Detection of 13C labeling of glutamate and glutamine in human brain by proton magnetic resonance spectroscopy.

A proton magnetic resonance spectroscopy (MRS) technique was used to measure 13C enrichments of glutamate and glutamine in a 3.5 × 1.8 × 2 cm3 voxel placed in the dorsal anterior cingulate cortex of five healthy participants after oral administration of [U-13C]glucose. Strong pseudo singlets of glutamate and glutamine were induced to enhance the signal strength of glutamate and glutamine. This study demonstrated that 13C labeling of glutamate and glutamine can be measured with the high sensitivity and spatial resolution of 1H MRS using a proton-only MRS technique with standard commercial hardware. Furthermore, it is feasible to measure 13C labeling of glutamate and glutamine in limbic structures, which play major roles in behavioral and emotional responses and whose abnormalities are involved in many neuropsychiatric disorders.

Carbonic anhydrase activity in the frontal lobe of human brain.

Carbonic anhydrase (CA) plays an important role in many biological processes. Recent technological advances have demonstrated the feasibility of measuring CA activity in the occipital lobe of human subjects in vivo. In this work we report, for the first time, in vivo measurement of CA activity in the frontal lobe of human brain, where structural and function abnormalities are strongly associated with symptoms of major psychiatric disorders. Despite the much larger magnetic field distortion in the frontal lobe, the pseudo first-order bicarbonate dehydration rate constant was determined with high precision using in vivo 13 C magnetic resonance magnetization transfer spectroscopy following oral administration of [U-13 C6 ]glucose. Nuclear Overhauser effect pulses were used to increase the signal-to-noise ratio; no proton decoupling was applied. The unidirectional dehydration rate constant of bicarbonate was found to be 0.26 ± 0.07 s-1 , which is not statistically different from the dehydration rate constant in the occipital lobe determined in our previous study, indicating that CA activity in the two brain regions is essentially indistinguishable. These results demonstrate the feasibility of characterizing CA activity in the frontal lobe for future psychiatric studies.

Cerebral phosphoester signals measured by 31P magnetic resonance spectroscopy at 3 and 7 Tesla.

Abnormal cell membrane metabolism is associated with many neuropsychiatric disorders. Free phosphomonoesters and phosphodiesters, which can be detected by in vivo 31P magnetic resonance spectroscopy (MRS), are important cell membrane building blocks. However, the quantification of phosphoesters has been highly controversial even in healthy individuals due to overlapping signals from macromolecule membrane phospholipids (MP). In this study, high signal-to-noise ratio (SNR) cerebral 31P MRS spectra were acquired from healthy volunteers at both 3 and 7 Tesla. Our results indicated that, with minimal spectral interference from MP, the [phosphocreatine (PCr)]/[phosphocholine (PC) + glycerophosphocholine (GPC)] ratio measured at 7 Tesla agreed with its value expected from biochemical constraints. In contrast, the 3 Tesla [PCr]/[PC+GPC] ratio obtained using standard spectral fitting procedures was markedly smaller than the 7 Tesla ratio and than the expected value. The analysis suggests that the commonly used spectral model for MP may fail to capture its complex spectral features at 3 Tesla, and that additional prior knowledge is necessary to reliably quantify the phosphoester signals at low magnetic field strengths when spectral overlapping is significant.

Quantification of in vivo transverse relaxation of glutamate in the frontal cortex of human brain by radio frequency pulse-driven longitudinal steady state.

PURPOSE: The principal excitatory neurotransmitter glutamate plays an important role in many central nervous system disorders. Because glutamate resides predominantly in glutamatergic neurons, its relaxation properties reflect the intracellular environment of glutamatergic neurons. This study developed an improved echo time-independent technique for measuring transverse relaxation time and demonstrated that this radio frequency (RF)-driven longitudinal steady state technique can reliably measure glutamate transverse relaxation in the frontal cortex, where structural and functional abnormalities have been associated with psychiatric symptoms. METHOD: Bloch and Monte Carlo simulations were performed to improve and optimize the RF-driven, longitudinal, steady-state (MARzss) technique to significantly shorten scan time and increase measurement precision. Optimized four-flip angle measurements at 0°,12°, 24°, and 36° with matched repetition time were used in nine human subjects (6F, 3M; 27-49 years old) at 7 Tesla. Longitudinal and transverse relaxation rates for glutamate were measured from a 2 x 2 x 2 cm3 voxel placed in three different brain regions: gray matter-dominated medial prefrontal lobe, white matter-dominated left frontal lobe, and gray matter-dominated occipital lobe. RESULTS: Compared to the original MARzss technique, the scan time per voxel for measuring glutamate transverse relaxation was shortened by more than 50%. In the medial frontal, left frontal, and occipital voxels, the glutamate T2 was found to be 117.5±12.9 ms (mean ± standard deviation, n = 9), 107.3±12.1 (n = 9), and 124.4±16.6 ms (n = 8), respectively. CONCLUSIONS: The improvements described in this study make the MARZSS technique a viable tool for reliably measuring glutamate relaxation from human subjects in a typical clinical setting. It is expected that this improved technique can be applied to characterize the intracellular environment of glutamatergic neurons in a variety of brain disorders.

