Browsing by Author "Wang, Hong"

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    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 Medicine
    Importance: 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.
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    Pathobiology of neuroinflammation and basal ganglia circuitry in Parkinson’s Disease
    (2017-05) Wilson, Jonathan Matthew; Stauffacher, Cynthia; Belecky-Adams, Teri; Merchant, Kalpana; Wang, Hong; Baucum, Anthony; Chernoff, Ellen
    Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and the most common movement disorder. A defining pathologic feature of PD is the progressive death of dopaminergic neurons in a basal ganglia nucleus termed the substantia nigra (SN). Another hallmark feature of PD pathology is the presence of Lewy bodies and Lewy neurites, which are cellular inclusions with aggregated protein depositions, representing pathology in neuronal cell bodies and neuritic processes. Recently, epidemiological and genetic studies support roles for neuroinflammation in the progression of PD. Two types of cells that play a critical role in regulating neuroinflammation are microglia and astrocytes, which are activated in the basal ganglia of PD patients. Studies within this dissertation characterized activation of microglial cells by alpha-synuclein (α-synuclein), the most abundant protein in Lewy bodies, which has been implicated in PD pathogenesis. To garner insights into molecular mechanisms associated with astrocyte proliferation and activation, genomic alterations during developmental stages of astrocytes were examined since they are likely to recapitulate the reactivity associated with gliosis in PD brain. The activation of these glial cells and pathology of neurons in the basal ganglia causes the hallmark symptoms of PD. The symptoms of PD are termed parkinsonism. These are thought to result, at least in part, from alterations in the balance of output of the neostriatal efferent neurons, due to the loss of dopaminergic neuronal innervation of these cells. Phosphodiesterase 10A (PDE10A) is preferentially expressed in neostriatal efferent pathways and PDE10A inhibitors (PDE10i) have been shown to target dopamine signaling mechanisms. Studies here have utilized PDE10i to understand the balance of activation of medium spiny neurons in the indirect pathway versus activation of the direct pathway, since recent findings show PDE10i lead to a decrease in thalamic drive to the motor cortex, a primary symptom of PD. In conclusion, the aims of this dissertation sought to identify neuroinflammatory mechanisms within activated microglia in response to α-synuclein and proliferating astrocytes. Also, this work evaluated an inhibition of PDE10A in neurons within a region important to the progression of PD.
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    ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death
    (Massachusetts Medical Society, 2013) Vander Lugt, Mark T.; Braun, Thomas M.; Hanash, Samir; Ritz, Jerome; Ho, Vincent T.; Antin, Joseph H.; Zhang, Qing; Wong, Chee-Hong; Wang, Hong; Chin, Alice; Gomez, Aurélie; Harris, Andrew C.; Levine, John E.; Choi, Sung W.; Couriel, Daniel; Reddy, Pavan; Ferrara, James L. M.; Paczesny, Sophie; Pediatrics, School of Medicine
    Background: No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation. Methods: We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation. Results: Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen. Conclusions: ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation.