Quantitative in vivo1H nuclear magnetic resonance spectroscopic imaging of neuronal loss in rat brain

doi:10.1016/0306-4522(95)00300-8

Neuroscience

Volume 69, Issue 4, December 1995, Pages 1095-1101

https://doi.org/10.1016/0306-4522(95)00300-8 Get rights and content

Abstract

The aim of this research was to determine whether in vivo nuclear magnetic resonance spectroscopic measurement of N-acetyl aspartate, a neuron specific brain marker, provides a quantitative index of neuronal loss. Five rats were injected unilaterally in the corpus striatum with kainic acid, an analogue of glutamate that causes excitotoxic degeneration of intrinsic neurons, and were subjected to nuclear magnetic resonance imaging and spectroscopic imaging. Measurements of N-acetyl aspartate were determined in vivo and compared to post mortem nuclear magnetic resonance spectroscopic measures of N-cetyl aspartate and choline acetyl transferase and glutamate decarboxylase activities, biochemical markers for striatal intrinsic neuronal integrity. Mean per cent neuronal survival of hemispheres with lesion versus the contralateral hemispheres measured 72 for glutamate decarboxylase and 71 for N-acetyl aspartate (in vivo), 74 for N-acetyl aspartate (in vitro), and 62 for choline acetyl transferase, respectively.

Our studies in rats have shown that estimates of neuronal loss through nuclear magnetic resonance spectroscopic measurements of N-acetyl aspartate are equivalent to traditional neuronal enzyme activity assays. The results unequivocally demonstrate that N-acetyl aspartate is a valid and sensitive neuronal marker with the capability of providing accurate assessments of neuronal loss in vivo.

Reference (26)

GideonP. et al.
In vivo relaxation of N-acetyl-aspartate, creatine plus phosphocreatine, and choline containing compounds during the course of brain infarction: a proton MRS study
Magn. Reson. Imag.
(1992)
MarcucciF. et al.
Distribution of N-acetyl- l-aspartic acid in rat brain
J. Neurochem.
(1966)
OlneyJ. et al.
Kainic acid: a powerful neurotoxic analogue of glutamate
Brain Res.
(1974)
SchwarczR. et al.
Striatal lesions with kainic acid: neurochemical characteristics
Brain Res.
(1977)
SimmonsM.L. et al.
Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies
Neuroscience
(1991)
BealM.F. et al.
Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid
J. Neurosci.
(1993)
BullG. et al.
Standardization of a radiochemical assay of choline acetyltransferase and a study of the activation of the enzyme in rabbit brain
J. Neurochem.
(1971)
BuxtonR.B. et al.
Quantitative proton chemical shift imaging
Magn. Reson. Med.
(1986)
ChongW. et al.
Localised cerebral proton MR spectroscopy in HIV infection and AIDS
AJNR
(1994)
CoyleJ. et al.
Lesion of striatal neurons with kainic acid provides a model for Huntington's chorea
Nature
(1976)

GuimaraesA. et al.

Quantitative magnetic resonance imaging of experimental neurotoxicity

JarvikJ. et al.

Proton MR spectroscopy of HIV-infected patients: characterization of abnormalities with imaging and clinical correlation

Radiology

(1993)

KamadaK. et al.

Localized proton spectroscopy of focal brain pathology in humans: Significant effects of edema on spin-spin relaxation time

Magn. Reson. Med.

(1994)

Cited by (57)

