In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greaterâ thanâ normal 1/T1 that is quenchable with antioxidant as measured by quenchâ assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proofâ ofâ concept data in models of ADâ like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. ADâ like models showed an abnormal gradient along the CA1 dorsalâ ventral axis of excessive free radical production as measured by Quest MRI, and redoxâ sensitive calcium dysregulation as measured by manganeseâ enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subâ field oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.â Berkowitz, B. A., Lenning J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafieâ Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J. 31, 4179â 4186 (2017). www.fasebj.orgâ Berkowitz, Bruce A., Lenning, Jacob, Khetarpal, Nikita, Tran, Catherine, Wu, Johnny Y., Berri, Ali M., Dernay, Kristin, Haacke, E. Mark, Shafieâ Khorassani, Fatema, Podolsky, Robert H., Gant, John C., Maimaiti, Shaniya, Thibault, Olivier, Murphy, Geoffrey G., Bennett, Brian M., Roberts, Robin, In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J. 31, 4179â 4186 (2017)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154241/1/fsb2fj201700229r.pd

Oxidative Stress and Light-Evoked Responses of the Posterior Segment in a Mouse Model of Diabetic Retinopathy Oxidative stress and light-evoked re- sponses of the posterior segment in a mouse model of diabetic retinopathy

PURPOSE. To test the hypothesis that in a mouse model of diabetic retinopathy, oxidative stress is linked with impaired light-evoked expansion of choroidal thickness and subretinal space (SRS). METHODS. We examined nondiabetic mice (wild-type, wt) with and without administration of manganese, nondiabetic mice deficient in rod phototransduction (transducin alpha knockout; GNAT1 À/À ), and diabetic mice (untreated or treated with the antioxidant a-lipoic acid [LPA]). Magnetic resonance imaging (MRI) was used to measure light-evoked increases in choroidal thickness and the apparent diffusion coefficient (ADC) at 88% to 100% depth into the retina (i.e., the SRS layer). RESULTS. Choroidal thickness values were similar (P > 0.05) between all untreated nondiabetic dark-adapted groups and increased significantly (P < 0.05) with light; this expansion was subnormal (P < 0.05) in both diabetic groups. Apparent diffusion coefficient values in the SRS layer robustly increased (P < 0.05) in a light duration-dependent manner, and this effect was independent of the presence of Mn 2þ . The light-stimulated increase in ADC at the location of the SRS was absent in GNAT1 À/À and diabetic mice (P > 0.05). In diabetic mice, the lightdependent increase in SRS ADC was significantly (P < 0.05) restored with LPA. CONCLUSIONS. Apparent diffusion coefficient MRI is a sensitive method for evaluating choroid thickness and its light-evoked expansion together with phototransduction-dependent changes in the SRS layer in mice in vivo. Because ADC MRI exploits an endogenous contrast mechanism, its translational potential is promising; it can also be performed in concert with manganese-enhanced MRI (MEMRI). Our data support a link between diabetes-related oxidative stress and rod, but not choroidal, pathophysiology