, China
^ex Northeastern University, China
^ey CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
^ez Shenzhen Bay Laboratory, Shenzhen, China
^fa Kyoto University, Kyoto, Japan
^fb Paediatric Research Institute Città della Speranza, Padova, Italy
^fc Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom
^fd Sapienza University of Rome, Rome, Italy
^fe Institute of Translational Pharmacology CNR, Rome, Italy
^ff University of Rome Tor Vergata, Rome, Italy
^fg ENEA—Frascati Research Centre, Rome, Italy
^fh Crick Institute, London, United Kingdom
^fi University of Rome, Rome, Italy
^fj University of Fribourg, Fribourg, Switzerland
^fk Open Humans Foundation, Sanford, NC, United States
^fl PersonalGenomes.org, Sanford, NC, United States
^fm Johns Hopkins University School of Medicine, Baltimore, MD, United States
^fn Veneto Institute of Oncology, San Giovanni Rotondo, Italy
^fo Brown University, Providence, RI, United States
^fp Remix Therapeutics, Cambridge, MA, United States
^fq University of Kansas Medical Center, Kansas City, KS, United States
^fr Case Western Reserve University, Cleveland, OH, United States
^fs Kiel University, Kiel, Germany
^ft Christian-Albrechts-University of Kiel, Kiel, Germany
^fu UConn Health, Farmington, CT, United States
^fv Oregon Health and Science University, Portland, OR, United States
^fw Third Rock Ventures, Boston, MA, United States
^fx Northwestern University, Evanston, IL, United States
^fy Rescindo Therapeutics Inc., Durham, NC, United States
^fz AccuraGen Inc., Menlo Park, CA, United States
^ga BioMarin, Novato, CA, United States
^gb Global Blood Therapeutics, South San Francisco, CA, United States
^gc Regional Hospital of Bolzano, Bolzano, Italy
^gd Ferrara University Hospital, Ferrara, Italy
^ge Mirano Hospital, Venice, Italy
^gf Fundacion Instituto Leloir, Buenos Aires, Argentina
^gg Milan Polyclinic, Milan, Italy
^gh University of Milan, Milan, Italy
^gi University of Utah School of Medicine, Salt Lake City, UT, United States
^gj AULSS 2 Marca Trevigiana, Treviso, Italy
^gk School of Public Health, University of Texas, Dallas, TX, United States
^gl University of South Florida, Tampa, FL, United States
^gm Cold Spring Harbor Laboratory, Cold Spring HarborNY, United States
^gn Hospital for Sick Children, Toronto, ON, Canada
^go Beckman Research Institute of City of Hope, Duarte, CA, United States
^gp National Institutes of Health, Bethesda, MD, United States
^gq Mount Sinai Health System, New York City, NY, United States
^gr Jackson Laboratory, Bar Harbor, ME, United States
^gs American University of Beirut Medical Center, Beirut, Lebanon
^gt University of Copenhagen, Copenhagen, Denmark
^gu QIMR Berghofer Medical Research Institute, Brisbane, Australia
^gv Geisinger Genomic Medicine Institute, Danville, PA, United States
^gw Intermountain Healthcare Precision Genomics, St. George, UT, United States
^gx University of California at Davis, Davis, CA, United States
^gy University of Washington School of Medicine, Seattle, WA, United States
^gz Empirico Inc., San Diego, CA, United States
^ha University of Tartu, Tartu, Estonia
^hb California Institute of Technology, Pasadena, CA, United States
^hc Iowa State University, Ames, IA, United States
^hd Massachusetts General Hospital, Boston, MA, United States
^he University of Texas Southwestern Medical Center, Dallas, TX, United States
^hf University of Maryland, Baltimore County, Baltimore, MD, United States
^hg Nationwide Children’s Hospital, Columbus, OH, United States
^hh Sema4, Stamford, CT, United States
^hi Khosla Ventures, Menlo Park, CA, United States
^hj Seer.bio, Redwood City, CA, United States
^hk University of Vermont, Burlington, VT, United States
^hl MyOme Inc, Palo Alto, CA, United States
^hm LunaPBC, San Diego, CA, United States
^hn SerImmune, Goleta, CA, United States
^ho Newcastle University, Newcastle upon Tyne, United Kingdom
^hp National Institute of Standards and Technology, Portland, OR, United States

Abstract
Background: The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors. Results: Performance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic. Conclusions: Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead. © The Author(s) 2024.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Serum soluble alpha-klotho klotho and cognitive functioning in older adults aged 60 and 79: an analysis of cross-sectional data of the National Health and Nutrition Examination Survey 2011 to 2014” (2024) BMC Geriatrics

Serum soluble alpha-klotho klotho and cognitive functioning in older adults aged 60 and 79: an analysis of cross-sectional data of the National Health and Nutrition Examination Survey 2011 to 2014
(2024) BMC Geriatrics, 24 (1), art. no. 245, .

Ge, S.^a , Dong, F.^b , Tian, C.^c , Yang, C.-H.^d , Liu, M.^e , Wei, J.^f

^a College of Sciences and Technology, University of Houston-Downtown, Houston, TX, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
^d Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC, United States
^e School of Nursing, Ningxia Medical University, No. 1160, Shengli Street, Xingqing District, Ningxia, Yinchuan, 410013, China
^f Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, United States

Abstract
Objectives: Klotho, consisting of membrane klotho and soluble alpha-klotho, is found to be associated with better cognitive outcomes in small samples of the aged population. We aimed to examine the association of serum soluble alpha-klotho with cognitive functioning among older adults using a nationally representative sample of U.S. older adults. Method: A total of 2,173 U.S. older adults aged 60–79 years in the National Health and Nutrition Examination Survey from 2011 to 2014 were included in this cross-sectional analysis. Serum soluble alpha-klotho was measured in the laboratory and analyzed with an ELISA kit. Cognitive function was measured using the Consortium to Establish a Registry for Alzheimer’s Disease Word Learning subtest (CERAD-WL) immediate and delayed memory, the Animal fluency test (AFT), and the Digit Symbol Substitution Test (DSST). Test-specific and global cognition z-scores were calculated based on sample means and standard deviations. Multivariable linear regression models were applied to examine the association of quartiles and continuous value of serum soluble alpha-klotho with test-specific and global cognition z-scores. Subgroup analysis was conducted by sex. The following covariates were included in the analysis- age, sex, race/ethnicity, education, depressive symptoms, smoking status, body mass index (BMI), physical activity, stroke, prevalent coronary heart disease, total cholesterol, and systolic blood pressure. All the information was self-reported or obtained from health exams. Results: Serum soluble alpha-klotho level in the lowest quartile was associated with lower z-scores for DSST (beta [β] =-0.13, 95% confidence interval [CI]: -0.25, -0.01). For subgroup analysis, serum soluble alpha-klotho level in the lowest quartile was associated with lower z-scores for DSST (β=-0.16, 95% CI: -0.32, -0.003) and global cognition (β=-0.14, 95% CI: -0.28, -0.01) among female participants. No association was found between continuous serum soluble alpha-klotho and cognitive functioning among the participants. Conclusions: Lower serum soluble alpha-klotho quartile was associated with poorer cognitive functioning among older women. Future studies are expected to examine the longitudinal association between klotho levels and cognitive outcomes. © The Author(s) 2024.

