Browsing by Author "Burnham, Samantha C."

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    Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial
    (American Medical Association, 2022) Pontecorvo, Michael J.; Lu, Ming; Burnham, Samantha C.; Schade, Andrew E.; Dage, Jeffrey L.; Shcherbinin, Sergey; Collins, Emily C.; Sims, John R.; Mintun, Mark A.; Neurology, School of Medicine
    Importance: Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes. Objective: To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease. Design, setting, and participants: TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-β. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels. Interventions: Randomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction. Main outcomes and measures: Change in plasma biomarker levels after donanemab treatment. Results: In TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, -0.04 [95% CI, -0.07 to -0.02]; P = .002 and -0.04 [95% CI, -0.07 to -0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-β 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P < .001 and R = 0.453 [95% CI, 0.306-0.579]; P < .001, respectively) following treatment. Additionally, plasma levels of pTau217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P < .001 and R = 0.393 [95% CI, 0.254-0.517]; P < .001, respectively). Conclusions and relevance: Significant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation.
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    Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume
    (Springer, 2022) Milicic, Lidija; Vacher, Michael; Porter, Tenielle; Doré, Vincent; Burnham, Samantha C.; Bourgeat, Pierrick; Shishegar, Rosita; Doecke, James; Armstrong, Nicola J.; Tankard, Rick; Maruff, Paul; Masters, Colin L.; Rowe, Christopher C.; Villemagne, Victor L.; Laws, Simon M.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Australian Imaging Biomarkers and Lifestyle (AIBL) Study; Medical and Molecular Genetics, School of Medicine
    The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer's Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.
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    Considerations for widespread implementation of blood-based biomarkers of Alzheimer's disease
    (Wiley, 2024) Mielke, Michelle M.; Anderson, Matthew; Ashford, J. Wesson; Jeromin, Andreas; Lin, Pei-Jung; Rosen, Allyson; Tyrone, Jamie; VandeVrede, Lawren; Willis, Deanna; Hansson, Oskar; Khachaturian, Ara S.; Schindler, Suzanne E.; Weiss, Joan; Batrla, Richard; Bozeat, Sasha; Dwyer, John R.; Holzapfel, Drew; Jones, Daryl Rhys; Murray, James F.; Partrick, Katherine A.; Scholler, Emily; Vradenburg, George; Young, Dylan; Braunstein, Joel B.; Burnham, Samantha C.; de Oliveira, Fabricio Ferreira; Hu, Yan Helen; Mattke, Soeren; Merali, Zul; Monane, Mark; Sabbagh, Marwan Noel; Shobin, Eli; Weiner, Michael W.; Udeh-Momoh , Chinedu T.; Medicine, School of Medicine
    Diagnosing Alzheimer's disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer's Disease BBM Workgroup convened to address these challenges and provide recommendations that underscore the importance of evidence-based guidelines, improved training for health-care professionals, patient empowerment through informed decision making, and the necessity of community-based studies to understand BBM performance in real-world populations. Multi-stakeholder engagement is essential to implement these recommendations and ensure credible guidance and education are accessible to all stakeholders.
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    Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease
    (Wiley, 2024) Mielke, Michelle M.; Anderson, Matthew; Ashford, J. Wesson; Jeromin, Andreas; Lin, Pei-Jung; Rosen, Allyson; Tyrone, Jamie; Vandevrede, Lawren; Willis, Deanna R.; Hansson, Oskar; Khachaturian, Ara S.; Schindler, Suzanne E.; Weiss, Joan; Batrla, Richard; Bozeat, Sasha; Dwyer, John R.; Holzapfel, Drew; Jones, Daryl Rhys; Murray, James F.; Partrick, Katherine A.; Scholler, Emily; Vradenburg, George; Young, Dylan; Braunstein, Joel B.; Burnham, Samantha C.; de Oliveira, Fabricio Ferreira; Hu, Yan Helen; Mattke, Soeren; Merali, Zul; Monane, Mark; Sabbagh, Marwan Noel; Shobin, Eli; Weiner, Michael; Udeh-Momoh, Chinedu T.; Medicine, School of Medicine
    Blood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational pathways for BBMs: one for current use for triaging and another for future use to confirm amyloid pathology. These pathways provide a standardized diagnostic approach with guidance on interpreting BBM test results. Integrating BBMs into clinical practice will simplify the diagnostic process and facilitate timely access to DMTs for eligible patients.