Features of brain MRI in dogs with treated and untreated mucopolysaccharidosis type I.

The mucopolysaccharidosis type I (MPS I) dog model has been important in the development of therapies for human patients. We treated dogs with enzyme replacement therapy (ERT) by various approaches. Dogs assessed included untreated MPS I dogs, heterozygous carrier dogs, and MPS I dogs treated with intravenous ERT as adults (beginning at age 13 to 16 mo), intrathecal and intravenous ERT as adults (beginning at age 13 to 16 mo), or intrathecal ERT as juveniles (beginning at age 4 mo). We then characterized the neuroimaging findings of 32 of these dogs (age, 12 to 30 mo). Whole and midsagittal volumes of the corpus callosum, measured from brain MRI, were significantly smaller in affected dogs compared with unaffected heterozygotes. Corpus callosum volumes in dogs that were treated with intrathecal ERT from 4 mo until 21 mo of age were indistinguishable from those of age-matched carrier controls. Dogs with MPS I showed cerebral ventricular enlargement and cortical atrophy as early as 12 mo of age. Ventricular enlargement was greater in untreated MPS I dogs than in age-matched dogs treated with intrathecal ERT as juveniles or adults. However, treated dogs still showed some ventricular enlargement or cortical atrophy (or both). Understanding the progression of neuroimaging findings in dogs with MPS I and their response to brain-directed therapy may improve preclinical studies for new human-directed therapies. In particular, corpus callosum volumes may be useful quantitative neuroimaging markers for MPS-related brain disease and its response to therapy.

Investigation of breast cancer using two-dimensional MRS.

Proton (1H) MRS enables non-invasive biochemical assay with the potential to characterize malignant, benign and healthy breast tissues. In vitro studies using perchloric acid extracts and ex vivo magic angle spinning spectroscopy of intact biopsy tissues have been used to identify detectable metabolic alterations in breast cancer. The challenges of 1H MRS in vivo include low sensitivity and significant overlap of resonances due to limited chemical shift dispersion and significant inhomogeneous broadening at most clinical magnetic field strengths. Improvement in spectral resolution can be achieved in vivo and in vitro by recording the MR spectra spread over more than one dimension, thus facilitating unambiguous assignment of metabolite and lipid resonances in breast cancer. This article reviews the recent progress with two-dimensional MRS of breast cancer in vitro, ex vivo and in vivo. The discussion includes unambiguous detection of saturated and unsaturated fatty acids, as well as choline-containing groups such as free choline, phosphocholine, glycerophosphocholine and ethanolamines using two-dimensional MRS. In addition, characterization of invasive ductal carcinomas and healthy fatty/glandular breast tissues non-invasively using the classification and regression tree (CART) analysis of two-dimensional MRS data is reviewed.

Two-dimensional 1H MR spectroscopy of the brain in human immunodeficiency virus (HIV)-infected children.

PURPOSE: To measure cerebral metabolites in brains of human immunodeficiency virus (HIV)-infected patients using two-dimensional (2D) proton ((1)H) magnetic resonance spectroscopy (MRS), which enables more sensitive detection of metabolites at lower concentrations and delineation of the components of the different choline (Ch) groups in the frequency domain when compared to one dimensional (1D) (1)H-MRS. MATERIALS AND METHODS: We examined metabolite/creatine (Cr) and metabolite/Ch ratios in the left frontal brain of 10 HIV-infected (mean age 13.7 +/- 4.7 years) and 11 control (mean age 15.3 +/- 4.6 years) adolescents and children using 2D localized chemical shift correlated spectroscopy (L-COSY). The integrated volume under each 2D metabolite peak was calculated with reference to the diagonal creatine methyl peak (Cr_d) or the diagonal choline trimethylamine peak (Ch_d). RESULTS: In the HIV-infected patients, myoinositol (mI)/Cr_d (P = 0.009) and mI/Ch_d (P = 0.006) were elevated. The ratios of the following metabolites were also significantly elevated (P < 0.05): mI-Ch/Cr_d, gamma-aminobutyrate (GABA)/ Cr_d, GABA/Ch_d, threonine-lactate (Thr-Lac)/Cr_d, Thr-Lac/Ch_d, and N-acetyl aspartate (NAA)/Cr_d. CONCLUSION: We have demonstrated for the first time the feasibility of 2D-MRS in HIV-infected children and adolescents to assess cerebral metabolites and found elevated mI and elevated GABA, in the left frontal brain of clinically stable HIV-infected patients. A larger study population is needed to confirm these pilot GABA findings.

Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression.

Proton magnetic resonance spectroscopy ((1)HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline (1)HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR=30/3000 ms, 3 x 3 x 3 cm(3) and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate+glutamine ([Glx]), glutamate ([Glu]), and creatine+phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.

Two-dimensional MR spectroscopic characterization of breast cancer in vivo.

The major goal of this work was to characterize invasive ductal carcinoma and healthy fatty breast tissues noninvasively using the classification and regression tree analysis (CART) of 2D MR spectral data. 2D L-COSY spectra were acquired in 14 invasive breast carcinoma and 21 healthy fatty breasts using a GE 1.5 Tesla MRI/MRS scanner equipped with a 2-channel phased-array breast MR coil. The 2D spectra were recorded in approximately 10 minutes using a minimum voxel size of 1 ml without any water suppression technique. For healthy breasts, spectra were acquired from at least one fatty region. 2D L-COSY spectra were recorded in a total of 43 voxels. Five diagonal and six cross peak volumes were integrated and at least eighteen ratios were selected as potential features for the statistical method, namely CART. The 2D L-COSY data showed a significant increase for the majority of these ratios in invasive breast carcinomas compared to healthy fatty tissues. Better accuracy of identifying carcinomas and fatty tissues is reported using CART analysis of different combinations of ratios calculated from the relative levels of water, choline, and saturated and unsaturated lipids. This is a first report on the statistical classification of 2D L-COSY in human breast carcinomas in vivo.