Pub Date : 2025-10-27DOI: 10.1001/jamaneurol.2025.4152
Yiran Zhang,Brian H Buck,Philip A Barber,Kausik Chatterjee,Brian Clarke,Philip M C Choi,Gary Hunter,Aravind Ganesh,Sachin M Mishra,David Williams,Bruce C V Campbell,Dar Dowlatshahi,Ken S Butcher,Kailash Krishnan,M Ivan Wiggam,Timothy J Kleinig,Keith W Muir,Charlotte Zerna,Thalia S Field,Mayank Goyal,Amy Y X Yu,Christine Roffe,Andrew M Demchuck,Mark W Parsons,Rodrigo Bazan,Sandeep Ankolekar,James Kennedy,Bijoy K Menon,Jennifer L Mandzia,Arthur Pille,Peter J Kelly,Martha Marko,Nishita Singh,Shabnam Vatanpour,Fabrico O Lima,Luciana Catanese,MacKenzie Horn,Darshan Ghia,Julia Ferrari,Stefen Greisenegger,Michael D Hill,Shelagh B Coutts,
ImportanceOutcomes following intravenous thrombolysis for minor ischemic stroke may vary based on the presence of disabling deficits.ObjectiveTo determine whether intravenous tenecteplase improves outcomes according to US National Institutes of Health Stroke Scale (NIHSS) score-based definitions of pretreatment disabling deficits.Design, Setting, and ParticipantsThis is a secondary analysis of the TEMPO-2 (Tenecteplase vs Standard of Care for Minor Ischemic Stroke With Proven Occlusion) randomized clinical trial, conducted between April 27, 2015, and January 19, 2024. Patients were followed up for 90 days. The TEMPO-2 trial was conducted across 48 sites globally among patients with minor ischemic stroke (NIHSS 0-5) and proven intracranial occlusion within 12 hours of onset. Patients were divided into having nondisabling vs disabling syndromes at presentation as per the TREAT Task Force consensus. Other established definitions of disabling stroke from the ARAMIS trial and the National Institute of Neurological Disorders and Stroke trial were explored. Data analysis was completed from July 2024 to September 2024.InterventionsIntravenous tenecteplase (0.25 mg/kg) vs nonthrombolytic standard of care.Main Outcomes and MeasuresThe primary outcome was a return to baseline modified Rankin scale score at 90 days.ResultsAmong 886 enrolled patients, 2 withdrew consent and 884 were included in the secondary analysis. Among 884 patients analyzed (369 women [41.7%]; median [IQR] age, 72 [61-80] years), 100 (11.3%) had disabling and 784 (88.7%) had nondisabling deficits. Patients with disabling deficits had higher median (IQR) baseline NIHSS scores (4 [3-5] vs 2 [1-3]), later presentations (onset to hospital arrival time: 288 [153-412] minutes vs 133 [70-310] minutes), and longer onset to treatment time (411 [307-560] minutes vs 278 [170-462] minutes) than those with nondisabling deficits. In the disabling group, the primary outcome following tenecteplase, compared with standard of care, occurred in 29 patients (54.7%) vs 32 patients (68.1%) (adjusted risk ratio [aRR], 0.81; 95% CI, 0.60-1.10). This neutral treatment effect was consistent in patients without disabling deficits (280 [73.9%] vs 306 [75.6%]; aRR, 0.98; 95% CI, 0.91-1.07; P for interaction = .32).Conclusions and RelevanceIn this secondary analysis of the TEMPO-2 randomized clinical trial, current definitions of disabling symptoms based on NIHSS score at baseline did not modify the neutral treatment effect of intravenous tenecteplase in patients with minor stroke and intracranial occlusion. Together with converging evidence comparing intravenous thrombolysis to nonthrombolytic standard of care, this analysis suggests the need to reevaluate thrombolysis in minor disabling stroke.Trial RegistrationClinicalTrials.gov Identifier: NCT02398656.