Author Keywords
Alpha-klotho; Cognitive function; Klotho; NHANES; Older adults

Document Type: Article
Publication Stage: Final
Source: Scopus

“Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson’s disease” (2024) Acta Neuropathologica

Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson’s disease
(2024) Acta Neuropathologica, 147 (1), art. no. 52, .

Rutledge, J.^a ^b , Lehallier, B.^b , Zarifkar, P.^b ^e , Losada, P.M.^b ^f , Shahid-Besanti, M.^b , Western, D.^c ^d , Gorijala, P.^c ^d , Ryman, S.^b ^g , Yutsis, M.^b , Deutsch, G.K.^b , Mormino, E.^b , Trelle, A.^h , Wagner, A.D.^f ^h , Kerchner, G.A.^b ⁱ , Tian, L.^j , Cruchaga, C.^c ^d , Henderson, V.W.^b ^k , Montine, T.J.^l , Borghammer, P.^m , Wyss-Coray, T.^b ^f ⁿ , Poston, K.L.^b ^f ⁿ ^o

^a Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
^b Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
^c Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^d NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
^f Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, United States
^g Translational Neuroscience, Mind Research Network, Albuquerque, NM, United States
^h Department of Psychology, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
ⁱ Roche Medical, Basel, Switzerland
^j Department of Biomedical Data Science, Stanford University School of Humanities and Sciences, Stanford University, Stanford, CA, United States
^k Department of Epidemiology and Population Health, Stanford University, Stanford, CA, United States
^l Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
^m Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
ⁿ The Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, United States
^o Department of Neurosurgery, Stanford University School of Medicine, Stanford University, Stanford, CA, United States

Abstract
Parkinson’s disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research—l-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography–mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as l-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research. © The Author(s) 2024.

Funding details
Texas Workforce CommissionTWCNS062684
McKnight Foundation
National Institutes of HealthNIHP50 AG047366, P30 AG066515, NS075097, NS115114, AG048076
Alzheimer’s AssociationAA

Document Type: Article
Publication Stage: Final
Source: Scopus

“Fatness but Not Fitness Linked to BrainAge: Longitudinal Changes in Brain Aging during an Exercise Intervention” (2024) Medicine and Science in Sports and Exercise

Fatness but Not Fitness Linked to BrainAge: Longitudinal Changes in Brain Aging during an Exercise Intervention
(2024) Medicine and Science in Sports and Exercise, 56 (4), pp. 655-662.

Wing, D.^a ^b , Eyler, L.T.^e ^g , Lenze, E.J.^c , Wetherell, J.L.^d ^e , Nichols, J.F.^a ^b , Meeusen, R.^f ^k , Godino, J.G.^a ^b , Shimony, J.S.^j , Snyder, A.Z.^j , Nishino, T.^c , Nicol, G.E.^c , Nagels, G.^h ⁱ , Roelands, B.^f ^k

^a Herbert Wertheim School of Public Health, University of California, San Diego, CA, United States
^b Exercise and Physical Activity Resource Center (EPARC), University of California, San Diego, CA, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Mental Health Service, VA San Diego Healthcare System, San Diego, CA, United States
^e Department of Psychiatry, University of California, San Diego, CA, United States
^f Human Physiology and Sports Physiotherapy Research Group, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium
^g Desert-Pacific Mental Illness Research, Education, Clinical Center, San Diego Veterans Administration Healthcare System, San Diego, CA, United States
^h Department of Neurology, UZ Brussel, Brussel, Belgium
ⁱ Center for Neurosciences (C4N) Vrije Universiteit Brussel (VUB), Brussels, Belgium
^j Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^k Brubotics, Vrije Universiteit Brussel, Brussels, Belgium

Abstract
WING, D., L. T. EYLER, E. J. LENZE, J. L. WETHERELL, J. F. NICHOLS, R. MEEUSEN, J. G. GODINO, J. S. SHIMONY, A. Z. SNYDER, T. NISHINO, G. E. NICOL, G. NAGELS, and B. ROELANDS. Fatness but Not Fitness Linked to BrainAge: Longitudinal Changes in Brain Aging during an Exercise Intervention. Med. Sci. Sports Exerc., Vol. 56, No. 4, pp. 655- 662, 2024. Purpose: Fitness, physical activity, body composition, and sleep have all been proposed to explain differences in brain health. We hypothesized that an exercise intervention would result in improved fitness and body composition and would be associated with improved structural brain health. Methods: In a randomized controlled trial, we studied 485 older adults who engaged in an exercise intervention (n = 225) or a nonexercise comparison condition (n = 260). Using magnetic resonance imaging, we estimated the physiological age of the brain (BrainAge) and derived a predicted age difference compared with chronological age (brain-predicted age difference (BrainPAD)). Aerobic capacity, physical activity, sleep, and body composition were assessed and their impact on BrainPAD explored. Results: There were no significant differences between experimental groups for any variable at any time point. The intervention group gained fitness, improved body composition, and increased total sleep time but did not have significant changes in BrainPAD. Analyses of changes in BrainPAD independent of group assignment indicated significant associations with changes in body fat percentage (r(479) = 0.154, P = 0.001), and visceral adipose tissue (VAT) (r(478) = 0.141, P = 0.002), but not fitness (r(406) = −0.075, P = 0.129), sleep (r(467) range, −0.017 to 0.063; P range, 0.171 to 0.710), or physical activity (r (471) = −0.035, P = 0.444). With linear regression, changes in body fat percentage and VAT significantly predicted changes in BrainPAD (β = 0.948, P = 0.003) with 1-kg change in VAT predicting 0.948 yr of change in BrainPAD. Conclusions: In cognitively normal older adults, exercise did not appear to impact BrainPAD, although it was effective in improving fitness and body composition. Changes in body composition, but not fitness, physical activity, or sleep impacted BrainPAD. These findings suggest that focus on weight control, particularly reduction of central obesity, could be an interventional target to promote healthier brains. © 2024 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
BRAIN HEALTH; EXERCISE INTERVENTION; MAXIMAL CARDIOVASCULAR FITNESS; SUCCESSFUL AGING; VISCERAL ADIPOSE TISSUE

Document Type: Article
Publication Stage: Final
Source: Scopus

“Individual Patient Comorbidities and Effect on Cochlear Implant Performance” (2024) Otology and Neurotology

Individual Patient Comorbidities and Effect on Cochlear Implant Performance
(2024) Otology and Neurotology, 45 (4), pp. E281-E288.

