Browsing by Author "Hsiung, Ging-Yuek Robin"

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    A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease
    (Springer Nature, 2021) Salloway, Stephen; Farlow, Martin; McDade, Eric; Clifford, David B.; Wang, Guoqiao; Llibre-Guerra, Jorge J.; Hitchcock, Janice M.; Mills, Susan L.; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason; Benzinger, Tammie L.S.; Gordon, Brian A.; Fagan, Anne M.; Coalier, Kelley A.; Cruchaga, Carlos; Goate, Alison A.; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Snider, B. Joy; Mummery, Catherine; Surti, G. Mustafa; Hannequin, Didier; Wallon, David; Berman, Sarah B.; Lah, James J.; Jimenez-Velazquez, Ivonne Z.; Roberson, Erik D.; van Dyck, Christopher H.; Honig, Lawrence S.; Sánchez-Valle, Raquel; Brooks, William S.; Gauthier, Serge; Galasko, Douglas R.; Masters, Colin L.; Brosch, Jared R.; Hsiung, Ging-Yuek Robin; Jayadev, Suman; Formaglio, Maité; Masellis, Mario; Clarnette, Roger; Pariente, Jérémie; Dubois, Bruno; Pasquier, Florence; Jack, Clifford R., Jr.; Koeppe, Robert; Snyder, Peter J.; Aisen, Paul S.; Thomas, Ronald G.; Berry, Scott M.; Wendelberger, Barbara A.; Andersen, Scott W.; Holdridge, Karen C.; Mintun, Mark A.; Yaari, Roy; Sims, John R.; Baudler, Monika; Delmar, Paul; Doody, Rachelle S.; Fontoura, Paulo; Giacobino, Caroline; Kerchner, Geoffrey A.; Bateman, Randall J.; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of Medicine
    Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.
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    Asian Cohort for Alzheimer’s Disease (ACAD) Study on Genetic and Non‐Genetic Risk Factors for Alzheimer’s Disease among Asian Americans and Canadians
    (Wiley, 2025-01-09) Wang, Li-San; Ho, Pei-Chuan; Tee, Boon Lead; Li, Clara; Gu, Yian; Yokoyama, Jennifer S.; Reyes-Dumeyer, Dolly; Faber, Kelley M.; Lee, Wan-Ping; Song, Yeunjoo E.; Tzuang, Marian; Vardarajan, Badri N.; Yang, Hyun-Sik; Choi, Yun-Beom; Feldman, Howard H.; Grill, Joshua D.; Henderson, Victor W.; Hsiung, Ging-Yuek Robin; Mayeux, Richard; Rosen, Howard J.; Varma, Rohit; Foroud, Tatiana M.; Kukull, Walter A.; Peavy, Guerry M.; Lee, Haeok; Yu, W. Haung; Chui, Helena C.; Jun, Gyungah R.; Park, Van Ta; Chow, Tiffany W.; The Asian Cohort for Alzheimer’s Disease Study; Medicine, School of Medicine
    Background: Asian Americans and Asian Canadians (ASACs) are the fastest growing minority group in the US and Canada. However, ASACs are under‐sampled in Alzheimer’s disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer’s Disease (ACAD), the first large dementia genetics cohort focusing on Chinese, Korean, and Vietnamese, launched in 2021 to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and diverse cultural and scientific training backgrounds: both are critical in leading AD and CBPR research. Method: Upon receipt of an NIA U19 grant in 2023, ACAD has expanded to 9 recruiting sites (7 US and 2 Canadian), a coordinating site, and an analysis site with a centralized data management system. ACAD developed a comprehensive study protocol including community outreach and recruitment strategies, the data collection packet (DCP), pre‐screening and sample collection procedures, and in English, Chinese (Mandarin and Cantonese), Korean, and Vietnamese. To ensure consistency, ACAD implemented a training curriculum for data/sample collect and for culturally appropriate recruitment approaches in collaboration with community partners, clinics, and nursing homes serving Asian communities. Result: As of December 2023, more than 2,400 people expressed interests in ACAD. A total of 683 of the 899 consented participants completed DCP data into the REDCap (604 Chinese, 54 Korean, and 25 Vietnamese), while 399 saliva samples and 285 blood samples were received. Participants aged 60 –103 years at enrollment, 67% were female, and 47% reported having a college or above education. Currently, ACAD is revising the study protocol in response to feedback received in its pilot phase, including the need to include additional neuropsychological tests and cultural tailored lifestyle questionnaires with an emphasis on immigration experiences. Conclusion: The ACAD team (including community partners) have learned valuable lessons and demonstrated the feasibility of recruiting ASACs in clinical research. With an expansion plan and in collaboration with other AD research focuses on racial minority populations, insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD.
