Human Brain Antioxidants During Oxidative Stress

The objective of this proposal is to advance the mission of improving the health and
well-being of older Americans by augmenting ongoing dementia prevention and treatment
initiatives. It undertakes research on dementia associated with both normal aging and AD. A
new scientist will develop a novel and powerful human brain antioxidant assay using
state-of-the art instrumentation. The approach will be translated to the clinical environment
so that it can be disseminated for use with new research. Specifically, the concentrations of
two important antioxidants, ascorbate (Asc) and glutathione (GSH) will be measured
noninvasively in the human brain. One aim is to measure whether a recent finding of lower
brain GSH concentration in the occipital cortex of cognitively normal elder subjects is also
found in the posterior cingulate cortex, and whether human brain Asc homeostasis persists in
both brain regions. A complementary specific aim is to determine whether lower brain GSH
concentration also occurs under the oxidative stress associated with Alzheimer's disease
(AD). At the same time, data measured in subjects with AD have potential to advance this
powerful new technology toward discovering an early stage biomarker. A sub aim is to make
this technology available to a wide range of physicians and investigators. As such, data
processing will be fully automated using commercially available software. This novel
noninvasive technology facilitates a paradigm shift from systemic assays to quantifying
antioxidants directly in the affected brain region. The approach will take advantage of state
of the art 7 T instrumentation while developing analogous methods on a clinical 3 T scanner.
The process of optimizing magnetic resonance spectroscopy (MRS) for quantification of brain
Asc and GSH concentrations necessitated reliable quantification of an extensive neurochemical
profile (i.e. 19 brain metabolites), which includes the four compounds that are typically
observed. Spectra acquired in stimulated echo acquisition mode (STEAM) will be de-convolved
quantitatively into contributions from the metabolites that contribute discernable resonances
using a linear combination model approach (LCModel). Reliable quantification of brain GSH and
Asc concentrations will first be achieved using ultra high field MRS with multiple transmit
coil technology and accompanying radiofrequency (B1) shimming, then translated to a lower
field clinical platform. Successful completion will determine whether low brain glutathione
concentration is widespread in the elder human brain and whether this difference is
exacerbated by AD.

Inclusion Criteria:

Age and gender match to AD patients: age range 65-89:

note that we anticipate that our patients will be predominantly male, so we are NOT likely
to enroll females for this portion of the study

Exclusion Criteria::

Claustrophobia Implanted metal devices Pregnancy > RDA dietary supplements

≥ 5 F+V per day Smoking Depression Poor health or systemic illness Medial history of or
evidence for cognitive problems Unstable medication usage Neurological problems Psychiatric
disorder Substance abuse Usage of investigational drugs Inability to complete cognitive
tests written in and calibrated for English speakers Inadequate vision or hearing to
accommodate participation MMSE (dementia) score ≤ 26