Dang, S.^a , Kallogjeri, D.^a ^b , Dizdar, K.^a , Lee, D.^a , Bao, J.W.^c , Varghese, J.^a , Walia, A.^a , Zhan, K.^a , Youssef, S.^a , Durakovic, N.^a , Wick, C.C.^a , Herzog, J.A.^a , Buchman, C.A.^a , Piccirillo, J.F.^a , Shew, M.A.^a

^a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St. LouisMO, United States
^b JAMA Otolaryngology-Head and Neck Surgery, Chicago, IL, United States
^c Miller School of Medicine, University of MiamiFL, United States

Abstract
Objective To examine the association between preoperative comorbidities and cochlear implant speech outcomes. Study Design Retrospective cohort. Setting Tertiary referral center. Patients A total of 976 patients who underwent cochlear implantation (CI) between January 2015 and May 2022. Adult patients with follow-up, preoperative audiologic data, and a standardized anesthesia preoperative note were included. Exposure Adult Comorbidity Evaluation 27 (ACE-27) based on standardized anesthesia preoperative notes. Main Outcome Measures Postoperative change in consonant-nucleus-consonant (CNC) score, AzBio Sentence score in quiet, and AzBio + 10 dB signal-to-noise ratio (SNR). Sentence score of the implanted ear at 3, 6, and 12 months. Results A total of 560 patients met inclusion criteria; 112 patients (20%) had no comorbidity, 204 patients (36.4%) had mild comorbidities, 161 patients (28.8%) had moderate comorbidities, and 83 patients (14.8%) had severe comorbidities. Mixed model analysis revealed all comorbidity groups achieved a clinically meaningful improvement in all speech outcome measures over time. This improvement was significantly different between comorbidity groups over time for AzBio Quiet (p = 0.045) and AzBio + 10 dB SNR (p = 0.0096). Patients with severe comorbidities had worse outcomes. From preop to 12 months, the estimated marginal mean difference values (95% confidence interval) between the no comorbidity group and the severe comorbidity group were 52.3 (45.7-58.9) and 32.5 (24.6-40.5), respectively, for AzBio Quiet; 39.5 (33.8-45.2) and 21.2 (13.6-28.7), respectively, for AzBio + 10 dB SNR; and 43.9 (38.7-49.0) and 31.1 (24.8-37.4), respectively, for CNC. Conclusions Comorbidities as assessed by ACE-27 are associated with CI performance. Patients with more severe comorbidities have clinically meaningful improvement but have worse outcome compared to patients with no comorbidities. © Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
ACE-27; Adult comorbidity; Adult comorbidity index 27; Cochlear implant; Cochlear implant outcomes; Medical comorbidity

Document Type: Article
Publication Stage: Final
Source: Scopus

“Predation without direction selectivity” (2024) Proceedings of the National Academy of Sciences of the United States of America

Predation without direction selectivity
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (12), pp. e2317218121.

Krizan, J.^a ^b , Song, X.^a ^c , Fitzpatrick, M.J.^a ^b , Shen, N.^a , Soto, F.^a , Kerschensteiner, D.^a ^d ^e

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Graduate program in Neuroscience, Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Graduate program in Biomedical Engineering, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Across the animal kingdom, visual predation relies on motion-sensing neurons in the superior colliculus (SC) and its orthologs. These neurons exhibit complex stimulus preferences, including direction selectivity, which is thought to be critical for tracking the unpredictable escape routes of prey. The source of direction selectivity in the SC is contested, and its contributions to predation have not been tested experimentally. Here, we use type-specific cell removal to show that narrow-field (NF) neurons in the mouse SC guide predation. In vivo recordings demonstrate that direction-selective responses of NF cells are independent of recently reported stimulus-edge effects. Monosynaptic retrograde tracing reveals that NF cells receive synaptic input from direction-selective ganglion cells. When we eliminate direction selectivity in the retina of adult mice, direction-selective responses in the SC, including in NF cells, are lost. However, eliminating retinal direction selectivity does not affect the hunting success or strategies of mice, even when direction selectivity is removed after mice have learned to hunt, and despite abolishing the gaze-stabilizing optokinetic reflex. Thus, our results identify the retinal source of direction selectivity in the SC. They show that NF cells in the SC guide predation, an essential spatial orienting task, independent of their direction selectivity, revealing behavioral multiplexing of complex neural feature preferences and highlighting the importance of feature-selective manipulations for neuroethology.

Author Keywords
direction-selective; ganglion cells; narrow-field cells; retina; superior colliculus

Document Type: Article
Publication Stage: Final
Source: Scopus

“Circadian Biology and the Neurovascular Unit” (2024) Circulation Research

Circadian Biology and the Neurovascular Unit
(2024) Circulation Research, 134 (6), pp. 748-769.

Li, W.^a ^b , Tiedt, S.^b ^c , Lawrence, J.H.^b ^d , Harrington, M.E.^b ^e , Musiek, E.S.^b ^d , Lo, E.H.^a ^b

^a Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
^b Consortium International pour la Recherche Circadienne sur l’AVC, Munich, Germany
^c Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Neuroscience Program, Smith College, Northampton, MA, United States

Abstract
Mammalian physiology and cellular function are subject to significant oscillations over the course of every 24-hour day. It is likely that these daily rhythms will affect function as well as mechanisms of disease in the central nervous system. In this review, we attempt to survey and synthesize emerging studies that investigate how circadian biology may influence the neurovascular unit. We examine how circadian clocks may operate in neural, glial, and vascular compartments, review how circadian mechanisms regulate cell-cell signaling, assess interactions with aging and vascular comorbidities, and finally ask whether and how circadian effects and disruptions in rhythms may influence the risk and progression of pathophysiology in cerebrovascular disease. Overcoming identified challenges and leveraging opportunities for future research might support the development of novel circadian-based treatments for stroke. © 2024 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
aging; central nervous system; cerebrovascular disorders; circadian clocks; stroke

Funding details
Corona-Stiftung
Ludwig-Maximilians-Universität MünchenLMU
National Institutes of HealthNIHR01AG081841

Document Type: Article
Publication Stage: Final
Source: Scopus

“In the face of ambiguity: Intrinsic brain organization in development predicts one’s bias toward positivity or negativity” (2024) Cerebral Cortex

In the face of ambiguity: Intrinsic brain organization in development predicts one’s bias toward positivity or negativity
(2024) Cerebral Cortex, 34 (3), art. no. bhae102, .

Harp, N.R.^a , Nielsen, A.N.^b , Schultz, D.H.^c ^d , Neta, M.^c ^d

^a Department of Psychiatry, Yale University, 300 George Street, New Haven, CT 06511, United States
^b Department of Neurology, Washington University, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^c Department of Psychology, University of Nebraska-Lincoln, 238 Burnett Hall, Lincoln, NE 68588, United States
^d Center for Brain, Biology, and Behavior, University of Nebraska-Lincoln, C89 East Stadium, Lincoln, NE 68588, United States

Abstract
Exacerbated negativity bias, including in responses to ambiguity, represents a common phenotype of internalizing disorders. Individuals differ in their propensity toward positive or negative appraisals of ambiguity. This variability constitutes one’s valence bias, a stable construct linked to mental health. Evidence suggests an initial negativity in response to ambiguity that updates via regulatory processes to support a more positive bias. Previous work implicates the amygdala and prefrontal cortex, and regions of the cingulo-opercular system, in this regulatory process. Nonetheless, the neurodevelopmental origins of valence bias remain unclear. The current study tests whether intrinsic brain organization predicts valence bias among 119 children and adolescents (6 to 17 years). Using whole-brain resting-state functional connectivity, a machine-learning model predicted valence bias (r = 0.20, P = 0.03), as did a model restricted to amygdala and cingulo-opercular system features (r = 0.19, P = 0.04). Disrupting connectivity revealed additional intra-system (e.g. fronto-parietal) and inter-system (e.g. amygdala to cingulo-opercular) connectivity important for prediction. The results highlight top-down control systems and bottom-up perceptual processes that influence valence bias in development. Thus, intrinsic brain organization informs the neurodevelopmental origins of valence bias, and directs future work aimed at explicating related internalizing symptomology. © 2024 The Author(s). Published by Oxford University Press. All rights reserved.

