Accuracy of Unenhanced MRI in the Detection of New Brain Lesions in Multiple Sclerosis.

Background Administration of a gadolinium-based contrast material is widely considered obligatory for follow-up imaging of patients with multiple sclerosis (MS). However, advances in MRI have substantially improved the sensitivity for detecting new or enlarged lesions in MS. Purpose To investigate whether the use of contrast material has an effect on the detection of new or enlarged MS lesions and, consequently, the assessment of interval progression. Materials and Methods In this retrospective study based on a local prospective observational cohort, 507 follow-up MR images obtained in 359 patients with MS (mean age, 38.2 years ± 10.3; 246 women, 113 men) were evaluated. With use of subtraction maps, nonenhanced images (double inversion recovery [DIR], fluid-attenuated inversion recovery [FLAIR]) and contrast material-enhanced (gadoterate meglumine, 0.1 mmol/kg) T1-weighted images were separately assessed for new or enlarged lesions in independent readings by two readers blinded to each other's findings and to clinical information. Primary outcome was the percentage of new or enlarged lesions detected only on contrast-enhanced T1-weighted images and the assessment of interval progression. Interval progression was defined as at least one new or unequivocally enlarged lesion on follow-up MR images. Results Of 507 follow-up images, 264 showed interval progression, with a total of 1992 new or enlarged and 207 contrast-enhancing lesions. Four of these lesions (on three MR images) were retrospectively detected on only the nonenhanced images, corresponding to 1.9% (four of 207) of the enhancing and 0.2% (four of 1992) of all new or enlarged lesions. Nine enhancing lesions were not detected on FLAIR-based subtraction maps (nine of 1442, 0.6%). In none of the 507 images did the contrast-enhanced sequences reveal interval progression that was missed in the readouts of the nonenhanced sequences, with use of either DIR- or FLAIR-based subtraction maps. Interrater agreement was high for all three measures, with intraclass correlation coefficients of 0.91 with FLAIR, 0.94 with DIR, and 0.99 with contrast-enhanced T1-weighted imaging. Conclusion At 3.0 T, use of a gadolinium-based contrast agent at follow-up MRI did not change the diagnosis of interval disease progression in patients with multiple sclerosis. © RSNA, 2019 See also the editorial by Saindane in this issue.

Predicting conversion from clinically isolated syndrome to multiple sclerosis-An imaging-based machine learning approach.

Magnetic resonance imaging (MRI) scans play a pivotal role in the evaluation of patients presenting with a clinically isolated syndrome (CIS), as these may depict brain lesions suggestive of an inflammatory cause. We hypothesized that it is possible to predict the conversion from CIS to multiple sclerosis (MS) based on the baseline MRI scan by studying image features of these lesions. We analyzed 84 patients diagnosed with CIS from a prospective observational single center cohort. The patients were followed up for at least three years. Conversion to MS was defined according to the 2010 McDonald criteria. Brain lesions were segmented based on 3D FLAIR and 3D T1 images. We generated brain lesion masks by a computer assisted manual segmentation. We also generated a set of automated segmentations using the Lesion Segmentation Toolbox for SPM to assess the influence of different segmentation methods. Shape and brightness features were automatically calculated from the segmented masks and used as input data to train an oblique random forest classifier. Prediction accuracies of the resulting model were validated through a three-fold cross-validation. Conversion from CIS to MS occurred in 66 of 84 patients (79%). The conversion or non-conversion was predicted correctly in 71 patients based on shape features derived from the computer assisted manual segmentation masks (84.5% accuracy). This predictor was more accurate than predicting conversion using dissemination in space at baseline according to the 2010 McDonald criteria (75% accuracy). While shape features strongly contributed to the accuracy of the predictor, including intensity features did not further improve performance. As patients who convert to definite MS benefit from early treatment, an early classification model is highly desirable. Our study shows that shape parameters of lesions can contribute to predicting the future course of CIS patients more accurately.

A novel imaging technique for better detecting new lesions in multiple sclerosis.

We developed a tool that performs longitudinal subtraction of 3D double inversion recovery (DIR) images in follow-up magnetic resonance (MR) examinations of patients with multiple sclerosis. As DIR sequences show a high lesion-to-parenchyma contrast, we hypothesized that such a tool might lead to increased sensitivity for new lesions as well as to speeding up the routine clinical work-up of follow-up MR imaging in multiple sclerosis by directly visualizing new lesions. DIR subtraction images of serial MR examinations were calculated in 106 patients with multiple sclerosis. Existence of new lesions was assessed in three different ways: by standard visual comparison, by FLAIR, and by DIR subtraction maps. A reference standard, to which the single modalities were compared, was defined by combining all information from all readouts and all readers. The presence and number of new lesions were determined and the time needed for analysis measured. Accuracy of detecting overall existence of new lesions using DIR subtraction maps was significantly higher than using visual comparison (96 vs. 86%, p = 0.013) or FLAIR subtraction maps (p < 0.001), with increased sensitivity and higher negative predictive value. Significantly more new lesions were detected when using DIR subtraction maps (p < 0.001). Analyzing subtraction maps took less than a third of the time needed for the standard visual comparison (p = 0.007). Thus, DIR subtraction maps improve the detection of new lesions in a clinical setting both in terms of accuracy and in terms of speed.

5-Methyl-1,2,3-thiadiazoles synthesized via ugi reaction and their fungicidal and antiviral activities.

