Citations 3
Neurodevelopmental effects of genetic frontotemporal dementia mutations revealed by total intracranial volume differences
So, Isis , Bouzigues, Arabella , Russell, Lucy L. , Foster, Phoebe H. , Ferry‐Bolder, Eve , Swieten, John C. van, Jiskoot, Lize C, Laforce, Robert, Graff, Caroline , Galimberti, Daniela , Vandenberghe, Rik, Xiong, Chengjie , Sorbi, Sandro, Pasquier, Florence, Ducharme, Simon , Butler, Christopher , Ber, Isabelle Le, Masellis, Mario, Moreno, Fermín , Borroni, Barbara , Kolander, Tyler, Mester, Carly , Brushaber, Danielle , Kantarci, Kejal , Heuer, Hilary W. , Forsberg, Leah K. , Boxer, Adam L. , Rosen, Howard J., Investigators, on behalf of Frontotemporal Dementia Prevention Initiative (FPI), Bocchetta, Martina , Jiskoot, Lize C. , Galimberti, Daniela , de Mendonça, Alexandre , Tartaglia, Maria Carmela , Rowe, James B , Synofzik, Matthis , Mester, Carly , Finger, Elizabeth C. , Kantarci, Kejal , Xiong, Chengjie , Russell, Lucy L , Bocchetta, Martina , Bouzigues, Arabella , Jiskoot, Lize C , Graff, Caroline , Borroni, Barbara , Swieten, John C. van , Seelaar, Harro , Sánchez‐Valle, Raquel , Laforce, Robert , Vandenberghe, Rik , Mendonça, Alexandre de , Tiraboschi, Pietro , Santana, Isabel , Gerhard, Alexander , Sorbi, Sandro , Otto, Markus , Pasquier, Florence , Ber, Isabelle Le , Rowe, James B. , Synofzik, Matthis , Rohrer, Jonathan D. , Boeve, Bradley F. , Investigators, on behalf of Frontotemporal Dementia Prevention Initiative (FPI)
Journal of Alzheimer’s Disease | November 19, 2025 | Volume: 109 | Issue: 1 | Pages: 278-290
Background Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD). Objective We investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations. Methods This cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of GRN , MAPT , or C9orf72 , and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education. Results Mutation carriers (mean ± SD age = 50.0 ± 13.2 years, sex = 55% female, n ( GRN ) = 298, n( MAPT ) = 187, n ( C9orf72 ) = 417) were compared to familial non-carriers (age = 48.0 ± 12.9 years, sex = 58% female, n ( GRN ) = 201, n( MAPT ) = 114), n ( C9orf72 ) = 217). Consistent with prior findings in young adults, GRN carriers showed larger TIV, on average by 20531 mm 3 , compared to familial non-carriers (95% CI [85.4, 40977], p = 0.049, η 2 p = 0.008). Larger TIV correlated with higher years of education in GRN carriers (95% CI [0.01, 0.24], r (295) = 0.12, p = 0.03) and GRN non-carriers (95% CI [0.08, 0.34], r(198) = 0.21, p = 0.002). MAPT carriers demonstrated smaller TIV than non-carriers, on average by 29896 mm 3 (95% CI [–58248, −1545], p = 0.039, η 2 p = 0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences. Conclusions In support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.
Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia
Liu, Xulin , Cortez, Kasey, Poos, Jackie M. , Illán‐Gala, Ignacio , Heuer, Hilary W. , Forsberg, Leah K. , Casaletto, Kaitlin B. , Memel, Molly , Barmada, Sami J. , Clark, David , Darby, Ryan, Domoto‐Reilly, Kimiko , Geschwind, Daniel H. , Ghoshal, Nupur , Graff‐Radford, Neill R. , Grant, Ian , Huey, Edward D. , Kantarci, Kejal, Mackenzie, Ian R. , Masdeu, Joseph C. , Mendez, Mario F. , Onyike, Chiadi U. , Pascual, Belén , Pressman, Peter , Ramos, Eliana Marisa , Roberson, Erik D. , Rogalskı, Emily , Bouzigues, Arabella , Russell, Lucy L. , Foster, Phoebe H. , Ferry‐Bolder, Eve , Masellis, Mario, Jiskoot, Lize C. , Laforce, Robert, Graff, Caroline , Galimberti, Daniela, Vandenberghe, Rik, Santana, Isabel, Xiong, Chengjie , Sorbi, Sandro , Otto, Markus , Pasquier, Florence, Ducharme, Simon , Butler, Christopher , Ber, Isabelle