Author Keywords
ambiguity; individual differences; machine learning; resting-state functional connectivity; valence bias

Document Type: Article
Publication Stage: Final
Source: Scopus

“Autosomal Dominant Alzheimer’s Disease Mutations in Human Microglia Are Not Sufficient to Trigger Amyloid Pathology in WT Mice but Might Affect Pathology in 5XFAD Mice” (2024) International Journal of Molecular Sciences

Autosomal Dominant Alzheimer’s Disease Mutations in Human Microglia Are Not Sufficient to Trigger Amyloid Pathology in WT Mice but Might Affect Pathology in 5XFAD Mice
(2024) International Journal of Molecular Sciences, 25 (5), art. no. 2565, .

Romero-Molina, C.^a , Neuner, S.M.^a , Ryszawiec, M.^a , Pébay, A.^b , Marcora, E.^a , Goate, A.^a , Dominantly Inherited Alzheimer Network^c

^a Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, United States
^b Department of Anatomy and Physiology, Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3010, Australia
^c Department of Neurology, Washington University, St. Louis, MO 63110, United States

Abstract
Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer’s Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk. © 2024 by the authors.

Author Keywords
Alzheimer’s disease; amyloid; microglia

Document Type: Article
Publication Stage: Final
Source: Scopus

“Embodied Resilience: A Quasi-Experimental Exploration of the Effects of a Trauma-Informed Yoga and Mindfulness Curriculum in Carceral Settings” (2024) International Journal of Yoga Therapy

Embodied Resilience: A Quasi-Experimental Exploration of the Effects of a Trauma-Informed Yoga and Mindfulness Curriculum in Carceral Settings
(2024) International Journal of Yoga Therapy, 34 (2024), .

Rousseau, D.^a , Bourgeois, J.W.^b , Johnson, J.^c , Ramirez, L.^d , Donahue, M.^e

^a Boston University, Mass
^b Texas Southern University-Center for Justice Research, Houston, United States
^c Nova Southeastern University, Ft. Lauderdale, Fla, Norway
^d Washington University, St. Louis, Mo, United States
^e Utah State University, Logan, United Kingdom

Abstract
Individuals who are incarcerated likely experience trauma or exacerbate existing trauma, which has significant health risks. Trauma-informed care aims to address the experienced trauma. The current study explored the effect of a trauma-informed yoga and mindfulness curriculum in carceral settings. In this quasi-experimental study, participants (n = 326) were assigned to either six weekly sessions of 60-minute group trauma-informed yoga and mindfulness or a waitlist control condition. Stress and mood were measured pre- and postclass, whereas coping, emotional awareness, emotional regulation, anxiety, anger management, compassion, self-compassion, forgiveness, and posttraumatic growth were measured pre- and postcurriculum. The trauma-informed group showed a significant increase in mood and decrease in stress after participation in class. Participants were more likely to use positive coping skills, experienced greater levels of forgiveness, and were more likely to experience posttraumatic growth after completing programming as compared to a control group. Qualitative data highlighted perceived improvements in mood, physical health, communication with peers, coping with anxiety and anger, focus and self-control, optimism, acceptance, and open-mindedness. The qualitative data also demonstrated the importance of supportive relationships outside of participants’ peers (i.e., instructors). Outcomes suggest benefit of a trauma-informed yoga and mindfulness curriculum in aiding people who are incarcerated in supporting mental and physical well-being and building resilience.

Author Keywords
incarceration; mindfulness; resilience; trauma-informed; yoga

Document Type: Article
Publication Stage: Final
Source: Scopus

“Basic Environmental Supports for Positive Brain and Cognitive Development in the First Year of Life” (2024) JAMA Pediatrics

Basic Environmental Supports for Positive Brain and Cognitive Development in the First Year of Life
(2024) JAMA Pediatrics, .

Luby, J.L.^a , Herzberg, M.P.^a , Hoyniak, C.^a , Tillman, R.^a , Lean, R.E.^a , Brady, R.^b , Triplett, R.^b , Alexopoulos, D.^b , Loseille, D.^b , Smyser, T.^a , Rogers, C.E.^a , Warner, B.^c , Smyser, C.D.^b , Barch, D.M.^a ^d

^a Department of Psychiatry, School of Medicine, Washington University in St. Louis, St Louis, MO, United States
^b Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychological & Brain Sciences, School of Medicine, Washington University in St. Louis, School of Medicine, St Louis, MO, United States

Abstract
Importance: Defining basic psychosocial resources to facilitate thriving in the first year of life could tangibly inform policy and enhance child development worldwide. Objective: To determine if key environmental supports measured as a thrive factor (T-factor) in the first year of life positively impact brain, cognitive, and socioemotional outcomes through age 3. Design, Setting, and Participants: This prospective longitudinal cohort study took place at a Midwestern academic medical center from 2017 through 2022. Participants included singleton offspring oversampled for those facing poverty, without birth complications, congenital anomalies, or in utero substance exposures (except cigarettes and marijuana) ascertained prenatally and followed up prospectively for the first 3 years of life. Data were analyzed from March 9, 2023, through January 3, 2024. Exposures: Varying levels of prenatal social disadvantage advantage and a T-factor composed of environmental stimulation, nutrition, neighborhood safety, positive caregiving, and child sleep. Main outcomes & measures: Gray and white matter brain volumes and cortical folding at ages 2 and 3 years, cognitive and language abilities at age 3 years measured by the Bayley-III, and internalizing and externalizing symptoms at age 2 years measured by the Infant-Toddler Social and Emotional Assessment. Results: The T-factor was positively associated with child cognitive abilities (β = 0.33; 95% CI, 0.14-0.52), controlling key variables including prenatal social disadvantage (PSD) and maternal cognitive abilities. The T-factor was associated with child language (β = 0.36; 95% CI, 0.24-0.49), but not after covarying for PSD. The association of the T-factor with child cognitive and language abilities was moderated by PSD (β = -0.32; 95% CI, -0.48 to -0.15 and β = -0.36; 95% CI, -0.52 to -0.20, respectively). Increases in the T-factor were positively associated with these outcomes, but only for children at the mean and 1 SD below the mean of PSD. The T-factor was negatively associated with child externalizing and internalizing symptoms over and above PSD and other covariates (β = -0.30; 95% CI, -0.52 to -0.08 and β = -0.32; 95% CI, -0.55 to -0.09, respectively). Increasing T-factor scores were associated with decreases in internalizing symptoms, but only for children with PSD 1 SD above the mean. The T-factor was positively associated with child cortical gray matter above PSD and other covariates (β = 0.29; 95% CI, 0.04-0.54), with no interaction between PSD and T-factor. Conclusions and Relevance: Findings from this study suggest that key aspects of the psychosocial environment in the first year impact critical developmental outcomes including cognitive, brain, and socioemotional development at age 3 years. This suggests that environmental resources and enhancement in the first year of life may facilitate every infant’s ability to thrive, setting the stage for a more positive developmental trajectory.. © 2024 American Medical Association. All rights reserved.

