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Open Access Publications from the University of California

Scholarly Works (17 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2012)
    Cover page: In vivo vs. ex vivo Magnetic Resonance Imaging In MiceCreative Commons 'BY-NC-SA' version 4.0 license
    • 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 (2015)
      Previous studies have revealed an increased fractional anisotropy and greater thickness in the anterior parts of the corpus callosum in meditation practitioners compared with control subjects. Altered callosal features may be associated with an altered inter-hemispheric integration and the degree of brain asymmetry may also be shifted in meditation practitioners. Therefore, we investigated differences in gray matter asymmetry as well as correlations between gray matter asymmetry and years of meditation practice in 50 long-term meditators and 50 controls. We detected a decreased rightward asymmetry in the precuneus in meditators compared with controls. In addition, we observed that a stronger leftward asymmetry near the posterior intraparietal sulcus was positively associated with the number of meditation practice years. In a further exploratory analysis, we observed that a stronger rightward asymmetry in the pregenual cingulate cortex was negatively associated with the number of practice years. The group difference within the precuneus, as well as the positive correlations with meditation years in the pregenual cingulate cortex, suggests an adaptation of the default mode network in meditators. The positive correlation between meditation practice years and asymmetry near the posterior intraparietal sulcus may suggest that meditation is accompanied by changes in attention processing.
        Cover page: Shifting brain asymmetry: the link between meditation and structural lateralization
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2017)
        Protective effects of pregnancy during MS have led to clinical trials of estriol, the pregnancy estrogen, in MS. Since estriol binds to estrogen receptor (ER) beta, ER beta ligand could represent a "next generation estriol" treatment. Here, ER beta ligand treatment was protective in EAE in both sexes and across genetic backgrounds. Neuroprotection was shown in spinal cord, sparing myelin and axons, and in brain, sparing neurons and synapses. Longitudinal in vivo MRIs showed decreased brain atrophy in cerebral cortex gray matter and cerebellum during EAE. Investigation of ER beta ligand as a neuroprotective treatment for MS is warranted.
          Cover page: Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2022)
          Estrogens have neuroprotective actions depending on estrogen type, dose, and timing in both preclinical models and in women during health and disease. Serum neurofilament light chain is a putative biomarker of neurodegeneration in multiple sclerosis, aging, and other neurodegenerative diseases. Here, oral treatment with an estrogen unique to pregnancy (estriol) using an 8 mg dose to induce a mid-pregnancy blood estriol level reduced serum neurofilament light chain in nonpregnant MS women at mean age of 37 years. This is consistent with estriol-mediated protection from neuro-axonal injury and supports the use of serum neurofilament light chain as a biomarker in MS.
            Cover page: Decreased neurofilament light chain levels in estriol‐treated multiple sclerosis
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2016)
            Traditionally, tissue visualization has required that the tissue of interest be serially sectioned and imaged, subjecting each tissue section to unique non-linear deformations, dramatically hampering one's ability to evaluate cellular morphology, distribution and connectivity in the central nervous system (CNS). However, optical clearing techniques are changing the way tissues are visualized. These approaches permit one to probe deeply into intact organ preparations, providing tremendous insight into the structural organization of tissues in health and disease. Techniques such as Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY) achieve this goal by providing a matrix that binds important biomolecules while permitting light-scattering lipids to freely diffuse out. Lipid removal, followed by refractive index matching, renders the tissue transparent and readily imaged in 3 dimensions (3D). Nevertheless, the electrophoretic tissue clearing (ETC) used in the original CLARITY protocol can be challenging to implement successfully and the use of a proprietary refraction index matching solution makes it expensive to use the technique routinely. This report demonstrates the implementation of a simple and inexpensive optical clearing protocol that combines passive CLARITY for improved tissue integrity and 2,2'-thiodiethanol (TDE), a previously described refractive index matching solution.
              Cover page: Optical Clearing of the Mouse Central Nervous System Using Passive CLARITY.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2014)
              Gray matter atrophy has been shown to be a strong correlate to clinical disability in multiple sclerosis (MS) and its most commonly used animal model, experimental autoimmune encephalomyelitis (EAE). However, the relationship between gray mater atrophy and the spinal cord pathology often observed in EAE has never been established. Here EAE was induced in Thy1.1-YFP mice and their brains imaged using in vivo magnetic resonance imaging (MRI). The brains and spinal cords were subsequently optically cleared using Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY). Axons were followed 5mm longitudinally in three dimensions in intact spinal cords revealing that 61% of the axons exhibited a mean of 22 axonal ovoids and 8% of the axons terminating in axonal end bulbs. In the cerebral cortex, we observed a decrease in the mean number of layer V pyramidal neurons and a decrease in the mean length of the apical dendrites of the remaining neurons, compared to healthy controls. MRI analysis demonstrated decreased cortical volumes in EAE. Cross-modality correlations revealed a direct relationship between cortical volume loss and axonal end bulb number in the spinal cord, but not ovoid number. This is the first report of the use of CLARITY in an animal model of disease and the first report of the use of both CLARITY and MRI.
                Creative Commons 'BY-NC-SA' version 4.0 license
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2016)

                Importance

                Multiple sclerosis (MS) is characterized by progressive gray matter (GM) atrophy that strongly correlates with clinical disability. However, whether localized GM atrophy correlates with specific disabilities in patients with MS remains unknown.

                Objective

                To understand the association between localized GM atrophy and clinical disability in a biology-driven analysis of MS.

                Design, setting, and participants

                In this cross-sectional study, magnetic resonance images were acquired from 133 women with relapsing-remitting MS and analyzed using voxel-based morphometry and volumetry. A regression analysis was used to determine whether voxelwise GM atrophy was associated with specific clinical deficits. Data were collected from June 28, 2007, to January 9, 2014.

                Main outcomes and measures

                Voxelwise correlation of GM change with clinical outcome measures (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores).

                Results

                Among the 133 female patients (mean [SD] age, 37.4 [7.5] years), worse performance on the Multiple Sclerosis Functional Composite correlated with voxelwise GM volume loss in the middle cingulate cortex (P < .001) and a cluster in the precentral gyrus bilaterally (P = .004). In addition, worse performance on the Paced Auditory Serial Addition Test correlated with volume loss in the auditory and premotor cortices (P < .001), whereas worse performance on the 9-Hole Peg Test correlated with GM volume loss in Brodmann area 44 (Broca area; P = .02). Finally, voxelwise GM loss in the right paracentral lobulus correlated with bowel and bladder disability (P = .03). Thus, deficits in specific clinical test results were directly associated with localized GM loss in clinically eloquent locations.

                Conclusions and relevance

                These biology-driven data indicate that specific disabilities in MS are associated with voxelwise GM loss in distinct locations. This approach may be used to develop disability-specific biomarkers for use in future clinical trials of neuroprotective treatments in MS.
                  Cover page: Disability-Specific Atlases of Gray Matter Loss in Relapsing-Remitting Multiple Sclerosis
                  • 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
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