Hope Center Member Publications: April 6, 2025

The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population
(2025) npj Parkinson’s Disease, 11 (1), art. no. 58, . 

Lange, L.M.^a b c , Levine, K.^d e , Fox, S.H.^f , Marras, C.^f , Ahmed, N.^f , Kuznetsov, N.^d e , Vitale, D.^d e , Iwaki, H.^c d e , Lohmann, K.^a , Marsili, L.^g , Espay, A.J.^g , Bauer, P.^h , Beetz, C.^h , Martin, J.^e , Factor, S.A.ⁱ , Higginbotham, L.A.ⁱ , Chen, H.^j , Leonard, H.^d e , Nalls, M.A.^d e , Mencacci, N.E.^k , Morris, H.R.^l m , Singleton, A.B.^c e , Klein, C.^a b , Blauwendraat, C.^c e , Fang, Z.-H.ⁿ , Atadzhanov, M.^fg , Nguyen, T.^ff , Nguyen, D.^ff , Koretsky, M.^ec , Makarious, M.B.^ec , Faghri, F.^ec , Beach, T.^fe , Xie, T.^fd , Dumanis, S.^fc , Walker, R.^fb , Alcalay, R.^fa , Albin, R.^ez , Lubbe, S.^ey , Puckelwartz, M.J.^ey , Farrer, M.^ex , Dean, M.^ev , Shulman, L.^ew , Ruffrage, L.^ev , Chahine, L.M.^eu , Marek, K.^et , Markopoulou, K.^es , Kieburtz, K.^er , Nuytemans, K.^eq , Galvelis, K.G.^ep , Shulman, J.^eo , Jankovic, J.^eo , Williamson, J.^ek , Inca-Martinez, M.^en , Mata, I.F.^en , Serrano, G.E.^em , Riley, E.^el , Shiamim, E.^ek , Song, Y.^ec , Kim, J.J.^ec , Hernandez, D.^ec , Hall, D.^ej , Foroud, T.^ei , Wegel, C.^eh , Ibanez, L.^eg , Cruchaga, C.^eg , Jonas, C.^ef , Sobering, A.K.^ee , Sherer, T.^ed , Chowdhury, S.^ed , Louie, N.^ed , Kuhl, M.^ed , Murphy, K.^ed , Solle, J.C.^ed , Comart, C.^ed , Fiske, B.^ed , Casey, B.^ed , Siddiqi, B.^ed , O’Grady, A.^ed , Sarmiento, I.J.K.^k , Bandres-Ciga, S.^ec , Screven, L.^ec , Andersh, K.^ec , Pantazis, C.B.^ec , Stott, S.^eb , Love, S.^ea , Lewis, P.A.^dz , Williams, N.^dy , Grosset, D.^dx , Bale, C.^dw , Carroll, C.^dv , Obese, V.^du , Jasaityte, S.^du , Weil, R.^du , Kaiyrzhanov, R.^du , Okunoye, O.^du , Wood, N.^du , Rizig, M.^du , Mok, K.Y.^du , Hardy, J.^du , Houlden, H.^du , Stafford, E.J.^du , Schapira, A.^du , Schrag, A.^du , Martínez-Carrasco, A.^du , Dey, S.^dt , Noyce, A.^dt , Genc, G.^ds , Ertan, S.^dr , Çakmak, Ö.Ö.^dr , Başak, A.N.^dr , Ben Sassi, S.^dq , Amouri, R.^dq , Wu, Y.^dp , Wu, R.-M.^dn , Wu, H.-C.^dp , Kung, P.-J.^do , Lin, C.-H.^dn , Tinkhauser, G.^dm , Krack, P.^dl , Zweier, C.^dl , Brolin, K.^dk , El-Sadig, S.^dj , Pastor, P.^di , Periñan, M.T.^dh , Beyer, K.^dg , Hoenicka, J.^df , Alvarez, I.^de , Cubo, E.^dd , Kim, Y.J.^dc , Jeon, B.^db , Bardien, S.^da , Carr, J.^da , Amod, F.^cz , Foo, J.N.^cy , Tan, E.-K.^cx , Umair, M.^cw , Mubarak, B.A.^cv , Iakovenko, E.^cu , Vinuela, A.^ct , Rosales, R.^cs , Doquenia, M.L.^cs , Cornejo-Olivas, M.^cr , Ur-Rehman, S.^cq , Tan, M.^cp , Pihlstrøm, L.^cp , Aasly, J.O.^co , Ojo, O.^cn , Okubadejo, N.^cn , Sanyaolu, A.^cn , Pitcher, T.L.^cm , Anderson, T.J.^cm , Ojha, R.^cl , Tserensodnom, B.^ck , Reyes-Pérez, P.^cj , Rodriguez-Violante, M.^ci , Martinez-Ramirez, D.^ch , Mohamed, W.^cg , Azmin, S.^cf , Murad, N.A.A.^ce , Norlinah, M.I.^cd , Tay, Y.W.^cc , Lim, S.-Y.^cc , Ahmad-Annuar, A.^cc , Tan, A.H.^cc , Krüger, R.^cb , Shambetova, C.^ca , Kaishibayeva, G.^bz , Karimova, A.^bz , Shiraishi, T.^by , Hattori, N.^bx , Funayama, M.^bx , Schirinzi, T.^bw , Parnetti, L.^bv , Annesi, G.^bu , Avenali, M.^bt , Valente, E.M.^bt , Gagliardi, M.^bs , Quattrone, A.^bs , Salari, M.^br , Borgohain, R.^bq , Rajan, R.^bp , Kukkle, P.L.^bo , Pal, P.^bn , KP, D.^bm , Kishore, A.^bl , Zhou, X.^bk , Chan, P.^bk , Ip, N.^bk , Cheung, N.Y.-F.^bj , Chan, G.H.-F.^bj , Medina, A.^bi , Stamelou, M.^bh , Stefanis, L.^bg , Tarnanas, I.^bf , Dagklis, I.^be , Dadiotis, E.^bd , Hadjigorgiou, G.^bd , Xiromerisiou, G.^bd , Akpalu, A.^bc , Groppa, S.^bb , Gasser, T.^ba , Sharma, M.^ba , Höglinger, G.^az , Hopfner, F.^az , Mollenhauer, B.^ay , Illarionova, A.ⁿ , Junker, J.^a , Trinh, J.^a , Madoev, H.^a , Vollstedt, E.-J.^a , Westenberger, A.^a , Corvol, J.-C.^ax , Brice, A.^aw , Zewde, Y.Z.^av , Kamel, W.A.^au , Salama, M.^at , Hernandez, A.^as , del Rio, M.J.^ar , Orozco, J.^aq , Arboleda, G.^ap , Luo, W.^ao , Chan, P.^an , Guo, J.^am , Shang, H.^al , Tang, B.^ak , Chana, P.^aj , Bustamante, M.L.^ai , Miranda, M.^ah , Olguin, P.^ag , Galleguillos, B.P.^ag , Fon, T.^af , Monchi, O.^ae , Fon, E.A.^ad , Camargos, S.^ac , Tumas, V.^ab , Awad, P.S.^aa , Rieder, C.^z , Schumacher-Schuh, A.F.^y , Zimprich, A.^x , Koks, S.^w , Rentería, M.E.^v , Ellis, M.^u , Kumar, K.^t , Hunter, J.^s , Shepherd, C.E.^r , Tavadyan, Z.^q , Khachatryan, S.^q , Kauffman, M.^p , Gatto, E.M.^o , the Global Parkinson’s Genetics Program (GP2)^fh

