Browsing by Subject "Network neuroscience"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Consistency of Graph Theoretical Measurements of Alzheimer’s Disease Fiber Density Connectomes Across Multiple Parcellation Scales
    (IEEE, 2022-12) Xu, Frederick; Garai, Sumita; Duong-Tran, Duy; Saykin, Andrew J.; Zha, Yize; Shen, Li; Radiology and Imaging Sciences, School of Medicine
    Graph theoretical measures have frequently been used to study disrupted connectivity in Alzheimer’s disease human brain connectomes. However, prior studies have noted that differences in graph creation methods are confounding factors that may alter the topological observations found in these measures. In this study, we conduct a novel investigation regarding the effect of parcellation scale on graph theoretical measures computed for fiber density networks derived from diffusion tensor imaging. We computed 4 network-wide graph theoretical measures of average clustering coefficient, transitivity, characteristic path length, and global efficiency, and we tested whether these measures are able to consistently identify group differences among healthy control (HC), mild cognitive impairment (MCI), and AD groups in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort across 5 scales of the Lausanne parcellation. We found that the segregative measure of transtivity offered the greatest consistency across scales in distinguishing between healthy and diseased groups, while the other measures were impacted by the selection of scale to varying degrees. Global efficiency was the second most consistent measure that we tested, where the measure could distinguish between HC and MCI in all 5 scales and between HC and AD in 3 out of 5 scales. Characteristic path length was highly sensitive to the variation in scale, corroborating previous findings, and could not identify group differences in many of the scales. Average clustering coefficient was also greatly impacted by scale, as it consistently failed to identify group differences in the higher resolution parcellations. From these results, we conclude that many graph theoretical measures are sensitive to the selection of parcellation scale, and further development in methodology is needed to offer a more robust characterization of AD’s relationship with disrupted connectivity.
  • Thumbnail Image
    Item
    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.