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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2021)

Gray matter (GM) atrophy is considered one of the best predictors of disability accumulation in multiple sclerosis (MS) yet the mechanisms underlying its progression are poorly understood. Currently, there are no directly neuroprotective therapies in MS that can halt the progression of GM atrophy. While GM atrophy has been established in the most commonly used mouse model for MS, experimental autoimmune encephalomyelitis (EAE), there is a lack of studies directly investigating associated pathologies of GM atrophy and methods of sparing GM volume. The projects in this dissertation were designed with the goal of characterizing changes in GM volume and associated pathology. In the second chapter, I investigated baseline sex differences in the C57BL/6 mouse brain. This was an important step in establishing the use of magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to identify differences in GM volume. Moreover, it highlighted the importance of performing experimental analyses within sex as we determined that differences exist in the brain in healthy mice. In the third chapter, I sought to utilize VBM to localize atrophy in vivo in a chronic mouse model of EAE and to identify the spatial relationship between downstream axonal damage in the spinal cord and gray matter loss. I found substantial GM volume loss throughout the brain particularly within the cortex, caudoputamen, and thalamus during EAE. Further, I found axonal damage in the spinal cord was negatively correlated to GM volume in motor and sensorimotor regions of the cerebral cortex. In the fourth chapter, I describe a network of pathology associated with GM atrophy that is disrupted by estriol treatment. I further identified ligation of ERbeta as method of inducing remyelination in GM. Lastly, in chapter five, I used VBM to identify sex differences in GM atrophy during EAE. Using voxel-wise regression analysis I found a sex-specific relationship between disability and GM atrophy in the somatosensory cortex in males. I further found evidence of increased neuronal loss and increased axonal transection in males with EAE compared to their healthy controls than females with EAE compared to their healthy controls. Localizing atrophy and related pathology will allow for us to investigate the molecular underpinnings of GM volume loss and potentially lead to the development of better neuroprotective therapies for patients with MS

    Cover page: Characterizing Gray Matter Atrophy and Preservation in Experimental Autoimmune Encephalomyelitis
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2023)
    Menopause is associated with cognitive deficits and brain atrophy, but the brain region and cell-specific mechanisms are not fully understood. Here, we identify a sex hormone by age interaction whereby loss of ovarian hormones in female mice at midlife, but not young age, induced hippocampal-dependent cognitive impairment, dorsal hippocampal atrophy, and astrocyte and microglia activation with synaptic loss. Selective deletion of estrogen receptor beta (ERβ) in astrocytes, but not neurons, in gonadally intact female mice induced the same brain effects. RNA sequencing and pathway analyses of gene expression in hippocampal astrocytes from midlife female astrocyte-ERβ conditional knock out (cKO) mice revealed Gluconeogenesis I and Glycolysis I as the most differentially expressed pathways. Enolase 1 gene expression was increased in hippocampi from both astrocyte-ERβ cKO female mice at midlife and from postmenopausal women. Gain of function studies showed that ERβ ligand treatment of midlife female mice reversed dorsal hippocampal neuropathology.
      Cover page: Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice.
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2017)
      Behaviorally relevant sex differences are often associated with structural differences in the brain and many diseases are sexually dimorphic in prevalence and progression. Characterizing sex differences is imperative to gaining a complete understanding of behavior and disease which will, in turn, allow for a balanced approach to scientific research and the development of therapies. In this study, we generated novel tissue probability maps (TPMs) based on 30 male and 30 female in vivo C57BL/6 mouse brain magnetic resonance images and used voxel-based morphometry (VBM) to analyze sex differences. Females displayed larger anterior hippocampus, basolateral amygdala, and lateral cerebellar cortex volumes, while males exhibited larger cerebral cortex, medial amygdala, and medial cerebellar cortex volumes. Atlas-based morphometry (ABM) revealed a statistically significant sex difference in cortical volume and no difference in whole cerebellar volume. This validated our VBM findings that showed a larger cerebral cortex in male mice and a pattern of dimorphism in the cerebellum where the lateral portion was larger in females and the medial portion was larger in males. These results are consonant with previous ex vivo studies examining sex differences, but also suggest further regions of interest.
        Cover page: In vivo magnetic resonance images reveal neuroanatomical sex differences through the application of voxel-based morphometry in C57BL/6 mice
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2018)

        Introduction

        Progressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%-70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing-remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol-treated compared to placebo-treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.

        Methods

        Sixty-two estriol- and forty-nine placebo-treated RRMS patients underwent clinical evaluations and brain MRI. Voxel-based morphometry (VBM) was used to evaluate voxelwise GM sparing from high-resolution T1-weighted scans.

        Results

        A region of treatment-induced sparing (TIS) was defined as the areas where GM was spared in estriol- as compared to placebo-treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability-specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol-treated subjects that was associated with better performance on the PASAT.

        Conclusions

        Discovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2020)

          Background

          Gray matter (GM) atrophy in brain is one of the best predictors of long-term disability in multiple sclerosis (MS), and recent findings have revealed that localized GM atrophy is associated with clinical disabilities. GM atrophy associated with each disability mapped to a distinct brain region, revealing a disability-specific atlas (DSA) of GM loss.

          Objective

          To uncover the mechanisms underlying the development of localized GM atrophy.

          Methods

          We used voxel-based morphometry (VBM) to evaluate localized GM atrophy and Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY) to evaluate specific pathologies in mice with experimental autoimmune encephalomyelitis (EAE).

          Results

          We observed extensive GM atrophy throughout the cerebral cortex, with additional foci in the thalamus and caudoputamen, in mice with EAE compared to normal controls. Next, we generated pathology-specific atlases (PSAs), voxelwise mappings of the correlation between specific pathologies and localized GM atrophy. Interestingly, axonal damage (end-bulbs and ovoids) in the spinal cord strongly correlated with GM atrophy in the sensorimotor cortex of the brain.

          Conclusion

          The combination of VBM with CLARITY in EAE can localize GM atrophy in brain that is associated with a specific pathology in spinal cord, revealing a PSA of GM loss.
            Cover page: Axonal damage in spinal cord is associated with gray matter atrophy in sensorimotor cortex in experimental autoimmune encephalomyelitis
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