Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2007-2441
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 5 1854-1859
Copyright © 2008 by The Endocrine Society
1H Magnetic Resonance Spectroscopy in Monocarboxylate Transporter 8 Gene Deficiency
Paul E. Sijens,
Lars A. Rödiger,
Linda C. Meiners and
Roelineke J. Lunsing
Departments of Radiology (P.E.S., L.A.R., L.C.M.) and Pediatric Neurology (R.J.L.), University Medical Center Groningen and University of Groningen, 9713 GZ Groningen, The Netherlands
Address all correspondence and requests for reprints to: Paul E. Sijens, Department of Radiology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: p.e.sijens{at}rad.umcg.nl.
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Abstract
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Context: In monocarboxylate transporter 8 (MCT8) gene deficiency, a syndrome combining thyroid and neurological abnormalities, the central nervous system has not yet been characterized by magnetic resonance (MR) spectroscopy.
Objective: We studied whether the degree of dysmyelinization in MCT8 gene deficiency according to MR imaging (MRI) is coupled with abnormalities in brain metabolism.
Design: MRI and MR spectroscopy of the brain were performed twice in two MCT8 gene deficiency patients, for the first time at age 8–10 months and for the second time at age 17–28 months. The results were compared with those obtained in controls of a similar age.
Results: Compared with controls, young children with MCT8 show choline and myoinositol level increases and N-acetyl aspartate decreases in supraventricular gray and white matter, phenomena associated with the degree of dysmyelinization according to MRI.
Conclusion: MCT8 gene deficiency results in deviant myelinization and general atrophy, which is substantiated by the MR spectroscopy findings of increased choline and myoinositol levels and decreased N-acetyl aspartate. The observations suggest that different mutations in the MCT8 gene lead to differences in the severity of the clinical spectrum, dysmyelinization, and MR spectroscopy-detectable changes in brain metabolism.
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Introduction
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The monocarboxylate transporter 8 (MCT8), encoded by the MCT8 gene located on Xq13.2, consists of 613 amino acids with 12 predicted transmembrane domains (1). MCT8 deficiency (Mendelian Inheritance in Man 300523) is a syndrome caused by mutations in the MCT8 gene and combines thyroid and neurological abnormalities (2, 3, 4, 5, 6, 7). MCT8 gene mutations have been found as the molecular cause of the previously recognized and well-defined X-linked mental retardation Allan-Herndon-Dudley syndrome, which is associated with elevated TSH and T3 levels, whereas T4 levels are decreased (3, 4). The phenotypes in MCT8 gene-deficient young men include hypotonia, X-linked psychomotor retardation, and elevated levels of serum T3. Brain magnetic resonance imaging (MRI) showed delayed myelinization or dysmyelinization (8, 9) and mild cortical atrophy with otherwise normal anatomy according to three studies (8, 9, 10). The purpose of this study was to provide the first documentation of the central nervous system (CNS) alterations in patients with MCT8 mutations.
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Patients and Methods
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Two patients with proven MCT8 gene mutations were examined twice by MRI and MR spectroscopy in clinical routine, patient 1 (P1) at the age of 8 months and 28 months and patient 2 (P2) at the age of 10 months and 17 months. P1 had a c.1690 G
A substitution in exon 6, which is located in the last transmembrane domain of MTC8 (p.G564A) and TSH level of 4.2 (normal value 0.5–4) mEq/liter, free T4 of 7.5 (11–19.5) pmol/liter, and free T3 of 8.3 (4.4–6.7) pmol/liter (11). He had severe motor and mental developmental delay with secondary microcephaly, hypotonia, progressive spasticity, athetoid movements of hands, and no crawling. P2 had a three-nucleotide deletion, c.del1497–1499, resulting in loss of phenylalanine (p.delF501) in the 10th transmembrane domain and TSH level of 4.1 (0.5–4) mEq/liter, free T4 of 8.6 (11–19.5) pmol/liter, and free T3 of 9.1 (4.4–6.7) pmol/liter (11). P2 had delayed motor development, mild mental retardation, macrocephaly, axial hypotonia, and bilateral spasticity. He crawled on his abdomen using his arms. P2's phenotype appeared to be milder, characterized by less severe hypotonia and better motor skills than P1.