1,2,3-Thiadiazoles, an important synthetic active substructure, are nowadays becoming one of the important branches in novel pesticide development. To develop pesticide candidates with diverse biological activities and probe their structure-activity relationship, three series of 5-methyl-1,2,3-thiadiazoles were rationally designed and synthesized using a simple and convenient one-step synthetic procedure via Ugi reaction. Biological activities of the target compounds including fungicidal activity, antivirus activity in vitro and in vivo, and systemic acquired resistance were systematically evaluated. The results indicated that compound III(10) showed broad-spectrum of activities against most fungi tested, and compounds I(10) and II(17) showed excellent potential antivirus activities as compared to positive control agent ribavirin. The preliminary structure-activity relationship was also discussed. The results of these studies indicated that the 5-position-substituted 1,2,3-thiadiazoles exhibited good antivirus activity and were worthy of further study in pesticide development.

Synthesis, crystal structure, and biological activity of 4-methyl-1,2,3-thiadiazole-containing 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles.

Heterocyclic compounds play an important role as the main sources of lead molecules of agrochemicals. Synthesis and biological activity of thiadiazole-containing 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazoles were seldom reported. To find novel lead compounds with various biological activities, a series of 6-substituted-3-(4-methyl-1,2,3-thiadiazolyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadizoles were rationally designed and synthesized according to the principle of combinations of bioactive substructures by the condensation of 3-(4-methyl-1,2,3-thiadiazolyl)-4-amino-1,2,4-triazole-5-thione with various carboxylic acids and phosphorus oxychloride. All newly synthesized compounds were identified by proton nuclear magnetic resonance ((1)H NMR), infrared spectroscopy (IR), electroionization mass spectrometry (EI/MS), and elementary analysis. The crystal structure of 3-(4-methyl-1,2,3-thiadiazolyl)-6-(4-methylphenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadizole was determined by X-ray diffraction crystallography. In this crystal, two intermolecular hydrogen bonds (N2...H-C12 and N3...H-C13), a weak intermolecular interaction (S...S), and the weak ppi-ppi intermolecular interaction were observed. Fungicide screening indicated that all of the target compounds showed certain extent of growth inhibition against fungi tested. 3-(4-Methyl-1,2,3-thiadiazolyl)-6-n-propyl[1,2,4]triazolo[3,4-b][1,3,4]thiadizole and 3-(4-methyl-1,2,3-thiadiazolyl)-6-trichloromethyl[1,2,4]triazolo[3,4-b][1,3,4]thiadizole were found to have potential wide spectrum of fungicide activity. The median effective concentrations (EC(50)) detected for 3-(4-methyl-1,2,3-thiadiazolyl)-6-trichloromethyl[1,2,4]triazolo[3,4-b][1,3,4]thiadizole to six fungi were from 7.28 micromol/L against Pellicularia sasakii (Shirai) to 42.49 micromol/L against Alternaria solani . The results indicated that thiadiazole-containing 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazoles were potential fungicide lead compounds.

Synthesis of 4-methyl-1,2,3-thiadiazole derivatives via Ugi reaction and their biological activities.

The Ugi reaction is a green and rapid one-pot reaction for lead derivation. To develop novel candidate pesticides with diverse biological activities, two series of 4-methyl-1,2,3-thiadiazole derivatives containing active substructures of 3-chloro-4-methylphenyl or 3-fluoro-4-methylphenyl, respectively, were rationally designed and synthesized via Ugi reaction according to the principle of combinations of bioactive substructures. All of the structures of newly synthesized compounds were confirmed by proton nuclear magnetic resonance and high-resolution mass spectrometry. Biological activities of the target compounds including fungicide activity, antivirus activity in vitro and in vivo, and systemic acquired resistance were evaluated systematically. The results indicated that derivatives containing 3-(trifluoromethyl)phenyl and 2-methylphenyl possessed a potential wide spectrum of fungicidal activity. Derivatives containing 3-(trifluoromethyl)phenyl and 4-hydroxyphenyl possessed good potential direct antivirus activities against tobacco mosaic virus (TMV) in vitro, and the replacement of Cl atom by F atom improved their direct inhibition activities against TMV in vitro. Derivatives containing phenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, and 4-hydroxyphenyl possessed good potential bioactivities in vivo including protection, inactivation, curative, and induction activities against TMV. These studies indicate that the newly synthesized 4-methyl-1,2,3-thiadiazole derivatives possessed good potential bioactivities, and a combination of bioactive substructures via Ugi reaction was an effective way to find bioactive compounds for novel pesticide development.

Synthesis and biological activity evaluation of 1,2,3-thiadiazole derivatives as potential elicitors with highly systemic acquired resistance.

Elicitors provide a broad spectrum of systemic acquired resistance by altering the physical and physiological status of the host plants and, therefore, are among the most successful directions in modern pesticide development for plant protection. To develop a novel elicitor with highly systemic acquired resistance, two series of thiazole- and oxadiazole-containing thiadiazole derivatives were rationally designed and synthesized according to the principle of combination of bioactive substructures in this work. Their structures were characterized by (1)H nuclear magnetic resonance (NMR), infrared (IR), high-resolution mass spectrometry (HRMS), or elemental analysis. Their potential systemic acquired resistance as an elicitor was also evaluated; bioassay results indicated that, among the 23 compounds synthesized, three compounds, 10a, 10d, and 12b, displayed better systemic acquired resistance than the positive control, tiadinil, a commercialized 1,2,3-thiadiazole-based elicitor. In addition, three other compounds, 10f, 12c, and 12j, exhibited a certain degree of fungus growth inhibition in vitro or in vivo. Our results demonstrated that, in combination of bioactive substructures is an interesting exploration for novel pesticide development, thiazole- and oxadiazole-containing thiadiazole derivatives are potential elicitors with good systemic acquired resistance.