The effect of growth hormone-releasing hormone on cognition and brain connectivity in adults with cognition ranging from normal to mild cognitive impairment

Cognitive decline with age and other clinical conditions are linked with reduced hypothalamic-pituitary-adrenal (HPA) axis function. Stimulating the HPA axis with supplemental growth hormone (GH) treatment can improve cognition, however, potential direct effects of stimulation with growth hormone releasing hormone (GHRH) are not established. In a double-blind, placebo-controlled pilot trial, we assessed 22 subjects with baseline cognition ranging from normal cognition to mild cognitive impairment before and after 10 weeks of treatment with low-dose tesamorelin (1 mg; GHRH analog) or placebo. We compared groupwise changes in body composition, fatigue, sleep, physical performance, glucose tolerance, cognitive function, and brain morphometry and functional connectivity. Low-dose GHRH treatment was not directly linked with significant changes in study measures. Using advanced machine learning (ML) models to further examine the data we identified potential treatment-related differences in areas of the brain related to cognitive function including the right anterior cingulate and left superior frontal occipital fasciculus. This pilot study highlights the potential benefits of pairing cognitive tests and neuroimaging with ML tools to achieve greater sensitivity for treatment-related effects. The clinical trial registration number is: NCT02553603.