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With a growing number of adults with autism spectrum disorder (ASD), more and more research has been conducted on majority male cohorts with ASD from young, adolescence, and some older age. Currently, males make up the majority of individuals diagnosed with ASD, however, recent research states that the gender ga

With a growing number of adults with autism spectrum disorder (ASD), more and more research has been conducted on majority male cohorts with ASD from young, adolescence, and some older age. Currently, males make up the majority of individuals diagnosed with ASD, however, recent research states that the gender gap is closing due to more advanced screening and a better understanding of how females with ASD present their symptoms. Little research has been published on the neurocognitive differences that exist between older adults with ASD compared to neurotypical (NT) counterparts, and nothing has specifically addressed older women with ASD. This study utilized neuroimaging and neuropsychological tests to examine differences between diagnosis and sex of four distinct groups: older men with ASD, older women with ASD, older NT men, and older NT women. In each group, hippocampal size (via FreeSurfer) was analyzed for differences as well as correlations with neuropsychological tests. Participants (ASD Female, n = 12; NT Female, n = 14; ASD Male, n = 30; NT Male = 22), were similar according to age, IQ, and education. The results of the study indicated that the ASD Group as a whole performed worse on executive functioning tasks (Wisconsin Card Sorting Test, Trails Making Test) and memory-related tasks (Rey Auditory Verbal Learning Test, Weschler Memory Scale: Visual Reproduction) compared to the NT Group. Interactions of sex by diagnosis approached significance only within the WCST non-perseverative errors, with the women with ASD performing worse than NT women, but no group differences between men. Effect sizes between the female groups (ASD female vs. NT female) showed more than double that of the male groups (ASD male vs. NT male) for all WCST and AVLT measures. Participants with ASD had significantly smaller right hippocampal volumes than NT participants. In addition, all older women showed larger hippocampal volumes when corrected for total intracranial volume (TIV) compared to all older men. Overall, NT Females had significant correlations across all neuropsychological tests and their hippocampal volumes whereas no other group had significant correlations. These results suggest a tighter coupling between hippocampal size and cognition in NT Females than NT Males and both sexes with ASD. This study promotes further understanding of the neuropsychological differences between older men and women, both with and without ASD. Further research is needed on a larger sample of older women with and without ASD.
ContributorsWebb, Christen Len (Author) / Braden, B. Blair (Thesis advisor) / Azuma, Tamiko (Committee member) / Dixon, Maria (Committee member) / Arizona State University (Publisher)
Created2019
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Description
Schizophrenia is a debilitating psychiatric disorder with poorly understood genetic and environmental factors. An allelic variant of complement component 4 (C4), a protein first identified in innate immune response is strongly associated with schizophrenia. In the brain, activity of C4 leads to dendritic pruning, a process that may

Schizophrenia is a debilitating psychiatric disorder with poorly understood genetic and environmental factors. An allelic variant of complement component 4 (C4), a protein first identified in innate immune response is strongly associated with schizophrenia. In the brain, activity of C4 leads to dendritic pruning, a process that may be causal in disease progression. Environmental factors, such as early life exposure to significant stressors also associate with increased risk of schizophrenia in later life. My hypothesis is that these factors do not act independently, but rather in tandem to influence disease etiology.
This hypothesis is supported by previous studies demonstrating that stress-induced elevation of glucocorticoids increases the transcription of C4. I propose that activated glucocorticoid receptors directly increase C4 protein expression as a transcription factor activator. Additionally, I propose that activated glucocorticoid receptors inhibit the expression of the transcription factor nuclear factor-light-chain-enhancer of activated B cells (NF-κB), thereby leading to decreased expression of the C4 inhibitor CUB and Sushi multiple domains 1 (CSMD1).
Glucocorticoid receptors and C4 are richly expressed in the hippocampus, a region critical in memory consolidation, spatial, and declarative memory. I propose that stress-induced upregulation of C4 activity in the hippocampus promotes excessive synaptic pruning, contributing to specific deficits and hippocampal shrinkage seen in schizophrenia. Stress exposure during fetal development and adolescence likely acts through the proposed mechanisms to increase hippocampal C4 activity and subsequent schizophrenia risk. These mechanisms may reveal novel interactions between environmental and genetic risk factors in the etiology of schizophrenia through complement activation.
ContributorsHoegh, Emily Marie (Author) / Orchinik, Miles (Thesis director) / Newbern, Jason (Committee member) / Talboom, Joshua (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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This pilot study evaluated whether Story Champs and Puente de Cuentos helped bilingual preschoolers increase their usage of emotional terms and ability to tell stories. Participants in this study included 10 Spanish-English bilingual preschoolers. Intervention was conducted in 9 sessions over 3 days using the Test of Narrative Retell to