^a Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
^b Department of Neurology, University Hospital Schleswig-Holstein, Luebeck, Germany
^c Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
^d DataTecnica, Washington, DC, United States
^e Center for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^f Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
^g University of Cincinnati, Cincinnati, OH, United States
^h CENTOGENE GmbH, Rostock, Germany
ⁱ Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^j Department of Epidemiology and Biostatistics, Michigan State University, Michigan, MI, United States
^k Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^l Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom
^m UCL Movement Disorders Centre, University College London, London, United Kingdom
ⁿ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^o Sanatorio de la Trinidad Mitre – INEBA, Buenos Aires, Argentina
^p Hospital JM Ramos Mejia, Buenos Aires, Argentina
^q Somnus Neurology Clinic, Yerevan, Armenia
^r Neuroscience Research Australia, Sydney, NSW, Australia
^s ANZAC Research Institute, Concord, NSW, Australia
^t Garvan Institute of Medical Research and Concord Repatriation General Hospital, Darlinghurst, NSW, Australia
^u Concord Hospital, Concord, NSW, Australia
^v QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
^w Murdoch University, Perth, WA, Australia
^x Medical University Vienna, Vienna, Austria
^y Universidade Federal do Rio Grande do Sul / Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
^z Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
^aa Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
^ab University of São Paulo, São Paulo, Brazil
^ac Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
^ad Montreal Neurological Institute, Montreal, QC, Canada
^ae Institut universitaire de gériatrie de Montréal, Montreal, QC, Canada
^af McGill University, Montreal, QC, Canada
^ag Universidad de Chile, Santiago, Chile
^ah Fundación Diagnosis, Santiago, Chile
^ai Faculty of Medicine Universidad de Chile, Santiago, Chile
^aj CETRAM, Santiago, Chile
^ak Central South University, Changsha, China
^al West China Hospital Sichuan University, Chengdu, China
^am Xiangya Hospital, Changsha, China
^an Capital Medical University, Beijing, China
^ao Zhejiang University, Hangzhou, China
^ap Universidad Nacional de Colombia, Bogotá, Colombia
^aq Fundación Valle del Lili, Santiago De Cali, Colombia
^ar University of Antioquia, Medellin, Colombia
^as University of Costa Rica, San Jose, Costa Rica
^at The American University in Cairo, Cairo, Egypt
^au Beni-Suef University, Beni Suef, Egypt
^av Addis Ababa University, Addis Ababa, Ethiopia
^aw Paris Brain Institute, Paris, France
^ax Sorbonne Université, Paris, France
^ay University Medical Center Göttingen, Göttingen, Germany
^az Department of Neurology, University Hospital, LMU Munich, Munich, Germany
^ba University of Tübingen, Tübingen, Germany
^bb University of Mainz, Mainz, Germany
^bc University of Ghana Medical School, Accra, Ghana
^bd University of Thessaly, Volos, Greece
^be Aristotle University of Thessaloniki, Thessaloniki, Greece
^bf Ionian University, Corfu, Greece
^bg Biomedical research Foundation of the Academy of Athens, Athens, Greece
^bh Diagnostic and Therapeutic Centre HYGEIA Hospital, Marousi, Greece
^bi Hospital San Felipe, Tegucigalpa, Honduras
^bj Queen Elizabeth Hospital, Kowloon, Hong Kong
^bk The Hong Kong University of Science and Technology, Kowloon, Hong Kong
^bl Aster Medcity, Kochi, India
^bm Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India
^bn National Institute of Mental Health & Neurosciences, Bengaluru, India
^bo Manipal Hospital, Delhi, India
^bp All India Institute of Medical Sciences, Delhi, India
^bq Nizam’s Institute Of Medical Sciences, Hyderabad, India
^br Shahid Beheshti University of Medical Science, Tehran, Iran
^bs Magna Graecia University of Catanzaro, Catanzaro, Italy
^bt University of Pavia, Pavia, Italy
^bu National Research Council, Cosenza, Italy
^bv University of Perugia, Perugia, Italy
^bw University of Rome Tor Vergata, Rome, Italy
^bx Juntendo University, Tokyo, Japan
^by Jikei University School of Medicine, Tokyo, Japan
^bz Institute of Neurology and Neurorehabilitation, Almaty, Kazakhstan
^ca Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan
^cb University of Luxembourg, Luxembourg, Luxembourg
^cc University of Malaya, Kuala Lumpur, Malaysia
^cd Universiti Kebangsaan Malaysia, Selangor, Malaysia
^ce UKM Medical Molecular Biology Institute, Kuala Lumpur, Malaysia
^cf Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
^cg International Islamic University, Kuala Lumpur, Malaysia
^ch Tecnologico de Monterrey, Monterrey, Mexico
^ci Instituto Nacional de Neurologia y Neurocirugia, Mexico City, Mexico
^cj Universidad Nacional Autónoma de México, Mexico City, Mexico
^ck Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
^cl Tribhuvan University, Kirtipur, Nepal
^cm University of Otago, Dunedin, New Zealand
^cn University of Lagos, Lagos, Nigeria
^co Norwegian University of Science and Technology, Trondheim, Norway
^cp Oslo University Hospital, Oslo, Norway
^cq University of Science and Technology Bannu, Bannu, Pakistan
^cr Universidad Cientifica del Sur, Lima, Peru
^cs Metropolitan Medical Center, Manila, Philippines
^ct University of Puerto Rico, San Juan, Puerto Rico
^cu Research Center of Neurology, Moscow, Russian Federation
^cv King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
^cw King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
^cx National Neuroscience Institute, Singapore, Singapore
^cy Nanyang Technological University, Singapore, Singapore
^cz University of KwaZulu-Natal, Durban, South Africa
^da Stellenbosch University, Stellenbosch, South Africa
^db Seoul National University Hospital, Seoul, South Korea
^dc Yongin Severance Hospital, Seoul, South Korea
^dd Hospital Universitario Burgos, Burgos, Spain
^de University Hospital Mutua Terrassa, Barcelona, Spain
^df Institut de Recerca Sant Joan de Deu, Barcelona, Spain
^dg Research Institute Germans Trias i Pujol, Barcelona, Spain
^dh Instituto de Biomedicina de Sevilla, Seville, Spain
^di University Hospital Germans Trias i Pujol, Barcelona, Spain
^dj Faculty of medicine university of Khartoum, Khartoum, Sudan
^dk Lund University, Lund, Sweden
^dl Inselspital Bern, University of Bern, Bern, Switzerland
^dm University Hospital Bern, Bern, Switzerland
^dn National Taiwan University Hospital, Taipei City, Taiwan
^do National Taiwan University, Taipei City, Taiwan
^dp Chang Gung Memorial Hospital, Taoyuan City, Taiwan
^dq National Institute Mongi Ben Hamida of Neurology, Tunis, Tunisia
^dr Koç University, Istanbul, Turkey
^ds Şişli Etfal Training and Research Hospital, Istanbul, Turkey
^dt Queen Mary University of London, London, United Kingdom
^du University College London, London, United Kingdom
^dv University of Plymouth, Plymouth, United Kingdom
^dw Parkinson’s UK, London, United Kingdom
^dx University of Glasgow, Glasgow, United Kingdom
^dy Cardiff University, Cardiff, United Kingdom
^dz Royal Veterinary College University of London, London, United Kingdom
^ea University of Bristol, Bristol, United Kingdom
^eb Cure Parkinson’s, London, United Kingdom
^ec National Institutes of Health, Bethesda, MD, United States
^ed The Michael J. Fox Foundation for Parkinson’s Research, New York, NY, United States
^ee Augusta University / University of Georgia Medical Partnership, Augusta, GA, United States
^ef Mid-Atlantic Permanente Medical Group, Bethesda, MD, United States
^eg Washington University, St. Louis, MO, United States
^eh Indiana University, Bloomington, IN, United States
^ei Indiana University School of Medicine, Indianapolis, IN, United States
^ej Rush University, Chicago, IL, United States
^ek Kaiser Permanente, Oakland, CA, United States
^el Coalition for Aligning Science, Washington, WA, United States
^em Banner Sun Health Research Institute, Sun City, AZ, United States
^en Cleveland Clinic, Cleveland, OH, United States
^eo Baylor College of Medicine, Houston, TX, United States
^ep Parkinson’s Foundation, Princeton, NJ, United States
^eq University of Miami Miller School of Medicine, Miami, FL, United States
^er Beth Israel Deaconess Medical Center, Boston, MA, United States
^es North Shore University Health System, Chicago, IL, United States
^et Institute for Neurodegenerative Disorders, New Haven, CT, United States
^eu University of Pittsburgh, Pittsburgh, PA, United States
^ev University of Alabama at Birmingham, Birmingham, AL, United States
^ew University of Maryland, Baltimore, MD, United States
^ex University of Florida – Neurology, Gainesville, FL, United States
^ey Northwestern University, Chicago, IL, United States
^ez University of Michigan, Ann Arbor, MI, United States
^fa Columbia University, New York, NY, United States
^fb James J. Peters Veterans Affairs Medical Center, New York, NY, United States
^fc Aligning Science Across Parkinson’s, Washington, WA, United States
^fd University of Chicago, Chicago, IL, United States
^fe Sun Health Research Institution, Sun City, AZ, United States
^ff Hue University, Huế, Viet Nam
^fg University of Zambia, Lusaka, Zambia