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    Brain volumetric deficits in MAPT mutation carriers: a multisite study
    (Wiley, 2021) Chu, Stephanie A.; Flagan, Taru M.; Staffaroni, Adam M.; Jiskoot, Lize C.; Deng, Jersey; Spina, Salvatore; Zhang, Liwen; Sturm, Virginia E.; Yokoyama, Jennifer S.; Seeley, William W.; Papma, Janne M.; Geschwind, Dan H.; Rosen, Howard J.; Boeve, Bradley F.; Boxer, Adam L.; Heuer, Hilary W.; Forsberg, Leah K.; Brushaber, Danielle E.; Grossman, Murray; Coppola, Giovanni; Dickerson, Bradford C.; Bordelon, Yvette M.; Faber, Kelley; Feldman, Howard H.; Fields, Julie A.; Fong, Jamie C.; Foroud, Tatiana; Gavrilova, Ralitza H.; Ghoshal, Nupur; Graff-Radford, Neill R.; Hsiung, Ging-Yuek Robin; Huey, Edward D.; Irwin, David J.; Kantarci, Kejal; Kaufer, Daniel I.; Karydas, Anna M.; Knopman, David S.; Kornak, John; Kramer, Joel H.; Kukull, Walter A.; Lapid, Maria I.; Litvan, Irene; Mackenzie, Ian R. A.; Mendez, Mario F.; Miller, Bruce L.; Onyike, Chiadi U.; Pantelyat, Alexander Y.; Rademakers, Rosa; Ramos, Eliana Marisa; Roberson, Erik D.; Tartaglia, Maria Carmela; Tatton, Nadine A.; Toga, Arthur W.; Vetor, Ashley; Weintraub, Sandra; Wong, Bonnie; Wszolek, Zbigniew K.; ARTFL/LEFFTDS Consortium; Van Swieten, John C.; Lee, Suzee E.; Medical and Molecular Genetics, School of Medicine
    Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.
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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.
