TY - JOUR
T1 - In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome
AU - Berkowitz, Bruce A.
AU - Lenning, Jacob
AU - Khetarpal, Nikita
AU - Tran, Catherine
AU - Wu, Johnny Y.
AU - Berri, Ali M.
AU - Dernay, Kristin
AU - Haacke, E. Mark
AU - Shafie-Khorassani, Fatema
AU - Podolsky, Robert H.
AU - Gant, John C.
AU - Maimaiti, Shaniya
AU - Thibault, Olivier
AU - Murphy, Geoffrey G.
AU - Bennett, Brian M.
AU - Roberts, Robin
N1 - Publisher Copyright:
© FASEB.
PY - 2017/9
Y1 - 2017/9
N2 - 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 greater-than-normal 1/T1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal–ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-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 subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.
AB - 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 greater-than-normal 1/T1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal–ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-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 subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.
KW - Dorsoventral CA1
KW - MRI
KW - Neurodegenerative disease
KW - Neurodevelopment disorders
KW - Reactive oxygen species
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UR - http://www.scopus.com/inward/citedby.url?scp=85028873786&partnerID=8YFLogxK
U2 - 10.1096/fj.201700229R
DO - 10.1096/fj.201700229R
M3 - Article
C2 - 28592637
AN - SCOPUS:85028873786
SN - 0892-6638
VL - 31
SP - 4179
EP - 4186
JO - FASEB Journal
JF - FASEB Journal
IS - 9
ER -