Le, Synofzik, Matthis , Moreno, Fermín , Boxer, Adam L. , Rosen, Howie, Rohrer, Jonathan D., Kantarci, Kejal , Galimberti, Daniela , Bocchetta, Martina , Moreno, Fermín , Boeve, Brad F, Roberson, Erik , Kantarci, Kejal , Pascual, Belen , Synofzik, Matthis , Xiong, Chengjie , Domoto-Reilly, Kimiko , Barmada, Sami , Otto, Markus , Illán-Gala, Ignacio , Galimberti, Daniela , Russell, Lucy L , Bocchetta, Martina , Bouzigues, Arabella , Jiskoot, Lize C , Graff, Caroline , Boer, Sterre C.M. de , Appleby, Brian S. , Bozoki, Andrea C , Cobigo, Yann , Dickerson, Bradford Clark , Galasko, Douglas , Hsiung, Ging‐Yuek Robin , Honig, Lawrence S. , Irwin, David J. , Léger, Gabriel C. , Litvan, Irene , Masdeu, Joseph C , Bayram, Ece , Swieten, John C. van , Seelaar, Harro , Sánchez‐Valle, Raquel , Laforce, Robert , Vandenberghe, Rik , Mendonça, Alexandre de , Tiraboschi, Pietro , Santana, Isabel , Gerhard, Alexander , Pasquier, Florence , Ber, Isabelle Le , Finger, Elizabeth C. , Rowe, James B. , Borroni, Barbara , Boeve, Bradley F. , Pijnenburg, Yolande A.L. , Rohrer, Jonathan D. , Tartaglia, Maria Carmela
Alzheimer's & Dementia | April 25, 2025 | Volume: 21 | Issue: 4 | Pages: No page available
AbstractINTRODUCTIONHigher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.METHODSWe included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex.RESULTSFemales with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe.DISCUSSIONFemales with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.Highlights Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.
Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells
Wang, Hui , Chang, Timothy S. , Dombroski, Beth A. , Cheng, Po‐Liang , Si, Yaqin , Tucci, Albert , Patil, Vishakha, Valiente‐Banuet, Leopoldo , Li, Chong , Farrell, Kurt , Molina‐Porcel, Laura , Rajput, Alex , Gearing, Marla , Newell, Kathy L. , Rábano‐Gutierrez, Alberto, Oertel, Wolfgang H. , Respondek, Gesine , Stamelou, María , Arzberger, Thomas , Roeber, Sigrun, Müller, Ulrich , Pástor, Pau , Ber, Isabelle Le, Beach, Thomas G. , Litvan, Irene , Rademakers, Rosa , Ross, Owen A. , Boxer, Adam L. , Seeley, Willian W., Lee, Edward B. , Silva, Rohan de , Crary, John F. , Goate, Alison , Friedman, Jeffrey S., Compta, Yaroslau , Coppola, Giovanni , Wang, Li‐San , Group, PSP Genetics Study, Tzeng, Jung‐Ying , Geschwind, Daniel H. , Schellenberg, Gerard D. , Si, Ya-Qin , Mclean, Catriona , Molina-Porcel, Laura , Rajput, Alex , Deyn, Peter Paul De , Le Bastard, Nathalie , Gearing, Marla , Donker Kaat, Laura , Van Swieten, John C , Ghetti, Bernardino F , Troakes, Claire , de Yébenes, Justo G , Meller, Tina , Oertel, Wolfgang H , Respondek, Gesine , Hopfner, Franziska , Pastor, Pau , Brice, Alexis , Dürr, Alexandra , Beach, Thomas G , Serrano, Geidy E , Hazrati, Lili‐Naz , Litvan, Irene , Ross, Owen A , Galasko, Douglas , Boxer, Adam , Miller, Bruce L , Deerlin, Vivianna M. Van , Lee, Edward B , White, Charles L , Morris, Huw R , Crary, John F , Goate, Alison M , Leung, Yuk Yee , Wang, Li-San , Dickson, Dennis W , Höglinger, Günter U , Tzeng, Jung-Ying , Schellenberg, Gerard D , Lee, Wan-Ping , Dombroski, Beth , Farrell, Kurt , McLean, Catriona , Kaat, Laura Donker , Swieten, John C. van , Dopper, Elise G.P. , Ghetti, Bernardino , Troakes, Claire , Müller, Ulrich, Hopfner, Franziska , Brice, Alexis , Ber, Isabelle Le , Serrano, Geidy E. , Galasko, Douglas , Miller, Bruce L. , White, Charles L. , Morris, Huw R. , Naj, Adam Christian , Group, PSP Genetics Study, Dalgard, Clifton L. , Dickson, Dennis W. , Höglinger, Günter U.
Movement Disorders | March 12, 2025 | Volume: 40 | Issue: 5 | Pages: 950-961
AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.