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.

Autism spectrum disorder (ASD) is highly comorbid with mood disorders, such as depression and anxiety. Previous research suggests difficulties in emotion regulation to be concordant with experiencing these comorbid symptoms. Understanding the neural correlates of emotion regulation in ASD and relationships with mood symptoms could provide insights for effective treatments. We employed an existing functional MRI paradigm to assess neural activation during an emotional regulation task in adults with ASD, and correlate activated regions with self-reported measures of depression and anxiety. We found the following regions to be significantly associated with emotion regulation (family-wise error corrected p<0.05): the bilateral insula, anterior cingulate, middle cingulate, precentral gyrus, angular gyrus, left dorsolateral PFC, right caudate/putamen, and left medial PFC. We found anxiety, but not depression, symptoms were negatively correlated with activation in the anterior cingulate, left insula, and left putamen, and showed a moderate relationship to the amygdala. These results expand current understanding of ASD and emotion regulation and suggest targets for future clinical intervention.

Cognitive function declines with normal age and disease states, such as Alzheimer's disease (AD). Loss of ovarian hormones at menopause has been shown to exacerbate age-related memory decline and may be related to the increased risk of AD in women versus men. Some studies show that hormone therapy (HT) can have beneficial effects on cognition in normal aging and AD, but increasing evidence suggests that the most commonly used HT formulation is not ideal. Work in this dissertation used the surgically menopausal rat to evaluate the cognitive effects and mechanisms of progestogens proscribed to women. I also translated these questions to the clinic, evaluating whether history of HT use impacts hippocampal and entorhinal cortex volumes assessed via imaging, and cognition, in menopausal women. Further, this dissertation investigates how sex impacts responsiveness to dietary interventions in a mouse model of AD. Results indicate that the most commonly used progestogen component of HT, medroxyprogesterone acetate (MPA), impairs cognition in the middle-aged and aged surgically menopausal rat. Further, MPA is the sole hormone component of the contraceptive Depo Provera, and my research indicates that MPA administered to young-adult rats leads to long lasting cognitive impairments, evident at middle age. Natural progesterone has been gaining increasing popularity as an alternate option to MPA for HT; however, my findings suggest that progesterone also impairs cognition in the middle-aged and aged surgically menopausal rat, and that the mechanism may be through increased GABAergic activation. This dissertation identified two less commonly used progestogens, norethindrone acetate and levonorgestrel, as potential HTs that could improve cognition in the surgically menopausal rat. Parameters guiding divergent effects on cognition were discovered. In women, prior HT use was associated with larger hippocampal and entorhinal cortex volumes, as well as a modest verbal memory enhancement. Finally, in a model of AD, sex impacts responsiveness to a dietary cognitive intervention, with benefits seen in male, but not female, transgenic mice. These findings have clinical implications, especially since women are at higher risk for AD diagnosis. Together, it is my hope that this information adds to the overarching goal of optimizing cognitive aging in women.