{"title":"Thrombolysis With Tenecteplase for Minor Disabling Stroke: Secondary Analysis of the TEMPO-2 Randomized Clinical Trial.","authors":"Yiran Zhang,Brian H Buck,Philip A Barber,Kausik Chatterjee,Brian Clarke,Philip M C Choi,Gary Hunter,Aravind Ganesh,Sachin M Mishra,David Williams,Bruce C V Campbell,Dar Dowlatshahi,Ken S Butcher,Kailash Krishnan,M Ivan Wiggam,Timothy J Kleinig,Keith W Muir,Charlotte Zerna,Thalia S Field,Mayank Goyal,Amy Y X Yu,Christine Roffe,Andrew M Demchuck,Mark W Parsons,Rodrigo Bazan,Sandeep Ankolekar,James Kennedy,Bijoy K Menon,Jennifer L Mandzia,Arthur Pille,Peter J Kelly,Martha Marko,Nishita Singh,Shabnam Vatanpour,Fabrico O Lima,Luciana Catanese,MacKenzie Horn,Darshan Ghia,Julia Ferrari,Stefen Greisenegger,Michael D Hill,Shelagh B Coutts, ","doi":"10.1001/jamaneurol.2025.4152","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.4152","url":null,"abstract":"ImportanceOutcomes following intravenous thrombolysis for minor ischemic stroke may vary based on the presence of disabling deficits.ObjectiveTo determine whether intravenous tenecteplase improves outcomes according to US National Institutes of Health Stroke Scale (NIHSS) score-based definitions of pretreatment disabling deficits.Design, Setting, and ParticipantsThis is a secondary analysis of the TEMPO-2 (Tenecteplase vs Standard of Care for Minor Ischemic Stroke With Proven Occlusion) randomized clinical trial, conducted between April 27, 2015, and January 19, 2024. Patients were followed up for 90 days. The TEMPO-2 trial was conducted across 48 sites globally among patients with minor ischemic stroke (NIHSS 0-5) and proven intracranial occlusion within 12 hours of onset. Patients were divided into having nondisabling vs disabling syndromes at presentation as per the TREAT Task Force consensus. Other established definitions of disabling stroke from the ARAMIS trial and the National Institute of Neurological Disorders and Stroke trial were explored. Data analysis was completed from July 2024 to September 2024.InterventionsIntravenous tenecteplase (0.25 mg/kg) vs nonthrombolytic standard of care.Main Outcomes and MeasuresThe primary outcome was a return to baseline modified Rankin scale score at 90 days.ResultsAmong 886 enrolled patients, 2 withdrew consent and 884 were included in the secondary analysis. Among 884 patients analyzed (369 women [41.7%]; median [IQR] age, 72 [61-80] years), 100 (11.3%) had disabling and 784 (88.7%) had nondisabling deficits. Patients with disabling deficits had higher median (IQR) baseline NIHSS scores (4 [3-5] vs 2 [1-3]), later presentations (onset to hospital arrival time: 288 [153-412] minutes vs 133 [70-310] minutes), and longer onset to treatment time (411 [307-560] minutes vs 278 [170-462] minutes) than those with nondisabling deficits. In the disabling group, the primary outcome following tenecteplase, compared with standard of care, occurred in 29 patients (54.7%) vs 32 patients (68.1%) (adjusted risk ratio [aRR], 0.81; 95% CI, 0.60-1.10). This neutral treatment effect was consistent in patients without disabling deficits (280 [73.9%] vs 306 [75.6%]; aRR, 0.98; 95% CI, 0.91-1.07; P for interaction = .32).Conclusions and RelevanceIn this secondary analysis of the TEMPO-2 randomized clinical trial, current definitions of disabling symptoms based on NIHSS score at baseline did not modify the neutral treatment effect of intravenous tenecteplase in patients with minor stroke and intracranial occlusion. Together with converging evidence comparing intravenous thrombolysis to nonthrombolytic standard of care, this analysis suggests the need to reevaluate thrombolysis in minor disabling stroke.Trial RegistrationClinicalTrials.gov Identifier: NCT02398656.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"50 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-20DOI: 10.1001/jamaneurol.2025.3916
Theresa A Zesiewicz,Peter A LeWitt,Elan D Louis
{"title":"Neuromodulation and Tremor Suppression in the Periphery.","authors":"Theresa A Zesiewicz,Peter A LeWitt,Elan D Louis","doi":"10.1001/jamaneurol.2025.3916","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3916","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"72 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145319183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-20DOI: 10.1001/jamaneurol.2025.3919
Lukas A Grajauskas