Dose-dependent influence of short-term intermittent ethanol intoxication on cerebral neurochemical changes in rats detected by ex vivo proton nuclear magnetic resonance spectroscopy
2014, Neuroscience
Citation Excerpt :
NAA is localized in neurons, neuroglial precursors, and immature oligodendrocytes (Biller et al., 2009; Paul and Medina, 2012). Miller and colleagues have demonstrated that NAA concentrations are positively correlated with neuronal densities and viability (Miller, 1991; Guimaraes et al., 1995; Biller et al., 2009). Furthermore, NAA is regarded as a key neuronal marker in neurodegenerative disorders (Miller, 1991).
The aim of this study was to quantitatively assess the effects of short-term intermittent ethanol intoxication on cerebral metabolite changes among sham controls (CNTL), low-dose ethanol (LDE)-exposed, and high-dose ethanol (HDE)-exposed rats, which were determined with ex vivo high-resolution spectra. Eight-week-old male Wistar rats were divided into three groups. Twenty rats in the LDE (n = 10) and the HDE (n = 10) groups received ethanol doses of 1.5 and 2.5 g/kg, respectively, through oral gavage every 8 h for 4 days. At the end of the 4-day intermittent ethanol exposure, one-dimensional ex vivo 500-MHz ¹H nuclear magnetic resonance spectra were acquired from 30 samples of the frontal cortex region (from the three groups). Normalized total N-acetylaspartate (tNAA: NAA + NAAG [N-acetylaspartyl-glutamate]), GABA, and glutathione (GSH) levels were significantly lower in the frontal cortex of the HDE-exposed rats than that of the LDE-exposed rats. Moreover, compared to the CNTL group, the LDE rats exhibited significantly higher normalized GABA levels. The six pairs of normalized metabolite levels were positively (+) or negatively (−) correlated in the rat frontal cortex as follows: tNAA and GABA (+), tNAA and aspartate (Asp) (+), myo-Inositol (mIns) and Asp (−), mIns and alanine (+), mIns and taurine (+), and mIns and tNAA (−). Our results suggested that short-term intermittent ethanol intoxication might result in neuronal degeneration and dysfunction, changes in the rate of GABA synthesis, and oxidative stress in the rat frontal cortex. Our ex vivo ¹H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy results suggested some novel metabolic markers for the dose-dependent influence of short-term intermittent ethanol intoxication in the frontal cortex.
Magnetic Resonance Imaging
2014, Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
The development of magnetic resonance imaging (MRI) has been one of the great medical advances in the twentieth century, enabling the creation of 3D images of the human body with excellent soft tissue contrast and spatial resolution. MRI is noninvasive and does not rely on harmful ionizing radiation. From its early applications in the diagnosis of brain pathology such as stroke, today it is used widely to diagnose and monitor disease processes throughout the body, giving new insights into cancer, heart disease, bowel disorders, and the musculoskeletal system. Advances in scanner hardware, with increasing magnet strength, novel pulse sequences, and improved imaging coils, have greatly enhanced image quality and intrinsic structural contrast. Furthermore, new areas of research into MRI contrast agents and molecular imaging have emerged, which enable pathology to be seen with even greater clarity. In this article, we first explore the history and basic principles of MRI – how the MR signal originates biologically and may be exploited for imaging. We then go on to discuss MR contrast agents, examining the role of the paramagnetic contrast agents in common clinical use. We then move to introduce advanced molecular MRI techniques such as advances in targeted and genetic reporter contrast agents. Finally, we look at MRI’s role in complementing histopathology, discussing MRI for noninvasive imaging of delicate and postmortem samples and the use of MR to image at a microscopic scale.
MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain
2010, NeuroToxicology
Citation Excerpt :
In fact, prefrontal cortical NAA levels were increased in MDMA treated rats (Fig. 3A). Given that NAA levels (as measured by 1H-MRS) correlate tightly with measures of neuronal viability in vitro in rodent models of neuronal injury (Guimaraes et al., 1995; Strauss et al., 1997), increased NAA may represent an increase in neuronal (mitochondria-dependent) activity or density. The major finding in this study that NAA levels are not decreased under conditions of MDMA-induced 5HT depletion (Figs. 2A and 3A) suggests that 1H-MRS assessment of NAA levels in MDMA users may not be an accurate index of drug-induced neurotoxicity in 5HT axon terminals.
In animals, repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) reduces markers of serotonergic activity and studies show similar serotonergic deficits in human MDMA users. Using proton-magnetic resonance spectroscopy (¹H-MRS) at 11.7 Tesla, we measured the metabolic neurochemical profile in intact, discrete tissue punches taken from prefrontal cortex, anterior striatum, and hippocampus of rats administered MDMA (5 mg/kg IP, 4× q 2 h) or saline and euthanized 7 days after the last injection. Monoamine content was measured with HPLC in contralateral punches from striatum and hippocampus to compare the MDMA-induced loss of 5HT innervation with constituents in the ¹H-MRS profile. When assessed 7 days after the last MDMA injection, levels of hippocampal and striatal serotonin (5HT) were significantly reduced, consistent with published animal studies. N-Acetylaspartate (NAA) levels were significantly increased in prefrontal cortex and not affected in anterior striatum or hippocampus; myo-inositol (INS) levels were increased in prefrontal cortex and hippocampus but not anterior striatum. Glutamate levels were increased in prefrontal cortex and decreased in hippocampus, while GABA levels were decreased only in hippocampus. The data suggest that NAA may not reliably reflect MDMA-induced 5HT neurotoxicity. However, the collective pattern of changes in 5HT, INS, glutamate and GABA is consistent with persistent hippocampal neuroadaptations caused by MDMA.
Metabolic alterations in medication-free patients with bipolar disorder: A 3T CSF-corrected magnetic resonance spectroscopic imaging study
2008, Psychiatry Research - Neuroimaging
Citation Excerpt :
Several animal and human studies have consistently shown a decline in NAA concentrations in disease states known to involve neuronal and/or axonal loss or dysfunction such as ischemia, inflammation, seizures, tumors, dementia and gliosis (Sager et al., 1995, 1999; Fukuzako et al., 1997; De Stefano et al., 2001). Animal models of chronic neuronal injury have shown correlations between the severity of the neuronal injury and NAA concentrations as measured by proton MRS (Simmons et al., 1991; Guimaraes et al., 1995). Taking these findings together, NAA is considered a putative neuronal marker reflecting neuronal density and/or viability.
The objective of this study was to determine whether cerebrospinal fluid(CSF)-corrected concentrations of N-acetylaspartate are lower in several brain regions of drug- and medication-free subjects with bipolar disorder as compared with matched healthy controls. Bipolar subjects (n = 21) and age- and sex-matched healthy control (n = 21) were studied using proton magnetic resonance spectroscopic imaging on a 3T magnetic resonance (MR) scanner. Spectra were quantified using the LCModel, and metabolite values were CSF-corrected to yield metabolite concentrations. Fourteen regions of interest and five metabolite concentrations in each subject were selected for statistical analysis. We found that bipolar subjects had significantly decreased N-acetylaspartate concentrations in both caudate heads and the left lentiform nucleus. Choline and creatine in the head of the right caudate were also significantly decreased in bipolar subjects. Significantly increased myo-inositol was found in the left caudate head in bipolar subjects. Bipolar subjects showed significantly decreased glutamate/glutamine concentrations in the frontal white matter bilaterally and in the right lentiform nucleus. No differences were found for other metabolites examined. These preliminary findings suggest decreased neuronal density or viability in the basal ganglia and neurometabolic abnormalities in the frontal lobes of subjects with bipolar disorder.
Occipital cortical proton MRS at 4 Tesla in human moderate MDMA polydrug users
2007, Psychiatry Research - Neuroimaging
Citation Excerpt :
MI levels could potentially be altered in MDMA users due to direct drug effects or secondary influences on glial function or metabolic processes. While NAA is often cited as a neuronal specific marker (Guimaraes et al., 1995), NAA is mitochondrially synthesized (Patel and Clark, 1979; Bates et al., 1996) developmentally detectable in some glial cells, and may be present in adult glia as well (Sager et al., 1999; Bhakoo and Pearce, 2000). Decreased NAA may serve as a reversible marker of neuronal injury (e.g. Kalra et al., 1998; de Stefano et al., 1995) and defense against cellular edema during osmotic stress (Taylor et al., 1995).
The recreational drug MDMA (3,4, methylenedioxymethamphetamine; sold under the street name of Ecstasy) is toxic to serotonergic axons in some animal models of MDMA administration. In humans, MDMA use is associated with alterations in markers of brain function that are pronounced in occipital cortex. Among neuroimaging methods, magnetic resonance spectroscopy (MRS) studies of brain metabolites N-acetylaspartate (NAA) and myoinositol (MI) at a field strength of 1.5 Tesla (T) reveal inconsistent results in MDMA users. Because higher field strength proton MRS has theoretical advantages over lower field strengths, we used proton MRS at 4.0 T to study absolute concentrations of occipital cortical NAA and MI in a cohort of moderate MDMA users (n = 9) versus non-MDMA using (n = 7) controls. Mean NAA in non-MDMA users was 10.47 mM (± 2.51), versus 9.83 mM (± 1.94) in MDMA users. Mean MI in non-MDMA users was 7.43 mM (± .68), versus 6.57 mM (± 1.59) in MDMA users. There were no statistical differences in absolute metabolite levels for NAA and MI in occipital cortex of MDMA users and controls. These findings are not supportive of MDMA-induced alterations in NAA or MI levels in this small sample of moderate MDMA users. Limitations to this study suggest caution in the interpretation of these results.
In vivo proton MR spectroscopy of the human brain
2006, Progress in Nuclear Magnetic Resonance Spectroscopy

