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Randomized Controlled Trial
. 2025 Sep 2;8(9):e2534941.
doi: 10.1001/jamanetworkopen.2025.34941.

Brain Frailty and Functional Outcomes After Thrombolysis for Acute Ischemic Stroke

Spencer P Loewen  1 , Nishita Singh  2 , Ibrahim Alhabli  3   4   5 , Fouzi Bala  6 , Brian Buck  7 , Faysal Benali  8 , William Betzner  1   3 , Kaden Lam  1   9 , Luciana Catanese  10 , Aleksander Tkach  11 , Dar Dowlatshahi  12 , Federico Carpani  13 , Thalia S Field  14 , Gary Hunter  15 , Houman Khosravani  16 , Aleksandra Pikula  17 , Michel Shamy  12 , Tolulope T Sajobi  3 , Mohammed Almekhlafi  3 , Rick Swartz  16 , Bijoy Menon  3 , Mahesh Kate  5 , Aravind Ganesh  3
Affiliations
Randomized Controlled Trial

Brain Frailty and Functional Outcomes After Thrombolysis for Acute Ischemic Stroke

Spencer P Loewen et al. JAMA Netw Open. .

Abstract

Importance: The cumulative burden of chronic vascular and neurodegenerative changes contributes to brain frailty, which may reduce the brain's capacity to recover from acute ischemic stroke (AIS). The association between brain frailty markers and poststroke outcomes after thrombolysis is unclear.

Objective: To evaluate associations between brain frailty assessed on non-contrast-enhanced computed tomography (NCCT) and magnetic resonance imaging (MRI) and functional outcome in patients with AIS treated with intravenous thrombolysis.

Design, setting, and participants: This cohort study was a post hoc analysis of the Alteplase compared to Tenecteplase (AcT) trial, an investigator-led, registry-linked, parallel-group, open-label, randomized clinical trial that enrolled patients between December 10, 2019, and January 25, 2022, at 22 primary and comprehensive stroke centers across Canada. Participants included adults 18 years or older diagnosed with ischemic stroke causing disabling neurological deficit, presenting within 4.5 hours of symptom onset, and meeting Canadian guidelines for thrombolysis. Markers of brain frailty (cortical and subcortical atrophy, white matter changes [Fazekas score, grouped as 0, 1-2, and 3-6], lacunes, chronic infarctions, and [on MRI] microbleeds, siderosis, and enlarged perivascular spaces) were retrospectively assessed while reviewers were blinded to outcome variables. Analyses were performed from July 24, 2024, to March 25, 2025.

Exposures: Patients underwent baseline NCCT and were randomized to receive intravenous thrombolysis with alteplase (0.9 mg/kg) or tenecteplase (0.25 mg/kg). Some patients also received posttreatment brain MRI.

Main outcomes and measures: The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score of 0-1) at 90 days. Secondary outcomes included 90-day ordinal mRS score (trichotomized as 0-2, 3-4, and 5-6), symptomatic intracerebral hemorrhage, and mortality. Sensitivity analyses were performed in patients with available MRI scans.

Results: Among the 1568 patients (median age, 74 [IQR, 63-83] years; 817 male [52.1%]) with interpretable NCCT findings, after correcting for multiple comparisons, higher total Fazekas score of 3 to 6 compared with 0 was associated with lower odds of a 90-day mRS score of 0 to 1 (adjusted odds ratio [OR], 0.40 [95% CI, 0.24-0.65]). Total Fazekas score (adjusted common OR [ACOR], 2.80 [95% CI, 1.88-4.16]), cortical atrophy (ACOR, 2.65 [95% CI. 1.63-4.32]), and total brain frailty score (ACOR, 3.15 [95% CI, 1.87-5.33]) were each associated with worse ordinal mRS, but were not associated with safety outcomes.

Conclusions and relevance: In this cohort study of patients with AIS treated with intravenous thrombolysis, brain frailty markers-particularly white matter changes, cortical atrophy, and total brain frailty-were associated with worse outcomes. Consideration of these neuroimaging markers may better inform clinicians and patients about treatment expectations from thrombolytic therapy.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Field reported receiving advisory board fees from Bayer AG and AstraZeneca and expert witness fees from the Canadian Medical Protective Association outside the submitted work. Dr Swartz reported receiving grant support from the Canadian Institutes of Health Research, receiving advisory board fees from F. Hoffmann–LaRoche Ltd, owning stock in FollowMD, and serving as the Bastable-Potts Chair in Stroke Research from Sunnybrook Health Sciences Center outside the submitted work. Dr Ganesh reported receiving stock options from SnapDx and Let’s Get Proof (Collavidence); personal fees from Alexion Pharmaceuticals Inc, Biogen Inc, Eisai Co Ltd, and Servier Canada; and grant support from Alberta Innovates, the Alzheimer Society of Canada, the Alzheimer Society of Alberta and Northwest Territories, Campus Alberta Neuroscience, Brain Canada, Panmure House, the Government of Canada INOVAIT and New Frontiers in Research programs, the Heart and Stroke Foundation of Canada, the France-Canada Research Fund, and the MSI Foundation outside the submitted work and having a patent for US17/317,771 issued for patient monitoring and cuff-based therapies being tested in small vessel disease through SnapDx. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Distribution of Modified Rankin Scale (mRS) Scores at 90 Days by Brain Frailty Measures Assessed on Non–Contrast-Enhanced Computed Tomography
Higher scores indicate worse findings. GCA indicates global cortical atrophy.
Figure 2.
Figure 2.. Adjusted Odds Ratios (AORs) for Modified Rankin Scale (mRS) Score of 0 to 1 by Measures of Brain Frailty Assessed on Non–Contrast-Enhanced Computed Tomography
Adjustments were made for age, sex, pretreatment National Institutes of Health Stroke Scale, and stroke symptom onset-to-needle time as fixed-effects variables and participating site as a random-effects variable. CC:IT indicates intercaudate distance to inner-table width ratio; GCA, global cortical atrophy; NA, not applicable.
Figure 3.
Figure 3.. Distribution of Modified Rankin Scale (mRS) Scores at 90 Days by Brain Frailty Measures Assessed on Magnetic Resonance Imaging
Higher scores indicate worse findings. EPVS indicates enlarged perivascular spaces; SVD, small vessel disease.
Figure 4.
Figure 4.. Adjusted Odds Ratios (AORs) for Modified Rankin Scale (mRS) Score of 0 to 1 by Measures of Brain Frailty Assessed on Magnetic Resonance Imaging
Adjustments were made for age, sex, pretreatment National Institutes of Health Stroke Scale, and stroke symptom onset-to-needle time as fixed-effects variables and participating site as a random-effects variable. CC:IT indicates intercaudate distance to inner-table width ratio; CMB, cerebral microbleeds; CSS, cortical superficial siderosis; EPVS, enlarged perivascular spaces; GCA, global cortical atrophy; NA, not applicable; SVD, small vessel disease.
See this image and copyright information in PMC

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