Determining the Rate of Carbonic Anhydrase Reaction in the Human Brain.

Carbonic anhydrase plays important role in life. This study sought to demonstrate the feasibility of detecting carbonic anhydrase activity in the human brain in vivo. After oral administration of [U-13C6]glucose, 13C saturation transfer experiments were performed with interleaved control spectra and carbon dioxide saturation spectra. Proton nuclear Overhauser effect pulses were used to increase signal to noise ratio; no proton decoupling was applied. Results showed that the 13C signal of bicarbonate was reduced by 72% ± 0.03 upon saturating carbon dioxide. The unidirectional dehydration rate constant of the carbonic anhydrase reaction was found to be 0.28 ± 0.02 sec-1 in the human brain. These findings demonstrate the feasibility of measuring carbonic anhydrase activity in vivo in the human brain, which makes it possible to characterize this important enzyme in patients with brain disorders.

(13)C MRS of human brain at 7 Tesla using [2-(13)C]glucose infusion and low power broadband stochastic proton decoupling.

PURPOSE: Carbon-13 ((13)C) MR spectroscopy (MRS) of the human brain at 7 Tesla (T) may pose patient safety issues due to high radiofrequency (RF) power deposition for proton decoupling. The purpose of present work is to study the feasibility of in vivo (13)C MRS of human brain at 7 T using broadband low RF power proton decoupling. METHODS: Carboxylic/amide (13)C MRS of human brain by broadband stochastic proton decoupling was demonstrated on a 7 T scanner. RF safety was evaluated using the finite-difference time-domain method. (13)C signal enhancement by nuclear Overhauser effect (NOE) and proton decoupling was evaluated in both phantoms and in vivo. RESULTS: At 7 T, the peak amplitude of carboxylic/amide (13)C signals was increased by a factor of greater than 4 due to the combined effects of NOE and proton decoupling. The 7 T (13)C MRS technique used decoupling power and average transmit power of less than 35 watts (W) and 3.6 W, respectively. CONCLUSION: In vivo (13)C MRS studies of human brain can be performed at 7 T, well below the RF safety threshold, by detecting carboxylic/amide carbons with broadband stochastic proton decoupling.

PET reveals inflammation around calcified Taenia solium granulomas with perilesional edema.

OBJECTIVE: Neurocysticercosis, an infection with the larval form of the tapeworm, Taeniasolium, is the cause of 29% of epilepsy in endemic regions. Epilepsy in this population is mostly associated with calcified granulomas; at the time of seizure recurrence 50% of those with calcifications demonstrate transient surrounding perilesional edema. Whether edema is consequence of the seizure, or a result of host inflammation directed against parasite antigens or other processes is unknown. To investigate whether perilesional edema is due to inflammation, we imaged a marker of neuroinflammation, translocater protein (TSPO), using positron emission tomography (PET) and the selective ligand (11)C-PBR28. METHODS: In nine patients with perilesional edema, degenerating cyst or both, PET findings were compared to the corresponding magnetic resonance images. Degenerating cysts were also studied because unlike perilesional edema, degenerating cysts are known to have inflammation. In three of the nine patients, changes in (11)C-PBR28 binding were also studied over time. (11)C-PBR28 binding was compared to the contralateral un-affected region. RESULTS: (11)C-PBR28 binding increased by a mean of 13% in perilesional edema or degenerating cysts (P = 0.0005, n = 13 in nine patients). Among these 13 lesions, perilesional edema (n=10) showed a slightly smaller increase of 10% compared to the contralateral side (P = 0.005) than the three degenerating cysts. In five lesions with perilesional edema in which repeated measurements of (11)C-PBR28 binding were done, increased binding lasted for 2-9 months. CONCLUSIONS: Increased TSPO in perilesional edema indicates an inflammatory etiology. The long duration of increased TSPO binding after resolution of the original perilesional edema and the pattern of periodic episodes is consistent with intermittent exacerbation from a continued baseline presence of low level inflammation. Novel anti-inflammatory measures may be useful in the prevention or treatment of seizures in this population.