The results of MR spectroscopy were compared with those obtained in five age-matched children, the control group. The first child had a previous episode of seizures due to hypoglycemia before the treatment of an insulinoma; the second a temporarily hypertonic phase, a normal developmental variant; the third a tethered spinal cord; the fourth plagiocephaly and mild tone regulation disorder, with normal development; and the fifth suffered from morbus Guillain Barre. None of the children showed signs of macroscopic brain damage at the time of MR spectroscopy (respective ages: 6, 7, 8, 22, and 34 months). The findings on MR spectroscopy (Table 1
, last column) and MRI in the control group were homogeneous.
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TABLE 1. Relative MR spectroscopy metabolite peak areas in the two patients with MCT8 mutations and in controls for a supraventricular volume of interest of 6 x 6 x 2 cm3
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The standard birdcage head coil of a single Magnetom Sonata system (Siemens AG, Erlangen, Germany) was used for MRI and 1H MR spectroscopy at 1.5 Tesla. MRI scanning included transverse T2-weighted fast spin echo, fluid-attenuated inversion recovery (FLAIR), inversion recovery, diffusion-weighted imaging, coronal T2-weighted fast spin echo, and sagittal T1-weighted spin echo sequences. Point-resolved spectroscopy two-dimensional chemical shift-imaging measurements with a repetition time of 1500 msec and an echo time of 135 msec were performed (12). In our experience, the loss of signal-to-noise ratio of metabolite signals due to T2 relaxation during the comparatively long echo time interval of 135 msec is more than offset by the improved baseline definition resulting in quantified metabolite peak areas of a better reproducibility than can be achieved with the use of very short echo times. Furthermore, at an echo time of 135 msec, the main lipid resonance at 1.3 ppm can be differentiated from the 1.32 lactate doublet being out of phase at that particular echo time (13). An axial MRI series was used as guidance for defining volume of interest, a 2-cm thick slab containing white and gray matter brain tissue cranial to the ventricles (supraventricular) (Fig. 1, A and B). The chemical shift-imaging-defined volume of interest was 6 x 6 x 2 cm3 subdivided into 36 voxels, the two central columns essentially containing gray matter and the four peripheral columns essentially white matter. The number of peaks fitted included the chemical shift ranges of 3.4–3.6 ppm for myoinositol (Ins), 3.1–3.3 ppm for choline (Cho), 2.9–3.1 ppm for creatine (Cr), 2.2–2.4 ppm for glutamate/glutamine (Glx), 1.9–2.1 for N-acetyl aspartate (NAA), and 1.2–1.4 for lactate (Lact), and their line widths and peak intensities were unrestricted. In P1 at age 8 months, an additional MR spectroscopy measurement was performed in the frontal lobe (Fig. 1, G and H). Using standard postprocessing protocols, the raw data were processed automatically, allowing for operator-independent quantifications. Due to limited patient examination times, absolute quantification requiring additional chemical shift imaging measurements without water suppression was not an option. We used an alternative method to facilitate tissue signal comparisons by expressing the metabolite signals in percentages of mean voxel peak area. The sum of the Ins, Cho, Cr, Glx, NAA, and Lact peak areas in the 6 x 6 voxels of each spectral map are normalized to a value of 3600% of the mean total metabolite signal (Ins+Cho+Cr+Glx+NAA+Lact) in the 36 voxels (14). The advantage of expressing the metabolite signals of all voxels in the same reference area is that the signals of all metabolites in gray and white matter brain tissue can be compared directly. As a consequence, the sum of the signals of the six metabolites in each voxel can be higher or lower than 100% (the average). In our data presentation (Table 1
), we averaged the relative metabolite peak areas in the gray matter (12 voxels) and white matter tissue (24 voxels).