Abstract
LRRK2-PD represents the most common form of autosomal dominant Parkinson’s disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic. © The Author(s) 2025.

Document Type: Article
Publication Stage: Final
Source: Scopus

A network correspondence toolbox for quantitative evaluation of novel neuroimaging results
(2025) Nature Communications, 16 (1), art. no. 2930, . 

Kong, R.^a , Spreng, R.N.^b , Xue, A.^a , Betzel, R.F.^c , Cohen, J.R.^d , Damoiseaux, J.S.^e f , De Brigard, F.^g , Eickhoff, S.B.^h i , Fornito, A.^j k l , Gratton, C.^m n , Gordon, E.M.^o , Holmes, A.J.^p q , Laird, A.R.^r , Larson-Prior, L.^s t , Nickerson, L.D.^u , Pinho, A.L.^v w , Razi, A.^j k l , Sadaghiani, S.^m n , Shine, J.M.^x , Yendiki, A.^y , Yeo, B.T.T.^a , Uddin, L.Q.^z aa

^a Centre for Translational MR Research and Centre for Sleep & Cognition, National University of Singapore, Singapore, Singapore
^b Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
^c Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
^d Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC, United States
^e Department of Psychology, Wayne State University, Detroit, MI, United States
^f Institute of Gerontology, Wayne State University, Detroit, MI, United States
^g Department of Philosophy, Duke University, Durham, NC, United States
^h Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
ⁱ Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany
^j School of Psychological Sciences, Monash University, Melbourne, VIC, Australia
^k Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia
^l Monash Biomedical Imaging, Monash University, Melbourne, VIC, Australia
^m Department of Psychology, University of Illinois, Urbana Champaign, IL, United States
ⁿ Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana Champaign, IL, United States
^o Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
^p Department of Psychiatry, Rutgers University, New Brunswick, NJ, United States
^q Center for Brain Health, Rutgers University, New Brunswick, NJ, United States
^r Department of Physics, Florida International University, Miami, FL, United States
^s Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^t Department of Neurosciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^u Department of Psychiatry, Harvard Medical School, McLean Hospital, Boston, MA, United States
^v Western Centre for Brain and Mind, Western University, London, ON, Canada
^w Department of Computer Science and Department of Psychology, Western University, London, ON, Canada
^x Brain and Mind Center, University of Sydney, Sydney, NSW, Australia
^y Department of Radiology, Massachusetts General Hospital, Boston, MA, United States
^z Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, United States
^aa Department of Psychology, University of California Los Angeles, Los Angeles, CA, United States

Abstract
The brain can be decomposed into large-scale functional networks, but the specific spatial topographies of these networks and the names used to describe them vary across studies. Such discordance has hampered interpretation and convergence of research findings across the field. We have developed the Network Correspondence Toolbox (NCT) to permit researchers to examine and report spatial correspondence between their novel neuroimaging results and multiple widely used functional brain atlases. We provide several exemplar demonstrations to illustrate how researchers can use the NCT to report their own findings. The NCT provides a convenient means for computing Dice coefficients with spin test permutations to determine the magnitude and statistical significance of correspondence among user-defined maps and existing atlas labels. The adoption of the NCT will make it easier for network neuroscience researchers to report their findings in a standardized manner, thus aiding reproducibility and facilitating comparisons between studies to produce interdisciplinary insights. © The Author(s) 2025.

Funding details
Western UniversityUWO
Natural Sciences and Engineering Research Council of CanadaNSERC
Canada First Research Excellence FundCFREF
Canadian Institutes of Health ResearchCIHR
SantéFRQSRF1AG078304, R01MH116226
SantéFRQS
Temasek FoundationTF2223-IMH-01
Temasek Foundation
National Medical Research CouncilNMRCOFLCG19May-0035, STaR20nov-0003, OFIRG24jan-0006, CTGIIT23jan-0001
National Medical Research CouncilNMRC
National Science FoundationNSF2237385
National Science FoundationNSF
Ministry of Health -SingaporeMOHCG21APR1009
Ministry of Health -SingaporeMOH
National Institutes of HealthNIHR21HD111805, R01MH120080, R01MH133334, U01DA050987
National Institutes of HealthNIH
NUHSRO/2020/124/TMR/LOA
National Institute on AgingNIAR01AG068563
National Institute on AgingNIA

Document Type: Article
Publication Stage: Final
Source: Scopus

A generalized epilepsy network derived from brain abnormalities and deep brain stimulation
(2025) Nature Communications, 16 (1), art. no. 2783, . 