{"title":"The Cost of Armor.","authors":"Lukas A Grajauskas","doi":"10.1001/jamaneurol.2025.3919","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3919","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImportanceOpen-label trials of antiseizure medications (ASMs) and devices suggest seizure reduction in focal treatment-resistant epilepsy (FTRE) may demonstrate treatment-related disease-modifying effects. Understanding FTRE trends can provide insight into treatment responses.ObjectiveTo determine whether seizure frequency in FTRE improves over time.Design, Setting, and ParticipantsThe Human Epilepsy Project 2 was a prospective, observational, multicenter study of patients with FTRE from May 2018 to September 2021 who were followed up for 18 to 36 months at 10 US-based comprehensive epilepsy centers. Analysis was performed from 2021 to 2024. Study data included seizure frequency, medication use, device use, surgeries tracked using daily electronic diaries, monthly check-ins, medical record review, and case report forms. Eligibility criteria included focal epilepsy diagnosis, age between 16 and 65 years, and failure of 4 or more ASMs (≥2 due to seizure control failure). Participants were recruited as a volunteer sample.ExposuresParticipants were treated with multiple interventions at their physicians' discretion.Main Outcomes and MeasuresThe primary outcome was seizure frequency trends, evaluated by quantifying seizure freedom rates and frequency reductions. Medication and device treatment responses were assessed by tracking ASM and device changes.ResultsOf 196 approached participants, 146 met eligibility criteria and were included in the study. Mean (SD) participant age was 40 (12) years, and epilepsy was diagnosed at a mean (SD) age of 19.8 (13.6) years. The cohort had 84 (57.5%) female participants. A total of 35 participants had implantable devices; 1 had epilepsy surgery during the study. Of 146 participants, 128 provided sufficient seizure data for analysis, and 2 were excluded as outliers. Seizure frequency was reduced in 86 participants (68.3%) during the second half of study participation compared to the first half. In the overall cohort, mean modeled monthly seizure frequency percentage reduction was 68.73% (95% CI, 52.92%-84.54%). From 0 to 12 months (cohort 1), mean modeled percentage reduction was 67.76% (95% CI, 19.42%-116.09%); for 12 to 24 months (cohort 2), 36.00% (95% CI, 9.27%-53.46%); and for longer than 24 months (cohort 3), 66.03% (95% CI, 48.25%-83.80%) (all P < .001). An ASM was added in 69 participants (54.7%), of whom 46 (66.7%) experienced seizure frequency reduction, including seizure freedom. Seizure trajectories in participants with devices did not significantly differ from those without devices.Conclusions and RelevanceFindings from the HEP2 study imply that FTRE improves over time, ASM additions had low probability of achieving seizure freedom but contributed to seizure reduction, and device-treated participants exhibited similar seizure trajectories to those without devices. Whether improvements reflected the natural history of FTRE or active management remains unclear, but our findings suggest cautious interpretat
{"title":"Seizure Frequency Trends Over Time in Treatment-Resistant Focal Epilepsy.","authors":"Ojas Potnis,Gabriel Biondo,Rachel Sukonik,Caitlin Grzeskowiak,Gary Cutter,Hamada Altalib,Ruben Kuzniecky,Daniel Lowenstein,Jacqueline French, ","doi":"10.1001/jamaneurol.2025.4085","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.4085","url":null,"abstract":"ImportanceOpen-label trials of antiseizure medications (ASMs) and devices suggest seizure reduction in focal treatment-resistant epilepsy (FTRE) may demonstrate treatment-related disease-modifying effects. Understanding FTRE trends can provide insight into treatment responses.ObjectiveTo determine whether seizure frequency in FTRE improves over time.Design, Setting, and ParticipantsThe Human Epilepsy Project 2 was a prospective, observational, multicenter study of patients with FTRE from May 2018 to September 2021 who were followed up for 18 to 36 months at 10 US-based comprehensive epilepsy centers. Analysis was performed from 2021 to 2024. Study data included seizure frequency, medication use, device use, surgeries tracked using daily electronic diaries, monthly check-ins, medical record review, and case report forms. Eligibility criteria included focal epilepsy diagnosis, age between 16 and 65 years, and failure of 4 or more ASMs (≥2 due to seizure control failure). Participants were recruited as a volunteer sample.ExposuresParticipants were treated with multiple interventions at their physicians' discretion.Main Outcomes and MeasuresThe primary outcome was seizure frequency