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

“Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder” (2024) AIDS and Behavior

Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder
(2024) AIDS and Behavior, .

Moskowitz, J.T.^a ^b ^l , Sharma, B.^c ^d , Javandel, S.^c , Moran, P.^j , Paul, R.^e , De Gruttola, V.^f , Tomov, D.^g , Azmy, H.^g , Sandoval, R.^c , Hillis, M.^c , Chen, K.P.^c , Tsuei, T.^c , Addington, E.L.^a ^b , Cummings, P.D.^a ^b , Hellmuth, J.^c , Allen, I.E.^h , Ances, B.M.^g , Valcour, V.^c ⁱ , Milanini, B.^k

^a Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^b Osher Center for Integrative Health, Northwestern University, Chicago, IL, United States
^c Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, United States
^d College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
^e Missouri Institute of Mental Health, University of Missouri-St. Louis, St. Louis, MO, United States
^f Division of Biostatistics, Herbert Wertheim School of Public Health, University of California San Diego, San Diego, CA, United States
^g Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Epidemiology & amp; Biostatistics, University of California, San Francisco, CA, United States
ⁱ Global Brain Health Institute, University of California, San Francisco, CA, United States
^j Osher Center for Integrative Health, University of California, San Francisco, CA, United States
^k Inovigate GmbH, Basel, Switzerland
^l Northwestern University Feinberg School of Medicine, 625 N. Michigan Ave, Suite 2700, Chicago, IL 60611, United States

Abstract
The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55 years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8 weeks) and one month later (16 weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8 weeks, however, the difference was not sustained at 16 weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16 weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.

Author Keywords
Aging; Cognition; HIV; HIV-associated neurocognitive disorder; Mindfulness Based Stress Reduction

Funding details
National Institutes of HealthNIHR01NR015223, K24MH098759

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

“Social anxiety moderates the association between adolescent irritability and bully perpetration” (2024) Development and Psychopathology

Social anxiety moderates the association between adolescent irritability and bully perpetration
(2024) Development and Psychopathology, .

Perino, M.T.^a , Lednicky, J.C.H.^a , Vogel, A.C.^a , Sylvester, C.M.^a , Barch, D.M.^a ^b , Luby, J.L.^a

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychology and Brain Sciences, Washington University in St Louis, St. Louis, MO, United States

Abstract
Background: Preliminary work suggests anxiety moderates the relationship between irritability and bullying. As anxiety increases, the link between irritability and perpetration decreases. We hypothesize that any moderation effect of anxiety is driven by social anxiety symptoms. We sought to explicate the moderating effect of anxiety, while clarifying relations to other aggressive behaviors. Methods: A sample of adolescents (n = 169, mean = 12.42 years of age) were assessed using clinician rated assessments of anxiety, parent reports of irritability and bullying behaviors (perpetration, generalized aggression, and victimization). Correlations assessed zero-order relations between variables, and regression-based moderation analyses were used to test interactions. Johnson Neyman methods were used to represent significant interactions. Results: Irritability was significantly related to bullying (r = .403, p 001). Social, but not generalized, anxiety symptoms significantly moderated the effect of irritability on bully perpetration (t(160)=-2.94, b=-.01, p=.0038, R2=.0229, F(1, 160)=8.635). As social anxiety symptoms increase, the link between irritability and perpetration decreases. Conclusions: Understanding how psychopathology interacts with social behaviors is of great importance. Higher social anxiety is linked to reduced relations between irritability and bullying; however, the link between irritability and other aggression remains positive. Comprehensively assessing how treatment of psychopathology impacts social behaviors may improve future intervention. © 2024 Cambridge University Press. All rights reserved.

Author Keywords
Bully perpetration; irritability; social anxiety

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

“MRI and pathology comparisons in Rasmussen’s encephalitis: a multi-institutional examination of hemispherotomy outcomes relative to imaging and histological severity” (2024) Child’s Nervous System

MRI and pathology comparisons in Rasmussen’s encephalitis: a multi-institutional examination of hemispherotomy outcomes relative to imaging and histological severity
(2024) Child’s Nervous System, .

Doherty, A.^a , Knudson, K.^c , Fuller, C.^d , Leach, J.L.^e , Wang, A.C.^f , Marupudi, N.^g , Han, R.H.^h , Tomko, S.ⁱ , Ojemann, J.^j , Smyth, M.D.^k , Mangano, F.^a ^b , Skoch, J.^a ^b

^a University of Cincinnati College of Medicine, Cincinnati, OH, United States
^b Division of Pediatric Neurosurgery, Cincinnati Children’s Hospital and Medical Center, Cincinnati, OH, United States
^c Department of Neurosurgery and Spine, ECU Health, Greenville, NC, United States
^d Pathology, SUNY Upstate Medical University, Syracuse, NY, United States
^e Radiology, Cincinnati Childrens Hospital and Medical Center, Cincinnati, OH, United States
^f Department of Neurosurgery, Mattel Children’s Hospital, University of California Los Angeles, Los Angeles, CA, United States
^g Department of Neurosurgery, Michigan Medicine, Ann Arbor, MI, United States
^h Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Neurology, Washington University, St. Louis Children’s Hospital, St. Louis, MO, United States
^j Department of Neurosurgery, Seattle Childrens Hospital, Seattle, WA, United States
^k Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States

Abstract
Purpose: Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into post-operative seizure outcomes, which in turn could guide decision-making for parents and healthcare providers. Methods: This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institution’s review board. Data was collected from all known pediatric cases of peri-insular functional hemispherotomy from the earliest available electronic medical records. Mean follow-up time was 4.9 years. Clinical outcomes were measured by last follow-up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values. Results: Twenty-seven patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted. Conclusions: Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort. © The Author(s) 2024.

Author Keywords
Hemispherotomy; HOPS; Rasmussen’s encephalitis; Seizure freedom

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

“The limited memory of value following value directed encoding” (2024) Memory and Cognition

The limited memory of value following value directed encoding
(2024) Memory and Cognition, .

Filiz, G., Dobbins, I.G.