Ji, G.-J.^{a b c d e} , Fox, M.D.^f , Morton-Dutton, M.^f , Wang, Y.^d , Sun, J.^a c , Hu, P.^a c , Chen, X.^a c , Jiang, Y.^a c , Zhu, C.^d , Tian, Y.^b c d , Zhang, Z.^g , Akkad, H.^f h , Nordberg, J.^i j , Joutsa, J.^i j , Torres Diaz, C.V.^k , Groppa, S.^l , Gonzalez-Escamilla, G.^l , Toledo, M.D.^m , Dalic, L.J.ⁿ , Archer, J.S.^o , Selway, R.^p , Stavropoulos, I.^q r , Valentin, A.^q r s , Yang, J.^t u , Isbaine, F.^v , Gross, R.E.^w , Park, S.^x , Gregg, N.M.^x , Cukiert, A.^y , Middlebrooks, E.H.^z , Dosenbach, N.U.F.^aa ab ac , Turner, J.^f , Warren, A.E.L.^f , Chua, M.M.J.^f , Cohen, A.L.^f o , Larivière, S.^f , Neudorfer, C.^f ad , Horn, A.^f ad , Sarkis, R.A.^f , Bubrick, E.J.^f , Fisher, R.S.^ae , Rolston, J.D.^f , Wang, K.^{a c d e af} , Schaper, F.L.W.V.J.^f

^a Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Anhui Province, Hefei, 230032, China
^b Department of Psychology and Sleep Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, China
^c Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, Hefei, 230032, China
^d The School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, 230032, China
^e Anhui Institute of Translational Medicine, Hefei, 230032, China
^f Center for Brain Circuit Therapeutics, Department of Neurology, Neurosurgery, Psychiatry, and Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
^g Department of Diagnostic Radiology, Jinling Hospital, the First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, China
^h Queen Square Institute of Cognitive Neuroscience, University College London, London, United Kingdom
ⁱ Neurocenter, Department of Clinical Neurophysiology, Turku University Hospital, Turku, Finland
^j Turku Brain and Mind Center, Clinical Neurosciences, University of Turku, Turku, Finland
^k Department of Neurourgery, Hospital Universitario La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
^l Movement Disorders and Neurostimulation, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Rhine Main Neuroscience Network (rmn2), Mainz, Germany
^m Department of Neurology, Hospital Universitario La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
ⁿ Department of Medicine (Austin Health), The University of MelbourneVIC, Australia
^o Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, United States
^p Department of Neurosurgery, King’s College Hospital NHS Foundation Trust, London, United Kingdom
^q Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom
^r Department of Clinical Neurophysiology, King’s College Hospital NHS Foundation Trust, London, United Kingdom
^s Department of Clinical Neurophysiology, Alder Hey Children’s Hospital Trust, Liverpool, United Kingdom
^t Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, OH, United States
^u Department of Neurosurgery, Emory University, 1365 Clifton Road NE, Suite B6200, Atlanta, GA 30322, United States
^v Departments of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States
^w Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, United States
^x Department of Neurology, Mayo Clinic, Rochester, MN, United States
^y Department of Neurosurgery, São Paulo, Brazil
^z Department of Radiology, Mayo Clinic, Jacksonville, FL, United States
^aa Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
^ab Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^ac Department of Biomedical Engineering, Washington University in St. Louis, St Louis, MO, United States
^ad MGH Neurosurgery & Center for Neurotechnology and Neurorecovery (CNTR) at MGH Neurology Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
^ae Department of Neurology and Neurological Sciences and Neurosurgery by courtesy, Stanford University School of Medicine, Palo AltoCA, United States
^af Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, 230088, China

Abstract
Idiopathic generalized epilepsy (IGE) is a brain network disease, but the location of this network and its relevance for treatment remain unclear. We combine the locations of brain abnormalities in IGE (131 coordinates from 21 studies) with the human connectome to identify an IGE network. We validate this network by showing alignment with structural brain abnormalities previously identified in IGE and brain areas activated by generalized epileptiform discharges in simultaneous electroencephalogram-functional magnetic resonance imaging. The topography of the IGE network aligns with brain networks involved in motor control and loss of consciousness consistent with generalized seizure semiology. To investigate therapeutic relevance, we analyze data from 21 patients with IGE treated with deep brain stimulation (DBS) for generalized seizures. Seizure frequency reduced a median 90% after DBS and stimulation sites intersect an IGE network peak in the centromedian nucleus of the thalamus. Together, this study helps unify prior findings in IGE and identify a brain network target that can be tested in clinical trials of brain stimulation to control generalized seizures. © The Author(s) 2025.

Funding details
Turun Yliopistollinen KeskussairaalaAUCS
Harvard University
Massachusetts General HospitalMGH
Suomen Lääketieteen Säätiö
Canadian Institutes of Health ResearchCIHR
Deutsches Zentrum für Luft- und RaumfahrtDLR
National Institute on AgingNIA
Simons FoundationSF
Sigrid Juséliuksen Säätiö
U01-DK140734
National Health and Medical Research CouncilNHMRC628725, 1108881
National Health and Medical Research CouncilNHMRC
Anhui Provincial Key Research and Development Plan202104j07020033
Anhui Provincial Key Research and Development Plan
202204295107020028, 202204295107020006
National Institute of Mental HealthNIMHK23MH120510
National Institute of Mental HealthNIMH
2024AH020004
National Institutes of HealthNIHR01NS127892
National Institutes of HealthNIH
EU Joint Programme – Neurodegenerative Disease ResearchJPNDR01 13478451, 2R01 MH113929, 1R01NS127892-01, UM1NS132358
EU Joint Programme – Neurodegenerative Disease ResearchJPND
Deutsche ForschungsgemeinschaftDFG424778381 – TRR 295
Deutsche ForschungsgemeinschaftDFG
National Natural Science Foundation of ChinaNSFC82371507, 31970979, 82090034, 32071054, U23A20424
National Natural Science Foundation of ChinaNSFC
American Epilepsy SocietyAES846534
American Epilepsy SocietyAES
UG3NS114438
U01DA041022, U01DA041134, U01DA051016, U01DA051039, U01DA041148, U01DA041174, U24DA041147, U01DA041120, U01DA041106, U01DA041089, U01DA041093, U01DA051038, U24DA041123, U01DA041117, U01DA051037, U01DA050989, U01DA050988, U01DA051018, U01DA041028, U01DA041048, U01DA041156, U01DA050987, U01DA041025
GXXT-2022-028
National Institute of Neurological Disorders and StrokeNINDSUH3NS109557A1
National Institute of Neurological Disorders and StrokeNINDS
Science Fund for Distinguished Young Scholars of Anhui Province1808085J23
Science Fund for Distinguished Young Scholars of Anhui Province

Document Type: Article
Publication Stage: Final
Source: Scopus

δ-Containing GABAA receptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex
(2025) Journal of Neurophysiology, 133 (4), pp. 1003-1013. 