trends, evaluated by quantifying seizure freedom rates and frequency reductions. Medication and device treatment responses were assessed by tracking ASM and device changes.ResultsOf 196 approached participants, 146 met eligibility criteria and were included in the study. Mean (SD) participant age was 40 (12) years, and epilepsy was diagnosed at a mean (SD) age of 19.8 (13.6) years. The cohort had 84 (57.5%) female participants. A total of 35 participants had implantable devices; 1 had epilepsy surgery during the study. Of 146 participants, 128 provided sufficient seizure data for analysis, and 2 were excluded as outliers. Seizure frequency was reduced in 86 participants (68.3%) during the second half of study participation compared to the first half. In the overall cohort, mean modeled monthly seizure frequency percentage reduction was 68.73% (95% CI, 52.92%-84.54%). From 0 to 12 months (cohort 1), mean modeled percentage reduction was 67.76% (95% CI, 19.42%-116.09%); for 12 to 24 months (cohort 2), 36.00% (95% CI, 9.27%-53.46%); and for longer than 24 months (cohort 3), 66.03% (95% CI, 48.25%-83.80%) (all P < .001). An ASM was added in 69 participants (54.7%), of whom 46 (66.7%) experienced seizure frequency reduction, including seizure freedom. Seizure trajectories in participants with devices did not significantly differ from those without devices.Conclusions and RelevanceFindings from the HEP2 study imply that FTRE improves over time, ASM additions had low probability of achieving seizure freedom but contributed to seizure reduction, and device-treated participants exhibited similar seizure trajectories to those without devices. Whether improvements reflected the natural history of FTRE or active management remains unclear, but our findings suggest cautious interpretat","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"99 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145319185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-20DOI: 10.1001/jamaneurol.2025.3905
William G Ondo,Wen Lv,Xiaodong Zhu,Yongsheng Hu,Stuart H Isaacson,Yuan Yuan,Alberto J Espay,David Kreitzman,Sheng-Han Kuo,Salima Brillman,Holly A Shill,Kelly E Lyons,Zhi Yang,Qi Zhao,Zhen Zhang,Rajesh Pahwa
ImportanceEssential tremor (ET) is the most common form of arm tremor. Transcutaneous peripheral nerve stimulation (TPNS) can modulate the central tremor-generating network.ObjectiveTo investigate whether an artificial intelligence (AI)-driven TPNS device is superior to a sham device in reducing ET.Design, Setting, and ParticipantsA randomized clinical trial was conducted from February 7 through August 9, 2024, in 12 outpatient neurology clinics in the United States and China. Participants were adults with upper-extremity tremor and a clinical diagnosis of ET, a tremor severity score of 2 or higher on 1 of the Essential Tremor Rating Assessment Scale (TETRAS) performance subscale tasks, a total performance subscale score of at least 7, and familiarity with operating a smartphone and connecting to Wi-Fi at home. They were randomized 2:1 to receive active TPNS or sham stimulation, stratified by use of ET medications and tremor severity. After the devices were fitted, the participants were instructed to use them during waking hours for 90 days.InterventionA wearable neuromodulation device that stimulates the radial, median, and ulnar nerves and uses AI to continuously adjust stimulation settings in real time.Main Outcome and MeasuresThe primary outcome was change in daily activities as measured by the modified Activities of Daily Living (mADL) subscale of TETRAS at 90 days in the intention-to-treat population.ResultsOf 133 screened, 125 were randomized to receive TPNS (n = 83) or sham (n = 42) treatment. The mean (SD) age was 64.9 (13.1) years, 62 (49.6%) were female and 63 (50.4%) male, and the mean (SD) tremor duration was 11.4 (13.1) years. At 90 days, the mADL score was reduced by 6.9 points (95% CI, 5.4-8.4) in the TPNS group vs 2.7 points (95% CI, 1.3-4.0) in the sham group (P < .001). Skin irritation, the most common device-related adverse event, occurred in 28 of 83 participants (33.7%) in the TPNS group and 2 of 42 (4.8%) in the sham group. Nausea, arthralgia, worsening of existing arthritis in the thumb, muscular weakness, and involuntary muscle contractions each occurred in 1 participant, all in the TPNS group.Conclusions and RelevanceThe TPNS device improved activities related to upper limb tremor at 90 days and could be an effective noninvasive ET treatment.Trial RegistrationClinicalTrials.gov Identifier: NCT06235190.
