Age-Related Changes in Topological Degradation of White Matter Networks and Gene Expression in Chronic Schizophrenia

Brain Connect. 2017 Nov;7(9):574-589. doi: 10.1089/brain.2017.0519.

Abstract

Current hypotheses stipulate core symptoms of schizophrenia (SZ) result from the brain's incapacity to integrate neural processes. Converging diffusion magnetic resonance imaging and graph theory studies provide evidence of macrostructural alterations in SZ. However, age-related topological changes within and between white matter (WM) networks and its relationship to gene expression with disease progression remain incompletely understood. This cross-sectional study uses network modeling to investigate changes in WM network organization with disease progression in chronic SZ as well its relationship with gene expression in healthy brains. First, we replicate prior findings demonstrating altered global WM network topology in SZ. Novel results show significantly altered age-related network degradation patterns in patients compared with controls. Specifically, controls show stereotyped, linear global network decline with age. In contrast, patients show nonlinear network decline with age. Further analysis reveals lack of significant topological decline in younger adult patients, which is subsequently followed by stereotyped linear decline in older adult patients. Node-specific analyses show significant topological differences in frontal and limbic regions of younger adult patients compared with age-matched controls, which become less pronounced with age in older adult patients compared with age-matched controls. Lastly, we show several gene expression profiles, including DISC1, are associated with age-related changes in WM disconnectivity. Together, these findings provide novel WM topological and genetic evidence supporting neurodevelopmental models of SZ, suggesting that network remodeling continues throughout the third decade of life before stabilizing.

Keywords: degeneration; diffusion tensor imaging; graph theory; neural networks; schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aging*
  • Anisotropy
  • Cross-Sectional Studies
  • Dysbindin / genetics
  • Dysbindin / metabolism
  • Female
  • Gene Expression / physiology*
  • Humans
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Microarray Analysis
  • Middle Aged
  • Models, Neurological
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Pathways / diagnostic imaging
  • Neural Pathways / pathology*
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Metabotropic Glutamate / metabolism
  • Schizophrenia / diagnostic imaging
  • Schizophrenia / genetics*
  • Schizophrenia / pathology*
  • White Matter / diagnostic imaging
  • White Matter / pathology*
  • Young Adult

Substances

  • DISC1 protein, human
  • DRD2 protein, human
  • DTNBP1 protein, human
  • Dysbindin
  • Nerve Tissue Proteins
  • Receptors, Dopamine D2
  • Receptors, Metabotropic Glutamate