Department of Psychological and Brain Sciences, Washington University in Saint Louis, 1 Brookings Dr, St. Louis, MO 63130, United States

Abstract
Items associated with higher values during encoding are later recognized and recalled better than are lower valued items. During recall paradigms, these value directed encoding (VDE) effects heavily depend upon learned strategies acquired during repeated testing with earnings feedback. However, because VDE effects also occur in single test recognition designs, precluding such learning, it has been suggested that high value may automatically induce good encoding. We tested this by manipulating encoding instructions (Experiments 1a and 1b) and manipulating concurrent levels of processing (LOP) requirements during encoding (Experiment 2a and 2b). Two main findings emerged. First, subject initiated strategies played a dominant role in VDE effects with little evidence for automaticity. This was demonstrated in Experiment 1 by a more than three-fold increase in the VDE recognition effect when instructions specifically encouraged selective elaboration of high-value items. It was also shown by the complete elimination of VDE recognition effects in Experiment 2 when LOP tasks were concurrently performed during encoding. Critically, the blocking of VDE effects occurred even though a catch trial procedure verified that value was being processed during encoding and remained even when subjects had unlimited time to process the materials during encoding. Second, the data showed, for the first time, that when subjects attempted to specify the value of recognized items, they heavily depended upon a recognition heuristic in which increases in recognition strength, even when nondiagnostic, were inferred to reflect high encoding value. The tendency for subjects to conflate recognition strength and value may have important implications for behavioral economics. © The Psychonomic Society, Inc. 2024.

Author Keywords
Recognition; The recognition heuristic; Value directed encoding; Value source memory

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

“Experiences With Mobile Health-Enabled Ambulatory Monitoring Among Stroke Survivors: A Qualitative Study” (2024) OTJR: Occupational Therapy Journal of Research

Experiences With Mobile Health-Enabled Ambulatory Monitoring Among Stroke Survivors: A Qualitative Study
(2024) OTJR: Occupational Therapy Journal of Research, .

Lau, S.C.L.^a , Bright, L.^a , Connor, L.T.^a , Baum, C.M.^a ^b

^a Washington University School of Medicine, St. Louis, MO, United States
^b Washington University in St. LouisMO, United States

Abstract
Inquiring into the experiences of stroke survivors toward ambulatory monitoring is crucial for optimizing user adoption, design, implementation, and sustainability of ambulatory monitoring in the stroke population. This study was aimed to identify facilitators and barriers for ambulatory monitoring among stroke survivors, as well as their suggestions for development and implementation of ambulatory monitoring. We conducted individual semi-structured interviews with 40 stroke survivors who received ambulatory monitoring. The interviews were analyzed using thematic content analysis. Six themes about facilitators associated with ambulatory monitoring emerged: (1) user support, (2) technological features, (3) convenience, (4) personal strategies, (5)social influence, and (6)time commitment. Three themes about barriers to using ambulatory monitoring emerged: (1) personal factors, (2) functionality, (3) study design. Three themes about suggestions emerged: (1) personalization, (2) functionality, and (3) interactive feedback. As mobile health technology is becoming more popular, the findings of this study provide timely implications and practical considerations for ambulatory monitoring in the stroke population. © The Author(s) 2024.

Author Keywords
measurement; qualitative research; stroke

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

“Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis” (2024) Molecular Psychiatry

Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis
(2024) Molecular Psychiatry, .

Warren, T.L.^a ^b ^c , Tubbs, J.D.^d ^e ^f ^g , Lesh, T.A.^b , Corona, M.B.^a ^b ^c , Pakzad, S.S.^b , Albuquerque, M.D.^b , Singh, P.^b , Zarubin, V.^b ^h , Morse, S.J.^a ^b ^c ⁱ , Sham, P.C.^d ^j ^k , Carter, C.S.^b ^l , Nord, A.S.^a ^b ^c

^a Department of Neurobiology, Physiology and Behavior, University of California, Davis, CA, United States
^b Department of Psychiatry and Behavioral Sciences, University of California, Davis, CA, United States
^c Center for Neuroscience, University of California, Davis, CA, United States
^d Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
^e Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
^f Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^g Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^h Department of Psychology, Northwestern University, Evanston, IL, United States
ⁱ Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^j Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
^k State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
^l Department of Psychiatry and Human Behavior, University of California, Irvine, CA, United States

Abstract
A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes. © The Author(s) 2024.

Funding details
National Institute of Mental HealthNIMHR01MH059883, F31MH129135
University of California, DavisUCDT32MH112507
National Institute of General Medical SciencesNIGMSR35GM119831

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

“Dark Adaptometry and Optical Coherence Tomography Angiography in Huntington Disease” (2024) Journal of Ophthalmic and Vision Research

Dark Adaptometry and Optical Coherence Tomography Angiography in Huntington Disease
(2024) Journal of Ophthalmic and Vision Research, 19 (1), pp. 18-24.

Shah, A.^a , Fuller, S.^b , Criswell, S.^a ^c ^d , Apte, R.S.^a

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
^b John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States

Abstract
Purpose: Huntington’s Disease (HD) is a fully penetrant neurodegenerative disease leading to cognitive and motor disturbances. The retina may serve as a structural and functional extension of the central nervous system to identify biomarkers of HD using noninvasive imaging technology such as optical coherence tomography angiography (OCTA) and dark adaptometry. Methods: This case–control study included 12 HD participants (24 eyes) recruited from the Huntington’s Disease Society of America Center of Excellence at Washington University in St. Louis along with 16 control participants (31 eyes). Disease-positive participants underwent imaging testing of retinal capillary density and foveal avascular zone utilizing OCTA along with dark adaptometry testing. Data were collected from November 2020 to February 2022. Results: Individuals with HD had a lower mean age-adjusted superficial foveal capillary density and a higher mean deep foveal capillary density compared to control subjects. There was no significant difference in the mean foveal avascular zone or in dark adaptometry testing between the two groups. Conclusion: This study suggests that changes in retinal biomarkers may exist in patients with HD and that additional investigations using multimodal techniques are warranted. © 2024 Shah et al.

Author Keywords
Imaging; Neurology; Ophthalmology; Retina

Document Type: Article
Publication Stage: Final
Source: Scopus

“Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis” (2024) JAMA Neurology

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis
(2024) JAMA Neurology, .

