Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease

PURPOSE AND BACKGROUND: Mitochondrial diseases are a group of inherited disorders caused by a derangement of mitochondrial respiration. The clinical manifestations are heterogeneous, and the diagnosis is often based on information acquired from multiple levels of inquiry. MR spectroscopy has previously been shown to help detect an abnormal accumulation of lactate in brain parenchyma and CSF in association with mitochondrial disorders, but the frequency of detection is largely unknown. We sought to examine the frequency of detectable elevations of CNS lactate by proton MR spectroscopy in a population of children and young adults with suspected mitochondrial disease. METHODS: MR spectroscopy data evaluated for the presence or absence of abnormal brain or CSF lactate were compared with other clinical indicators of mitochondrial dysfunction for 29 patients with suspected mitochondrial disease during the years 1990 to 2000. Based on an independent review of the final diagnoses, the patients were divided into groups based on the probability of mitochondrial disorder. RESULTS: A total of 32 scans from 29 patients were reviewed. Of eight patients thought to have a definitive mitochondrial disorder on the basis of genetic, biochemical, or pathologic features, five were found to have abnormal brain or CSF lactate levels revealed by MR spectroscopy (for one patient in whom two images were acquired, one was negative and the other positive). Among the studies conducted using a multisection spectroscopic imaging technique, five of six showed elevated lactate in the brain parenchyma, six of six showed elevated lactate in the CSF, and five of six showed elevated lactate in both brain and CSF. Of 16 patients who were highly suspected of having mitochondrial disorders on the basis of clinical grounds alone but who were lacking genetic, biochemical, or pathologic confirmation, four had abnormal lactate levels shown by MR spectroscopy. Mitochondrial disorder was excluded for five patients, none of whom had CNS lactate shown by MR spectroscopy. CONCLUSION: Detection of CNS lactate by MR spectroscopy is useful in the diagnosis of mitochondrial disease. In our series of patients with confirmed mitochondrial disease, a high level of lactate shown by MR spectroscopy correlated well with other markers of mitochondrial disease. As with all other means used to diagnose mitochondrial disorders, MR spectroscopy does not depict elevated lactate in all cases. Abnormal CNS concentrations of lactate may be undetected by MR spectroscopy because of differences in the type of mitochondrial disorder, timing, severity, or location of the affected tissues and the site of interrogation.     

Proton MR spectroscopy of brain abnormalities in neonates born to HIV-positive mothers.

PURPOSETo examine the sensitivity of proton MR spectroscopy for detecting early central nervous system abnormalities in neonates born to human immunodeficiency virus (HIV)-positive mothers.METHODSAsleep, unsedated, and continuously monitored by electrocardiography, 10 newborns, 5 with HIV-positive and 5 with HIV-negative mothers, were studied within the first 10 days of life in a 1.5-T scanner. After T1- and T2-weighted images were obtained, proton spectra were performed using voxels of interest (3.4 cm3) in the deep parietooccipital white matter. Peaks were identified as N-acetyl-aspartate (2.0 ppm), creatine and phosphocreatine (3.0 ppm), choline (3.2 ppm), and inositol (3.5 ppm). Peak areas were used to calculate metabolic ratios: N-acetyl-aspartate to creatine, inositol to creatine, and creatine to choline.RESULTSAll newborns of HIV-positive mothers had abnormal proton spectra compared with control infants; a nonspecific amino acid peak in the 2.1- to 2.6-ppm area was elevated, broad, and overlapping the N-acetyl-aspartate peak in all the HIV-exposed newborns and in only 1 of the 5 control newborns. The choline-to-creatine ratio was higher in HIV-exposed newborns at 2.3 +/- 0.4 (normal term, 0.9 +/- 0.3), as was the N-acetyl-aspartate-to-creatine ratio at 2.6 +/- 0.9 (for control subjects, 1.2 +/- 0.4). MR images from these brain regions were all considered normal. Because acquired immunodeficiency syndrome develops in only a small fraction of neonates born to HIV-seropositive mothers, the above spectral abnormalities found in all our subjects may result from indirect effects of HIV, such as intrauterine growth retardation.CONCLUSIONSThese findings indicate that proton MR spectroscopy might play an important role in detecting early central nervous system complications in newborns of HIV-seropositive mothers.     

