Structural changes of the amygdala subnuclei and limbic white matter tracts in healthy aging and major depressive disorder

  • Author / Creator
    Aghamohammadi Sereshki, Arash
  • The world population is dramatically aging. Several factors affect brain in healthy aging. The apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF) and catechol-O-methyl transferase (COMT) might be involved in neurodegenerative diseases, depression and cognitive decline in healthy aging. Also, it has been suggested that depression can increase the risk of dementia and cognitive decline. Furthermore, exposure to childhood maltreatment and chronic stress increase risks of developing neuropsychiatric disorders, and changes in cognitive functions.
    However, our knowledge is limited in first, how the brain changes in healthy aging differ from pathological aging; second, the effects of APOE, BDNF and COMT polymorphisms on the brain structures; and third, the underlying mechanisms of major depressive disorder (MDD) and detrimental effects of early adverse environment.
    Amygdala is a group of subnuclei with different connectivity profiles and functions in the limbic system. Previously, amygdala volumetric changes in both healthy aging and MDD were reported. However, most of the previous in vivo studies of the human amygdala were at the level of the total structure and not its subnuclei. Uncinate fasciculus is one of the major limbic tracts which connects the amygdala to the orbitofrontal cortex. Cingulum bundle is another major tract of the limbic system which connects the cingulate cortex to its neighboring structures. Healthy aging studies of limbic white matter tracts can improve our understanding of healthy cognitive aging which might be related to cognitive decline with advanced age. Also, our knowledge is very limited regarding the effects of APOE, BDNF and COMT on the limbic tracts.
    MDD is one of the major causes of disability worldwide. Reduction in hippocampal volume is one of the most replicated findings of MDD and childhood maltreatment studies. However, similar to the amygdala, the hippocampus consists of different subregions and subfields, and findings regarding the effects of MDD and childhood maltreatment on the amygdala are inconsistent. All these studies investigated the total amygdala and not the amygdala subnuclei. Currently, there is a gap in literature about the effects of MDD and childhood maltreatment on the amygdala subnuclei and hippocampal subregions/subfields.
    The first aim of this thesis was developing a novel segmentation method using ultra-high-resolution magnetic resonance imaging (MRI) to study five major amygdala subnuclei (basolateral (i.e. lateral, basal, accessory basal nuclei), cortical and centromedial groups). The results demonstrated the feasibility of reliable studying of the human amygdala subnuclei groups in vivo which approximately correspond to the amygdala subnuclei location and orientation in histological references.
    The second aim was investigating the effects of healthy aging, APOE and BDNF polymorphisms on volumes of amygdala subnuclei in a large cohort of healthy individuals using our new amygdala segmenting method. We found that amygdala subnuclei were nonuniformly affected by aging and that age-related associations were sex specific. We also did not find any significant effects of APOE and BDNF polymorphisms on the amygdala subnuclei volumes.
    The third aim was investigating the effects of MDD and childhood adversity on volumes of amygdala subnuclei and hippocampal subregions/subfields using ultra-high-resolution MRI. We did not find significant effects of MDD on volumes of the amygdala subnuclei. However, history of childhood adversity was negatively associated with the anterior hippocampus in both hemispheres limited to the CA1-3 subfield, while these effects were limited to the basolateral group of the amygdala in the right hemisphere.
    The fourth aim was investigating the effects of healthy aging, APOE, BDNF and COMT on the uncinate fasciculus, rostral, dorsal and parahippocampal cingulum in a large cohort of healthy individuals. We found that while microstructural integrity of the uncinate fasciculus, rostral cingulum and dorsal cingulum were reduced with age, the parahippocampal cingulum microstructural integrity did not associate with age. Moreover, the COMT Met/Met genotype was associated with better microstructural integrity of the right rostral cingulum compared to the Val/+ genotype across life span.

    In summary, our experiments revealed: first, susceptibility of the basolateral group to both healthy aging and childhood maltreatment; second, vulnerability of the CA1-3 and the anterior hippocampus to childhood maltreatment; third, relative resiliency of the parahippocampal cingulum, but not uncinate fasciculus, rostral and dorsal cingulum in aging; and finally, the advantage of the COMT Met/Met over the valine carriers in microstructural integrity of the right rostral cingulum.

  • Subjects / Keywords
  • Graduation date
    Fall 2019
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
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