Lu, X.^a , Shu, H.-J.^a , Lambert, P.M.^a b , Benz, A.^a , Zorumski, C.F.^a c , Mennerick, S.^a c

^a Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Medical Scientist Training Program, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
In medial prefrontal cortex (mPFC), fast-spiking parvalbumin (PV) interneurons regulate excitability and microcircuit oscillatory activity important for cognition. Although PV interneurons inhibit pyramidal neurons, they themselves express δ subunits of GABAA receptors important for slow inhibition. However, the specific contribution of δ-containing GABAA receptors to the function of PV interneurons in mPFC is unclear. We explored cellular, synaptic, and local-circuit activity in PV interneurons and pyramidal neurons in mouse mPFC after selectively deleting δ subunits in PV interneurons (cKO mice). In current-clamp recordings, cKO PV interneurons exhibited a higher frequency of action potentials and higher input resistance than wild-type (WT) PV interneurons. Picrotoxin increased firing and GABA decreased firing in WT PV interneurons but not in cKO PV interneurons. The δ-preferring agonist THIP reduced spontaneous inhibitory postsynaptic currents disproportionately in WT pyramidal neurons compared with cKO pyramidal neurons. In WT slices, depolarizing the network with 400 nM kainate increased firing of pyramidal neurons but had little effect on PV interneuron firing. In contrast, kainate application in cKO slices preferentially activated PV interneurons rather than pyramidal neurons. At the population level, kainate induced broadband increases in local field potentials in WT but not in cKO slices. These results on cells and network activity can be understood through increased excitability of cKO PV interneurons. In summary, our study demonstrates that δ-containing GABAA receptors in mPFC PV interneurons play a crucial role in regulating their excitability and the phasic inhibition of pyramidal neurons, elucidating intricate mechanisms governing cortical circuitry.NEW & NOTEWORTHY We reveal the critical role of δ-containing GABAA receptors in parvalbumin interneurons in the medial prefrontal cortex, important for human neuropsychiatric disorders. We demonstrate these receptors’ importance in regulating neuronal excitability and network dynamics. δ-containing receptors act as a brake on interneuron activity, maintaining the excitation-inhibition balance in cortical circuits. Our findings provide insights into how disruptions in inhibitory signaling alter network function through a receptor subtype that is a target of neurotherapeutics.

Author Keywords
medial prefrontal cortex;  neuronal excitability;  parvalbumin interneurons;  δ-containing GABAA receptors

Document Type: Article
Publication Stage: Final
Source: Scopus

Pmp2+ Schwann Cells Maintain the Survival of Large-Caliber Motor Axons
(2025) Journal of Neuroscience, 45 (13), art. no. e1362242025, . 

Kozlowski, M.M.^a , Strickland, A.^b , Benitez, A.M.^a , Schmidt, R.E.^c , Bloom, A.J.^b d , Milbrandt, J.^b d , DiAntonio, A.^a d

^a Departments of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Departments of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Departments of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO 63110, United States

Abstract
Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability,i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1, Cldn14, and Pmp2 (a.k.a. PMP2+SCs) that preferentially myelinate large-caliber motor axons. PMP2+ SCs are decreased in both amyotrophic lateral sclerosis(ALS) model mice and ALS patient nerves. Thus, PMP2+ SC dysfunction could contribute to motor-selective neuropathies. We engineered a tamoxifen-inducible Pmp2-CreERT2 mouse and expressed diphtheria toxin in PMP2+ SCs to assess the consequences of ablating this SC subtype in male and female mice. Loss of PMP2+ SCs led to significant loss of large-caliber motor axons with concomitant behavioral, electrophysiological, and ultrastructural defects. Subsequent withdrawal of tamoxifen restored both PMP2+ SCs and large-caliber motor axons and improved behavioral and electrophysiological readouts. Together, our findings highlight that the survival of large-caliber motor axons relies on PMP2+ SCs, demonstrating that malfunction of a specific SC subtype can lead to selective neuronal vulnerability. Copyright © 2025 the authors.

Author Keywords
glia;  motor axons;  neuropathy;  PMP2;  Schwann cells;  selective neuronal vulnerability

Funding details
National Institutes of HealthNIHR37NS065053, R01-NS105645
National Institutes of HealthNIH

Document Type: Article
Publication Stage: Final
Source: Scopus

Dementia in a resource-constrained sub-Saharan African setting: A comprehensive retrospective analysis of prevalence, risk factors, and management at the only neuropsychiatric facility in Northeastern Nigeria
(2025) Alzheimer’s and Dementia, 21 (3), art. no. e14538, . 

Wakawa, I.A.^a b , Musami, U.B.^a b , Kwairanga, S.H.^c d , Ogualili, P.N.^a e , Mahmood, M.Y.^a , Fugu, M.A.^a b , Gimba, M.M.^f , Allamin, M.M.^a , Abbas, Z.U.^a , Sunkani, M.K.^a , Yaganami, Z.B.^a , Kadau, F.M.^a , Sani, N.M.^a , Danmallam, P.^a , Nanjul, L.^a , Babazau, L.^d g , Muhammad, Z.^b d h , Goni, B.W.^d i j , Machina, B.K.^k l , Karch, C.M.^m , Udeh-Momoh, C.^n o p q , Karikari, T.K.^r s , Onyike, C.U.^t , Maina, M.B.^d u

^a Department of Medical Services, Federal Neuropsychiatric Hospital, Borno, Maiduguri, Nigeria
^b Department of Mental Health, College of Medical Sciences, University of Maiduguri, Borno, Maiduguri, Nigeria
^c Department of Human Anatomy, Faculty of Basic and Allied Medical Sciences, College of Medical Science, Gombe State University, Gombe, Tudun Wada, Nigeria
^d Biomedical Science Research and Training Centre Damaturu, Yobe, Damaturu, Nigeria
^e Geriatric Unit, Department of Medical Services, Federal Neuropsychiatric Hospital, Borno, Maiduguri, Nigeria
^f Department of Health Information, Federal Neuropsychiatric Hospital, Borno, Maiduguri, Nigeria
^g Department of Medical Laboratory Services, Yobe State University Teaching Hospital, Damaturu, Nigeria
^h Department of Human Physiology, College of Medical Sciences, Yobe State University, Damaturu, Yobe, Damaturu, Nigeria
ⁱ Department of Medicine, Yobe State University Teaching Hospital, Damaturu, Nigeria
^j Department of Medicine University of Maiduguri, University of Maiduguri Teaching Hospital, Borno, Maiduguri, Nigeria
^k Department of Psychiatry, Yobe State Specialist Hospital, Yobe, Damaturu, Nigeria
^l Department of Psychiatry, Yobe State University Teaching Hospital, Damaturu, Nigeria
^m Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
ⁿ Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
^o Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
^p School of Public Health Sciences, Wake Forest University School of MedicineNC, United States
^q Brain and Mind Institute, Aga Khan University, Nairobi, Kenya
^r Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
^s Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^t Department of Psychiatry and Behavioural Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^u Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, United Kingdom

