title: Brain Structure and Function Associated with Younger Adults in Growth Hormone Receptor-Deficient Humans.
abstract: Growth hormone receptor deficiency (GHRD) results in short stature, enhanced insulin sensitivity, and low circulating levels of insulin and insulin-like growth factor 1 (IGF-1). Previous studies in mice and humans suggested that GHRD has protective effects against age-related diseases, including cancer and diabetes. Whereas GHRD mice show improved age-dependent cognitive performance, the effect of GHRD on human cognition remains unknown. Using MRI, we compared brain structure, function, and connectivity between 13 people with GHRD and 12 unaffected relatives. We assessed differences in white matter microstructural integrity, hippocampal volume, subregional volumes, and cortical thickness and surface area of selected regions. We also evaluated brain activity at rest and during a hippocampal-dependent pattern separation task. The GHRD group had larger surface areas in several frontal and cingulate regions and showed trends toward larger dentate gyrus and CA1 regions of the hippocampus. They had lower mean diffusivity in the genu of the corpus callosum and the anterior thalamic tracts. The GHRD group showed enhanced cognitive performance and greater task-related activation in frontal, parietal, and hippocampal regions compared with controls. Furthermore, they had greater functional synchronicity of activity between the precuneus and the rest of the default mode network at rest. The results suggest that, compared with controls, GHRD subjects have brain structure and function that are more consistent with those observed in younger adults reported in previous studies. Further investigation may lead to improved understanding of underlying mechanisms and could contribute to the identification of treatments for age-related cognitive deficits.SIGNIFICANCE STATEMENTPeople and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans, it is unknown whether cognitive function and brain structure are affected by GHRD. Using MRI, we examined cognition in an Ecuadorian population with GHRD and their unaffected relatives. The GHRD group showed better memory performance than their relatives. The differences in brain structure and function that we saw between the two groups were not consistent with variations typically associated with brain deficits. This study contributes to our understanding of the connection between growth genes and brain aging in humans and provides data indicating that GHR inhibition has the potential to protect against age-dependent cognitive decline.
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California 90089.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nashiro
authors.affiliation: Universidad San Francisco de Quito, Quito, Ecuador 170157, vlongo@usc.edu jguevara@usfq.edu.ec.|Institute of Endocrinology, Metabolism, and Reproduction, Quito, Ecuador 170523.
authors.forename: Jaime
authors.initials: J
authors.lastname: Guevara-Aguirre
authors.affiliation: Imaging Genetics Center, Keck School of Medicine, University of Southern California, Marina del Rey, California 90292.
authors.forename: Meredith N
authors.initials: MN
authors.lastname: Braskie
authors.affiliation: Imaging Genetics Center, Keck School of Medicine, University of Southern California, Marina del Rey, California 90292.
authors.forename: George W
authors.identifier: 0000-0002-2486-3957
authors.initials: GW
authors.lastname: Hafzalla
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California 90089.
authors.forename: Rico
authors.initials: R
authors.lastname: Velasco
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California 90089.
authors.forename: Priya
authors.initials: P
authors.lastname: Balasubramanian
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California 90089.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: Imaging Genetics Center, Keck School of Medicine, University of Southern California, Marina del Rey, California 90292.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California 90089.
authors.forename: Mara
authors.identifier: 0000-0003-4331-6112
authors.initials: M
authors.lastname: Mather
authors.affiliation: Department of Radiology, Children's Hospital Los Angeles/Keck School of Medicine of University of Southern California, Los Angeles, California 90027.
authors.forename: Marvin D
authors.initials: MD
authors.lastname: Nelson
authors.affiliation: Institute of Endocrinology, Metabolism, and Reproduction, Quito, Ecuador 170523.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Guevara
authors.affiliation: Universidad San Francisco de Quito, Quito, Ecuador 170157.
authors.forename: Enrique
authors.identifier: 0000-0001-6979-5655
authors.initials: E
authors.lastname: Teran
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California 90089, vlongo@usc.edu jguevara@usfq.edu.ec.|Longevity Institute, University of Southern California, Los Angeles, California 90089.|Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, and.|FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milano, Italy 20139.
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
mesh_terms: D000328:Adult; D016880:Anisotropy; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology* / Q000502:physiology*; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007328:Insulin / Q000097:blood / Q000378:metabolism; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D046150:Laron Syndrome / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D010775:Photic Stimulation; D011986:Receptors, Somatotropin / Q000235:genetics; D012463:Saliva / Q000378:metabolism; D055815:Young Adult
chemical_list: D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D010100:Oxygen
keywords: IGF-1; MRI; aging; cognition; growth hormone receptor deficiency; insulin