MRS study of the effects of minocycline on markers of neuronal and microglial integrity in ALS.

OBJECTIVE: Magnetic resonance spectroscopy (MRS) allows to monitor brain metabolites noninvasively in amyotrophic lateral sclerosis (ALS). The objective of this study was to use MRS to monitor the effect of minocycline treatment (200 mg/day) over a short period (6 weeks) on the brain metabolites in the precentral gyrus and brainstem in newly diagnosed ALS patients. METHODS: Ten ALS patients (not on riluzole treatment) were recruited and submitted to single-voxel proton MRS longitudinal examinations (1) before minocycline treatment, (2) 3 weeks and (3) 6 weeks after initiation of treatment. RESULTS: Results did not show the expected decrease of N-acetylaspartate/creatine (NAA/Cr) in the precentral gyrus, and an increased NAA/Cr ratio in the brainstem suggested neuronal recovery. The myo-inositol (mI)/Cr ratio was unchanged in the precentral gyrus, but increased in the brainstem, indicating a glial reaction. CONCLUSIONS: MRS results suggest that minocycline treatment could be beneficial in the early stages of ALS.

Noninvasive quantitation of human liver steatosis using magnetic resonance and bioassay methods.

The purpose was to evaluate the ability of three magnetic resonance (MR) techniques to detect liver steatosis and to determine which noninvasive technique (MR, bioassays) or combination of techniques is optimal for the quantification of hepatic fat using histopathology as a reference. Twenty patients with histopathologically proven steatosis and 24 control subjects underwent single-voxel proton MR spectroscopy (MRS; 3 voxels), dual-echo in phase/out of phase MR imaging (DEI) and diffusion-weighted MR imaging (DWI) examinations of the liver. Blood or urine bioassays were also performed for steatosis patients. Both MRS and DEI data allowed to detect steatosis with a high sensitivity (0.95 for MRS; 1 for DEI) and specificity (1 for MRS; 0.875 for DEI) but not DWI. Strong correlations were found between fat fraction (FF) measured by MRS, DEI and histopathology segmentation as well as with low density lipoprotein (LDL) and cholesterol concentrations. A Bland-Altman analysis showed a good agreement between the FF measured by MRS and DEI. Partial correlation analyses failed to improve the correlation with segmentation FF when MRS or DEI data were combined with bioassay results. Therefore, FF from MRS or DEI appear to be the best parameters to both detect steatosis and accurately quantify fat liver noninvasively.

Diffusion-weighted imaging and magnetization transfer imaging of tardive and edentulous orodyskinesia.

Oral dyskinesias occur in elderly individuals in relation to drug use (tardive dyskinesia, TD) or edentulousness (edentulous orodyskinesia, EOD) but their characterization remains incomplete. Our aim was to investigate whether magnetic resonance techniques such as diffusion-weighted imaging (DWI) and magnetization transfer imaging (MTI) of the brain could be used to differentiate dyskinetic patients from control subjects. Eight drug-treated patients with TD, 12 EOD patients, 8 drug-treated patients without TD, and 10 control subjects were recruited and examined by DWI and MTI. Measurements in the caudate nucleus, putamen, and globus pallidus yielded globally different apparent diffusion coefficient (ADC) values between drug treated patients with TD and control subjects but the magnetization transfer ratios showed no significant variations. The discrimination between dyskinetic patients and control subjects offered by ADC values was however slightly poorer than the discrimination offered by the previously published choline/creatine ratios measured by MR spectroscopy in the basal ganglia. The results are consistent with the pathophysiological hypothesis of damage to cholinergic interneurons.

Quantitative MRS study of Baló's concentric sclerosis lesions.

Baló's concentric sclerosis (BCS) lesions display specific metabolite changes detected by magnetic resonance spectroscopy (MRS). We report on two cases of BCS lesions examined by MRS; the first case was evaluated 36 days after the onset of symptoms, whereas the second case was evaluated 9 days after the onset of symptoms. MRS data were obtained from single voxels located in the lesion and in the contralateral region. Relative to the creatine/phosphocreatine peak, BCS lesions displayed decreases of N-acetyl aspartate and increases of choline, myo-inositol (mI), glutamine/glutamate (Glx), lactate and lipid+macromolecule signals, in agreement with previous reports. In addition, previously unreported decreases of mI (-19% to -29%) and increases of Glx (+55% to +198%) were measured; these could be useful in characterizing BCS lesions.

Proton magnetic resonance spectroscopy study of dyskinesia patients.

