Browsing by Author "Gorno Tempini, Maria Luisa"

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    Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
    (Springer Nature, 2025-04-25) Pottier, Cyril; Küçükali, Fahri; Baker, Matt; Batzler, Anthony; Jenkins, Gregory D.; van Blitterswijk, Marka; Vicente, Cristina T.; De Coster, Wouter; Wynants, Sarah; Van de Walle, Pieter; Ross, Owen A.; Murray, Melissa E.; Faura, Júlia; Haggarty, Stephen J.; van Rooij, Jeroen G. J.; Mol, Merel O.; Hsiung, Ging-Yuek R.; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Asmann, Yan; McDonnell, Shannon K.; Baheti, Saurabh; Josephs, Keith A.; Whitwell, Jennifer L.; Bieniek, Kevin F.; Forsberg, Leah; Heuer, Hilary; Lago, Argentina Lario; Geier, Ethan G.; Yokoyama, Jennifer S.; Oddi, Alexis P.; Flanagan, Margaret; Mao, Qinwen; Hodges, John R.; Kwok, John B.; Domoto-Reilly, Kimiko; Synofzik, Matthis; Wilke, Carlo; Onyike, Chiadi; Dickerson, Bradford C.; Evers, Bret M.; Dugger, Brittany N.; Munoz, David G.; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Suh, EunRan; Gefen, Tamar; Geula, Changiz; Weintraub, Sandra; Diehl-Schmid, Janine; Farlow, Martin R.; Edbauer, Dieter; Woodruff, Bryan K.; Caselli, Richard J.; Donker Kaat, Laura L.; Huey, Edward D.; Reiman, Eric M.; Mead, Simon; King, Andrew; Roeber, Sigrun; Nana, Alissa L.; Ertekin-Taner, Nilufer; Knopman, David S.; Petersen, Ronald C.; Petrucelli, Leonard; Uitti, Ryan J.; Wszolek, Zbigniew K.; Ramos, Eliana Marisa; Grinberg, Lea T.; Gorno Tempini, Maria Luisa; Rosen, Howard J.; Spina, Salvatore; Piguet, Olivier; Grossman, Murray; Trojanowski, John Q.; Keene, C. Dirk; Jin, Lee-Way; Prudlo, Johannes; Geschwind, Daniel H.; Rissman, Robert A.; Cruchaga, Carlos; Ghetti, Bernardino; Halliday, Glenda M.; Beach, Thomas G.; Serrano, Geidy E.; Arzberger, Thomas; Herms, Jochen; Boxer, Adam L.; Honig, Lawrence S.; Vonsattel, Jean P.; Lopez, Oscar L.; Kofler, Julia; White, Charles L., III; Gearing, Marla; Glass, Jonathan; Rohrer, Jonathan D.; Irwin, David J.; Lee, Edward B.; Van Deerlin, Vivianna; Castellani, Rudolph; Mesulam, Marsel M.; Tartaglia, Maria C.; Finger, Elizabeth C.; Troakes, Claire; Al-Sarraj, Safa; Dalgard, Clifton L.; Miller, Bruce L.; Seelaar, Harro; Graff-Radford, Neill R.; Boeve, Bradley F.; Mackenzie, Ian Ra; van Swieten, John C.; Seeley, William W.; Sleegers, Kristel; Dickson, Dennis W.; Biernacka, Joanna M.; Rademakers, Rosa; Neurology, School of Medicine
    Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
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    Functional connectivity associations with markers of disease progression in GRN mutation carriers
    (Wiley, 2025-01-03) Flagan, Taru M.; Chu, Stephanie A.; Häkkinen, Suvi; Zhang, Liwen; McFall, David; Heller, Carolin; Rohrer, Jonathan D.; Brown, Jesse A.; Lee, Alex Jihun; Fernhoff, Kristen; Pasquini, Lorenzo; Mandelli, Maria Luisa; Gorno Tempini, Maria Luisa; Yokoyama, Jennifer S.; Sturm, Virginia; Appleby, Brian; Dickerson, Brad C.; Domoto-Reilly, Kimiko; Foroud, Tatiana M.; Geschwind, Daniel H.; Ghoshal, Nupur; Graff-Radford, Neill R.; Grossman, Murray; Hsiung, Ging-Yuek Robin; Huang, Eric J.; Huey, Edward D.; Kantarci, Kejal; Karydas, Anna M.; Kaufer, Daniel; Knopman, David S.; Litvan, Irene; MacKenzie, Ian R.; Mendez, Mario F.; Onyike, Chiadi U.; Petrucelli, Leonard; Ramos, Eliana Marisa; Roberson, Erik D.; Rojas, Julio C.; Tartaglia, Maria Carmela; Toga, Arthur W.; Weintraub, Sandra; Forsberg, Leah K.; Heuer, Hilary W.; Boeve, Brad F.; Boxer, Adam L.; Rosen, Howard J.; Miller, Bruce L.; Moreno, Fermin; Seeley, William W.; Lee, Suzee E.; ARTFL/LEFFTDS Consortia; Medicine, School of Medicine
    Background: Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Method: Utilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity. Result: NfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers. Conclusion: In presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.