Currently, the availability and quantity of electronic support tools that oncology health care providers have access too is not the issue, but rather the quality within these tools due to the lack of individualization that they provide. This paper is a modest attempt to suggest the creation of an electronic prediction support tool called the Invasive Ductal Carcinoma Treatment Timeline Predictor (IDCTTP): a tool intended to increase the individualization and quality of patient care by taking a full timeline approach at each patient’s treatment plan. By being specifically focused on treatment plans for patients with stage III invasive ductal carcinoma, a type of breast cancer, this tool will initiate the process of individualization. It will then increase patients’ quality of care further by providing each distinctive stage III IDC patient with a full timeline approach: producing an initial prediction for a treatment plan, a second predicted plan in case of recurrence, and an alternative prediction in case original treatments are unsuccessful. This tool will also consider additional components such as patients’ financial situations, the potential for modifying or opting out of treatment due to side effects, and the constant medical debate of efficacy versus toxicity. For each stage III IDC patient that uses the IDCTTP, the result will be an electronic prediction tool that can give her the support that she needs to make those difficult decisions regarding her breast cancer treatment plan.

The aim of this study was to determine whether IUD administration, with and without the presence of Levo, and with and without the presence of the ovaries, impacts cognition in a rat model. Rats received either Sham or Ovariectomy (Ovx) surgery (removal of the ovaries), plus either no IUD, a Blank IUD (without Levo), or a Levo-releasing IUD (Levo IUD), enabling us to evaluate the effects of Ovx and the effects of IUD administration on cognition. Two weeks after surgery, all treatment groups were tested on the water radial arm maze, Morris water maze, and visible platform task to evaluate cognition. At sacrifice, upon investigation of the uteri, it was determined that some of the IUDs were no longer present in animals from these groups: Sham\u2014Blank IUD, Ovx\u2014Blank IUD, and Sham\u2014Levo IUD. Results from the remaining three groups showed that compared to Sham animals with no IUDs, Ovx animals with no IUDs had marginally impaired working memory performance, and that Ovx animals with Levo IUDs as compared to Ovx animals with no IUDs had marginally enhanced memory performance, not specific to a particular memory type. Results also showed that Ovx animals with Levo IUDs had qualitatively more cells in their vaginal smears and increased uterine horn weight compared to Ovx animals with no IUDs, suggesting local stimulation of the Levo IUDs to the uterine horns. Overall, these results provide alternative evidence to the hypothesis that the Levo IUD administers Levo in solely a localized manner, and suggests that the possibility for the Levo IUD to affect reproductive cyclicity in ovary-intact animals is not rejected. The potential for the Levo IUD to exert effects on cognition suggests that either the hormone does in fact systemically circulate, or that the Levo IUD administration affects cognition by altering an as yet undetermined hormonal or other feedback between the uterus and the brain.

Hormone therapy (HT) containing 17beta-estradiol (E2) can greatly reduce physiological symptoms associated with declines in ovarian hormones that are seen with menopause. HT containing E2 has also been shown to play a beneficial role in cognitive function. There is discrepancy, however, surrounding which dose of E2 is the most optimal for cognition. A previous rodent behavioral study in our laboratory evaluated the effects of different doses of E2 on spatial memory performance, and results indicated that rats treated with a low E2 dose (0.3 g E2) made fewer working memory incorrect (WMI) errors, indicating enhanced spatial memory performance, compared to vehicle (0.1ml sesame oil)- and high E2 (3.0 g E2)- treated groups. This finding warranted the present investigation with the overarching aim to evaluate underlying neuromolecular mechanisms that may be modulating these cognitive effects. Both the insulin-like growth factor-1 receptor (IGF1-R) and extracellular regulated kinase (Erk) 2 have been observed to mediate E2-induced memory enhancements. We used the Western Blot to measure IGF1-R and activated Erk1/2 expression in brain regions involved in learning and memory, including the dorsal hippocampus, ventral CA1/CA2 hippocampus, entorhinal cortex, and perirhinal cortex. Results demonstrated a linear relationship between IGF1-R expression and administered E2 dose in the perirhinal cortex, whereby IGF1-R expression increased as the dose of E2 increased. Additionally, in the perirhinal cortex, IGF1-R expression tended to increase as activated Erk1 increased for all treatment groups. Further, number of WMI errors tended to decrease as IGF1-R expression and activated Erk1 expression in the perirhinal cortex tended to increase in the low E2 treatment group. Collectively, these findings suggest a downstream-dependent relationship between IGF1-R and activated Erk1 in the perirhinal cortex that may be contributing to the enhancements in spatial memory performance observed in animals in the low E2 treatment group. These findings are a crucial piece in the greater understanding of what underlying molecular mechanisms may be modulating a cognitively beneficial dose of E2, and further contribute to the search for a HT that would be beneficial for cognition in menopausal women.

