P4‐258: Genome‐wide screen for variants that modify the known relationship between cerebrospinal fluid Beta‐Amyloid 42 and ptau levels

Abstract

suggests that PIO improves or protects neuronal mitochondrial function and increases mitochondrial biogenesis in vivo and in vitro. Additionally, results of behavioral studies indicate that TZD treatment may ameliorate some of the cognitive deficits in murine models of Alzheimer’s disease (AD) and human AD. This initial exploration examined the effects of low-dose PIO treatment on brain functional connectivity in awake rats using fMRI. Methods: Awake, adult male Wistar rats were acclimated to the scanning procedure for approximately 7 days. A baseline scan was performed 2.53h after dosing with vehicle (citric acid) using a 4.7 Tesla/30cm horizontal magnet and blood-oxygen-level-dependent (BOLD) imaging. Thereafter, rats were dosed orally with vehicle or 1 of 4 dosages of PIO (0.04, 0.08, 0.16, 0.32 mg/kg). One group of vehicleand one group of PIO-treated rats were scanned after the 2nd dosing; all rats were scanned after the last (7th) daily dose (n1⁄45 for each group). Results: For region of interest (ROI) analysis, each brain was demarcated into 57 ROIs and cross-correlation coefficients between pairs of ROIs were calculated to evaluate functional connectivity between ROIs. Seventeen ROI pairs showed significant (P<0.005, uncorrected) changes in functional connectivity on Day 7 of treatment with PIO compared with vehicle. Significant changes were seen in two pairs of ROIs on day 2 of dosing with PIO compared to the control group. Using the CA1 region of the hippocampus as a seed region, a voxel-by-voxel analysis indicated increased connectivity between the seed and the hypothalamus and ventral thalamus after 7 days of dosing. Conclusions: Our results indicate that administration of pioglitazone at doses lower than those used to treat T2D leads to changes in functional connectivity in conscious rats, as assessed by fMRI BOLD imaging; some changesmay occur within 2 days of treatment. These results provide preliminary evidence that low doses of PIO lead to changes in the brain and support the hypothesis that this drug may be a beneficial pharmacotherapy for neurodegenerative diseases such as AD.