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FIG. 1. MR spectroscopy of MCT8 P1 vs. control, both at age 8 months. A–F, Supraventricular 6 x 6 x 2 cm3 volume of interest, spectral map, and metabolic map of Cho/NAA in P1 (A–C) and in control (D) and summed gray matter spectra in P1 (E) and in control (F); G and H, frontal 6 x 4 x 2 cm3 volume of interest projected on T2-weighted MR image (G) and metabolic map of Cho (H) showing high signal intensities in voxels containing T2 intense tissue.
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Results
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On MRI, P1 differed from the controls in that the supratentorial ventricles, especially the frontal horns, and the bifrontoparietal peripheral cerebrospinal fluid spaces had widened (Fig. 1G, T2-weighted fast spin echo series with TR/TE 4200/111 msec). The gyration pattern was normal. At an age of 8 months, the degree of myelinization and the small size of the corpus callosum fit an age of 3 months at most (Fig. 2A). At the age of 28 months, the signal intensity of the myelinated white matter was diffusely elevated on the FLAIR MRI series and diffusely decreased on inversion recovery (Fig. 3A). The other findings were unchanged, giving the aspect of white matter hypoplasia and atrophy.
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FIG. 2. T2-weighted MR images at the level of the forehorn (top row) and ventricles (second row) (TR/TE 4200/111 msec) showing hyperintense signal in the white matter of P1 (A, age 8 months) compared with P2 (B, age 10 months) and a control of 8 months old (C). The similarity of the hypointense white matter areas in B and C indicates a closer to normal myelinization pattern in P2 as compared with P1.
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FIG. 3. FLAIR MR images at the level of the forehorn (top row) and ventricles (second row) (TR/TE/TI 8500/119/2500 msec) and inversion recovery (third row, ventricles) (TR/TE/TI 7000/39/350) showing increased FLAIR and decreased inversion recovery signal intensity in the white matter of patiPnt 1 (A, age 28 months) and, to a lesser degree, P2 (B, age 17 months) compared with a control of similar age (C).
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At an age of 10 months, the MRI results of P2 showed a widened supratentorial ventricular system with emphasis on the frontal horns, widened peripheral cerebrospinal fluid spaces bifrontal, and a small corpus callosum, again a picture suggesting white matter hypoplasia and atrophy. Bifrontal myelination was delayed but to a lesser extent than in P1 (Fig. 2). In P2, myelinization was near normal at the second examination (age 17 months, Fig. 3), whereas the other MRI findings persisted, like in P1. In both patients, no abnormalities were found on diffusion-weighted MRI.
In P1, MR spectroscopy showed Cho increases and NAA decreases as compared with controls both in gray and white matter brain tissue (Table 1). The difference between the findings in P1 compared with a representative control of the same age (8 months old) is illustrated by comparisons of the metabolic maps of the ratio of Cho/NAA (compare Fig. 1, C and D). The differences between P1 and the controls, up to a factor of 2, are reflected by the numerical values (the automated color scaling from zero to maximum value is of little use in comparing C with D). The summarized gray matter spectra of P1 and the same control in Fig. 1, E and F, provide further illustration of the MCT8 spectral characteristics. The second examination of P1 indicates that there was little change in brain metabolism between age 8 months and age 28 months (Table 1). The MR spectroscopy observations at both examinations in P2, whose degree of dysmyelinization according to MRI was less severe both at age 8–10 months and at age 17–28 months, were limited to mere trends of increased Cho and decreased NAA. In both patients, the levels of Ins tended to be increased.
The additional MR spectroscopy examination of a second volume of interest positioned in the frontal lobe of P1 illustrates that comparatively high Cho signals were found in areas of comparatively high signal intensity in T2-weighted MRI (Fig. 1, G and H).
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Discussion
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This study presents the first documentation by MR spectroscopy of CNS alterations in patients with MCT8 deficiency. The results of MRI were in agreement with previous MRI observations in MCT8 deficiency by Holden et al. (8), abnormal myelinization and atrophy, and Kakinuma et al. (9), high-signal lesions on T2-weighted MRI in the white matter (putamen) and atrophy. Our MR spectroscopy findings in both patients (four examinations) showed trends of increased Cho and Ins and decreased NAA in the white and gray matter. In P1, who had a considerable delay of myelinization on MRI, the Cho and NAA levels differed significantly from the controls. In a study on CNS demyelinization, Cho and Ins increases have been associated with glial proliferation and concomitant NAA decreases with reductions of axonal density in demyelinating plaques (15). Our MR spectroscopy observations are thus in line with dysmyelinization in MCT8 patients. Discussed below are differences and commonalities observed by MR spectroscopy and MRI with 1) MCT8 deficiency genotype, 2) congenital hypothyroidism, and 3) the severity of the clinical spectrum.
