Browsing by Author "Wong, Bonnie"

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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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    Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia
    (Elsevier, 2021) Barker, Megan S.; Manoochehri, Masood; Rizer, Sandra J.; Appleby, Brian S.; Brushaber, Danielle; Dev, Sheena I.; Devick, Katrina L.; Dickerson, Bradford C.; Fields, Julie A.; Foroud, Tatiana M.; Forsberg, Leah K.; Galasko, Douglas R.; Ghoshal, Nupur; Graff-Radford, Neill R.; Grossman, Murray; Heuer, Hilary W.; Hsiung, Ging-Yuek; Kornak, John; Litvan, Irene; Mackenzie, Ian R.; Mendez, Mario F.; Pascual, Belen; Rankin, Katherine P.; Rascovsky, Katya; Staffaroni, Adam M.; Tartaglia, Maria Carmela; Weintraub, Sandra; Wong, Bonnie; Boeve, Bradley F.; Boxer, Adam L.; Rosen, Howard J.; Goldman, Jill; Huey, Edward D.; Cosentino, Stephanie; ALLFTD consortium; Medical and Molecular Genetics, School of Medicine
    Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.
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    Temporal order of clinical and biomarker changes in familial frontotemporal dementia
    (Springer Nature, 2022) Staffaroni, Adam M.; Quintana, Melanie; Wendelberger, Barbara; Heuer, Hilary W.; Russell, Lucy L.; Cobigo, Yann; Wolf, Amy; Goh, Sheng-Yang Matt; Petrucelli, Leonard; Gendron, Tania F.; Heller, Carolin; Clark, Annie L.; Taylor, Jack Carson; Wise, Amy; Ong, Elise; Forsberg, Leah; Brushaber, Danielle; Rojas, Julio C.; VandeVrede, Lawren; Ljubenkov, Peter; Kramer, Joel; Casaletto, Kaitlin B.; Appleby, Brian; Bordelon, Yvette; Botha, Hugo; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Fields, Julie A.; Foroud, Tatiana; Gavrilova, Ralitza; Geschwind, Daniel; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathon; Graff-Radford, Neill; Grossman, Murray; Hall, Matthew G. H.; Hsiung, Ging-Yuek; Huey, Edward D.; Irwin, David; Jones, David T.; Kantarci, Kejal; Kaufer, Daniel; Knopman, David; Kremers, Walter; Lago, Argentina Lario; Lapid, Maria I.; Litvan, Irene; Lucente, Diane; Mackenzie, Ian R.; Mendez, Mario F.; Mester, Carly; Miller, Bruce L.; Onyike, Chiadi U.; Rademakers, Rosa; Ramanan, Vijay K.; Ramos, Eliana Marisa; Rao, Meghana; Rascovsky, Katya; Rankin, Katherine P.; Roberson, Erik D.; Savica, Rodolfo; Tartaglia, M. Carmela; Weintraub, Sandra; Wong, Bonnie; Cash, David M.; Bouzigues, Arabella; Swift, Imogen J.; Peakman, Georgia; Bocchetta, Martina; Todd, Emily G.; Convery, Rhian S.; Rowe, James B.; Borroni, Barbara; Galimberti, Daniela; Tiraboschi, Pietro; Masellis, Mario; Finger, Elizabeth; van Swieten, John C.; Seelaar, Harro; Jiskoot, Lize C.; Sorbi, Sandro; Butler, Chris R.; Graff, Caroline; Gerhard, Alexander; Langheinrich, Tobias; Laforce, Robert; Sanchez-Valle, Raquel; de Mendonça, Alexandre; Moreno, Fermin; Synofzik, Matthis; Vandenberghe, Rik; Ducharme, Simon; Le Ber, Isabelle; Levin, Johannes; Danek, Adrian; Otto, Markus; Pasquier, Florence; Santana, Isabel; Kornak, John; Boeve, Bradley F.; Rosen, Howard J.; Rohrer, Jonathan D.; Boxer, Adam L.; Frontotemporal Dementia Prevention Initiative (FPI) Investigators; Medicine, School of Medicine
    Unlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN, and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes, and plasma neurofilament light chain (NfL) in 796 carriers and 412 non-carrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations employing model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. F-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.