This pilot study evaluated whether Story Champs and Puente de Cuentos helped bilingual preschoolers increase their usage of emotional terms and ability to tell stories. Participants in this study included 10 Spanish-English bilingual preschoolers. Intervention was conducted in 9 sessions over 3 days using the Test of Narrative Retell to measure results. Results did not find significant gains in either emotional term usage or ability to tell stories, but the results were promising as a pilot study.
ContributorsSato, Leslie Mariko (Author) / Restrepo, Maria (Thesis director) / Dixon, Maria (Committee member) / Department of Speech and Hearing Science (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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The aim of this study was to explore cross-sectional and longitudinal aging differences in immediate and delayed visual and verbal memory abilities in individuals with Autism Spectrum Disorder (ASD) compared with neurotypicals (NTs). We measured hippocampal size, fornix fractional anisotropy (FA), and hippocampal and fornix freewater to understand how aging

The aim of this study was to explore cross-sectional and longitudinal aging differences in immediate and delayed visual and verbal memory abilities in individuals with Autism Spectrum Disorder (ASD) compared with neurotypicals (NTs). We measured hippocampal size, fornix fractional anisotropy (FA), and hippocampal and fornix freewater to understand how aging impacts memory structures. Longitudinal findings highlight vulnerabilities in immediate verbal memory and hippocampal volume, while cross-sectional findings indicate fornix freewater may increase at a faster rate in adults with ASD. Future research will examine cognitive and structural sex differences and will study how cognitive measures correlate with structural measures.

ContributorsSullivan, Georgia Rose (Author) / Braden, B. Blair (Thesis director) / Ofori, Edward (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
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Description
Background: The hippocampus is a critical brain structure for memory formation and other aspects of cognition. The hippocampus and the white matter tracts connecting it to other parts of the brain are known to lose volume and integrity with aging. For populations with prior compromised hippocampal integrity, such as those

Background: The hippocampus is a critical brain structure for memory formation and other aspects of cognition. The hippocampus and the white matter tracts connecting it to other parts of the brain are known to lose volume and integrity with aging. For populations with prior compromised hippocampal integrity, such as those with autism spectrum disorder (ASD), it is less well known how the hippocampus and its connections will respond to aging. In children with ASD, there may be an initial period of enlarged hippocampi, after which there is a trajectory of faster decline in volume compared to neurotypicals (NT). We have previously identified reduced hippocampal volumes and fornix white matter integrity in middle-age and older adults with ASD compared to matched NT adults. However, freewater (FW) may be a more sensitive structural integrity measure of the hippocampal complex. FW is present in the brain as cerebrospinal fluid but also accumulates within the extracellular spaces indicative of reduced gray matter density and increased axon degeneration. FW shows promise as a more sensitive biomarker for Parkinson’s and Alzheimer’s disease. This study evaluated age-related hippocampal complex FW differences in adults with and without ASD across the adult lifespan. We hypothesized that adults with ASD would demonstrate a larger age association with increasing FW in the hippocampus and fornix, compared to NT adults, and that FW would be a more sensitive brain measure than traditional fractional anisotropy (FA).

Methods: The study consisted of 79 participants with ASD (59 male, 20 female; ages 18-70, mean=40.27 [±17] years) and 77 NT participants (46 male, 31 female; ages 18-71, mean=40.33 [±16] years). Hippocampal and fornix FW and FA values were generated from diffusion tensor images obtained along 32 directions using a b-value of 2500 s/mm2 in the axial direction with 3 mm slice resolution. These images were then processed for eddy current, distortion, b-vec and motion correction, skull stripped, and non-linear registered using Advanced Normalization Tools (ANTs) to the subject’s T1 image. FW and FA maps were calculated using custom written MatLab code and standard atlases containing the hippocampus and fornix were applied.

Results: The right hippocampus showed a significant diagnosis by age interaction (p=0.018), such that the increase in FW with age was greater for adults with ASD. The left hippocampus diagnosis by age interaction approached significance (p=0.055). Similarly, the right fornix showed a significant diagnosis by age interaction (p=0.044), with increases in FW with age as greater for adults with ASD, and the left fornix diagnosis by age interaction approached significance (p=0.053). FA values showed no significant diagnosis by age interactions.

Conclusion: In the hippocampus and fornix, the association between increasing FW and increasing age was more pronounced for adults with ASD than matched NT adults. This may mean that as adults with ASD age, these regions will degenerate faster than their NT peers, which could have implications for accelerated age-related memory decline. However, a notable limitation is the cross-sectional nature of the study. Our ongoing longitudinal study will inform a more definitive picture of brain aging with ASD.
ContributorsAlvar, Jocelyn R (Author) / Braden, Brittany Blair (Thesis director) / Ofori, Edward (Committee member) / School of Life Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
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Description
Down Syndrome (DS), caused by the trisomy 21, is the most common intellectual developmental disorder. Children with DS display deficits in ample memory tasks attributed to alterations in memory-related brain structures, including the hippocampus. Although, many studies in DS focused on development of the brain during prenatal stages, little