Relation between MCT8 genotype and abnormalities detected by MRI/MR spectroscopy
MCT8 is a transporter responsible for the influx of free T3 into neurons, which is of importance for brain development (1). The critical role played by MCT8 in the biological function in brain development, which may, at least in part, be due to altered thyroid hormone transport, was demonstrated in 2003, after which different groups reported patients with a severe neurological presentation and mutations in MTC8 (7, 16). For a metabolic defect, one should expect problems in all metabolically active cerebral cells. The two MRI and MR spectroscopy sessions of both patients indicated that the delay in bifrontal myelinization and the metabolite abnormalities (both in gray and white matter brain tissue) were consistently less severe in P2 than in P1. Our study has thus been the first to provide evidence that the abnormalities on MRI are associated with abnormalities on MR spectroscopy known to relate to dysmyelinization (Cho increases) and damage to neurons (NAA decreases). On T2-weighted MRI, this is reflected by increased white matter signal and atrophy of both the white and gray matter.
Relation between hypothyroidism and abnormalities detected by MRI/MR spectroscopy
Previously published MR spectroscopy data of the brain in MCT8 gene deficiency are not available. Congenital hypothyroidism, most commonly caused by defects in thyroid development leading to reduced T3 and T4 levels and increases in TSH, has been investigated by MR spectroscopy in a total of eight patients (17, 18, 19). The trends observed in those studies were brain Cho level increases (17, 18, 19) and NAA decreases (18), quite similar to our observations in the MCT8 deficiency patients. Furthermore, brain Cho and NAA levels in congenital hypothyroidism tended to normalize under T4 therapy (17, 18). It would thus appear that increases in the level of TSH as observed in MCT8 gene mutation patients and in congenital hypothyroidism are coupled with brain Cho level increases and NAA decreases known to relate to dysmyelinization and damage to neurons (previous paragraph). In our study, thyroid function tests indicated that in P2, the free T4 level decreases and free T3 level increases, and thyroid hormone levels were very similar to those in P1 (8.6 vs. 7.5 pmol/liter, 9.1 vs. 8.3 pmol/liter and 4.1 vs. 4.2 mEq/liter, respectively). Free T4 and thyroid hormone levels were closest to normal in P2, whereas free T3 was most normal in P1, the patient showing the severest changes on both MRI and MR spectroscopy examinations. It thus seems likely that the MCT8 phenotype is not solely explained by a decrease in T3 transport. MCT8 could transport one or several other metabolites as well. Of note, the neurological phenotype is different compared with patients with severe untreated congenital hypothyroidism. Unlike our observations in MCT8 gene deficiency, in the studies of congenital hypothyroidism, MR spectroscopy abnormalities did not come with any abnormality in MRI patterns (17, 19) or just mild atrophy (18). In a larger study of 14 congenital hypothyroidism patients examined by MRI alone, brain anatomy was reported as normal in all patients without differences in myelinization patterns compared with controls (20). These observations would indicate that congenital hypothyroidism differs from MCT8 gene deficiency in that the MR spectroscopy observed brain metabolism alterations (Cho increases and NAA decreases), and increases in the level of TSH are not expressed in brain MRI patterns. In MRI evaluations of children, timing is important, however. Whereas in our own data of MCT8 gene deficiency patients the MR spectroscopy observations at age 8–10 months and at age 17–28 months were similar, at the latter time point, the MRI patterns in both patients had progressed to more closely resemble those in controls. The number of thorough MRI documentations of congenital hypothyroidism is small, and we hold the opinion that in that particular disorder, both the MR spectroscopy-observed alterations in brain metabolism and the TSH level increases also relate to MRI-observable changes in myelinization patterns.