Oral dyskinesias may occur spontaneously or be induced by medications such as antipsychotics and antidepressants. In this study, single voxel proton magnetic resonance spectroscopy was used to compare metabolite levels in the striatum for (1) 12 patients with drug-induced tardive dyskinesia (TD), (2) 12 patients with spontaneous oral dyskinesia (SOD), (3) 8 antidepressant-treated patients without TD, and (4) 8 control subjects. Statistically significant reductions in the choline/creatine (Cho/Cr) ratio were measured for the drug-treated patients with TD (-13%, P = 0.020) and SOD patients (-12%, P = 0.034) relative to control subjects. In comparison with antidepressant-treated patients without TD, drug-treated patients with TD showed a non statistically significant reduction in Cho/Cr (-11%, P = 0.079). All other metabolite ratios (N-acetylaspartate (NAA)/Cr, myo-inositol (mI)/Cr, glutamine + glutamate (Glx)/Cr, macromolecule + lipid (MM+Lip)/Cr, NAA/Cho) were unaffected by either type of dyskinesia. The observed Cho/Cr reduction in dyskinesia patients suggests decreased membrane phosphatidylcholine turnover, which provides free choline as precursor of molecules responsible for cellular signal transduction.

Comparison of the phytoestrogen trans-resveratrol (3,4',5-trihydroxystilbene) structures from x-ray diffraction and solution NMR.

The NMR-derived solution structure of trans-3,4',5-trihydroxystilbene (resveratrol) was compared with two recent literature crystal x-ray structures, resveratrol in complex with human transthyretin (TTR-RES) from 1DVS.pdb and resveratrol bound to chalcone synthase (CHS-RES) from 1CGZ.pdb. 1H and 13C NMR spectra of resveratrol were acquired in DMSO-d6. Assignments were obtained from an analysis of DQF-COSY, TOCSY, DEPT, HMQC/HSQC, HMBC and INADEQUATE NMR spectra. Past 1H and 13C NMR literature assignments are corrected. The dihedral angle 2-1-1'-2' provides an indication of the relative spatial orientation of the two phenolic rings. Values of 1.62, - 54.10 and 12.6 +/- 1.1 degrees were found for the 1DVS.pdb, 1CGZ.pdb and NMR resveratrol structures, respectively. The 1DVS.pdb resveratrol structure is 'flat' with the two phenolic rings along the same plane. The 1CGZ.pdb structure has these two rings almost orthogonal to each other, and the NMR structure has these two rings much closer to being along the same plane. The angles 1-alpha--alpha' and 1'-alpha'--alpha are along the same trace and of similar magnitude for the 1CGZ.pdb and NMR resveratrol structures. For the 1DVS.pdb resveratrol structure, these angles are about 7-10 degrees greater, with alpha and alpha' being 180 degrees out-of-phase from the other two structures. The alpha rings did not overlap, with the NMR result representing a 'median model' of the two x-ray structures.

Comparison of 17beta-estradiol structures from x-ray diffraction and solution NMR.

The NMR-derived structure of estrogen (17beta-estradiol, E2), the drug of choice for postmenopausal women, was compared with a recent literature crystal x-ray structure of Fab-bound E2. 1H and 13C NMR spectra of E2 were acquired in DMSO-d6. Assignments were obtained from an analysis of DQF-COSY, TOCSY, HETCOR, HMQC and HMBC 2D NMR spectra. The 1H and 13C NMR assignments are the first reported for E2 in DMSO-d6. Two solution structures, S1 and S2, were obtained with molecular modeling using NOE constraints. S1 overlaps with the crystal structure for all rings. S2 shows prominent differences in the C-ring (C9--C11--C12--C13) segment, which deviates from a chair conformation, and excellent overlap in the A-, B- and D-rings of E2. The C-ring in S2 adopts a boat conformation as opposed to a chair conformation in the x-ray and S1 structures. The S2 structure is about 6 degrees more twisted than the bound x-ray and S1 models. The S1, S2 and x-ray structures had ring bowing values of 10.1 +/- 0.3, 11 +/- 1 and 10.37 degrees , respectively. Of the 100 solution conformers generated, 83 had S1 conformation and 17 had S2 conformation, with average internal energies of 112 +/- 2 and 141 +/- 2 kcal mol(-1), respectively. The 100 S1- and S2- derived conformers showed a r.m.s.d. of 0.72 A for all atoms. The x-ray, S1 and S2 C18--O17 distances were 2.93, 2.92 +/- 0.01 and 2.93 +/- 0.01 A, respectively, and the O3--O17 distances were 11.06, 11.18 +/- 0.12, and 10.89 +/- 0.05 A, respectively.

