Browsing by Author "White, Launia J."

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    Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders
    (Elsevier, 2022) Gendron, Tania F.; Heckman, Michael G.; White, Launia J.; Veire, Austin M.; Pedraza, Otto; Burch, Alexander R.; Bozoki, Andrea C.; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Foroud, Tatiana; Forsberg, Leah K.; Galasko, Douglas R.; Ghoshal, Nupur; Graff-Radford, Neill R.; Grossman, Murray; Heuer, Hilary W.; Huey, Edward D.; Hsiung, Ging-Yuek R.; Irwin, David J.; Kaufer, Daniel I.; Leger, Gabriel C.; Litvan, Irene; Masdeu, Joseph C.; Mendez, Mario F.; Onyike, Chiadi U.; Pascual, Belen; Ritter, Aaron; Roberson, Erik D.; Rojas, Julio C.; Tartaglia, Maria Carmela; Wszolek, Zbigniew K.; Rosen, Howard; Boeve, Bradley F.; Boxer, Adam L.; ALLFTD consortium; Petrucelli, Leonard; Medical and Molecular Genetics, School of Medicine
    Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.
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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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    Serum Hormone Levels and Normal Breast Histology Among Premenopausal Women
    (Springer Nature, 2022) Sherman, Mark E.; de Bel, Thomas; Heckman, Michael G.; White, Launia J.; Ogony, Joshua; Stallings-Mann, Melody; Hilton, Tracy; Degnim, Amy C.; Vierkant, Robert A.; Hoskin, Tanya; Jensen, Matthew R.; Pacheco-Spann, Laura; Henry, Jill E.; Storniolo, Anna Maria; Carter, Jodi M.; Winham, Stacey J.; Radisky, Derek C.; van der Laak, Jeroenpeop; Medicine, School of Medicine
    Purpose: Breast terminal duct lobular units (TDLUs) are the main source of breast cancer (BC) precursors. Higher serum concentrations of hormones and growth factors have been linked to increased TDLU numbers and to elevated BC risk, with variable effects by menopausal status. We assessed associations of circulating factors with breast histology among premenopausal women using artificial intelligence (AI) and preliminarily tested whether parity modifies associations. Methods: Pathology AI analysis was performed on 316 digital images of H&E-stained sections of normal breast tissues from Komen Tissue Bank donors ages ≤ 45 years to assess 11 quantitative metrics. Associations of circulating factors with AI metrics were assessed using regression analyses, with inclusion of interaction terms to assess effect modification. Results: Higher prolactin levels were related to larger TDLU area (p < 0.001) and increased presence of adipose tissue proximate to TDLUs (p < 0.001), with less significant positive associations for acini counts (p = 0.012), dilated acini (p = 0.043), capillary area (p = 0.014), epithelial area (p = 0.007), and mononuclear cell counts (p = 0.017). Testosterone levels were associated with increased TDLU counts (p < 0.001), irrespective of parity, but associations differed by adipose tissue content. AI data for TDLU counts generally agreed with prior visual assessments. Conclusion: Among premenopausal women, serum hormone levels linked to BC risk were also associated with quantitative features of normal breast tissue. These relationships were suggestively modified by parity status and tissue composition. We conclude that the microanatomic features of normal breast tissue may represent a marker of BC risk.
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    Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence
    (BMC, 2022-07-11) Ogony, Joshua; de Bel, Thomas; Radisky, Derek C.; Kachergus, Jennifer; Thompson, E. Aubrey; Degnim, Amy C.; Ruddy, Kathryn J.; Hilton, Tracy; Stallings‑Mann, Melody; Vachon, Celine; Hoskin, Tanya L.; Heckman, Michael G.; Vierkant, Robert A.; White, Launia J.; Moore, Raymond M.; Carter, Jodi; Jensen, Matthew; Pacheco‑Spann, Laura; Henry, Jill E.; Storniolo, Anna Maria; Winham, Stacey J.; van der Laak, Jeroen; Sherman, Mark E.; Medicine, School of Medicine
    Background: Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. Methods: Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher's exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models. Results: Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. Conclusions: Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.