In-vivo Measurements of the Antioxidant Glutathione at 7T and 3T Magnetic Field Strengths

UCSF Professor of Radiology and Biomedical Imaging
Director, Substance Abuse Neuroimaging DVA Medical Center Center for Imaging of Neurodegenerative Diseases (CIND)
Co-Director, San Francisco Treatment Research Center School of Medicine, UCSF

In the general public and most research communities, the primary health consequences of smoking are perceived to be cancer, cardiovascular disease, chronic pulmonary disease as well as acute pulmonary consequences of smoke exposure in the young and critically ill patients. However, comparatively little research has focused on the detrimental effects of chronic tobacco smoking on the human brain and on cognitive functioning.  The FDA needs information about the newly emerging cerebral (and cognitive) consequences of tobacco use to properly assume their regulatory responsibilities.
The main goals of this brain imaging study are to obtain pilot data for measuring the antioxidant glutathione (GSH) in human brain at 7 Tesla (T) magnetic field strength and to compare these GSH measurements to those at the more typical and clinically used 3T magnetic field strength. GSH is the primary antioxidant in the human brain, and low GSH levels are an accepted biomarker of oxidative stress. Chronic cigarette smoking is associated with significant cerebral oxidative stress. As such, GSH constitutes a practical in vivo biomarker of oxidative stress-related brain damage and neurocognitive deficits in smokers. Our goals are directly responsive to the FDA CTP research priorities.
Previous neuroimaging research has described significant structural and metabolic deficits in the brain of chronic smokers (with and without substance dependence) as well as related neurocognitive deficits in smokers. However, we or others have not specifically measured in vivo GSH as a function of smoking severity. Our Center for Imaging of Neurodegenerative Diseases (CIND) at the SF VA Medical Center recently installed an ultrahigh-field 7T MR scanner that promises to improve the accuracy and reliability of 1H MR spectroscopic measurement of brain GSH over similar measurements at lower field (e.g., 3T). Here we propose
     a) to implement, test, and compare two highly sensitive MRS methods for GSH detection at 7T;
     b) to demonstrate their practical utility by quantifying GSH in the brain of smokers vs. non-smokers at 7T; and
     c) to compare GSH levels measured at 3T and 7T magnetic field strengths.
We hypothesize that the GSH antioxidant levels are significantly lower in smokers than non-smokers and that GSH measures obtained at 7T and 3T strongly correlate. We will also determine the better acquisition method at 7T and statistical power needed for future GSH studies at either field strength. Confirmed hypotheses in these chronic smokers will support decreased cerebral GSH as a practical in vivo biomarker of smoking-induced cerebral oxidative stress and related brain damage. This pilot work will open the door to more detailed assessments of relative neurotoxicity and oxidative stress responses to tobacco use, including smokeless tobacco and dual products, and to incorporating corresponding brain measures in animal models of tobacco use impact.