Relation between severity of the clinical spectrum and MRI/MR spectroscopy results
To our knowledge, the number of previous MRI-documented cases of MCT8 deficiency amounts to a total of three (8, 9, 10). Thus, literature data offer little information with regard to the relationship between the degree of MCT8 deficiency-caused psychomotor retardation and the degree of dysmyelinization and atrophy on MRI. In our own study of two patients, P1 appeared to be the more severely affected case, as clinically apparent by the severity of his degree of psychomotor retardation compared with P2. On the MRI, he showed the severest white matter abnormality, most likely as a result of dysmyelinization, and on MR spectroscopy, the level of Cho was increased and NAA decreased in both gray and white matter brain tissue, observations less clear in P2. In in vitro T3 uptake studies in P1, the p.G564A substitution resulted in complete loss of MCT8 function, probably due to the dramatic amino acid change at a significant position in the protein. In P2, the MCT8 protein with the p.delF501 clearly had residual transport activity, implying that the amino acid Phe501 has less influence on the functionality of MCT8. The increase of Ins at 10 months of life and normalization afterward in P2 (Table 1) could reflect a slower but nearly complete course of myelinization. The highest Ins level in P1 being observed at 28 months of age might reflect a reaction of a severely delayed or false myelinization, being clinically mirrored by a more severe failure of neurological development (progressive spasticity).
An uncertainty in our study is that identification of Ins, a metabolite not quantified in previous MR spectroscopy studies of congenital hyperthyroidism (17, 18, 19), on spectra acquired with a long TE (here, 135 msec) is not straightforward. The complication is that Gly has a long T2 relaxation time and also resonates at 3.54 ppm (21). Considering that in previous brain MR spectroscopy studies Gly has been considered to be the dominating component of the 3.54 ppm peak in nonketonic hyperglycemia only, it is reasonable to assume that in the spectra of MCT8 gene deficiency patients, Gly contributions are negligible.
In conclusion, MCT8 deficiency results in deviant myelinization and general atrophy that is substantiated by the MR spectroscopy findings of increased Cho and Ins levels and decreased NAA. The outcomes suggest that different mutations in the MCT8 gene lead to differences in severity of the clinical spectrum, dysmyelinization, and MR spectroscopy-detectable alterations in brain metabolism.
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Footnotes
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Disclosure statement: P.E.S., L.A.R., L.C.M., and R.J.L. have nothing to declare.
First Published Online March 4, 2008
Abbreviations: Cho, Choline; CNS, central nervous system; Cr, creatine; FLAIR, fluid-attenuated inversion recovery; Glx, glutamate/glutamine; Ins, myoinositol; Lact, lactate; MCT8, monocarboxylate transporter 8; MRI, magnetic resonance imaging; NAA, N-acetyl aspartate; P1, patient 1.
Received November 2, 2007.
Accepted February 20, 2008.
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References
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- Friesema EC, Ganguli S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ 2003 Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278:40128–40135[Abstract/Free Full Text]
- Schwartz CE, May MM, Carpenter NJ, Rogers RC, Martin J, Bialer MG, Ward J, Sanabria J, Marsa S, Lewis JA, Echeverri R, Lubs HA, Voeller K, Simensen RJ, Stevenson RE 2005 Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8 gene). Am J Hum Genet 77:41–53[CrossRef][Medline]
- Dumitrescu AM, Liao XH, Best TB, Brockman K, Refetoff S 2004 A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 74:168–175[CrossRef][Medline]