Proton MR spectroscopy in metabolic assessment of musculoskeletal lesions

OBJECTIVE: The purposes of this review are to describe the principles and method of MR spectroscopy, summarize current published data on musculoskeletal lesions, and report additional cases that have been analyzed with recently developed quantitative methods. CONCLUSION: Proton MR spectroscopy can be used to identify key tissue metabolites and may serve as a useful adjunct to radiographic evaluation of musculoskeletal lesions. A pooled analysis of 122 musculoskeletal tumors revealed that a discrete choline peak has a sensitivity of 88% and specificity of 68% in the detection of malignancy. Modest improvements in diagnostic accuracy in 22 of 122 cases when absolute choline quantification was used encourage the pursuit of development of choline quantification methods.     

Proton MR spectroscopy of the brain in infants

Proton magnetic resonance spectroscopy (MRS) was used to study the brain of 2 normal and 15 abnormal infants aged from 33 weeks postmenstrual age (PMA) to 14 months postnatal age. Eleven of the infants were examined on at least two occasions. The principal clinical diagnoses in the abnormal infants were perinatal ischemic and hemorrhagic brain injury. All proton spectra demonstrated peaks that were assigned to N-acetylaspartate (NAA), choline containing compounds (Cho), and creatine plus phosphocreatine (Cr). The NAA/Cho and NAA/Cr ratios increased with age, while the Cho/Cr ratio decreased with age in the majority of infants. The NAA/Cho ratio was generally lower in abnormal infants, but the difference was not apparent before 40 weeks (PMA). This ratio was lowest in infants with the severest degree of neurological abnormality. Proton and phosphorus MRS was compared in seven infants. In those with severe brain lesions, early phosphorus spectra were abnormal. On follow-up the phosphorus spectra became normal, but the proton spectra showed persistently low NAA/Cho and NAA/Cr ratios. Proton MRS provides new information that may be complementary to phosphorus MRS in the diagnosis and monitoring of brain development in normal and neurologically damaged infants.     

Proton MR spectroscopy in patients with pyogenic brain abscess: MR spectroscopic imaging versus single-voxel spectroscopy

Purpose

Single-voxel spectroscopy (SVS) has been the gold standard technique to diagnose the pyogenic abssess. Two-dimensional magnetic resonance spectroscopic imaging (MRSI) is able to provide spatial distribution of metabolic concentration, and is potentially more suitable for differential diagnosis between abscess and necrotic tumors. Therefore, the purpose of this study was to evaluate the equivalence of MRSI and SVS in the detection of the metabolites in pyogenic brain abscesses.

Materials and methods

Forty-two patients with pyogenic abscesses were studied by using both SVS and MRSI methods. Two neuroradiologists reviewed the MRS data independently. A κ value was calculated to express inter-reader agreement of the abscesses metabolites, and a correlation coefficient was calculated to show the similarity of two spectra. After consensus judgment of two readers, the binary value of metabolites of pyogenic abscesses (presence or absence) was compared between SVS and MRSI.

Results

The consistency of spectral interpretation of the two readers was very good (κ ranged from 0.95 to 1), and the similarity of two spectra was also very high (cc = 0.9 ± 0.05). After consensus judgment of two readers, the sensitivities of MRSI ranged from 91% (acetate) to 100% (amino acids, succinate, lactate, lipid), and the specificities of MRSI were 100% for detecting all metabolites with SVS as reference.

Conclusion

SVS and MRSI provide similar metabolites in the cavity of pyogenic brain abscess. With additional metabolic information of cavity wall and contralateral normal-appearing brain tissue, MRSI would be a more suitable technique to differentiate abscesses from necrotic tumors.     

Proton MR spectroscopy and MRI-volumetry in mild traumatic brain injury

BACKGROUND AND PURPOSE: More than 85% of brain traumas are classified as "mild"; MR imaging findings are minimal if any and do not correspond to clinical symptoms. Our goal, therefore, was to quantify the global decline of the neuronal marker N-acetylaspartate (NAA), as well as gray (GM) and white matter (WM) atrophy after mild traumatic brain injury (mTBI). MATERIALS AND METHODS: Twenty patients (11 male, 9 female; age range, 19-57 years; median, 35 years) with mTBI (Glasgow Coma Scale score 13-15 with loss of consciousness for at least 30 seconds) and 19 age- and sex-matched control subjects were studied. Seven patients were studied within 9 days of TBI; the other 13 ranged from 1.2 months to 31.5 years (average and median of 4.6 and 1.7 years, respectively) after injury. Whole-brain NAA (WBNAA) concentration was obtained in all subjects with nonlocalizing proton MR spectroscopy. Brain volume and GM and WM fractions were segmented from T1-weighted MR imaging and normalized to the total intracranial volume, suitable for intersubject comparisons. The data were analyzed with least squares regression. RESULTS: Patients with mTBI exhibited, on average, a 12% WBNAA deficit that increased with age, compared with the control subjects (p<.05). Adjusted for age effects, patients also suffered both global atrophy (-1.09%/year; P=.029) and GM atrophy (-0.89%/year; P=.042). Patients with and without visible MR imaging pathology, typically punctate foci of suspected shearing injury, were indistinguishable in both atrophy and WBNAA. CONCLUSION: WBNAA detected neuronal/axonal injury beyond the minimal focal MR-visible lesions in mTBI. Combined with GM atrophy, the findings may provide further, noninvasive insight into the nature and progression of mTBI.     

