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Levetiracetam modulates brain metabolic networks and transcriptomic signatures in the 5XFAD mouse model of Alzheimer’s disease
(Frontiers Media, 2024-01-24) Burton, Charles P.; Chumin, Evgeny J.; Collins, Alyssa Y.; Persohn, Scott A.; Onos, Kristen D.; Pandey, Ravi S.; Quinney, Sara K.; Territo, Paul R.; Radiology and Imaging Sciences, School of Medicine
Introduction: Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer's disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core. Methods: Chronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling. Results: Pharmacokinetics of LEV showed a sex and dose dependence in Cmax, CL/F, and AUC0-∞, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e., positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling. Discussion: This study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value toward informing clinical study design.
An Integrative Literature Review: Understanding Grief Through Interactions with Clay
(2024) Downs, Abigail; Misluk, Eileen; Mower, Ashleigh
Exploring How Expressive Art Interventions Impact Adults with Amputations
(2022) Murphy, Baley; Misluk; Alpers, Joan
This study aims to understand how expressive art therapy interventions can impact adults with amputations. The 44 resources implemented in this thesis helped build a literary foundation and formulated themes seen within the literature. These themes included distorted self-image, feelings of loss and grief, complications with adjustment in daily life and with a prosthesis, phantom limb pain, changes to independent living and autonomy, and inadequate education pre- and-post-amputation. Four groups were proposed to inform, provide insight, and address the psychophysiological needs of individuals with amputations. Art therapy was utilized in all four groups. Three of the four groups integrated guided imagery, yoga, and boxing to enhance the therapeutic experience and achieve goals. Various needs of individuals with amputations were identified through an integrative narrative review research study. A literature matrix was used for data organization, and for data categorization, a thematic analysis was used (Betts & Deaver, 2019). These proposed groups can be used to track progress within the rehabilitation setting. These groups can increase a sense of safety, feelings of control and coherent communication, emotion regulation, strength through yoga and boxing exercises, acceptance of new body/ limitations, autonomy, mastery, strength, and confidence, foster a sense of community, and allow participants to self-reflect on their amputation journey. Expressive art therapies are beneficial for individuals with limb loss and should be implemented in rehabilitation to provide a transitional object that can help ease the transition from hospital to home.
Edge time series components of functional connectivity and cognitive function in Alzheimer's disease
(Springer, 2024) Chumin, Evgeny J.; Cutts, Sarah A.; Risacher, Shannon L.; Apostolova, Liana G.; Farlow, Martin R.; McDonald, Brenna C.; Wu, Yu‑Chien; Betzel, Richard; Saykin, Andrew J.; Sporns, Olaf; Radiology and Imaging Sciences, School of Medicine
Understanding the interrelationships of brain function as measured by resting-state magnetic resonance imaging and neuropsychological/behavioral measures in Alzheimer’s disease is key for advancement of neuroimaging analysis methods in clinical research. The edge time-series framework recently developed in the field of network neuroscience, in combination with other network science methods, allows for investigations of brain-behavior relationships that are not possible with conventional functional connectivity methods. Data from the Indiana Alzheimer’s Disease Research Center sample (53 cognitively normal control, 47 subjective cognitive decline, 32 mild cognitive impairment, and 20 Alzheimer’s disease participants) were used to investigate relationships between functional connectivity components, each derived from a subset of time points based on co-fluctuation of regional signals, and measures of domain-specific neuropsychological functions. Multiple relationships were identified with the component approach that were not found with conventional functional connectivity. These involved attentional, limbic, frontoparietal, and default mode systems and their interactions, which were shown to couple with cognitive, executive, language, and attention neuropsychological domains. Additionally, overlapping results were obtained with two different statistical strategies (network contingency correlation analysis and network-based statistics correlation). Results demonstrate that connectivity components derived from edge time-series based on co-fluctuation reveal disease-relevant relationships not observed with conventional static functional connectivity.
Postoperative Pancreatic Fistula Following Traumatic Splenectomy: A Morbid and Costly Complication
(Elsevier, 2022-12) Arnold, Peter; Belchos, Jessica; Meagher, Ashley; Robbins, Christopher; Sparks Joplin, Tasha; Ortiz, Damaris; Ferries, Ian; Hartwell , Jennifer; Surgery, School of Medicine
Introduction: Development of clinically relevant postoperative pancreatic fistula (CR-POPF) in adult splenectomies following trauma occur in 1%-3% of cases. We hypothesized that the use of sutures in splenic hilum ligation compared to staples was associated with a reduced rate of CR-POPF incidence. Methods: Adult trauma patients (age ≥17 y) that underwent nonelective splenectomy from 2010 to 2020 were retrospectively evaluated from the trauma registries of all three adult level 1 trauma centers in Indiana. Patients were excluded if they were pregnant, currently incarcerated, expired within 72 h of admission, or had a pancreatic injury diagnosed preoperatively or intraoperatively. A Firth logistic regression using a penalized-maximum likelihood estimate for rare events was used for univariate predictive modeling (SPSS 28.0) of surgical technique on CR-POPF development. Results: Four hundred nineteen adult splenectomies following trauma were conducted; 278 were included. CR-POPF developed in 14 cases (5.0%). Sutures alone were used in 200 cases: seven developed CR-POPF (3.5%). Staples alone or in combination with sutures were used in 74 cases: seven developed CR-POPF (9.5%). There was no statistically significant difference between the use of sutures alone compared to the use of staples alone (P = 0.123) or in combination (P = 0.100) in CR-POPF incidence. Conclusions: Our 10-y retrospective review of CR-POPF finds the complication to be rare but morbid. This study was underpowered to show any difference in surgical technique. However, we do propose a new institutional norm that CR-POPF develop in 5% of splenectomies after trauma and conclude that further study of optimal technique for emergent splenectomy is warranted.