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Clinical Trial
. 2025 Aug 1;8(8):e2528907.
doi: 10.1001/jamanetworkopen.2025.28907.

Poststroke Cardiorespiratory Exercise for Brain Volume and Cognition: A Randomized Clinical Trial

Amy Brodtmann  1   2   3 , Leonid Churilov  2 , Kimberley Adkins  1 , Ruwayda Haibe  1 , Stephanie Tucker  1 , Mohamed Salah Khlif  1 , Emilio Werden  3 , Laura J E McCambridge  3 , Rachael Telfer  1 , Sharon Kramer  1 , Barbara R Cardoso  4   5 , Matthew Pase  5   6 , Nathalie Launder  2 , Natalia Egorova-Brumley  7 , Stanley Hughwa Hung  8 , Louise M Burrell  2   9 , Gavin Williams  10   11 , Vincent Thijs  2   9 , Julie Bernhardt  3 , Liam Johnson  10   11   12 , Kathryn S Hayward  2   10 ; PISCES-ZODIAC Investigators
Affiliations
Clinical Trial

Poststroke Cardiorespiratory Exercise for Brain Volume and Cognition: A Randomized Clinical Trial

Amy Brodtmann et al. JAMA Netw Open. .

Abstract

Importance: Stroke increases the risk of cognitive impairment and dementia without proven prevention therapies. Cardiorespiratory exercise (CRX) preserves brain health.

Objective: To determine whether a CRX intervention preserves hippocampal volume (HV) and cognition in patients after ischemic stroke.

Design, setting, and participants: The Post-Ischemic Stroke Cardiovascular Exercise Study (PISCES)-Zoom Delivered Intervention Against Cognitive Decline (ZODIAC) is a phase 2b assessor-blinded randomized clinical trial performed at 4 metropolitan health care services in Melbourne, Australia. Eligible participants included adult patients who survived ischemic stroke without comorbidities prohibiting exercise or diagnosed cognitive disorder. Participants were recruited from May 26, 2016, to March 20, 2020, for PISCES in-person training and from November 9, 2020, to February 12, 2024, for ZODIAC remotely delivered home training. A total of 6921 participants were screened for eligibility, 130 were recruited, 107 were randomized (34 in PISCES and 73 in ZODIAC), and 104 continued to intervention. Study visits at 2, 4, and 12 months post stroke included brain magnetic resonance imaging and cognitive testing. Participants were randomized (1:1), stratified by baseline function (modified Rankin Scale score of 0-1 vs 2-3) and total brain volume. Primary, secondary efficacy, and safety outcome analyses were conducted using modified intention-to-treat (mITT) principle and per protocol.

Intervention: Participants received 8 weeks of three 60-minute sessions/wk. Participants in the CRX group received prescribed intensity progressive aerobic and resistance training; the control group received balance and stretching training.

Main outcomes and measures: The primary outcome was relative change in HV calculated as the difference between HV at times 1 and 2 divided by HV at time 1. Secondary outcome consisted of 12-month executive function test results (Trial Making Test, Part B [TMT-B]), adjusted for baseline TMT-B and mRS score.

Results: The 104 participants included in primary outcome mITT analysis (55 in the control and 49 in the CRX groups; mean [SD] age, 64 [14] years; 67 [64.4%] male; equivalent baseline mRS score). One hundred participants (33 in PISCES and 67 in ZODIAC) completed 4-month assessments, and 97 (31 in PISCES and 66 in ZODIAC) completed 12-month assessments. There were no intervention-related serious adverse events. Mean (SD) difference in relative change in HV between the CRX (-0.26% [2.12%]) and control (-0.11% [2.35%]) groups was -0.10% (95% CI, -1.10% to 0.87%; P = .83). The CRX group (n = 43) performed better than the control group (n = 51) on the adjusted TMT-B at 12 months (adjusted mean difference, -3.75 [95% CI, -5.02 to -2.49] seconds).

Conclusions and relevance: In this randomized clinical trial of fitness training, CRX was safe but did not preserve HV more than a control condition. CRX may benefit cognitive preservation following ischemic stroke.

Trial registration: anzcrt.org Identifier: ACTRN12616000942459.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Brodtmann reported receiving grant support from the Rapid Applied Research Translation Medical Research Future Fund and the National Health and Medical Research Council (NHMRC) and grant support for salary from the National Heart Foundation during the conduct of the study; personal fees for scientific advisory board service from Eli Lilly and Company, F. Hoffmann–La Roche AG, Eisai Co Ltd, Novo Nordisk A/S, and Medicines Australia outside the submitted work; serving as an honorary medical adviser for Dementia Australia; and serving on the Brain Health Collective for the Australian Football League. Dr Adkins reported receiving grant support from the NHMRC during the conduct of the study. Dr Pase reported receiving grant support from the Stroke Foundation during the conduct of the study and grant support from the NHMRC, Alzheimer’s Drug Discovery Foundation (ADDF), the Brain Foundation, the Alzheimer Association, and the National Institutes of Health and personal fees from ADDF outside the submitted work. Dr Egorova-Brumley reported receiving grant support from the Australian Research Council outside the submitted work. Dr Thijs reported receiving personal fees from Boehringer Ingelheim, Medtronic PLC, AtriCure Inc, Bayer AG, and Abbott Laboratories outside the submitted work. Dr Hayward reported receiving grant support from the National Heart Foundation during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Flowchart of Modified Intention-to-Treat Analyses
PISCES indicates Post-Ischemic Stroke Cardiovascular Exercise Study; ZODIAC, Zoom Delivered Intervention Against Cognitive Decline.
Figure 2.
Figure 2.. Modified Intention-to-Treat Subgroup Analyses for Change in Hippocampal Volume at 4 Months
mRS indicates modified Rankin Scale; PISCES, Post-Ischemic Stroke Cardiovascular Exercise Study; and ZODIAC, Zoom Delivered Intervention Against Cognitive Decline.
See this image and copyright information in PMC

Comment in

  • doi: 10.1001/jamanetworkopen.2025.28921

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