The Effect of the PPAR Gamma Agonist Rosiglitazone on Age-Related Changes in Grey Matter Magnetic Resonance Relaxometry in the Rat

Rosiglitazone, a peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) agonist, has an anti-inflammatory effect in the brain, decreasing interleukin-1[beta] concentrations in hippocampus and restoring the age-related deficit in long-term potentiation. It also attenuates learning and memory deficits in a mouse model of Alzheimer's disease. Evidence suggests that activation of microglia and astrocytes contribute to age-related neuroinflammatory changes. In this study, relaxometry measurements were assessed in hippocampus of young and aged rats because there have been recent reports in the literature linking spin-lattice (T1) and spin-spin (T2) relaxation times to astrocytic activation and microglial activation respectively. Male Wistar rats aged 3 and 18 months (n = 5-6 per group) were treated either with 3 mg/day rosiglitazone maleate or with vehicle only for 56 days and MR images obtained under anesthesia using a 7-Tesla MRI scanner (Bruker) with slices selected to give optimal regions of interest in dorsal hippocampus (Fig. 1). Images were acquired using rapid acquisition with relaxation enhancement (RARE) and echo-train multi-slice-multi-echo (MSME) sequences, from which T1 and T2 maps were generated, respectively; and a fast imaging with steady-state precession (FISP) protocol, from which both T1 and T2 maps were generated. Data from manually-selected regions of interest were analyzed using software scripts in IDL language (ITTVIS). One- or two-way analyses of variance (ANOVA) with Fischer's post-test were used to statistically assess the data. Tissue from the animals was examined for markers of astrogliosis and microglial activation. T1 in hippocampus and cortex (p < 0.01, Fig. 2) were significantly increased with age whilst T2 in hippocampus (p < 0.05) and cortex (p < 0.01, Fig. 3) were significantly decreased with age. Treatment with rosiglitazone significantly attenuated the age-related T1 increase in both regions (p < 0.05, Fig. 2) and it increased T2 relaxation time in hippocampus of aged, but not young rats (p < 0.05, Fig. 3). The data demonstrate an age-related increase in T1 in hippocampus and cortex, which is attenuated by rosiglitazone; this correlates with astrocytosis (Fig. 4). We also show a decrease in T2 relaxation time in hippocampus and cortex, which correlates with an increase in microglial activation (Fig. 5), and report that rosiglitazone-treatment of aged rats increases hippocampal T2. Sample regions of interest T1 relaxation time measured by RARE T2 relaxation time measured by FISP (left): Staining for astrocytosis Staining for a marker of microglial activation