Proton MR spectroscopy in Wilson disease: analysis of 36 cases

BACKGROUND AND PURPOSE: Wilson disease (WD) is rare but one of the few metabolic disorders that can possibly benefit from effective available treatments. The literature regarding proton MR spectroscopy (MRS) in WD is scarce and controversial. The purpose of this study was to determine the brain metabolic changes due to WD by using MRS. To our knowledge, this is the first time that MRS was performed in such a large sample of patients with WD. METHODS: Thirty-six patients with WD and 37 healthy volunteers were examined with MRS in the parieto-occipital cortex, frontal white matter, and basal ganglia (BG). Ratios of the following metabolites were calculated in relation to creatine (Cr): N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and glutamine/glutamate (Glx). The mean peak line width was measured on each spectrum. RESULTS: Compared with control subjects, patients with WD had significantly decreased NAA/Cr ratios in the three studied areas (P < .005) and an increased mI/Cr ratio in the BG (P < .001). Cho/Cr and Glx/Cr did not differ between the groups. The mean peak line in the BG was wider in patients than in control subjects. CONCLUSION: WD is unequivocally associated with MRS changes that could possibly be assigned to neuronal loss (in the three studied areas), to gliosis, and to iron and/or copper deposition in the BG.     

Proton MR spectroscopy-detectable major neurotransmitters of the brain: biology and possible clinical applications

Neurotransmitters are chemical substances that, by definition, allow communication between neurons and permit most neuronal-glial interactions in the CNS. Approximately 80% of all neurons use glutamate, and almost all interneurons use GABA. A third neurotransmitter, NAAG, modulates glutamatergic neurotransmission. Concentration changes in these molecules due to defective synthetic machinery, receptor expression, or errors in their degradation and metabolism are accepted causes of several neurologic disorders. Knowledge of changes in neurotransmitter concentrations in the brain can add useful information in making a diagnosis, helping to pick the right drug of treatment, and monitoring patient response to drugs in a more objective manner. Recent advances in (1)H-MR spectroscopy hold promise in providing a more reliable in vivo detection of these neurotransmitters. In this article, we summarize the essential biology of 3 major neurotransmitters: glutamate, GABA, and NAAG. Finally we illustrate possible applications of (1)H-MR spectroscopy in neuroscience research.     

Proton MR spectroscopy of the brain in AIDS dementia complex.

Proton MR spectroscopy of the brain has been undertaken in 8 healthy volunteers and in 11 patients with human immunodeficiency virus infection and varying stages of AIDS dementia complex (ADC). Spectral appearances in patients with no ADC or early ADC were not significantly different from normal volunteers. Spectra from patients with moderate to severe ADC exhibited significant reductions in levels of N-acetyl aspartate (NAA) relative to creatine (Cr) and also showed elevations in choline containing compounds (relative to Cr). Because NAA is though to be a metabolic marker for normally functioning neurons, these findings suggest the presence of neuronal injury or loss in moderate to severe ADC. The significance of these findings is discussed.     

Proton MR spectroscopy of the brain in patients treated with TIPS

PURPOSE: To evaluate the utility of proton MR spectroscopy (MRS) for the early detection of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunting (TIPS). MATERIAL AND METHODS: Six patients, who underwent TIPS for treatment of portal hypertension, were examined by MRS I week before and 1 week after TIPS. They were simultaneously clinically examined for number connection test, blood NH3 level, liver function test and the Fischer ratio. RESULT: Three of 6 patients showed overt HE 1 to 5 weeks after TIPS and the other 3 patients did not show overt HE. The overt HE group showed the larger ratio of the amounts of glutamine and glutamate/myo-inositol (Glx/MI) than that of non-overt HE group (p<0.05). CONCLUSION: The Glx/MI ratio estimated by MRS was useful for early detection of HE after TIPS.     