Propofol decreases in vivo binding of 11C-PBR28 to translocator protein (18 kDa) in the human brain.

UNLABELLED: The PET radioligand (11)C-PBR28 targets translocator protein (18 kDa) (TSPO) and is a potential marker of neuroimmune activation in vivo. Although several patient populations have been studied using (11)C-PBR28, no investigators have studied cognitively impaired patients who would require anesthesia for the PET procedure, nor have any reports investigated the effects that anesthesia may have on radioligand uptake. The purpose of this study was to determine whether the anesthetic propofol alters brain uptake of (11)C-PBR28 in healthy subjects. METHODS: Ten healthy subjects (5 men; 5 women) each underwent 2 dynamic brain PET scans on the same day, first at baseline and then with intravenous propofol anesthesia. The subjects were injected with 680 ± 14 MBq (mean ± SD) of (11)C-PBR28 for each PET scan. Brain uptake was measured as total distribution volume (V(T)) using the Logan plot and metabolite-corrected arterial input function. RESULTS: Propofol decreased V(T), which corrects for any alteration of metabolism of the radioligand, by about 26% (P = 0.011). In line with the decrease in V(T), brain time-activity curves showed decreases of about 20% despite a 13% increase in plasma area under the curve with propofol. Reduction of V(T) with propofol was observed across all brain regions, with no significant region X condition interaction (P = 0.40). CONCLUSION: Propofol anesthesia reduces the V(T) of (11)C-PBR28 by about 26% in the brains of healthy human subjects. Given this finding, future studies will measure neuroimmune activation in the brains of autistic volunteers and their age and sex-matched healthy controls using propofol anesthesia. We recommend that future PET studies using (11)C-PBR28 and concomitant propofol anesthesia, as would be required in impaired populations, include a control arm to account for the effects of propofol on brain measurements of TSPO.

In vivo detection of 13C isotopomer turnover in the human brain by sequential infusion of 13C labeled substrates.

This study demonstrates the feasibility of simultaneously detecting human brain metabolites labeled by two substrates infused in a sequential order. In vivo (13)C spectra of carboxylic/amide carbons were acquired only during the infusion of the second substrate. This approach allowed dynamic detection of (13)C labeling from two substrates with considerably different labeling patterns. [2-(13)C]glucose and [U-(13)C(6)]glucose were used to generate singlet and doublet signals of the same carboxylic/amide carbon atom, respectively. Because of the large one-bond (13)C-(13)C homonuclear J coupling between a carboxylic/amide carbon and an aliphatic carbon (~50 Hz), the singlet and doublet signals of the same carboxylic/amide carbon were well distinguished. The results demonstrated that different (13)C isotopomer patterns could be simultaneously and distinctly measured in vivo in a clinical setting at 3T.

In vivo 13C magnetic resonance spectroscopy of human brain on a clinical 3 T scanner using [2-13C]glucose infusion and low-power stochastic decoupling.

This study presents the detection of [2-(13)C]glucose metabolism in the carboxylic/amide region in the human brain, and demonstrates that the cerebral metabolism of [2-(13)C]glucose can be studied in human subjects in the presence of severe hardware constraints of widely available 3 T clinical scanners and with low-power stochastic decoupling. In the carboxylic/amide region of human brain, the primary products of (13)C label incorporation from [2-(13)C]glucose into glutamate, glutamine, aspartate, gamma-aminobutyric acid, and N-acetylaspartate were detected. Unlike the commonly used alkanyl region where lipid signals spread over a broad frequency range, the carboxylic carbon signal of lipids was found to be confined to a narrow range centered at 172.5 ppm and present no spectral interference in the absence of lipid suppression. Comparison using phantoms shows that stochastic decoupling is far superior to the commonly used WALTZ sequence at very low decoupling power at 3 T. It was found that glutamine C1 and C5 can be decoupled using stochastic decoupling at 2.2 W, although glutamine protons span a frequency range of approximately 700 Hz. Detailed specific absorption rate analysis was also performed using finite difference time domain numerical simulation.