Gülin Öz

In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T.

A comprehensive comparative study of metabolite quantification from the human brain was performed on the same 10 subjects at 4T and 7T using MR scanners with identical consoles, the same type of RF coils, and identical pulse sequences and data analysis. Signal‐to‐noise ratio (SNR) was increased by a factor of 2 at 7T relative to 4T in a volume of interest selected in the occipital cortex using half‐volume quadrature radio frequency (RF) coils. Spectral linewidth was increased by 50% at 7T, which resulted in a 14% increase in spectral resolution at 7T relative to 4T. Seventeen brain metabolites were reliably quantified at both field strengths. Metabolite quantification at 7T was less sensitive to reduced SNR than at 4T. The precision of metabolite quantification and detectability of weakly represented metabolites were substantially increased at 7T relative to 4T. Because of the increased spectral resolution at 7T, only one‐half of the SNR of a 4T spectrum was required to obtain the same quantification precision. The Cramér‐Rao lower bounds (CRLB), a measure of quantification precision, of several metabolites were lower at both field strengths than the intersubject variation in metabolite concentrations, which resulted in a strong correlation between metabolite concentrations of individual subjects measured at 4T and 7T. Magn Reson Med, 2009.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

Neuroglial metabolism in the awake rat brain: CO2 fixation increases with brain activity

Glial cells are thought to supply energy for neurotransmission by increasing nonoxidative glycolysis; however, oxidative metabolism in glia may also contribute to increased brain activity. To study glial contribution to cerebral energy metabolism in the unanesthetized state, we measured neuronal and glial metabolic fluxes in the awake rat brain by using a double isotopic-labeling technique and a two-compartment mathematical model of neurotransmitter metabolism. Rats (n = 23) were infused simultaneously with 14C-bicarbonate and [1-13C]glucose for up to 1 hr. The 14C and 13C labeling of glutamate, glutamine, and aspartate was measured at five time points in tissue extracts using scintillation counting and 13C nuclear magnetic resonance of the chromatographically separated amino acids. The isotopic 13C enrichment of glutamate and glutamine was different, suggesting significant rates of glial metabolism compared with the glutamate-glutamine cycle. Modeling the 13C-labeling time courses alone and with 14C confirmed significant glial TCA cycle activity (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(V_{\mathrm{PDH}}^{(\mathrm{g})},{\sim}0.5\) \end{document} μmol · gm-1 · min-1) relative to the glutamate-glutamine cycle (VNT) (∼0.5-0.6 μmol · gm-1 · min-1). The glial TCA cycle rate was ∼30% of total TCA cycle activity. A high pyruvate carboxylase rate (VPC, ∼0.14-0.18 μmol · gm-1 · min-1) contributed to the glial TCA cycle flux. This anaplerotic rate in the awake rat brain was severalfold higher than under deep pentobarbital anesthesia, measured previously in our laboratory using the same 13C-labeling technique. We postulate that the high rate of anaplerosis in awake brain is linked to brain activity by maintaining glial glutamine concentrations during increased neurotransmission.

Assessment of brain iron and neuronal integrity in patients with Parkinson's disease using novel MRI contrasts

Postmortem demonstration of increased iron in the substantia nigra (SN) is a well‐appreciated finding in Parkinsons disease (PD). Iron facilitates generation of free radicals, which are thought to play a role in dopamine neuronal loss. To date, however, magnetic resonance imaging (MRI) has failed to show significant in vivo differences in SN iron levels in subjects with PD versus control subjects. This finding may be due to the limitations in tissue contrasts achievable with conventional T1‐ and T2‐weighted MRI sequences that have been used. With the recent development of novel rotating frame transverse (T2ρ) and longitudinal (T1ρ) relaxation MRI methods that appear to be sensitive to iron and neuronal loss, respectively, we embarked on a study of 8 individuals with PD (Hoehn & Yahr, Stage II) and 8 age‐matched control subjects. Using these techniques with a 4T MRI magnet, we assessed iron deposits and neuronal integrity in the SN. First, T2ρ MRI, which is reflective of iron‐related dynamic dephasing mechanisms (e.g., chemical exchange and diffusion in the locally different magnetic susceptibilities), demonstrated a statistically significant difference between the PD and control group, while routine T2 MRI did not. Second, T1ρ measurements, which appear to reflect upon neuronal count, indicated neuronal loss in the SN in PD. We show here that sub‐millimeter resolution T1ρ and T2ρ MRI relaxation methods can provide a noninvasive measure of iron content as well as evidence of neuronal loss in the midbrain of patients with PD.

Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 tesla proton MRS.

Background Parkinson disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. However, postmortem evidence indicates that the pathology of lower brainstem regions, such as the pons and medulla, precedes nigral involvement. Consistently, pontomedullary damage was implicated by structural and PET imaging in early PD. Neurochemical correlates of this early pathological involvement in PD are unknown. Methodology/Principal Finding To map biochemical alterations in the brains of individuals with mild-moderate PD we quantified neurochemical profiles of the pons, putamen and substantia nigra by 7 tesla (T) proton magnetic resonance spectroscopy. Thirteen individuals with idiopathic PD (Hoehn & Yahr stage 2) and 12 age- and gender-matched healthy volunteers participated in the study. γ-Aminobutyric acid (GABA) concentrations in the pons and putamen were significantly higher in patients (N = 11, off medications) than controls (N = 11, p<0.001 for pons and p<0.05 for putamen). The GABA elevation was more pronounced in the pons (64%) than in the putamen (32%). No other neurochemical differences were observed between patients and controls. Conclusion/Significance The GABA elevation in the putamen is consistent with prior postmortem findings in patients with PD, as well as with in vivo observations in a rodent model of PD, while the GABA finding in the pons is novel. The more significant GABA elevation in the pons relative to the putamen is consistent with earlier pathological involvement of the lower brainstem. This study provides in vivo evidence for an alteration in the GABAergic tone in the lower brainstem and striatum in early-moderate PD, which may underlie disease pathogenesis and may provide a biomarker for disease staging.

N-acetylcysteine boosts brain and blood glutathione in gaucher and Parkinson diseases

Objective This study aimed to determine if the antioxidant N-acetylcysteine (NAC) is able to alter peripheral and central redox capabilities in patients with Parkinson disease (PD) or Gaucher disease (GD). Methods The study included nondemented adult subjects: 3 with PD, 3 with GD, and 3 healthy controls. Baseline brain glutathione (GSH) concentrations were measured using 7-T magnetic resonance spectroscopy (MRS). Baseline blood reduced-to-oxidized GSH ratios were determined for each subject. Brain GSH concentrations and blood redox ratios were then determined during and at specified time points after a single, 150-mg/kg NAC infusion. Results N-acetylcysteine increased blood GSH redox ratios in those with PD and GD and healthy controls, which was followed by an increase in brain GSH concentrations in all subjects. Conclusions This is the first demonstration that with MRS, it is possible to directly measure and monitor increases in brain GSH levels in the human brain in response to a single, intravenous administration of NAC. This work shows the potential utility of MRS monitoring, which could assist in determining dosing regimens for clinical trials of this potentially useful antioxidant therapy for PD disease, GD, and other neurodegenerative disorders.

Human Brain Glycogen Metabolism During and After Hypoglycemia

OBJECTIVE We tested the hypotheses that human brain glycogen is mobilized during hypoglycemia and its content increases above normal levels (“supercompensates”) after hypoglycemia. RESEARCH DESIGN AND METHODS We utilized in vivo 13C nuclear magnetic resonance spectroscopy in conjunction with intravenous infusions of [13C]glucose in healthy volunteers to measure brain glycogen metabolism during and after euglycemic and hypoglycemic clamps. RESULTS After an overnight intravenous infusion of 99% enriched [1-13C]glucose to prelabel glycogen, the rate of label wash-out from [1-13C]glycogen was higher (0.12 ± 0.05 vs. 0.03 ± 0.06 μmol · g−1 · h−1, means ± SD, P < 0.02, n = 5) during a 2-h hyperinsulinemic-hypoglycemic clamp (glucose concentration 57.2 ± 9.7 mg/dl) than during a hyperinsulinemic-euglycemic clamp (95.3 ± 3.3 mg/dl), indicating mobilization of glucose units from glycogen during moderate hypoglycemia. Five additional healthy volunteers received intravenous 25–50% enriched [1-13C]glucose over 22–54 h after undergoing hyperinsulinemic-euglycemic (glucose concentration 92.4 ± 2.3 mg/dl) and hyperinsulinemic-hypoglycemic (52.9 ± 4.8 mg/dl) clamps separated by at least 1 month. Levels of newly synthesized glycogen measured from 4 to 80 h were higher after hypoglycemia than after euglycemia (P ≤ 0.01 for each subject), indicating increased brain glycogen synthesis after moderate hypoglycemia. CONCLUSIONS These data indicate that brain glycogen supports energy metabolism when glucose supply from the blood is inadequate and that its levels rebound to levels higher than normal after a single episode of moderate hypoglycemia in humans.