View all citing articles on Scopus

View full text

Article preview

Neuroscience

Abstract

Reference (26)

In vivo relaxation of N-acetyl-aspartate, creatine plus phosphocreatine, and choline containing compounds during the course of brain infarction: a proton MRS study

Magn. Reson. Imag.

Distribution of N-acetyl- l-aspartic acid in rat brain

J. Neurochem.

Kainic acid: a powerful neurotoxic analogue of glutamate

Brain Res.

Striatal lesions with kainic acid: neurochemical characteristics

Brain Res.

Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies

Neuroscience

Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid

J. Neurosci.

Standardization of a radiochemical assay of choline acetyltransferase and a study of the activation of the enzyme in rabbit brain

J. Neurochem.

Quantitative proton chemical shift imaging

Magn. Reson. Med.

Localised cerebral proton MR spectroscopy in HIV infection and AIDS

AJNR

Lesion of striatal neurons with kainic acid provides a model for Huntington's chorea

Nature

Quantitative magnetic resonance imaging of experimental neurotoxicity

Proton MR spectroscopy of HIV-infected patients: characterization of abnormalities with imaging and clinical correlation

Radiology

Localized proton spectroscopy of focal brain pathology in humans: Significant effects of edema on spin-spin relaxation time

Magn. Reson. Med.

Cited by (57)

Dose-dependent influence of short-term intermittent ethanol intoxication on cerebral neurochemical changes in rats detected by ex vivo proton nuclear magnetic resonance spectroscopy

Magnetic Resonance Imaging

MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain

Metabolic alterations in medication-free patients with bipolar disorder: A 3T CSF-corrected magnetic resonance spectroscopic imaging study

Occipital cortical proton MRS at 4 Tesla in human moderate MDMA polydrug users

In vivo proton MR spectroscopy of the human brain