{"title":"Transcutaneous Peripheral Nerve Stimulation for Essential Tremor: A Randomized Clinical Trial.","authors":"William G Ondo,Wen Lv,Xiaodong Zhu,Yongsheng Hu,Stuart H Isaacson,Yuan Yuan,Alberto J Espay,David Kreitzman,Sheng-Han Kuo,Salima Brillman,Holly A Shill,Kelly E Lyons,Zhi Yang,Qi Zhao,Zhen Zhang,Rajesh Pahwa","doi":"10.1001/jamaneurol.2025.3905","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3905","url":null,"abstract":"ImportanceEssential tremor (ET) is the most common form of arm tremor. Transcutaneous peripheral nerve stimulation (TPNS) can modulate the central tremor-generating network.ObjectiveTo investigate whether an artificial intelligence (AI)-driven TPNS device is superior to a sham device in reducing ET.Design, Setting, and ParticipantsA randomized clinical trial was conducted from February 7 through August 9, 2024, in 12 outpatient neurology clinics in the United States and China. Participants were adults with upper-extremity tremor and a clinical diagnosis of ET, a tremor severity score of 2 or higher on 1 of the Essential Tremor Rating Assessment Scale (TETRAS) performance subscale tasks, a total performance subscale score of at least 7, and familiarity with operating a smartphone and connecting to Wi-Fi at home. They were randomized 2:1 to receive active TPNS or sham stimulation, stratified by use of ET medications and tremor severity. After the devices were fitted, the participants were instructed to use them during waking hours for 90 days.InterventionA wearable neuromodulation device that stimulates the radial, median, and ulnar nerves and uses AI to continuously adjust stimulation settings in real time.Main Outcome and MeasuresThe primary outcome was change in daily activities as measured by the modified Activities of Daily Living (mADL) subscale of TETRAS at 90 days in the intention-to-treat population.ResultsOf 133 screened, 125 were randomized to receive TPNS (n = 83) or sham (n = 42) treatment. The mean (SD) age was 64.9 (13.1) years, 62 (49.6%) were female and 63 (50.4%) male, and the mean (SD) tremor duration was 11.4 (13.1) years. At 90 days, the mADL score was reduced by 6.9 points (95% CI, 5.4-8.4) in the TPNS group vs 2.7 points (95% CI, 1.3-4.0) in the sham group (P < .001). Skin irritation, the most common device-related adverse event, occurred in 28 of 83 participants (33.7%) in the TPNS group and 2 of 42 (4.8%) in the sham group. Nausea, arthralgia, worsening of existing arthritis in the thumb, muscular weakness, and involuntary muscle contractions each occurred in 1 participant, all in the TPNS group.Conclusions and RelevanceThe TPNS device improved activities related to upper limb tremor at 90 days and could be an effective noninvasive ET treatment.Trial RegistrationClinicalTrials.gov Identifier: NCT06235190.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"51 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145319184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-13DOI: 10.1001/jamaneurol.2025.3869
Ming Lu,Min Jung Kim,Emily C Collins,Sergey Shcherbinin,Amy K Ellinwood,Yuma Yokoi,Dawn A Brooks,Oskar Hansson,David S Knopman,John R Sims,Mark A Mintun
ImportanceAccumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit.ObjectiveTo assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD.Design, Setting, and ParticipantsThis was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025.InterventionsParticipants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks.Main Outcomes and MeasuresParticipants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker.ResultsAnalyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]).Conclusions and RelevanceThe findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies.Trial Registra
{"title":"Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial.","authors":"Ming Lu,Min Jung Kim,Emily C Collins,Sergey Shcherbinin,Amy K Ellinwood,Yuma Yokoi,Dawn A Brooks,Oskar Hansson,David S Knopman,John R Sims,Mark A Mintun","doi":"10.1001/jamaneurol.2025.3869","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3869","url":null,"abstract":"ImportanceAccumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit.ObjectiveTo assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD.Design, Setting, and ParticipantsThis was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025.InterventionsParticipants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks.Main Outcomes and MeasuresParticipants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker.ResultsAnalyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]).Conclusions and RelevanceThe findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies.Trial Registra","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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