Browsing by Author "Snyder, Allison"

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    Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders
    (Springer Nature, 2025-03-12) Sheth, Udit; Öijerstedt, Linn; Heckman, Michael G.; White, Launia J.; Heuer, Hilary W.; Lago, Argentina Lario; Forsberg, Leah K.; Faber, Kelley M.; Foroud, Tatiana M.; Rademakers, Rosa; Ramos, Eliana Marisa; Appleby, Brian S.; Bozoki, Andrea C.; Darby, R. Ryan; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Galasko, Douglas R.; Ghoshal, Nupur; Graff-Radford, Neill R.; Grant, Ian M.; Hales, Chadwick M.; Hsiung, Ging-Yuek Robin; Huey, Edward D.; Irwin, David; Kwan, Justin Y.; Litvan, Irene; Mackenzie, Ian R.; Masdeu, Joseph C.; Mendez, Mario F.; Onyike, Chiadi U.; Pascual, Belen; Pressman, Peter S.; Roberson, Erik D.; Snyder, Allison; Tartaglia, M. Carmela; Seeley, William W.; Dickson, Dennis W.; Rosen, Howard J.; Boeve, Bradley F.; Boxer, Adam L.; Petrucelli, Leonard; Gendron, Tania F.; Medical and Molecular Genetics, School of Medicine
    Background: Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing to inconsistent findings. Therefore, we evaluated plasma GFAP as a FTD biomarker and compared its performance to that of neurofilament light (NfL) protein, a leading FTD biomarker. Methods: We availed ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources to conduct a comprehensive cross-sectional and longitudinal examination of the susceptibility/risk, prognostic, and predictive performance of GFAP and NfL in the largest series of well-characterized presymptomatic FTD mutation carriers and participants with sporadic or familial FTD syndromes. Utilizing single molecule array technology, we measured GFAP and NfL in plasma from 161 controls, 127 presymptomatic mutation carriers, 702 participants with a FTD syndrome, and 67 participants with mild behavioral and/or cognitive changes. We used multivariable linear regression and Cox proportional hazard models adjusted for co-variates to examine the biomarker utility of baseline GFAP and NfL concentrations or their rates of change. Results: Compared to controls, GFAP and NfL were elevated in each FTD syndrome but GFAP, unlike NfL, poorly discriminated controls from participants with mild symptoms. Similarly, both baseline GFAP and NfL were higher in presymptomatic mutation carriers who later phenoconverted, but NfL better distinguished non-converters from phenoconverters. We additionally observed that GFAP and NfL were associated with disease severity indicators and survival, but NfL far outperformed GFAP. Nevertheless, we validated findings that the GFAP/NfL ratio may discriminate frontotemporal lobar degeneration with tau versus TDP-43 pathology. Conclusions: Our head-to-head comparison of plasma GFAP and NfL as biomarkers for FTD indicate that NfL consistently outmatched GFAP as a prognostic and predictive biomarker for participants with a FTD syndrome, and as a susceptibility/risk biomarker for people at genetic risk of FTD. Our findings underscore the need to include leading biomarkers in investigations evaluating new biomarkers if the field is to fully ascertain their performance and clinical value.
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    Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia
    (Wiley, 2025) Memel, Molly; Staffaroni, Adam M.; Ilan-Gala, Ignacio; Garcia Castro, Jesús; Kornak, John; Tartaglia, Carmela M.; Saloner, Rowan; VandeBunte, Anna M.; Paolillo, Emily W.; Cadwallader, Claire J.; Chen, Coty; Gorno-Tempini, Maria Luisa; Mandelli, Malu; Apostolova, Liana; Graff-Radford, Neil; Litvan, Irene; Bayram, Ece; Pressman, Peter S.; Miyagawa, Toji; Mackenzie, Ian; Goldman, Jill; Darby, Richard R.; Appleby, Brian S.; Petrucelli, Len; Gendron, Tania; Heuer, Hilary W.; Forseberg, Leah K.; Rojas, Julio C.; Boeve, Brad F.; Brushaber, Nellie; Domoto-Reilly, Kimiko; Ghoshal, Nupur; Lapid, Maria; Pascual, Belen; Lee, Suzee; Ramos, Eliana Marisa; Ramanan, Vijay; Rademakers, Rosa; Rascovsky, Katya; Pantelyat, Alex; Masdeu, Joseph C.; Snyder, Allison; Boxer, Adam L.; Rosen, Howard J.; Casaletto, Kaitlin; ALLFTD Consortium; Neurology, School of Medicine
    Introduction: Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). Methods: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed-effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). Results: While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. Discussion: In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations. Highlights: Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.