With no known cure, Alzheimer's disease (AD) is the most common dementia, affecting more than 5.5 million Americans. Research has shown that women who undergo surgical menopause (i.e. removal of the ovaries) before the onset of natural menopause are at a greater risk for AD. It is hypothesized that this greater relative risk of developing AD is linked to ovarian hormone deprivation associated with surgical menopause. The purpose of these studies was to evaluate the behavioral changes that occur after a short-term (ST) and a long-term (LT) ovarian hormone deprivation in a mouse model of AD. Wildtype (Wt) or APP/PS1 (Tg) mutation mice underwent either a sham surgery or an ovariectomy (Ovx) surgery at three months of age. Study 1 consisted of a short-term cohort that was behaviorally tested one month following surgery on a battery of spatial memory tasks including, the Morris water maze, delayed matched-to-sample water maze, and visible platform task. Study 2 consisted of a long-term cohort that was behaviorally tested on the same cognitive battery three months following surgery. Results of Study 1 revealed that genotype interacted with surgical menopause status, such that after a short-term ovarian hormone deprivation, Ovx induced a genotype effect while Sham surgery did not. Results of Study 2 showed a similar pattern of effects, with a comparable interaction between genotypes and surgical menopause status. These findings indicate that the cognitive impact of ovarian hormone deprivation depends on AD-related genotype. Neuropathology evaluations in these mice will be done in the near future and will allow us to test relations between surgical menopause status, cognition, and AD-like neuropathology.

Menopause is associated with a wide array of negative symptoms. As average lifespan increases due to advances in healthcare and technology, more women are spending a larger portion of their lives in a menopausal state low in estrogen and progesterone. Hormone therapies such as Conjugated Equine Estrogens (CEE) and the bioidentical estrogen, 17-estradiol (E2), are commonly prescribed to treat the negative symptoms of menopause. Our laboratory has previously shown that CEE has differential effects on cognitive ability depending on whether menopause is transitional (VCD) or surgical (ovariectomy, OVX). Further, the negative impact of CEE on cognitive function in a transitional ovary-intact model of menopause was associated with high levels of serum androstenedione; the primary hormone circulating in a follicle-deplete menopausal state. Here, we investigate the cognitive effects of these two common hormone therapies separately, and in conjunction with the hormone androstenedione, in a "blank-slate" OVX mouse model. We assessed cognitive ability using two behavioral tasks such at the Water Radial Arm Maze (WRAM, measuring spatial working and reference memory) and the Morris water maze (MM, measuring spatial reference memory). In the WRAM, every treatment group saw impaired performance compared to Vehicle but the combination group of E2 plus Androstenedione. In the MM, the combination group of E2 plus Androstenedione actually enhanced performance in the maze compared to every other comparable group. Translationally, these results suggest that CEE given in the presence of an androstenedione-dominant hormone milieu is impairing to cognition, E2 in this same manner is not. These results yield valuable insight into optimal hormone therapies for menopausal women.

Estradiol (E2) and Levonorgestrel (Levo) are two hormones commonly used in hormone therapy (HT) to decrease symptoms associated with menopause. Both of these hormones have been shown to have beneficial effects on cognition when given alone in a rodent model of menopause. However, it is unknown whether these hormones, when taken in combination, are beneficial or harmful to cognition. This is a critically important question given that these hormones are most often given in combination versus separately. This thesis is composed of two studies examining the cognitive effects of E2 and Levo using a rat model of surgical menopause. Study 1 assessed how the dose of E2 treatment in rats impacted cognitive performance, and found that low dose E2 enhanced working memory performance. Next, based on the results from Study 1, Study 2 used low dose E2 in combination with different doses of Levo to examine the cognitive effects of several E2 to Levo ratio combinations. The results from Study 2 demonstrated that the combination of low dose E2 with a high dose of Levo at a 1:2 ratio impaired cognition, and that the ratio currently used in HT, 3:1, may also negatively impact cognition. Indeed, there was a dose response effect indicating that working and reference memory performance was incrementally impaired as Levo dose increased. The findings in this thesis suggest that the E2 plus Levo combination is likely not neutral for cognitive function, and prompts further evaluation in menopausal women, as well as drug discovery research to optimize HT using highly controlled preclinical models.

