Blood Biomarkers as Surrogate Endpoints of Treatment Responses to Aerobic Exercise and/or Cognitive Training in Amnestic Mild Cognitive Impairment

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Project Summary The objective of the parent R01 is to investigate blood neuropathological and neurotrophic biomarkers as surrogate endpoints for treatment responses to 3 interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise; cognitive training; and combined aerobic exercise and cognitive training (ACT). The first goal of this supplement is to provide financial sources, so the parent R01 has sufficient funding to take advantage of the revised enrollment timeline of the ACT Trial to preserve the parent R01's overall impact within the original scope of the award. The parent R01 is built on the ACT trial, a multi-site Phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (n=128). The ACT Trial paused its enrollment in March 2020 due to the Covid- 19 shutdown of research at the University of Rochester (UR) and the University of Minnesota (UMN) sites. We could not enroll the participants in the ACT Trial in 2020. The ACT Trial has re-configured its study timeline to account for the lost recruitment period due to enrollment pause. It also added a 3rd study site at the Arizona State University (ASU) to recruit. It extended its recruitment period to the end of August 31, 2022, with a hard- stop recruitment ending date of September 30, 2022. All data collections will end on Feb-March 2024. However, the parent R01 will end on May 31, 2022, and will not have sufficient funding left to take advantage of the revised enrollment timeline of the ACT Trial. Hence, we need this administrative supplement to extend the recruitment and data collection period to maximize sample size and accomplish the scope of the parent R01. The second goal of this supplement is to increase the parent R01's impact by investigating blood neuroinflammation biomarkers as surrogate endpoints for treatment responses to 3 interventions in aMCI. Neuroinflammation modulates disease progression of AD. In addition, recent evidence suggests that exercise modulate neuroinflammation through plasma clusterin. Furthermore, blood glial fibrillary acidic protein (GFAP) has emerged as a biomarker for neuroinflammation. This evidence suggests that blood neuroinflammation biomarkers such as plasma GFAP and clusterin could serve as surrogate endpoints for intervention exercise- related treatment responses. This addition is within the scope of the parent R01. The specific aims for the first goal are: (1). Continue enrolling participants following the ACT Trial scheduled to August 31, 2022, or September 30, 2022, if not meeting the enrollment goal by August 31, 2022; (2). Complete all blood collections by March 2024. The specific aims for the second goal are: (3). Determine the effects of interventions on blood neuroinflammation biomarkers in aMCI; (4). Evaluate blood neuroinflammation biomarkers as surrogate endpoints for predicting cognitive responses to interventions in aMCI.