Cross, A.H.^b , Gelfand, J.M.^c , Thebault, S.^d , Bennett, J.L.^e , Christian von Büdingen, H.^f , Cameron, B.^g , Carruthers, R.ⁱ , Edwards, K.^j , Fallis, R.^k , Gerstein, R.^l , Giacomini, P.S.^m , Greenberg, B.ⁿ , Hafler, D.A.^o , Ionete, C.^l , Kaunzner, U.W.^p ^q , Kodama, L.^g , Lock, C.^s , Longbrake, E.E.^o , Musch, B.^g , Pardo, G.^r ^t , Piehl, F.^u , Weber, M.S.^x , Yuen, S.^x , Ziemssen, T.^v , Bose, G.^w , Freedman, M.S.^w , Anania, V.G.^x , Ramesh, A.^x , Winger, R.C.^x , Jia, X.^x , Herman, A.^x , Harp, C.^h , Bar-Or, A.^a ^d

^a Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, 3 Gates Building, Philadelphia, PA 19104, United States
^b Washington University School of Medicine, St Louis, MO, United States
^c University of California, San Francisco, United States
^d Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^e University of Colorado Anschutz Medical Campus, Aurora, United States
^f F. Hoffmann-La Roche, Basel, Switzerland
^g Genentech, South San Francisco, CA, United States
^h Yuen, Anania, Ramesh, Herman Winger, Jia, China
ⁱ University of British Columbia, Vancouver, BC, Canada
^j MS Center of Northeastern, Latham, New York, United States
^k Ohio State University Wexner Medical Center, Columbus, United States
^l University of Massachusetts Medical School, Worcester, United States
^m McGill University, Montreal, QC, Canada
ⁿ The University of Texas Southwestern Medical Center, Dallas, United States
^o Yale School of Medicine, New Haven, CT, United States
^p Weill Cornell Medicine, New York, NY, United States
^q Stanford University, Stanford, CA, United States
^r Oklahoma Medical Research Foundation, Oklahoma City, United States
^s Karolinska Institutet, Solna, Sweden
^t Institute of Neuropathology, Department of Neurology, University Medical Center, Göttingen, Germany
^u Fraunhofer Institute for Translational Medicine and Pharmacology, Göttingen, Germany
^v Center of Clinical Neuroscience, Carl Gustav Carus University Clinic, Dresden, Germany
^w Department of Medicine in Neurology, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada

Abstract
IMPORTANCE Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. OBJECTIVE To identify CSF biological measures associated with progressive MS pathobiology. DESIGN, SETTING, AND PARTICIPANTS This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). EXPOSURES Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. MAIN OUTCOMES AND MEASURES Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). RESULTS The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = –0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = –0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). CONCLUSIONS AND RELEVANCE In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression. © 2024 Cross AH et al. JAMA Neurology.

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

“Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials” (2024) Journal of Prevention of Alzheimer’s Disease

Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials
(2024) Journal of Prevention of Alzheimer’s Disease, .

Liu, H.^a , Li, J.^b , Ziegemeier, E.^a , Adams, S.^a , McDade, E.^a , Clifford, D.B.^a , Cao, Y.^c , Wang, G.^c , Li, Y.^a ^c , Mills, S.L.^a , Santacruz, A.M.^b , Belyew, S.^a , Grill, J.D.^d , Snider, B.J.^a , Mummery, C.J.^e , Surti, G.^f , Hannequin, D.^g , Wallon, D.^g , Berman, S.B.^h , Jimenez-Velazquez, I.Z.ⁱ , Roberson, E.D.^j , van Dyck, C.H.^k , Honig, L.S.^l , Sanchez-Valle, R.^m , Brooks, W.S.ⁿ , Gauthier, S.^o , Galasko, D.^p , Masters, C.L.^q , Brosch, J.^r , Hsiung, G.Y.R.^s , Jayadev, S.^t , Formaglio, M.^u , Masellis, M.^v , Clarnette, R.^w , Pariente, J.^x , Dubois, B.^y , Pasquier, F.^z , Bateman, R.J.^a , Llibre-Guerra, J.J.^a

^a Department of Neurology, Washington University School of Medicine, 4488 Forest Park 00328, St Louis, MO 63108, United States
^b Department of Medicine, University of Missouri, Columbia, MO, United States
^c Division of Biostatistics, Washington University in St Louis, St Louis, MO, United States
^d Departments of Psychiatry & amp; Human Behavior and Neurobiology & amp; Behavior at the University of California, Irvine, United States
^e University College of London, London, United Kingdom
^f Brown University, Providence, RI, United States
^g Centre Hospitalier Universitaire de Rouen, Rouen, France
^h University of Pittsburgh, Pittsburgh, PA, United States
ⁱ University of Puerto Rico School of Medicine, San Juan, PR, United States
^j University of Alabama at Birmingham, Birmingham, AL, United States
^k Yale University School of Medicine, New Haven, CT, United States
^l Columbia University Irving Medical Center, New York, NY, United States
^m Hospital Clínic i Provincial de Barcelona, IDIBAPS-Universitat de Barcelona, Barcelona, Spain
ⁿ Neuroscience Research Australia and University of New South Wales Medicine, Kensington, NSW, Australia
^o McGill University Research Center for Studies in Aging, Montreal, Canada
^p University of California, San Diego, CA, United States
^q The Florey Institute, University of Melbourne, Melbourne, Australia
^r Indiana University School of Medicine, Indianapolis, IN, United States
^s University of British Columbia, Vancouver, Canada
^t University of Washington School of Medicine, Seattle, WA, United States
^u Neurological Hospital, Centre Hospitalier Universitaire de Lyon, Bron, France
^v Sunnybrook Research Institute, Toronto, Canada
^w Australian Alzheimer’s Research Foundation, University of Western Australia, Perth, Australia
^x Centre Hospitalier Universitaire de Toulouse, Toulouse, France
^y Neurological Institute of the Salpetriere, University Hospital, Paris, France
^z Centre Hospitalier Régional Universitaire de Lille, Lille, France

Abstract
Background: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). Methods: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants’ clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. Results: Survey responses were received over a sixteen-month window during 2020–2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial’s demographic distribution. Participants’ decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. Conclusion: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4–7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden. © Serdi 2024.

Author Keywords
Alzheimer’s Disease (AD); Clinical trial satisfaction; Dominantly Inherited Alzheimer Network-Trial Unit (DIAN-TU); Dominantly Inherited Alzheimer’s Disease (DIAD); Home Health Nursing (HHN)

Funding details
Alzheimer’s AssociationAA
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
Eli Lilly and Company
Japan Agency for Medical Research and DevelopmentAMED
GHR FoundationGHR
Korea Health Industry Development InstituteKHIDI
National Institute on AgingNIAU19AG032438
National Institutes of HealthNIHU01AG042791
Foundation for the National Institutes of HealthFNIHR01AG046179, R01AG053267-S1

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

“Is Multidimensional Poverty Associated to Dementia Risk? The Case of Older Adults in Pakistan” (2024) Innovation in Aging

Is Multidimensional Poverty Associated to Dementia Risk? The Case of Older Adults in Pakistan
(2024) Innovation in Aging, 8 (2), art. no. igae007, .