Abstract
INTRODUCTION: Dementia prevalence is increasing in sub-Saharan Africa, potentially due to population growth and aging. Resource-constrained settings such as Northeastern Nigeria face challenges in dementia management. METHODS: We assessed dementia burden and management at the Federal Neuropsychiatric Hospital Maiduguri, the only neuropsychiatric facility in Northeastern Nigeria. This retrospective analysis included patient records from 1999 to 2023 for individuals 60 year of age and older with a dementia diagnosis. RESULTS: Of the 1216 cases reported, Alzheimer’s disease (60.5%) was the most common subtype, followed by vascular dementia (24.5%). Hypertension (41.6%) was the most frequent comorbidity. Memory loss was present in all cases, whereas behavioral symptoms like agitation presented in some cases. Treatments included cognitive enhancers (donepezil), supplements (gingko biloba), and non-drug therapies (psychoeducation). DISCUSSION: The increasing burden of dementia at this sole facility highlights the urgent need for targeted interventions and further research to understand the underlying factors contributing to dementia in this population. Highlights: Dementia trends and management in a neuropsychiatric facility serving over 26 million people in Northeastern Nigeria. Alzheimer’s disease accounted for 60.5% of the dementia cases reported, with hypertension as the leading comorbidity. There is an urgent need for improved diagnostic tools and health care infrastructure to address dementia in resource-constrained settings. The findings lay the foundation for developing a dementia cohort as part of the Northern Nigeria Dementia Research Group. © 2025 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  dementia;  dementia management;  Northeastern Nigeria;  resource-constrained settings;  sub-Saharan Africa;  vascular dementia

Funding details
Rainwater Charitable FoundationRCF
Defence and Security AcceleratorDASAG2‐SCH‐2022‐11‐12245
Defence and Security AcceleratorDASA
Alzheimer’s AssociationAASAGA23‐1141999
Alzheimer’s AssociationAA
Medical Research CouncilMRCMR/Y019822/1
Medical Research CouncilMRC
National Institutes of HealthNIHRO1‐AG074562
National Institutes of HealthNIH
Global Brain Health InstituteGBHIUFRA‐424
Global Brain Health InstituteGBHI

Document Type: Article
Publication Stage: Final
Source: Scopus

A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease
(2025) Nature Medicine, art. no. e200018, . 

Oh, H.S.-H.^a b c , Urey, D.Y.^b c , Karlsson, L.^d , Zhu, Z.^e , Shen, Y.^f g , Farinas, A.^b c h , Timsina, J.^f g , Duggan, M.R.ⁱ , Chen, J.^j , Guldner, I.H.^k , Morshed, N.^l m , Yang, C.^f g , Western, D.^f g , Ali, M.^f g , Le Guen, Y.^k n , Trelle, A.ⁱ , Herukka, S.-K.^o , Rauramaa, T.^p , Hiltunen, M.^q , Lipponen, A.^q , Luikku, A.J.^r , Poston, K.L.^b c k , Mormino, E.^k , Wagner, A.D.^c s , Wilson, E.N.^b c k , Channappa, D.^b c k , Leinonen, V.^r , Stevens, B.^l m t , Ehrenberg, A.J.^u v w , Gottesman, R.F.^x , Coresh, J.^y , Walker, K.A.ⁱ , Zetterberg, H.^{z aa ab ac ad ae} , Bennett, D.A.^af , Franzmeier, N.^e ag ah , Hansson, O.^d ai , Cruchaga, C.^f g , Wyss-Coray, T.^b c k

^a Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, United States
^b The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, United States
^c Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
^d Clinical Memory Research Unit, Department of Clinical Sciences in Malmö, Lund University, Lund, Sweden
^e Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
^f Department of Psychiatry, Washington University, St. Louis, MO, United States
^g NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, United States
^h Graduate Program in Neuroscience, Stanford University, Stanford, CA, United States
ⁱ Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
^j Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States
^k Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
^l Boston Children’s Hospital, F.M. Kirby Neurobiology Center, Boston, MA, United States
^m Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
ⁿ Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
^o Department of Neurology, Kuopio University Hospital and Institute of Clinical Medicine – Neurology, University of Eastern Finland, Kuopio, Finland
^p Department of Pathology, Kuopio University Hospital and Institute of Clinical Medicine – Pathology, University of Eastern Finland, Kuopio, Finland
^q Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
^r Department of Neurosurgery, Kuopio University Hospital and Institute of Clinical Medicine – Neurosurgery, University of Eastern Finland, Kuopio, Finland
^s Department of Psychology & Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
^t Howard Hughes Medical Institute, Boston, MA, United States
^u Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
^v Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, United States
^w Department of Neuroscience, University of California, Berkeley, Berkeley, CA, United States
^x Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
^y Departments of Population Health and Medicine, New York University Grossman School of Medicine, New York, NY, United States
^z Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
^aa Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^ab Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
^ac UK Dementia Research Institute at UCL, London, United Kingdom
^ad Hong Kong Center for Neurodegenerative Diseases, Hong Kong
^ae Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
^af Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^ag Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^ah Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, The Sahlgrenska Academy, Gothenburg, Sweden
^ai Memory Clinic, Skåne University Hospital, Malmö, Sweden

Abstract
Rates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20–40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case–control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ+ and phosphorylated tau+ (A+T1+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10–4) and A+T1+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10–16) over a 15-year follow-up, adjusting for CSF pTau181:Aβ42, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia. © The Author(s) 2025.