MR imaging-guided focused ultrasound surgery of breast cancer: correlation of dynamic contrast-enhanced MRI with histopathologic findings.

PURPOSE: To assess the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters to monitor residual tumor following non-invasive MRI-guided focused ultrasound surgery (MRIgFUS) of breast tumors. METHODS: DCE-MRI data were acquired before and after the MRIgFUS treatment of small breast tumors (d < 3.5 cm) for 17 patients. The lesion was surgically resected and the presence of residual tumor was determined by histopathological analysis. The percentage of residual tumor was correlated with three DCE-MRI parameters measured at the maximally enhancing site of each tumor: increase in signal intensity (ISI), maximum difference function (MDF) and positive enhancement integral (PEI). RESULTS: A good correlation was found between the ISI (r = 0.897), MDF (r = 0.789) and PEI (r = 0.859) parameters and the percentage of residual viable tumor determined by histopathology. A receiver operator characteristic curve analysis yielded a cutoff value for ISI at 20% with a sensitivity of 77% and a specificity of 100%. CONCLUSION: These results suggest that parameters from DCE-MRI data could provide a reliable non-invasive method for assessing residual tumor following MRIgFUS treatment of breast tumors.

Feasibility of magnetic resonance imaging-guided focused ultrasound surgery as an adjunct to tamoxifen therapy in high-risk surgical patients with breast carcinoma.

PURPOSE: To evaluate the feasibility of treating breast neoplasms with use of magnetic resonance (MR) imaging-guided focused ultrasound (US) surgery. MATERIALS AND METHODS: Twenty-four female patients, each with a single biopsy-proven breast carcinoma, who were considered to be at increased surgical risk or who had refused surgery underwent MR imaging-guided focused US surgery as an adjunct to their chemotherapeutic regimen of tamoxifen. Follow-up included routine studies to rule out metastatic disease and MR studies with and without contrast material infusion in the treated breast (10 days and 1, 3, and 6 months after the treatment session). Percutaneous biopsy was performed after 6-month follow-up, and if residual tumor was present, a second MR imaging-guided focused US surgery treatment session was performed, followed by repeat biopsy 1 month later. RESULTS: Twenty-three of 24 patients completed the protocol, with only one minor complication associated with the treatment sessions (second-degree skin burn resolved with local treatment). Follow-up MR studies demonstrated a varying hypointense treatment margin (range, 1-11 mm), which represents destruction of tissue beyond the visible tumor. Absence of enhancement may be an indicator of tumor destruction (18 of 19 patients with negative biopsy results) whereas persistent enhancement suggested tumor residue (three of five patients with residual tumor). Overall, 19 of 24 patients (79%) had negative biopsy results after one or two treatment sessions. CONCLUSION: MR imaging-guided focused US surgery of breast tumors is a safe, repeatable, and promising method of focal tumor destruction.

MR imaging-guided focused US ablation of breast cancer: histopathologic assessment of effectiveness-- initial experience.

PURPOSE: To evaluate the effectiveness of noninvasive magnetic resonance (MR) imaging-guided focused ultrasonographic (US) ablation of breast carcinomas. MATERIALS AND METHODS: Before undergoing tumor resection, 12 patients with invasive breast carcinomas were treated with MR imaging-guided focused US ablation consisting of multiple sonications of targeted points that were monitored with temperature-sensitive MR imaging. The patients were treated with either one of two focused US systems. The effectiveness of the treatment was determined at histopathologic analysis of the resected mass that was performed to determine the volumes of necrosed and residual tumor. Complications resulting from the procedure were assessed by means of questionnaires, medical examinations, and MR image analysis. RESULTS: US ablation was well tolerated by the patients, and with the exception of minor skin burns in two patients, no complications occurred. Histopathologic analysis of resected tumor sections enabled quantification of the amount of necrosed and residual tumor and visualization of the surrounding hemorrhage. In three patients treated with one of the US systems, a mean of 46.7% of the tumor was within the targeted zone and a mean of 43.3% of the cancer tissue was necrosed. In nine patients treated with the other US system, a mean of 95.6% of the tumor was within the targeted zone and a mean of 88.3% of the cancer tissue was necrosed. Residual tumor was identified predominantly at the periphery of the tumor mass; this indicated the need to increase the total targeted area (ie, with an increased number of sonications). CONCLUSION: Thermal coagulation of small breast tumors by means of MR imaging-guided focused US appears to be a promising noninvasive ablation procedure.