Trani, J.-F.^a ^b , Zhu, Y.^c , Park, S.^a , Babulal, G.M.^d

^a Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States
^b National Conservatory of Arts and Crafts, Paris, France
^c School of Social Work, Adelphi University, Garden City, NY, United States
^d Department of Neurology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Background and Objectives: Multidimensional poverty is associated with dementia. We aimed at establishing this association in Pakistan. Research Design and Methods: A cross-sectional study was conducted in Punjab and Sindh, Pakistan, between March 30, 2002, and August 22, 2022, among adults aged 50 and older. Multidimensional poverty measures were composed of 6 dimensions and 15 indicators. Poverty was compared between adults with and without dementia using the Rowland Universal Dementia Assessment Scale, adjusting for sex, age, marital status, and household size. Associations between dementia and poverty were investigated using a multivariate logistic regression model. Results: We found that 594 (72.7%), 171 (20.9%), and 52 (6.4%) had no, mild, and moderate-to-severe dementia, respectively. More women than men had dementia (11.4% vs 2.9%). Approximately 40.4% of adults with dementia were found to be deprived in 4 or more dimensions compared to 8.9% without dementia, and the difference in multidimensional poverty between them was 348.6%. Education, health, living conditions, and psychological well-being were the main contributors to poverty. Poverty in 4 or more dimensions was strongly associated with dementia (odds ratio [OR], 5.02; 95% confidence interval [CI], 2.07–12.16) after adjusting for sex, marital status, age, and household size, with greater odds for older women (OR, 2.02; 95% CI, 1.41–2.90). Discussion and Implications: Our findings suggest that early improvement in social determinants of health through targeted structural policies may prevent dementia later in life. Improving access to free, quality education, health care including mental health care and basic living standards, and employment should reduce the collective risk of dementia. © The Author(s) 2024.

Author Keywords
Alzheimer’s disease; Rural areas; Social and environmental determinants of health; Socioeconomic justice

Funding details
Alzheimer’s AssociationAAAARG-NTF-21-851241
National Institute on AgingNIAR01AG074302

Document Type: Article
Publication Stage: Final
Source: Scopus

“Psychological Aspects of Nerve Gap Reconstruction: Addressing Patient Perspectives and Expectations” (2024) Journal of Hand Surgery Global Online

Psychological Aspects of Nerve Gap Reconstruction: Addressing Patient Perspectives and Expectations
(2024) Journal of Hand Surgery Global Online, .

DeMartini, S., Faust, A., Navarro, B., Dy, C.J.

Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: Preoperative expectations play a major role in determining patient satisfaction after surgery. The aim of this study was to characterize patient’s preoperative expectations and postoperative perceptions of nerve gap repair surgery. Methods: We conducted a search of Embase, Scopus, and Web of Science databases for peer-reviewed articles that studied patient expectations, perceptions, and impressions of nerve gap repair in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies related to lumbar plexus radiculopathy, reimplantation, or patient satisfaction scores without patient testimony were excluded. Primary and secondary outcomes were patient’s preoperative expectations and postoperative perceptions of nerve gap repair surgery, respectively. Results: We included 11 studies evaluating a total of 462 patients. One study evaluated only patient expectations, six studies evaluated only patient perspectives, and four studies evaluated both. Patients were generally overly optimistic in their expectations of surgery. Postoperative satisfaction ranged from 82% to 86%, and 81% to 87% of patients would choose to undergo their surgery again knowing what they know now. Conclusions: Patient expectations in nerve gap repair are optimistic, and at times unrealistic. Patient satisfaction with nerve gap repair is high and subject to influence from preoperative education and postoperative outcomes of functional and sensory recovery. Clinical relevance: Surgeons should be aware that patient expectations of their postoperative outcomes can have substantial impacts on their perceived management and overall satisfaction. More emphasis should be placed on preoperative education and expectation management to optimize patient satisfaction. © 2024 The Authors

Author Keywords
Expectation; Gap; Nerve; Perspective; Reconstruction

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

“Pneumococcal Meningitis Induces Hearing Loss and Cochlear Ossification Modulated by Chemokine Receptors CX3CR1 and CCR2” (2024) JARO – Journal of the Association for Research in Otolaryngology

Pneumococcal Meningitis Induces Hearing Loss and Cochlear Ossification Modulated by Chemokine Receptors CX3CR1 and CCR2
(2024) JARO – Journal of the Association for Research in Otolaryngology, .

Hirose, K.^a , Li, S.Z.^a , Gill, R.^a ^b , Hartsock, J.^a ^c

^a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^b Department of Obstetric and Gynecology, Washington University, St. Louis, MO, United States
^c Turner Scientific, Jacksonville, IL, United States

Abstract
Purpose: Pneumococcal meningitis is a major cause of hearing loss and permanent neurological impairment despite widely available antimicrobial therapies to control infection. Methods to improve hearing outcomes for those who survive bacterial meningitis remains elusive. We used a mouse model of pneumococcal meningitis to evaluate the impact of mononuclear phagocytes on hearing outcomes and cochlear ossification by altering the expression of CX3CR1 and CCR2 in these infected mice. Methods: We induced pneumococcal meningitis in approximately 500 C57Bl6 adult mice using live Streptococcus pneumoniae (serotype 3, 1 × 105 colony forming units (cfu) in 10 µl) injected directly into the cisterna magna of anesthetized mice and treated these mice with ceftriaxone daily until recovered. We evaluated hearing thresholds over time, characterized the cochlear inflammatory response, and quantified the amount of new bone formation during meningitis recovery. We used microcomputed tomography (microCT) scans to quantify cochlear volume loss caused by neo-ossification. We also performed perilymph sampling in live mice to assess the integrity of the blood-perilymph barrier during various time intervals after meningitis. We then evaluated the effect of CX3CR1 or CCR2 deletion in meningitis symptoms, hearing loss, macrophage/monocyte recruitment, neo-ossification, and blood labyrinth barrier function. Results: Sixty percent of mice with pneumococcal meningitis developed hearing loss. Cochlear fibrosis could be detected within 4 days of infection, and neo-ossification by 14 days. Loss of spiral ganglion neurons was common, and inner ear anatomy was distorted by scarring caused by new soft tissue and bone deposited within the scalae. The blood-perilymph barrier was disrupted at 3 days post infection (DPI) and was restored by seven DPI. Both CCR2 and CX3CR1 monocytes and macrophages were present in the cochlea in large numbers after infection. Neither chemokine receptor was necessary for the induction of hearing loss, cochlear fibrosis, ossification, or disruption of the blood-perilymph barrier. CCR2 knockout (KO) mice suffered the most severe hearing loss. CX3CR1 KO mice demonstrated an intermediate phenotype with greater susceptibility to hearing loss compared to control mice. Elimination of CX3CR1 mononuclear phagocytes during the first 2 weeks after meningitis in CX3CR1-DTR transgenic mice did not protect mice from any of the systemic or hearing sequelae of pneumococcal meningitis. Conclusions: Pneumococcal meningitis can have devastating effects on cochlear structure and function, although not all mice experienced hearing loss or cochlear damage. Meningitis can result in rapid progression of hearing loss with fibrosis starting at four DPI and ossification within 2 weeks of infection detectable by light microscopy. The inflammatory response to bacterial meningitis is robust and can affect all three scalae. Our results suggest that CCR2 may assist in controlling infection and maintaining cochlear patency, as CCR2 knockout mice experienced more severe disease, more rapid hearing loss, and more advanced cochlear ossification after pneumococcal meningitis. CX3CR1 also may play an important role in the maintenance of cochlear patency. © The Author(s) under exclusive licence to Association for Research in Otolaryngology 2024.

Author Keywords
Cochlea; Inflammation; Labyrinthitis ossificans; Meningitis

Funding details
National Institute on Deafness and Other Communication DisordersNIDCDDC011315

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