Funding details
National Science FoundationNSF
Erling-Perssons Stiftelse
Hope Center for Neurological Disorders, Washington University in St. Louis
Chan Zuckerberg InitiativeCZI
National Institute for Health and Care ResearchNIHR
National Institute of Neurological Disorders and StrokeNINDS
Milky Way Research FoundationMWRF
UCLH Biomedical Research CentreNIHR BRC
Horizon 2020 Framework ProgrammeH2020
National Institute on Deafness and Other Communication DisordersNIDCD
Lunds UniversitetLU
Olav Thon Stiftelsen
University College LondonUCL
GHR FoundationGHR
Cure Alzheimer’s FundCAF
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Sigrid Juséliuksen Säätiö
European Research CouncilERCZEN24-1069572, 101096455, SG-23-1061717
European Research CouncilERC
Alzheimer’s AssociationAAP30AG066444, P01AG03991, P01AG026276, ZEN-22-848604
Alzheimer’s AssociationAA
University Hospital FoundationUHF2022-1259, 2020-O000028
University Hospital FoundationUHF
101053962
ALFGBG-71320
UK Dementia Research InstituteUK DRIADSF-21-836085-C, 1F32AG079666-01, ADSF-21-836089-C, UKDRI-1003, 5T32AG222-30, ADSF-21-836083-C
UK Dementia Research InstituteUK DRI
National Heart, Lung, and Blood InstituteNHLBI75N92022D00001, U01HL096899, U01HL096814, 75N92022D00002, U01HL096812, 75N92022D00003, 75N92022D00004, U01HL096902, 75N92022D00005, U01HL096917
National Heart, Lung, and Blood InstituteNHLBI
Itä-Suomen YliopistoISY2022-01018, 2019-02397, ADSF-24-1284326-C, 2023-00356
Itä-Suomen YliopistoISY
Alzheimer’s Drug Discovery FoundationADDF201809-2016862
Alzheimer’s Drug Discovery FoundationADDF
AlzheimerfondenAF-980907
Alzheimerfonden
U01AG46152, R01AG15819, P30AG10161, R01AG17917, U01AG61356, P30AG72975
U24AG021886, AG072255
R01AG048076, 2022-Projekt0080, R21AG058859
1412/22
National Institutes of HealthNIHRF1AG053303, 1K99AG088304-01, P01AG003991, R01AG044546, U01AG058922, U24 AG021886, RF1AG058501
National Institutes of HealthNIH
338182, 328287
VetenskapsrådetVR2022-00775, ERAPERMED2021-184
VetenskapsrådetVR
UL1TR003142
JPND2021-00694
National Institute on AgingNIAP50AG047366, P30AG066515
National Institute on AgingNIA
ADSF-21-831381-C, ADSF-24-1284328-C, ADSF-21-831377-C, ADSF-21-831376-C, 22HLT07
H2020 Marie Skłodowska-Curie ActionsMSCA860197
H2020 Marie Skłodowska-Curie ActionsMSCA
Knut och Alice Wallenbergs Stiftelse2022-0231
Knut och Alice Wallenbergs Stiftelse
FO2022-0270
HjärnfondenFO2021-0293
Hjärnfonden

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

Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease
(2025) Nature Medicine, art. no. e76494, . 

Horie, K.^a b c , Salvadó, G.^d , Koppisetti, R.K.^a e , Janelidze, S.^d , Barthélemy, N.R.^a b , He, Y.^a b , Sato, C.^a b , Gordon, B.A.^f g , Jiang, H.^b , Benzinger, T.L.S.^f g h , Stomrud, E.^d i , Holtzman, D.M.^b g h , Mattsson-Carlgren, N.^d i j , Morris, J.C.^b g , Palmqvist, S.^d i , Ossenkoppele, R.^d k l , Schindler, S.E.^b g , Hansson, O.^d , Bateman, R.J.^a b g h

^a The Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Eisai Inc., Nutley, NJ, United States
^d Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^g Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^h Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Memory Clinic, Skåne University Hospital, Malmö, Sweden
^j Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
^k Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, Netherlands
^l Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands

Abstract
Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer’s disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts (n = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma eMTBR-tau243 showed strong associations with tau positron emission tomography binding (β = 0.72, R2 = 0.56) and cognitive performance (β = 0.60, R2 = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials. © The Author(s) 2025.

Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
Horizon 2020 Framework ProgrammeH2020
Department of Neurology, University of Pittsburgh
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Lunds UniversitetLU
Foundation for Barnes-Jewish HospitalFBJH
GHR FoundationGHR
Cure Alzheimer’s FundCAF
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. LouisKGAD
University Hospital FoundationUHF2020-O000028
University Hospital FoundationUHF
National Institute on AgingNIAR01AG083740
National Institute on AgingNIA
2022-Projekt0080, 2022-Projekt0107
HjärnfondenFO2023-0163, FO2021-0293, FO2022-0204
Hjärnfonden
School of Medicine, Washington University in St. LouisWUSMP30 AG066444, P01 AG03991, P01 AG026276
School of Medicine, Washington University in St. LouisWUSM
WASP/DDLS22-066
1412/22
National Institutes of HealthNIHR01AG070941
National Institutes of HealthNIH
VetenskapsrådetVR2022-00775, 2018-02052, ERAPERMED2021-184, 2021-02219
VetenskapsrådetVR
H2020 Marie Skłodowska-Curie ActionsMSCAAF-980942, AARF-22-972612, A2024007F, 101061836
H2020 Marie Skłodowska-Curie ActionsMSCA
2022-1259
European Research CouncilERCADG-101096455
European Research CouncilERC
Coins for Alzheimer’s Research TrustCARTR01NS065667
Coins for Alzheimer’s Research TrustCART
Alzheimer’s AssociationAAZEN24-1069572, SG-23-1061717
Alzheimer’s AssociationAA
AlzheimerfondenAF-994075, AF-994229, AF-980907
Alzheimerfonden
Knut och Alice Wallenbergs Stiftelse2022-0231
Knut och Alice Wallenbergs Stiftelse

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

Long-Term Outcome of Unilateral Magnetic Resonance Imaging–Guided Focused Ultrasound for Fragile X Tremor Ataxia Syndrome
(2025) Movement Disorders Clinical Practice, . 

Di Luca, D.G.^a , Ushe, M.^a , Norris, S.A.^a b , Alfradique-Dunham, I.^a , Glasser, M.^b c d , Nazeri, A.^b , Kotzbauer, P.^a , Willie, J.T.^e

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States

Author Keywords
fragile X syndrome;  magnetic resonance imaging;  neuromodulation

Funding details
Biogen
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Dysphonia InternationalNSDA
National Institutes of HealthNIHR01 NS124789
National Institutes of HealthNIH

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

Amyloid PET in Sporadic Early- Versus Late-Onset Alzheimer’s Disease: Comparison of the LEADS and ADNI Cohorts
(2025) Annals of Neurology, . 

Lagarde, J.^a , Maiti, P.^a , Schonhaut, D.R.^a , Blazhenets, G.^a , Zhang, J.^a , Eloyan, A.^b , Thangarajah, M.^b , Taurone, A.^b , Allen, I.E.^c , Soleimani-Meigooni, D.N.^a , Zeltzer, E.^a , Windon, C.^a , Abu Raya, M.^a d , Vrillon, A.^a , Smith, K.^a , Shankar, R.^a , Amuiri, A.^a , Rocha, S.^a , Hammers, D.B.^e , Dage, J.L.^e , Nudelman, K.N.^f , Kirby, K.^e , Aisen, P.^g , Koeppe, R.^h , Landau, S.M.ⁱ , Carrillo, M.C.^j , Touroutoglou, A.^k , Brickhouse, M.^k , Vemuri, P.^l , Beckett, L.^m , Raman, R.^g , Atri, A.ⁿ , Day, G.S.^o , Duara, R.^p , Graff-Radford, N.R.^o , Honig, L.S.^q , Jones, D.T.^r , Masdeu, J.C.^s , Mendez, M.F.^t , Womack, K.^u , Musiek, E.^u , Onyike, C.U.^v , Riddle, M.^w , Grant, I.M.^x , Rogalski, E.^y , Johnson, E.C.B.^z , Salloway, S.^w , Sha, S.^aa , Turner, R.S.^ab , Wingo, T.S.^z ac , Wolk, D.A.^ad , Dickerson, B.C.^k , Apostolova, L.G.^e f ae , La Joie, R.^a , Rabinovici, G.D.^a af , the LEADS Consortium for the Alzheimer’s Disease Neuroimaging Initiative^ag

