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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01634841.

Keywords: cognitive reserve; cortical thickness; gene expression; immune response; synaptic transmission.

Copyright © 2019 the authors.

Figures

Figure 1.

Enrichment analysis workflow. Outline of the processing of gene expression data from regional probe level to enrichment map for the identification of functionally coherent clusters of gene sets. First, regions associated with YoE in healthy older adults are identified. Then, individual tissue sample coordinates are assigned to the nearest point of the reconstructed MRI brain surface, and for each gene the median expression levels within and outside YoE-related cortical areas are calculated and subtracted (delta score). Finally, genes are ranked according to their delta score (differential expression within YoE-related areas), and the ranked list is submitted to GSEA to search for significantly over- or under-represented gene sets in YoE-related areas. Identified gene sets are then clustered and organized into a network layout to identify groupings of functionally related gene sets into overarching functional pathways.

Figure 2.

Top, Regions showing greater cortical thickness in healthy older adults with high YoE compared with low YoE individuals. For anatomical reference, overlapping anatomical regions as delineated in the Desikan–Killiany atlas are shown (bottom). G, Gyrus; S, sulcus; trFp, transverse frontopolar; Fmg, fronto-marginal; Forb, frontal orbital (including H-shaped); G-rec, gyrus rectus; Fsuborb, frontal suborbital; supF, superior frontal.

Figure 3.

Heat map of the clustered leading edge genes of the positively enriched gene sets. Rows correspond to the gene sets listed in Table 2 and columns correspond to their respective leading-edge gene as detailed in Table 3. Color coding from white to dark red reflects degree of relative upregulation (delta score). The upper part shows the enrichment map of the clustered gene sets, containing six different clusters representing the overarching functional pathways. Node size represents the gene set size and line thickness shows the degree of overlap (shared genes) between the two gene sets it connects.