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    Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
    (Springer, 2019-02-09) Pottier, Cyril; Ren, Yingxue; Perkerson, Ralph B.; Baker, Matt; Jenkins, Gregory D.; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; van Rooij, Jeroen G. J.; Murray, Melissa E.; Christopher, Elizabeth; McDonnell, Shannon K.; Fogarty, Zachary; Batzler, Anthony; Tian, Shulan; Vicente, Cristina T.; Matchett, Billie; Karydas, Anna M.; Hsiung, Ging-Yuek Robin; Seelaar, Harro; Mol, Merel O.; Finger, Elizabeth C.; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Heutink, Peter; Synofzik, Matthis; Matthis, Carlo; Prudlo, Johannes; Rizzu, Patrizia; Simon-Sanchez, Javier; Edbauer, Dieter; Roeber, Sigrun; Diehl-Schmid, Janine; Evers, Bret M.; King, Andrew; Mesulam, M. Marsel; Weintraub, Sandra; Geula, Changiz; Bieniek, Kevin F.; Petrucelli, Leonard; Ahern, Geoffrey L.; Reiman, Eric M.; Woodruff, Bryan K.; Caselli, Richard J.; Huey, Edward D.; Farlow, Martin R.; Grafman, Jordan; Mead, Simon; Grinberg, Lea T.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Snowden, Julie; Mann, David; Ertekin-Taner, Nilufer; Uitti, Ryan J.; Wszolek, Zbigniew K.; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Hodges, John R.; Piguet, Olivier; Geier, Ethan G.; Yokoyama, Jennifer S.; Rissman, Robert A.; Rogaeva, Ekaterina; Keith, Julia; Zinman, Lorne; Tartaglia, Maria Carmela; Cairns, Nigel J.; Cruchaga, Carlos; Ghetti, Bernardino; Kofler, Julia; Lopez, Oscar L.; Beach, Thomas G.; Arzberger, Thomas; Herms, Jochen; Honig, Lawrence S.; Vonsattel, Jean Paul; Halliday, Glenda M.; Kwok, John B.; White, Charles L.; Gearing, Marla; Glass, Jonathan; Rollinson, Sara; Pickering-Brown, Stuart; Rohrer, Jonathan D.; Trojanowski, John Q.; Van Deerlin, Vivianna; Bigio, Eileen H.; Troakes, Claire; Al-Sarraj, Safa; Asmann, Yan; Miller, Bruce L.; Graff-Radford, Neill R.; Boeve, Bradley F.; Seeley, William W.; Mackenzie, Ian R. A.; van Swieten, John C.; 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) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
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    Psychotropic medication usage in sporadic versus genetic behavioral-variant frontotemporal dementia
    (Wiley, 2025) Vargas-Gonzalez, Juan-Camilo; Dimal, Nico; Cortez, Kasey; Heuer, Hilary; Forsberg, Leah K.; Appleby, Brian S.; Barmada, Sami; Bozoki, Andrea; Clark, David; Cobigo, Yann; Darby, R. Ryan; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Galasko, Douglas R.; Geschwind, Daniel H.; Ghoshal, Nupur; Graff-Radford, Neill R.; Grant, Ian M.; Irwin, David; Hsiung, Ging-Yuek Robin; Honig, Lawrence S.; Kantarci, Kejal; Léger, Gabriel C.; Litvan, Irene; Mackenzie, Ian R.; Masdeu, Joseph C.; Mendez, Mario F.; Onyike, Chiadi U.; Pascual, Belen; Pressman, Peter; Ramos, Eliana Marisa; Roberson, Erik D.; Rogalski, Emily; Boeve, Brad F.; Boxer, Adam L.; Rosen, Howie J.; Tartaglia, Maria Carmela; ALLFTD Consortium Investigators; Neurology, School of Medicine
    Introduction: Psychotropic medication (PM) use in behavioral-variant frontotemporal dementia (bvFTD) is higher than in other dementias. However, no information exists on whether PM use differs between sporadic and genetic bvFTD. Methods: We analyzed data from sporadic and genetic bvFTD participants with PM prescriptions in the Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects study. We estimated ordinal odds ratio (OOR) of having more PM comparing sporadic and genetic bvFTD. Finally, we explored the neuropsychiatric symptom (NPS) combinations using classification and regression trees (CART). Results: We included 263 with sporadic and 193 with genetic bvFTD. The OOR for sporadic bvFTD to be on PM was 1.75 (95% confidence interval: 1.21 to 2.53) for the fully adjusted model. CART revealed the most common NPS combination was apathy + personality changes in 18% of participants. Discussion: Participants with sporadic bvFTD were twice as likely to be on PM compared to genetic bvFTD. The reason for increased PM usage in sporadic bvFTD participants should be further investigated. Highlights: We report on patients with behavioral variant frontotemporal dementia (bvFTD). We evaluated the psychotropic medication (PM) prescription at baseline in the cohort. Patients with sporadic bvFTD had more prescriptions for PM than genetic patients. The frequency of symptoms combination was different in sporadic and genetic bvFTD.