Abstract
BACKGROUND: Studies of multidomain lifestyle interventions show mixed results on preventing or delaying cognitive decline in aging. A better understanding of central and peripheral mechanisms underlying these interventions could help explain these mixed findings. OBJECTIVE: The HELI (Hersenfuncties na LeefstijlInterventie) study aims to investigate the brain and peripheral mechanisms of a multidomain lifestyle intervention in older adults at risk of cognitive decline. METHODS: The HELI study is a 6-month multicenter, randomized, controlled multidomain lifestyle intervention trial powered to include 104 Dutch older adults at risk of cognitive decline. Individuals were deemed at risk when scoring ≥2 points on a lifestyle-modifiable risk factor scale (eg, overweight, physical inactivity, hypertension, and hypercholesterolemia). The intervention consisted of 5 domains (diet, physical activity, stress management and mindfulness, cognitive training, and sleep) and participants were randomized to one of two groups: (1) a high-intensity coaching group with weekly supervised online and on-site group meetings, exercises, and lifestyle-specific course materials, and (2) a low-intensity coaching group receiving general lifestyle health information sent through email every 2 weeks. The primary study outcomes are changes between baseline and 6-month follow-up in (1) brain activation in dorsolateral prefrontal cortex (dlPFC) and hippocampus and task accuracy during a functional magnetic resonance imaging (fMRI) working memory task, (2) arterial spin labeling-quantified cerebral blood flow in dlPFC and hippocampus, (3) systemic inflammation from blood plasma (interleukin-6, tumor necrosis factor-α, high-sensitivity C-reactive protein) and (4) microbiota profile from feces (gut microbiome diversity [Shannon and phylogenetic diversity] and richness [Chao1]). In addition, we will investigate intervention-induced gut-immune-brain links by assessing relations between effects in primary brain and gut outcomes. Secondary study outcomes include (1) structural and neurochemical magnetic resonance imaging (MRI), (2) anthropometric measurements, (3) neuropsychological test battery scores, (4) lifestyle-related questionnaire and smartwatch measures, and peripheral measures from (5) fecal, (6) blood, and (7) breath analyses. RESULTS: This work was supported by a Crossover grant (Maintaining Optimal Cognitive Functioning In Aging [MOCIA] 17611) of the Dutch Research Council (NWO), granted in December 2019. The MOCIA program is a public-private partnership. Between April 2022 and October 2023, we successfully included 102 older Dutch adults (mean age 66.6, SD 4.3 years; 67/102, 65.7% female) with ≥2 lifestyle-modifiable risk factors of cognitive aging (median risk 3, IQR 2-3). The most common self-reported lifestyle-modifiable risk factors at baseline were overweight or obesity (76/102, 74.5%), followed by hypertension (58/102, 56.9%), hypercholesterolemia (57/102, 55.9%), and physical inactivity (57/102, 55.9%). CONCLUSIONS: The HELI study aims to enhance our understanding of the working mechanisms of multidomain lifestyle interventions through its comprehensive characterization of central and peripheral markers. We intend to achieve this aim by assessing lifestyle intervention-induced changes in functional and structural MRI brain measures, as well as peripheral measures of the gut-immune-brain axis involved in cognitive aging.