MRS Measurement of Glutamate and GABA Metabolism in Brain

13C is a stable (i.e., non-radioactive) isotope of carbon with a natural abundance of ~1%.
Following infusion of [13C]glucose and/or [13C]acetate, in vivo MRS (magnetic resonance
spectroscopy) can monitor the rate of flux of the 13C atom from glucose and/or acetate to
glutamate to glutamine. Thus, this procedure can provide measure of glutamate (GLU) and
glutamine (GLN) turnover in brain. We have established parameters to obtain these
measurements in nonhuman primate brain. The current protocol seeks approval to optimize MRS
parameters and to develop new MRS techniques for human brain using the GE 3T, the Siemens 3T,
and the Siemens 7T device.

Study population: All subjects will be aged 18 65 years, without serious medical illnesses
and meet criteria listed in Section VI A.

Design: Subjects will receive either oral administration of [13C]glucose or an intravenous
infusion of [13C]glucose and/or [13C]acetate to approximately double their plasma glucose
levels. The plasma acetate level will remain within the physiological range observed in
humans (Lebon et al, 2002). While lying in the 3T or 7T device, serial data acquisitions will
be obtained over ~2 h to optimize the experimental conditions so as to measure the 13C
signals from GLU, GLN and other metabolisms in brain.

Outcome measures: The primary goal of this study is to measure GLU/GLN turnover in brain.
With no additional data acquisition, we can also obtain information on the synthesis of GABA,
the major inhibitory neurotransmitter in brain. GLU is converted to GABA via the enzyme
glutamic acid decarboxylase (GAD). While monitoring the transfer of 13C signal from GLU to
GLN, we can simultaneously measure the transfer of 13C signal from GLU to GABA and thereby
measure the activity of GAD (Li et al 2005). In addition to directly measure 13C signals, 13C
labeling to brain metabolites can also be measured indirectly by detecting proton MRS during
infusion of

[13C]glucose and/or [13C]acetate.

- INCLUSION CRITERIA:

- 18-65 years of age

- able to give written informed consent

- healthy based on medical history and physical exam

- enrolled in Protocol 01-M-0254 or Protocol 17-M-0181

EXCLUSION CRITERIA:

- Any current Axis 1 diagnosis

- Clinically significant laboratory abnormalities

- Positive HIV test

- Metallic foreign bodies that would be affected by the magnetic resonance imaging (MRI)
magnet, or fear of enclosed spaces likely to make the subject unable to undergo an MRI
scan.

- History of neurological illness or injury with the potential to affect study data
interpretation, such as multiple sclerosis, Parkinson s disease, seizure disorder or
traumatic brain injury

- Prescription psychotropic medication; drug free less than 8 weeks (anticholinergics,
benzodiazepine, fluoxetine, antipsychotics, and anticonvulsants)

- Serious medical illness as determined from H&P or laboratory testing including
Diabetes

- Inability to lie flat on camera bed for about two and a half hours

- Pregnant or breastfeeding

- Current substance use disorder based on DSM-5

- NIMH employees and staff and their immediate family members will be excluded from the
study per NIMH policy.