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J Neurosci. 2019 Jun 5;39(23):4566-4575. doi: 10.1523/JNEUROSCI.2370-18.2019. Epub 2019 Apr 8.

Characterizing the Molecular Architecture of Cortical Regions Associated with High Educational Attainment in Older Individuals.

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Departament de Medicina, Facultat de Medicina i Ciències de la Salut,
Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
Department of Neurology, Focus Program Translational Neuroscience, Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
Departament de Medicina, Facultat de Medicina i Ciències de la Salut.
Lipid Clinic, Endocrinology and Nutrition Service, IDIBAPS, Hospital Clínic, 08036, Barcelona, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos iii, 28029, Madrid, Spain, and.
German Center for Neurodegenerative Diseases-Rostock/Greifswald, 18147, Rostock, Germany


Neuroimaging investigations have revealed interindividual variations in anatomy, metabolism, activity, and connectivity of specific cortical association areas through which years of education (YoE), as a common proxy of cognitive reserve, may operate in the face of age- or pathology-associated brain changes. However, the associated molecular properties of YoE-related brain regions and the biological pathways involved remain poorly understood. In the present study we first identified brain areas that showed an association between cortical thickness and YoE among 122 cognitively healthy older human individuals (87 female). We subsequently characterized molecular properties of these regions by studying brain-wide microarray measurements of regional gene expression. In accordance with previous studies, we observed that YoE were associated with higher cortical thickness in medial prefrontal, anterior cingulate, and orbitofrontal areas. Compared with the rest of the cortex, these regions exhibited a distinct gene expression profile characterized by relative upregulation of gene sets implicated in ionotropic and metabotropic neurotransmission as well as activation of immune response. Our genome-wide expression profile analysis of YoE-related brain regions points to distinct molecular pathways that may underlie a higher capacity for plastic changes in response to lifetime intellectual enrichment and potentially also a higher resilience to age-related pathologic brain changes.SIGNIFICANCE STATEMENT We combined a neuroimaging-based analysis with a transcriptome-wide gene expression approach to investigate the molecular-functional properties of cortical regions associated with educational attainment, as a commonly used proxy for cognitive reserve, in older individuals. The strongest association with education was observed in specific areas of the medial prefrontal cortex, and these areas exhibited a distinct gene expression profile characterized by relative upregulation of gene sets implicated in neurotransmission and immune responses. These findings complement previous neuroimaging studies in the field and point to novel biological pathways that may mediate the beneficial effects of high educational attainment on adaptability to cope with, or prevent, age-related brain changes. The identified genes and pathways now warrant further exploration in mechanistic studies.


cognitive reserve; cortical thickness; gene expression; immune response; synaptic transmission

[Available on 2019-12-05]

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