HAI Book 2025 - Flipbook - Page 182
Engels-Domínguez, Nina
34
Evaluating tVNS effects on cognitive outcomes and modulating
factors in asymptomatic older adults: study design of the WALLe Trial
Nina Engels-Domínguez1,2, Jill Grube1, Haley Fenlon1, Emma Wiklund1, Lukas Heinrich1,2,
Marion Baillet1, Maxime van Egroo1,2, Kathryn Papp3,4, Joost Riphagen1, Ronald Garcia1,5,
Roberta Sclocco1,6,7, Keith Johnson3,4,8, Vitaly Napadow1,6,7, Heidi Jacobs1,2
1
The Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA, US
2
Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre
Limburg, Maastricht University, Maastricht, NL
3
Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard
Medical School, Boston, MA, US
4
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
5
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
6
Department of Radiology, Logan University, Chesterfield, MO, US
7
Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School,
Boston, MA, US
8
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, US
Background: The locus coeruleus (LC) is among the earliest regions to harbor tau, and the associated aberrant
activity patterns may promote Alzheimer9s disease (AD) pathology. Transcutaneous vagus nerve stimulation
(tVNS), a non-invasive neuromodulation technique stimulating the auricular vagus nerve branch, modulates LC
activity and shows potential for delaying cognitive decline in older individuals. The WALLe Trial aims to evaluate
the impact of tVNS on cognitive outcomes and identify demographic, neurophysiological, and blood-based
biomarker factors predicting positive tVNS-responses in asymptomatic older adults (Table 1).
Study Design: This ongoing single-site trial, enriched for APOE-e4 carriage, compares respiration-gated tVNS
versus sham stimulation. Its enrollment target is 140 asymptomatic adults aged 60-85, recruited via online and
printed advertisements and the MGB-Biobank. After consent and eligibility screening, participants are
randomized into one of four arms, receiving sham or tVNS in a cross-over design during LC-dedicated 7T-MRimaging (visits 2-3). After a 3-to-5-week wash-out period, participants are quasi-randomized to either daily sham
or tVNS sessions for 10 days (visits 4-13). Visits 14-15 are cognitive follow-ups. Blood sampling, cognitive testing,
pupillometry and other autonomic measurements are collected (Figure 1). The primary outcome is change in facename association performance (FNAME; Figure 2), evaluated during fMRI (visits 2-3) and behavioral assessments
(visits 4-15). Participants remain blinded to study condition and receive remuneration.
Results: To date, 89 participants (age: mean=68.17, SD=5.46, range=60.0-85.9; education: mean=17.01, SD=2.01,
range=10-20; female=51.7%; APOE-e4 carrier=29.2%) have enrolled, with n=52 completing the trial. Current noncompletion rates are 12.4% for screen-fails, 7.9% for drop-outs and 1.1% for no-shows. No serious adverse events
or stopping rules occurred. The next expected milestone is reaching 75% of the enrollment target.
Conclusion: The WALLe Trial investigates tVNS effects on cognitive outcomes in AD by integrating cognitive,
neuroimaging and blood-based biomarker measures, holding promise to inform the design and target population
of preventive intervention strategies in preclinical stages.
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