Direct, noninvasive measurement of brain glycogen metabolism in humans

The concentration and metabolism of the primary carbohydrate store in the brain, glycogen, is unknown in the conscious human brain. This study reports the first direct detection and measurement of glycogen metabolism in the human brain, which was achieved using localized 13C NMR spectroscopy. To enhance the NMR signal, the isotopic enrichment of the glucosyl moieties was increased by administration of 80 g of 99% enriched [1-13C]glucose in four subjects. 3 h after the start of the label administration, the 13C NMR signal of brain glycogen C1 was detected (0.36+/-0.07 micromol/g, mean+/-S.D., n=4). Based on the rate of 13C label incorporation into glycogen and the isotopic enrichment of plasma glucose, the flux through glycogen synthase was estimated at 0.17+/-0.05 micromol/(gh). This study establishes that brain glycogen can be measured in humans and indicates that its metabolism is very slow in the conscious human. The noninvasive detection of human brain glycogen opens the prospect of understanding the role and function of this important energy reserve under various physiological and pathophysiological conditions.

Proton MRS of the unilateral substantia nigra in the human brain at 4 tesla: Detection of high GABA concentrations

Parkinsons disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra (SN), the cause of which is unknown. Characterization of early SN pathology could prove beneficial in the treatment and diagnosis of PD. The present study shows that with the use of short‐echo (5 ms) Stimulated‐Echo Acquisition Mode (STEAM) spectroscopy and LCModel, a neurochemical profile consisting of 10 metabolites, including γ‐aminobutyric acid (GABA), glutamate (Glu), and glutathione (GSH), can be measured from the unilateral SN at 4 tesla. The neurochemical profile of the SN is unique and characterized by a fourfold higher GABA/Glu ratio compared to the cortex, in excellent agreement with established neurochemistry. The presence of elevated GABA levels in SN was validated with the use of editing, suggesting that partial volume effects were greatly reduced. These findings establish the feasibility of obtaining a neurochemical profile of the unilateral human SN by single‐voxel spectroscopy in small volumes. Magn Reson Med, 2006.

Regional neurochemical profiles in the human brain measured by ¹H MRS at 7 T using local B₁ shimming.

Increased sensitivity and chemical shift dispersion at ultra‐high magnetic fields enable the precise quantification of an extended range of brain metabolites from 1H MRS. However, all previous neurochemical profiling studies using single‐voxel MRS at 7 T have been limited to data acquired from the occipital lobe with half‐volume coils. The challenges of 1H MRS of the human brain at 7 T include short T2 and complex B1 distribution that imposes limitations on the maximum achievable B1 strength. In this study, the feasibility of acquiring and quantifying short‐echo (TE = 8 ms), single‐voxel 1H MR spectra from multiple brain regions was demonstrated by utilizing a 16‐channel transceiver array coil with 16 independent transmit channels, allowing local transmit B1 (B1+) shimming. Spectra were acquired from volumes of interest of 1–8 mL in brain regions that are of interest for various neurological disorders: frontal white matter, posterior cingulate, putamen, substantia nigra, pons and cerebellar vermis. Local B1+ shimming substantially increased the transmit efficiency, especially in the peripheral and ventral brain regions. By optimizing a STEAM sequence for utilization with a 16‐channel coil, artifact‐free spectra were acquired with a small chemical shift displacement error (<5% /ppm/direction) from all regions. The high signal‐to‐noise ratio enabled the quantification of neurochemical profiles consisting of at least nine metabolites, including γ‐aminobutyric acid, glutamate and glutathione, in all brain regions. Significant differences in neurochemical profiles were observed between brain regions. For example, γ‐aminobutyric acid levels were highest in the substantia nigra, total creatine was highest in the cerebellar vermis and total choline was highest in the pons, consistent with the known biochemistry of these regions. These findings demonstrate that single‐voxel 1H MRS at ultra‐high field can reliably detect region‐specific neurochemical patterns in the human brain, and has the potential to objectively detect alterations in neurochemical profiles associated with neurological diseases. Copyright