Alzheimer's disease affects a large number of Americans every year, and research on the causes and possible prevention continues to increase. Alzheimer's disease is a form of dementia that causes problems with memory, thinking, and behavior and is thought to be caused by beta-amyloid plaques that form in the brain. In recent years, dogs have been used more and more as an animal model looking at Alzheimer's disease and cognitive dysfunction. Dogs serve as a reliable animal model because effected dogs naturally form the same beta-amyloid plaques that affected humans do as they age. Previous research has shown that older dogs perform worse on various memory tasks than do younger dogs, however researchers have struggled to find a test for dog cognitive dysfunction that is brief and can be performed in the home. The current study aimed to find a brief memory task that requires few materials, but is still reliable. The results of this study do not support the hypothesis that older dogs would perform worse than younger dogs if tested to find a treat with varying time delays of 15, 30, and 45 seconds. The results of this experiment showed a main effect of age (F = 8.40, d.f. 1, 19, p < 0.01) and delay (F = 15.14, d.f. 2, 30, p < 0.01), but age-delay interaction was not significant (F = 2.53, d.f. 2, 30, p = 0.09). Future studies should be performed using a larger sample size and this same protocol to attempt to raise the participation level of the dogs.

Chronic stress often leads to cognitive deficits, especially within the spatial memory domain mediated by the hippocampus. When chronic stress ends and a no-stress period ensues (i.e., washout, WO), spatial ability improves, which can be better than non-stressed controls (CON). The WO period is often the same duration as the chronic stress paradigm. Given the potential benefit of a post-stress WO period on cognition, it is important to investigate whether this potential benefit of a post-stress WO period has long-lasting effects. In this project, chronic restraint (6hr/d/21d) in Sprague-Dawley rats was used, as it is the minimum duration necessary to observe spatial memory deficits. Two durations of post-stress WO were used following the end of chronic restraint, 3 weeks (STR-WO3) and 6 weeks (STR-WO6). Immediately after chronic stress (STR-IMM) or the WO periods, rats were tested on various cognitive tests. We corroborated past studies that chronic stress impaired spatial memory (STR-IMM vs CON). Interestingly, STR-WO3 and STR-WO6 failed to demonstrate improved spatial memory on a radial arm water maze task, performing similarly as STR-IMM. Performance outcomes were unlikely from differences in anxiety or motivation because rats from all conditions performed similarly on an open field task and on a simple object recognition paradigm, respectively. However, performance on object placement was unusual in that very few rats explored, suggesting some degree of anxiety or fear in all groups. One possible interpretation of the unusual results of the 3 week washout group may be attributed to the different spatial memory tasks used across studies or external factors from the study. Further exploration of these other factors led to the conclusion that they did not play a role and the STR-WO3 RAWM data were anomalous to other studies. This suggests that a washout period following chronic stress may not be fully understood.

Drospirenone (DRSP) is a novel, pharmacologically unique synthetic progestin with properties more similar to the endogenous progestogen, progesterone, than any other progestin currently on the market. While a significant amount of research has been conducted on the risks associated with DRSP, the impact of DRSP on cognition, especially in reference to learning and memory, is not well understood. However, it is imperative to fully understand the cognitive effects of DRSP, both alone and in combination with EE (as taken in a combined oral contraceptive [COC]), so that women and their physicians can make a fully-informed decision when deciding to take a DRSP-containing COC. Study 1 examined the effects of three doses of DRSP in order to determine the optimal dose for combining with EE, and found that the medium dose of DRSP (30 µg/day) enhanced spatial working memory performance. In Study 2, the medium dose of DRSP from Study 1 was combined with low (0.125 µg/day) and high (0.3 µg/day) doses of EE to examine the effects of DRSP as taken with EE in a COC. The results from Study 2 indicated that when DRSP was combined with a low, but not high, dose of EE, spatial working memory impairments were seen at the highest working memory load. Anxiety-like behavior was evaluated using the OFT, and DRSP was shown to decrease measures of anxiety-like behavior. Additionally, while treatment with a high dose of EE decreased several measures of anxiety-like behavior, a low dose of EE did not, suggestive of a dose response. Taken together, the findings presented from both studies suggest that some of the cognitive effects of the combination of DRSP with EE are different than those of either hormone administered on its own. Further exploration in a preclinical, ovary-intact animal model is a next step to fully understand these effects in the translational context of a contraceptive, given that women taking an EE-DRSP combination are typically ovary-intact.

Sports related concussions, or mild traumatic brain injuries (mTBI), have recently increased in prevalence, and thus gained a great deal of recognition from the public and the media. While the acute symptoms associated with concussions are well known, which include headaches, dizziness, vomiting, and fatigue, recent research has indicated that there can be severe chronic consequences of multiple conditions. Most notably, a disease called Chronic Traumatic Encephalopathy (CTE) has been linked to multiple mTBIs, which produces symptoms similar to Alzheimer's disease and dementia, in addition to personality changes, increased suicidality, and in some cases death. This knowledge has led the NFL to take steps to protect their players, and increase both the understanding and awareness of the problems associated with multiple concussions. This comes with many problems, however, as players and fans alike are quick to resist any type of change to the rules or policies present in football, in fear that it may damage the integrity of the game. The NFL is thus forced into a difficult position, and must balance public opinion and player safety. There are things that can be done, however, that do not threaten the game itself, such as investing in concussion research and safety equipment design that will more effectively protect the brain from concussions.