- Friesema EC, Grueters A, Biebermann H, Krude H, von Moers A, Reeser M, Barett TG, Mancilla EE, Svensson J, Kester MH, Kuiper GG, Balkassmi S, Uitterlinden AG, Koehrle J, Rodien P, Halestap AP, Visser TJ 2004 Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 364:1435–1437[CrossRef][Medline]
- Maranduba CM, Friesema EC, Kok F, Kester MH, Jansen J, Sertie AL, Passos-Bueno MR, Visser TJ 2006 Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (ADHS) due to a novel mutation in the MCT8 thyroid transporter. J Med Genet 43:457–460[Abstract/Free Full Text]
- Jansen J, Friesema EC, Kester MH, Milici C, Reeser M, Gruters A, Barrett TG, Mancilla EE, Svensson J, Wemeau JL, Busi da Silva Canalli MH, Lundgren J, McEntagart ME, Hopper N, Arts WF, Visser TJ 2007 Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothryronine. J Clin Endocrinol Metab 92:2378–2381[Abstract/Free Full Text]
- Friesema ECH, Jansen J, Heuer H, Trajkovic M, Bauer K, Visser TJ 2006 Mechanisms of disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8. Nat Clin Pract Endocrinol Metab 2:512–523[CrossRef][Medline]
- Holden KR, Zuniga OF, May MM, Su H, Molinero MR, Rogers RC, Schwartz CE 2005 X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype. J Child Neurol 20:852–857[Abstract/Free Full Text]
- Kakinuma H, Masatsune I, Takahashi H 2005 A novel mutation in the monocarboxylate transporter 8 gene in a boy with putamen lesions and low free T4 levels in cerebral fluid. J Pediatr 147:552–554[CrossRef][Medline]
- Biebermann H, Ambrugger P, Tarnow P, von Moers A, Schweizer U, Grueters A 2005 Extended clinical phenotype and functional studies of a loss-of-function mutation A150V in the thyroid hormone specific transporter gene MCT8. Eur J Endocrinol 153:359–366[Abstract/Free Full Text]
- Visser WE, Jansen J, Kester MH, Brouwer OF, Lunsing RJ, Lundgren J, Mancilla E, Friesema EC, Visser TJ 2007 Differences in T3 transport in fibroblasts from MCT8 patient reflect phenotypic variability. Thyroid 17:1172
- Sijens PE, van den Bent MJ, Nowak PJCM, van Dijk P, Oudkerk M 1997 1H Chemical shift imaging reveals loss of brain tumor choline signal after administration of Gd-contrast. Magn Reson Med 37:222–225[Medline]
- Sijens PE, Oudkerk M 2002 1H chemical shift imaging characterization of human brain tumor and edema. Eur Radiol 12:2056–2061[Medline]
- Sijens PE, Oudkerk M, de Leeuw FE, de Groot JC, Achten E, Heijboer R, Hofman A, Breteler MM 1999 1H chemical shift imaging of the human brain at age 60–90 years reveals metabolic differences between women and men. Magn Reson Med 42:24–31[CrossRef][Medline]
- Bitsch A, Bruhn H, Vougioukas V, Stringaris A, Lassmann H, Frahm J, Bruck W 1999 Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. Am J Neuroradiol 20:1619–1627[Abstract/Free Full Text]
- Schwarz CE, Stevenson RE 2007 The MTC8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. Best Pract Res Clin Endocrinol Metab 21:307–321[CrossRef][Medline]
- Gupta RK, Bhatia V, Popatni H, Gujral RB 1995 Brain metabolite changes on in vivo proton magnetic resonance spectroscopy in children with congenital hyperthyroidism. J Pediatr 126:389–392[CrossRef][Medline]
- Jagannathan NR, Tandon N, Raghunathan R, Kochupillai N 1998 Reversal of abnormalities of myelination by thyroxine therapy in congenital hypothyroidism; localized in vivo proton magnetic resonance spectroscopy (MRS) study. Dev Brain Res 109:179–186[CrossRef][Medline]
- Penrice J, Cady EB, Lorek A, Wylezinska M, Amess PN, Aldridge RF, Stewart A, Wyatt JS, Reynolds E 1996 Proton magnetic resonance spectroscopy of the brain in normal preterm and term infants, and perinatal hypoxia-ischemia. Pediatr Res 40:6–14[Medline]
- Siragusa V, Boffelli S, Weber G, Triulzi F, Orezzi S, Scotti G, Chiumello G 1997 Brain magnetic resonance imaging in congenital hypothyroid infants at diagnosis. Thyroid 7:761–764[Medline]
- Ross BD, Bluml S 1999 New aspects of brain physiology. NMR Biomed 9:279–296[CrossRef]
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Abstract
Introduction