MR imaging of the brain: metabolic and toxic white matter diseases

Metabolic disorders of the brain are rare, complex and confusing. The diagnostic modality of choice nowadays is MRI. The high diagnostic sensitivity, however, is coupled with a lack of specificity and usually results in the depiction of similar appearing but clinically diverse white matter processes. For this reason it is essential to perform the MRI as early as possible during the course of the disease and to keep in close contact to the referring clinician to optimize image interpretation. Another precondition is to know the natural course of brain myelination and to know how this appears on the individual MR machine with different parameters. In some diseases like phenylketonuria MRI seems to be an excellent tool to monitor dietary treatment and patient compliance. In patients after radio- and / or chemotherapy MRI reveals the radiation induced leucencephalopathy and can usually differentiate between a recurrent malignancy.     

Proton MR spectroscopy of polymicrogyria and heterotopia

BACKGROUND AND PURPOSE: Proton MR spectroscopy of the brain allows noninvasive in vivo assessment of metabolites, which may be useful in understanding the biology of malformations of cortical development. The aim of this study was to determine the MR spectroscopic characteristics of polymicrogyria and heterotopia compared with those of normal frontal lobe white matter. METHODS: We recruited 22 patients with radiographic findings characteristic of polymicrogyria, nine patients with radiographic findings characteristic of heterotopia, and 10 control subjects into the study. The MR imaging technique consisted of high-spatial-resolution axial dual-echo and gradient-echo 3D volume imaging. A single-voxel point-resolved technique (1600/135 [TR/TE]) was used to acquire spectra from the region of neocortical malformation and from frontal lobe white matter in control subjects. The differences in N-acetyl moieties (NA)/creatine (Cr), NA/choline (Cho), and Cho/Cr ratios among patients with heterotopia, those with polymicrogyria, and control subjects were compared by using the Kruskal-Wallis test followed by the Mann-Whitney U (Wilcoxon) test. RESULTS: No statistically significant differences were noted in the NA/Cr, NA/Cho, and Cho/Cr ratios between the polymicrogyria group and controls, the heterotopia group and controls, or the polymicrogyria and heterotopia groups. CONCLUSION: Both heterotopia and polymicrogyria are malformations of cortical development that occur at a relatively late stage of brain development. The neurons and glia in these lesions are mature, and the metabolites appear to be similar to those of normal adult frontal white matter.     

Proton MR spectroscopy of Wernicke encephalopathy

Two patients with acute thiamine deficiency were examined with thalamic single-voxel proton MR spectroscopy. T2-weighted images exhibited increased signal intensity. N-acetylaspartate (NAA)/creatine (Cr) ratios were low without detectable lactate. Owing to substantially decreased choline (Cho) T2, the Cho/Cr ratio was not decreased. After thiamine therapy, the NAA/Cr ratio increased, paralleling clinical improvement and reduction in the areas of signal-intensity changes.     

Proton MR spectroscopy of the prostate

PURPOSE: To summarize current technical and biochemical aspects and clinical applications of proton magnetic resonance spectroscopy (MRS) of the human prostate in vivo. MATERIAL AND METHODS: Pertinent radiological and biochemical literature was searched and retrieved via electronic media (medline, pubmed. Basic concepts of MRS of the prostate and its clinical applications were extracted. RESULTS: Clinical MRS is usually based on point resolved spectroscopy (PRESS) or spin echo (SE) sequences, along with outer volume suppression of signals from outside of the prostate. MRS of the prostate detects indicator lines of citrate, choline, and creatine. While healthy prostate tissue demonstrates high levels of citrate and low levels of choline that marks cell wall turnover, prostate cancer utilizes citrate for energy metabolism and shows high levels of choline. The ratio of (choline+creatine)/citrate distinguishes between healthy tissue and prostate cancer. Particularly when combined with magnetic resonance (MR) imaging, three-dimensional MRS imaging (3D-CSI, or 3D-MRSI) detects and localizes prostate cancer in the entire prostate with high sensitivity and specificity. Combined MR imaging and 3D-MRSI exceed the sensitivity and specificity of sextant biopsy of the prostate. When MRS and MR imaging agree on prostate cancer presence, the positive predictive value is about 80-90%. Distinction between healthy tissue and prostate cancer principally is maintained after various therapeutic treatments, including hormone ablation therapy, radiation therapy, and cryotherapy of the prostate. CONCLUSIONS: Since it is non-invasive, reliable, radiation-free, and essentially repeatable, combined MR imaging and 3D-MRSI of the prostate lends itself to the planning of biopsy and therapy, and to post-therapeutic follow-up. For broad clinical acceptance, it will be necessary to facilitate MRS examinations and their evaluation and make MRS available to a wider range of institutions.     

Proton MR spectroscopy of craniopharyngiomas.

