Early-onset Alzheimer’s Disease (EOAD) patients have a greater risk of developing seizures. Consequently, EOAD patients who develop seizures have worsened comorbidities, including mortality and behavioral outcomes. The causal relationship between chronic seizures and AD is still unknown. Neuroinflammation has been postulated as one of the links between these two disorders. Our lab has previously demonstrated that young mice with a presenilin 1 (PS1) genetic variant and amyloid precursor protein (APP) overexpression, mimicking an EOAD phenotype and genotype, subjected to chronic seizure are at high risk of mortality. This behavior was not observed in young mice with an EOAD-associated presenilin 2 (PS2) genetic variation. We hypothesize that chronic kindled seizures evoked in 2 months-old APP/PS1 mice worsen neuroinflammation and other neuropathological hallmarks of EOAD, including β-amyloid (Aβ) accumulation in the brain. To address this, 2-month-old male and female APP/PS1 and PS2 mice were subjected to seizures through a corneal kindling model of chronic seizures. The right brain hemisphere was collected before and after mice achieve the kindled criterion (five consecutive 5 Racine scale scores). Brains were harvested and cryopreserved for immunohistochemistry. My role in the project was to process tissues for immunohistochemistry. 20-µm thick sections of hippocampus from each mouse were sectioned on a cryostat and slide-mounted before processing with commercially available antibodies for molecular markers of neuroinflammation and neuropathology. Photomicrographs were collected and images were analyzed as the number of immunoreactive cells for each molecular and protein marker. We anticipate increased neuroinflammation and Aβ accumulation in kindled APP/PS1 mice versus their respective wild types and non-kindled littermates. We do not expect differences in PS2 variant animals. These results add to a larger research study in the laboratory to suggest that targeting seizures, and its inflammatory response, may be a potential therapeutic strategy to mitigate the behavioral and neuropathological burden of AD.

People living with epilepsy (PWE) often have a poorer quality of life (QoL) compared to the general population. Anti-seizure medicines (ASMs) are used to control seizures in PWE but are often associated with side-effects that lead to reduced adherence. Poor adherence is associated with reduced seizure control which can also negatively impact QoL. A rat model of acquired epilepsy was used to evaluate how poor adherence to the ASM, perampanel (PER), impacts an animal’s engagement with environmental enrichment, which is provided to promote species-specific behaviors and general well-being. Cardboard enrichment was provided to single-housed male Sprague Dawley rats with acquired epilepsy and I scored their level of engagement at the start of each day: i.e.,1 being no engagement; 4 being completely engaged. Animals were observed for 8 weeks: 4 weeks without PER and 4 weeks with PER in a fully adherent (100%) or variably nonadherent (50%) dosing paradigm (10 mg/kg/day, p.o.). I recorded data on the number of days till first engagement with the enrichment, days till max, and max enrichment score. After compiling the data, I found no significant differences in the max enrichment score or days till max score amongst the 100% or 50% treatment groups. Interestingly, when compared to their pretreatment baseline, fully adherent rats took less time to initially engage with their enrichment, i.e., 6-9 days, compared to 9-12 days, respectively. In contrast, nonadherent rats did not show a similar improvement in their enrichment behavior when treatment was initiated. These results suggest that fully adherent rats were more willing to interact with their enrichment whereas, poor medication adherence may have a direct negative impact on QoL. Further investigation is necessary to determine if this is due to a difference in seizure control between the groups.

With the sharp uptick of diagnosed depression cases since the start of COVID-19, it is likely that someone close to us suffers or has suffered from depression. The standby period when starting a new anti-depressant medication exceeds practical justification when patients must often wait two or more weeks before the efficacy of new medication can be assessed. This waiting game often leads to a loss of hope when other options have been unsuccessful. Predicting the effectiveness of a new medication based on a patient’s individualized makeup is vital to the medication onboarding process. Tests based on metabolizing properties and Pharmacogenomic capabilities provide a pathway into predictive care. The ability to assay target genes while identifying subpopulations can simultaneously reduce the likelihood of potential adverse drug reactions, as well as entice pharmaceutical companies to mass-produce medication directed to those with specific mutations to prevent adverse reactions. This research consists of a literature review detailing forms of potential adverse drug reaction prediction. Methods include the use of information from various scientific articles and the recognition of connections and disconnects between sources. It’s expected that metabolizing genes will be the primary component in efficacy prediction due to drug-gene interactions. The implications of reducing the waiting period for those suffering from depression is crucial to patient well-being. As rates of depression diagnoses increase, the implementation of personalized treatment will aid in decreasing the timespan of treatment. Particular drug manufacturers will lose money if their drug is proven ineffective ahead of time for specific individuals, though patients and physicians alike will benefit from quicker treatment options. Current tests are not mainstream due to ongoing research and strict guidelines that must be followed before clinical implementation. As innovation continues, preventative and personalized medicine will be a prominent supplementation to the treatment of individuals with depression.

Oritavancin and dalbavancin are mechanistically similar to vancomycin and daptomycin and are among the longest-acting antimicrobials in clinical use with half-lives up to 14-days. This long duration of action increases antimicrobial exposure but prolongs the mutant selection window: the concentration range that selects for resistant mutants. Previous work shows that these drugs readily select for resistance and cross-resistance to vancomycin and daptomycin in Staphylococcus aureus. We hypothesized a similar cross-resistance selection potential against colonizing opportunistic pathogens including enterococci. While less virulent than S. aureus, enterococci are leading causes of multi-drug resistant infections among elderly and immunocompromised patients. To test this hypothesis, we serially passaged two strains of Enterococcus faecalis and three strains of Enterococcus faecium for 21-days in escalating concentrations of oritavancin or dalbavancin to facilitate the evolution of resistance. Minimum inhibitory concentrations (MICs) for oritavancin, dalbavancin, vancomycin, and daptomycin were performed by broth microdilution on isolates recovered from screening plates. Whole genome sequencing (WGS) was performed to characterize genotypic mechanisms of resistance. Resistance phenotype stability was assessed by passaging isolates on drug-free media and repeated MIC testing. Among dalbavancin-passaged enterococci, only daptomycin cross-resistance emerged. Serial passage in oritavancin selected for cross-resistance to dalbavancin in all strains, and cross-resistance to vancomycin among vancomycin-susceptible enterococci. Cross-resistance to daptomycin was not observed. WGS revealed fewer mutations than expected. Despite elevated MICs, no mutations were detected in E. faecalis. Only one strain of E. faecium acquired mutations in the vanZ and rodA gene. The absence of mutations in our evolved strains requires further investigation, including repeating WGS and screening for gene copy number variants that may have been missed by our initial analysis. Our data suggests that clinicians should exercise caution when using oritavancin to treat enterococcal infections due to the potential for cross-resistance to first-line antibiotics, such as daptomycin and vancomycin.