Browsing by Author "Fields, Julie A."

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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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    Longitudinal Clinical, Neuropsychological, and Neuroimaging Characterization of a Kindred with a 12-Octapeptide Repeat Insertion in PRNP: The Next Generation
    (Taylor & Francis, 2020-08) Townley, Ryan A.; Polsinelli, Angelina J.; Fields, Julie A.; Machulda, Mary M.; Jones, David T.; Graff-Radford, Jonathan; Kantarci, Kejal M.; Lowe, Val J.; Rademakers, Rosa V.; Baker, Matt C.; Kumar, Neeraj; Boeve, Bradley F.; Neurology, School of Medicine
    Background: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. Method: Clinical, neuropsychological, and neuroimaging characterization of a kindred. Results: Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. Conclusions and relevance: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection.
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    Mayo Normative Studies: Amyloid and Neurodegeneration Negative Normative Data for the Auditory Verbal Learning Test and Sex-Specific Sensitivity to Mild Cognitive Impairment/Dementia
    (IOS Press, 2024) Stricker, Nikki H.; Christianson, Teresa J.; Pudumjee, Shehroo B.; Polsinelli, Angelina J.; Lundt, Emily S.; Frank, Ryan D.; Kremers, Walter K.; Machulda, Mary M.; Fields, Julie A.; Jack, Clifford R., Jr.; Knopman, David S.; Graff-Radford, Jonathan; Vemuri, Prashanthi; Mielke, Michelle M.; Petersen, Ronald C.; Neurology, School of Medicine
    Background: Conventional normative samples include individuals with undetected Alzheimer's disease neuropathology, lowering test sensitivity for cognitive impairment. Objective: We developed Mayo Normative Studies (MNS) norms limited to individuals without elevated amyloid or neurodegeneration (A-N-) for Rey's Auditory Verbal Learning Test (AVLT). We compared these MNS A-N- norms in female, male, and total samples to conventional MNS norms with varying levels of demographic adjustments. Methods: The A-N- sample included 1,059 Mayo Clinic Study of Aging cognitively unimpaired (CU) participants living in Olmsted County, MN, who are predominantly non-Hispanic White. Using a regression-based approach correcting for age, sex, and education, we derived fully-adjusted T-score formulas for AVLT variables. We validated these A-N- norms in two independent samples of CU (n = 261) and mild cognitive impairment (MCI)/dementia participants (n = 392) > 55 years of age. Results: Variability associated with age decreased by almost half in the A-N- norm sample relative to the conventional norm sample. Fully-adjusted MNS A-N- norms showed approximately 7- 9% higher sensitivity to MCI/dementia compared to fully-adjusted MNS conventional norms for trials 1- 5 total and sum of trials. Among women, sensitivity to MCI/dementia increased with each normative data refinement. In contrast, age-adjusted conventional MNS norms showed greatest sensitivity to MCI/dementia in men. Conclusions: A-N- norms show some benefits over conventional normative approaches to MCI/dementia sensitivity, especially for women. We recommend using these MNS A-N- norms alongside MNS conventional norms. Future work is needed to determine if normative samples that are not well characterized clinically show greater benefit from biomarker-refined approaches.
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    Plasma‐derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms: A community‐based study
    (Wiley, 2023-07-30) Krell-Roesch, Janina; Zaniletti, Isabella; Syrjanen, Jeremy A.; Kremers, Walter K.; Algeciras-Schimnich, Alicia; Dage, Jeffrey L.; van Harten, Argonde C.; Fields, Julie A.; Knopman, David S.; Jack, Clifford R., Jr.; Petersen, Ronald C.; Vassilaki, Maria; Geda, Yonas E.; Neurology, School of Medicine
    Introduction: We examined associations between plasma-derived biomarkers of Alzheimer's disease (AD) and neuropsychiatric symptoms (NPS) in community-dwelling older adults. Methods: Cross-sectional study involving 1005 persons ≥50 years of age (mean 74 years, 564 male, 118 cognitively impaired), who completed plasma-derived biomarker (amyloid beta 42 [Aβ42]/Aβ40, phosphorylated tau 181 [p-tau181], p-tau217, total tau [t-tau], neurofilament light [NfL]), and NPS assessment. Results: P-tau181 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.41-3.00, p < 0.001), p-tau217 (OR 1.70, 95% CI 1.10-2.61, p = 0.016), and t-tau (OR 1.44, 95% CI 1.08-1.92, p = 0.012) were associated with appetite change. We also found that p-tau181 and p-tau217 were associated with increased symptoms of agitation (OR 1.93, 95% CI 1.20-3.11, p = 0.007 and OR 2.04, 95% CI 1.21-3.42, p = 0.007, respectively), and disinhibition (OR 2.39, 95% CI 1.45-3.93, p = 0.001 and OR 2.30, 95% CI 1.33-3.98, p = 0.003, respectively). Aβ42/Aβ40 and NfL were not associated with NPS. Conclusion: Higher plasma-derived p-tau181 and p-tau217 levels are associated with increased symptoms of appetite change, agitation, and disinhibition. These findings may support the validity of plasma tau biomarkers for predicting behavioral symptoms that often accompany cognitive impairment. Highlights: We studied 1005 community-dwelling persons aged ≥ 50 years. Higher plasma tau levels are associated with increased neuropsychiatric symptoms Aβ42/Aβ40 and NfL are not associated with neuropsychiatric symptoms. Clinicians should treat neuropsychiatric symptoms in persons with high plasma-derived tau.
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    Proposed research criteria for prodromal behavioural variant frontotemporal dementia
    (Oxford University Press, 2022) Barker, Megan S.; Gottesman, Reena T.; Manoochehri, Masood; Chapman, Silvia; Appleby, Brian S.; Brushaber, Danielle; Devick, Katrina L.; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Fields, Julie A.; Forsberg, Leah K.; Galasko, Douglas R.; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Neill R.; Grossman, Murray; Heuer, Hilary W.; Hsiung, Ging-Yuek; Knopman, David S.; Kornak, John; Litvan, Irene; Mackenzie, Ian R.; Masdeu, Joseph C.; Mendez, Mario F.; Pascual, Belen; Staffaroni, Adam M.; Tartaglia, Maria Carmela; Boeve, Bradley F.; Boxer, Adam L.; Rosen, Howard J.; Rankin, Katherine P.; Cosentino, Stephanie; Rascovsky, Katya; Huey, Edward D.; ALLFTD Consortium; Neurology, School of Medicine
    At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.
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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.