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Browsing by Author "Zimmer, Jennifer A."
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Item Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study(MDPI, 2021-04-28) Hendrix, James A.; Airey, David C.; Britton, Angela; Burke, Anna D.; Capone, George T.; Chavez, Ronelyn; Chen, Jacqueline; Chicoine, Brian; Costa, Alberto C.S.; Dage, Jeffrey L.; Doran, Eric; Esbensen, Anna; Evans, Casey L.; Faber, Kelley M.; Foroud, Tatiana M.; Hart, Sarah; Haugen, Kelsey; Head, Elizabeth; Hendrix, Suzanne; Hillerstrom, Hampus; Kishnani, Priya S.; Krell, Kavita; Ledesma, Duvia Lara; Lai, Florence; Lott, Ira; Ochoa-Lubinoff, Cesar; Mason, Jennifer; Nicodemus-Johnson, Jessie; Proctor, Nicholas Kyle; Pulsifer, Margaret B.; Revta, Carolyn; Rosas, H. Diana; Rosser, Tracie C.; Santoro, Stephanie; Schafer, Kim; Scheidemantel, Thomas; Schmitt, Frederick; Skotko, Brian G.; Stasko, Melissa R.; Talboy, Amy; Torres, Amy; Wilmes, Kristi; Woodward, Jason; Zimmer, Jennifer A.; Feldman, Howard H.; Mobley, William; Medical and Molecular Genetics, School of MedicineWith improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.Item Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial(American Medical Association, 2023) Sims, John R.; Zimmer, Jennifer A.; Evans, Cynthia D.; Lu, Ming; Ardayfio, Paul; Sparks, JonDavid; Wessels, Alette M.; Shcherbinin, Sergey; Wang, Hong; Monkul Nery, Emel Serap; Collins, Emily C.; Solomon, Paul; Salloway, Stephen; Apostolova, Liana G.; Hansson, Oskar; Ritchie, Craig; Brooks, Dawn A.; Mintun, Mark; Skovronsky, Daniel M.; TRAILBLAZER-ALZ 2 Investigators; Neurology, School of MedicineImportance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, setting, and participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main outcomes and measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.