^a Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
^b Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
^c Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
^d Global Brain Health Institute, The university of California, San Francisco, CA, United States
^e Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
^f Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^g Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
^h Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, United States
ⁱ Department of Neuroscience, University of California, Berkeley, Berkeley, CA, United States
^j Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
^k Frontotemporal Disorders Unit and Massachusetts Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^l Department of Radiology, Mayo Clinic, Rochester, MN, United States
^m Department of Public Health Sciences, University of California, Davis, Davis, CA, United States
ⁿ Banner Sun Health Research Institute, Sun City, AZ, United States
^o Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^p Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL, United States
^q Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^r Department of Neurology, Mayo Clinic, Rochester, MN, United States
^s Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
^t Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
^u Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^v Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^w Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
^x Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^y Healthy Aging & Alzheimer’s Research Care Center, Department of Neurology, University of Chicago, Chicago, IL, United States
^z Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^aa Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, United States
^ab Department of Neurology, Georgetown University, Washington, DC, United States
^ac Department of Neurology, UC Davis Alzheimer’s Disease Research Center, University of California, Davis, Davis, CA, United States
^ad Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ae Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
^af Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States

Abstract
Objective: Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large-scale comparative studies. Methods: Three hundred ninety-nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early-onset Alzheimer’s Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition. Results: The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74–82) than in ADNI (71%, 95% CI = 67–75, p = 0.02). Lower Mini-Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid-positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD. Interpretation: Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025. © 2025 American Neurological Association.

Funding details
BioClinica
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
Biogen
Fondation pour la Recherche sur Alzheimer
Alzheimer’s Disease Neuroimaging InitiativeADNI
Alzheimer’s Drug Discovery FoundationADDF
Alzheimer’s AssociationAALDRFP‐21‐818464
Alzheimer’s AssociationAA
National Institutes of HealthNIHU01 AG024904, R56‐AG057195, U01‐AG6057195
National Institutes of HealthNIH
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
U.S. Department of DefenseDOD
National Institute on AgingNIAU24 AG072122
National Institute on AgingNIA

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

Cerebrospinal fluid proteomics identification of biomarkers for amyloid and tau PET stages
(2025) Cell Reports Medicine, art. no. 102031, . 

Wang, Z.^a , Chen, Y.^b , Gong, K.^c d , Zhao, B.^a , Ning, Y.^a , Chen, M.^a , Li, Y.^a , Ali, M.^c d , Timsina, J.^c d , Liu, M.^c d , Cruchaga, C.^{c d e f g} , Jia, J.^{a h i j k}

^a Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, 100053, China
^b The First Clinical Medical School, Hebei North University, Zhangjiakou, 075000, China
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, United States
^g Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, United States
^h Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, 100053, China
ⁱ Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, 100053, China
^j Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100053, China
^k Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China

Abstract
Accurate staging of Alzheimer’s disease (AD) pathology is crucial for therapeutic trials and prognosis, but existing fluid biomarkers lack specificity, especially for assessing tau deposition severity, in amyloid-beta (Aβ)-positive patients. We analyze cerebrospinal fluid (CSF) samples from 136 participants in the Alzheimer’s Disease Neuroimaging Initiative using more than 6,000 proteins. We apply machine learning to predict AD pathological stages defined by amyloid and tau positron emission tomography (PET). We identify two distinct protein panels: 16 proteins, including neurofilament heavy chain (NEFH) and SPARC-related modular calcium-binding protein 1 (SMOC1), that distinguished Aβ-negative/tau-negative (A−T−) from A+ individuals and nine proteins, such as HCLS1-associated protein X-1 (HAX1) and glucose-6-phosphate isomerase (GPI), that differentiated A+T+ from A+T− stages. These signatures outperform the established CSF biomarkers (area under the curve [AUC]: 0.92 versus 0.67–0.70) and accurately predicted disease progression over a decade. The findings are validated in both internal and external cohorts. These results underscore the potential of proteomic-based signatures to refine AD diagnostic criteria and improve patient stratification in clinical trials. © 2025 The Authors

Author Keywords
Alzheimer’s disease;  Alzheimer’s disease continuum;  amyloid PET;  Aβ;  biological staging;  CSF biomarkers;  dementia;  p-tau;  proteomics;  tau PET

Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
Chan Zuckerberg InitiativeCZI
National Institutes of HealthNIHP30AG066444, P01AG026276, P01AG03991, RF1AG053303, RF1AG074007, RF1AG058501, R01AG044546, U01AG058922
National Institutes of HealthNIH
Alzheimer’s AssociationAAZEN-22-848604
Alzheimer’s AssociationAA

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

Meningeal lymphatics-microglia axis regulates synaptic physiology
(2025) Cell, . 

Kim, K.^a b , Abramishvili, D.^a b , Du, S.^a b , Papadopoulos, Z.^a b c , Cao, J.^a b , Herz, J.^a b , Smirnov, I.^a b , Thomas, J.-L.^d e , Colonna, M.^b , Kipnis, J.^a b

^a Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, United States
^b Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^c Neuroscience Graduate Program, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^d Department of Neurology, Yale University School of Medicine, New Haven, CT, United States
^e Paris Brain Institute, Université Pierre et Marie Curie Paris 06, UMRS1127, Sorbonne Université, Paris, France

Abstract
Meningeal lymphatics serve as an outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, but the neural mechanisms underlying these changes have remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (Il6). IL-6 drives inhibitory synapse phenotypes via a combination of trans- and classical IL-6 signaling. Restoring meningeal lymphatic function in aged mice reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline. © 2025 The Author(s)

Author Keywords
aging;  E/I balance;  IL-6;  meningeal lymphatics;  meningeas;  microglia;  neuroimmunology;  synapse;  VEGF-C;  VEGFR3

Funding details
Washington University in St. LouisWUSTL
Institute of Clinical and Translational SciencesICTS
University of EdinburghED
Korea Advanced Institute of Science and TechnologyKAIST
National Institutes of HealthNIH
University of QueenslandUQ
National Center for Research ResourcesNCRR
Genome Technology Access CenterGTACP30 CA91842
Genome Technology Access CenterGTAC
National Cancer InstituteNCIP30 CA91842
National Cancer InstituteNCI
National Center for Advancing Translational SciencesNCATSUL1 TR000448
National Center for Advancing Translational SciencesNCATS
National Institute of General Medical SciencesNIGMSR24GM136766, P41 GM103422
National Institute of General Medical SciencesNIGMS
National Research Foundation of KoreaNRF2021R1A6A3A14045044
National Research Foundation of KoreaNRF
National Institute on AgingNIAAG078106, AG034113
National Institute on AgingNIA

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