Down Syndrome (DS), caused by the trisomy 21, is the most common intellectual developmental disorder. Children with DS display deficits in ample memory tasks attributed to alterations in memory-related brain structures, including the hippocampus. Although, many studies in DS focused on development of the brain during prenatal stages, little is known about the cellular evolution of the hippocampus in postnatal periods in DS. Therefore, here we examined the neurochemical spatiotemporal development of neuronal profiles in pediatric postnatal hippocampus in DS and neurotypical developing (NTD) controls. A quantitative and qualitative neuronal distribution was performed in hippocampal sections containing the proper hippocampus, dentate gyrus (DG) and subiculum obtained at autopsy from 1 day to 3 year-old infants in DS and NTD age-matched controls using antibodies against the non-phosphorylated high-molecular-weight neurofilament, a marker of differentiated neurons (SMI-32), the calcium binding protein calbindin D-28k (CAB), and the migration neuronal marker microtubule-associated protein doublecortin (DCX). In addition, Aβ and phosphorylated tau was also immunohistochemically examined in the hippocampus using 6E10, Aβ1-42 and the phosphorylated CP-13 and AT8 tau antibodies, respectively. We found APP/Aβ immunoreactivity, but not Aβ1-42, in diffuse-like plaques in the hippocampus from 1 day to 3 year old infants and young children in DS and NTD cases. By contrast, phosphorylated fetal tau was not immunodetected in the hippocampus at any age in both groups. SMI-32 immunolabeled neurons were observed in the hilus, CA2 field and subiculum in early postnatal cases in DS and NTD. The number of SMI-32 immunoreactive (ir) granule cells in the DG were significantly decreased in DS compared to NTD. While a strong DCX immunoreactivity was observed in the granule cells of the DG in the hippocampus in both groups at early postnatal stages, a more accelerated reduction was observed in DS. CAB-ir neuronal distribution in the postnatal hippocampus was comparable between the youngest and the oldest infants in NTD and DS. In addition, strong positive correlations were observed between DG-DCX-ir cells numbers and both DG-CAB-ir and DG-SMI-32-ir values as well as negative correlations between the brain weight and DG granule cell-ir numbers for all markers in DS. These findings suggest that neuronal maturation and migration in the hippocampus are compromised in early postnatal stages of the development in DS and may contribute to the intellectual disabilities observed in this group.
ContributorsMoreno, David (Co-author) / Perez, Sylvia E. (Co-author, Thesis director) / Velazquez, Ramon (Thesis director) / Schafernak, Kristian T. (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
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Description
Major Depressive Disorder (MDD) affects over 300 million people worldwide, with the hippocampus showing decreased volume and activity in patients with MDD. The current study investigated whether a novel preclinical model of depression, unpredictable intermittent restraint (UIR), would decrease hippocampal neuronal dendritic complexity. Adult Sprague Dawley rats (24 male, 24

Major Depressive Disorder (MDD) affects over 300 million people worldwide, with the hippocampus showing decreased volume and activity in patients with MDD. The current study investigated whether a novel preclinical model of depression, unpredictable intermittent restraint (UIR), would decrease hippocampal neuronal dendritic complexity. Adult Sprague Dawley rats (24 male, 24 female) were equally divided into 4 groups: control males (CON-M), UIR males (UIR-M), control females (CON-F) and UIR females (UIR-F). UIR groups received restraint and shaking on an orbital shaker on a randomized schedule for 30 or 60 minutes/day for two to six days in a row for 26 days (21 total UIR days) before behavioral testing commenced. UIR continued and was interspersed between behavioral test days. At the end of behavioral testing, brains were processed. The behavior is published and not part of my honor’s thesis; my contribution involved quantifying and analyzing neurons in the hippocampus. Several neuronal types are found in the CA3 subregion of the hippocampus and I focused on short shaft (SS) neurons, which show different sensitivities to stress than the more common long shaft (LS) variety. Brains sections were mounted to slides and Golgi stained. SS neurons were drawn using a microscope with camera lucida attachment and quantified using the number of bifurcations and dendritic intersections as metrics for dendritic complexity in the apical and basal areas separately. The hypothesis that SS neurons in the CA3 region of the hippocampus would exhibit apical dendritic simplification in both sexes after UIR was not supported by our findings. In contrast, following UIR, SS apical dendrites were more complex in both sexes compared to controls. Although unexpected, we believe that the UIR paradigm was an effective stressor, robust enough to illicit neuronal adaptations. It appears that the time from the end of UIR to when the brain tissue was collected, or the post-stress recovery period, and/or repeated behavioral testing may have played a role in the observed increased neuronal complexity. Future studies are needed to parse out these potential effects.
ContributorsAcuna, Amanda Marie (Author) / Conrad, Cheryl (Thesis director) / Corbin, William (Committee member) / Olive, M. Foster (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2020-12