To date, only a few cases of craniopharyngiomas have been studied by magnetic resonance (MR) spectroscopy. We report our spectroscopy experiences with five patients having surgically proven craniopharyngiomas. Proton MR spectroscopy images were obtained using the single-voxel mode with spin-echo point resolved spectroscopy. Very prominent peaks centered at 1-1.5ppm were noted in spectroscopic analysis, which probably corresponded to lipid/cholesterol peaks, correlating with the histological findings revealing high amounts of cholesterol in the cyst fluids.     

Proton MR spectroscopy of the brain in 14 patients with Parkinson disease.

PURPOSETo determine whether the proton spectra from patients with clinically diagnosed Parkinson disease differ from the spectra of age-matched healthy subjects with respect to the major cerebral metabolite resonances as well as lactate.METHODSFourteen patients with Parkinson disease (38 to 81 years of age) and 13 healthy control subjects (37 to 81 years of age) were studied using image-guided, single-voxel (27-cm3 volume) proton MR spectroscopy of the occipital lobe.RESULTSThe peak area ratios of N-acetyl aspartate to creatine and N-acetyl aspartate to choline for Parkinson patients did not show a statistically significant difference from the corresponding ratios for control subjects. There was a very significant increase in the ratio of lactate to N-acetyl aspartate for patients with Parkinson disease, with the greatest increase (threefold) manifested by the subgroup (n = 4) with dementia. The difference in N-acetyl aspartate to choline between women (n = 7) with Parkinson disease and healthy women (n = 9) approached significance. No dependence of the peak ratios on age, duration of Parkinson disease, or medication (L-dopa) regimen was found.CONCLUSIONPreliminary results indicating an increase in cerebral lactate in patients with Parkinson disease support the hypothesis that Parkinson disease is a systemic disorder characterized by an impairment of oxidative energy metabolism. The larger increases for Parkinson patients with dementia may be diagnostically useful in assessing clinical course and in differentiating Parkinson disease from other causes of dementia. Additional studies are needed, though, to quantitate lactate changes and identify potential contributions from lipid resonances better.     

Proton MR spectroscopy of tumefactive demyelinating lesions

BACKGROUND AND PURPOSE: Tumefactive demyelinating lesions (TDLs) can simulate intracranial neoplasms in clinical presentation and MR imaging appearance, and surgical biopsy is often performed in suspected tumors. Proton MR spectroscopy has been applied in assessing various intracranial diseases and is increasingly used in diagnosis and clinical management. Our purpose was to determine if multivoxel proton MR spectroscopy can be used to differentiate TDLs and high-grade gliomas. METHODS: Conventional MR images, proton MR spectra, and medical records were retrospectively reviewed in six patients with TDLs diagnosed by means of biopsy or by documented clinical improvement, with or without supporting laboratory testing and follow-up imaging. Proton MR spectra of 10 high-grade gliomas with similar conventional MR imaging appearances were used for comparison. In contrast-enhancing, central, and perilesional areas of each lesion, peak heights of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were measured and the lactate peak noted. Cho/Cr and NAA/Cr ratios of corresponding regions in TDLs and gliomas were compared. RESULTS: No significant differences in mean Cho/Cr ratios were found in the corresponding contrast-enhancing, central, or perilesional areas of TDLs and gliomas. The mean central-region NAA/Cr ratio in gliomas was significantly lower than that of TDLs, but mean NAA/Cr ratios in other regions were not significantly different. A lactate peak was identified in four of six TDLs and three of 10 gliomas. CONCLUSION: In the cases examined, the NAA/Cr ratio in the central region of TDLs and high-grade gliomas differed significantly. However, overall metabolite profiles of both lesions were similar; this finding emphasizes the need for the cautious interpretation of spectroscopic findings.     

Proton MR spectroscopy in neuroborreliosis: a preliminary study

We report results of a magnetic resonance spectroscopy (MRS) study in 12 patients with neuroborreliosis. We used a PRESS sequence, placing an 8 cm³ voxel in normal-appearing white matter of the frontal lobe. Peaks indicating N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), lipids (Lip) and lactate (Lac) were identified and ratios of NAA/Cr, Cho/Cr, mI/Cr, Lip/Cr, Lac/Cr calculated. Significant increases in Cho/Cr and Lip/Cr were noted. No abnormality was found in mean NAA/Cr and Lac/Cr, but in four patients there was a decreased NAA peak; mI/Cr ratio was slightly increased. Although the spectroscopic profile in patients with neuroborreliosis seems to be nonspecific, MRS might be useful for assessing tissue damage of the central nervous system.