Bruno F. Pastorello

Formaldehyde increases MAGIC gel dosimeter melting point and sensitivity

Polymeric gel dosimeters are being used to verify three-dimensional (3D) dose distributions of different types of radiotherapy treatments, especially the most complexes ones. An important factor that can limit the wider use of this kind of dosimeter is temperature, as gel melting can destroy 3D information. This work shows that adding formaldehyde to the gel preparation increases the melting point, allowing its use in warmer environments, including up to body temperature. An addition of 3% in mass of the formaldehyde solution to a MAGIC type gel dosimeter increased its melting point from 25 to 69 degrees C. Also important were a 12.5% increase in gel sensitivity and an expressive decrease in relaxation rate R2 uncertainty.

Anterior cingulate Glutamate-Glutamine cycle metabolites are altered in euthymic bipolar I disorder.

Bipolar disorder (BD) has been consistently associated with abnormalities in the Glutamate/GABA-Glutamine cycle. Magnetic resonance spectroscopy (MRS) studies have reported increased brain Glutamate (Glu) and Glx (Glu+Glutamine) in subjects with BD. However, data on separate measures of GABA and Glutamine (Gln) in BD are sparse due to overlapping resonant signals. The development of new sequence methods in the quantification of these metabolites has allowed a better understanding of the Glu/GABA-Gln cycle but data on this field of research remains sparse in BD. Eighty-eight subjects (50 euthymic BD and 38 HC) underwent 3T proton magnetic resonance spectroscopy (1H MRS) in the anterior cingulate cortex (ACC; 2×2×4.5cm(3)) using a two-dimensional JPRESS sequence. GABA, Glutamine (Gln) and Glutamate (Glu) were quantified with the ProFit program. Using image segmentation and known creatine (Cre) concentrations for white and grey matter, metabolite concentrations were calculated for the excited MRS voxel. GABA levels did not differ between groups. Gln level was higher in euthymic BD patients than in healthy controls. The Glu level and Glu/Gln ratio were lower in BD patients than in controls. The use of anticonvulsants was associated with Gln increase but did not affect Glu or Glu/Gln. Neither lithium nor antipsychotic use influenced metabolite levels. The ACC MRS findings indicate that the glutamatergic function in euthymic medicated BD patients is altered relative to controls. Whether this feature is a metabolic signature of euthymic BD subjects should be the focus of future studies.

DORSAL ANTERIOR CINGULATE LACTATE AND GLUTATHIONE LEVELS IN EUTHYMIC BIPOLAR I DISORDER: 1H-MRS STUDY

Objective: Oxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls. Methods: Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm3) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program. Results: Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed. Conclusion: This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis.

Human Variability of fMRI Brain Activation in Response to Oculomotor Stimuli

Assessing interindividual variability of brain activation is of practical importance to the use of functional magnetic resonance imaging (fMRI) in the clinical context. The main objective of this study is to analyze the variability of the oculomotor system through horizontal optokinetic, pursuit and saccadic eye movement stimulations by means of fMRI. We found significant activation of many cortical and subcortical structures. The frequency of activation demonstrates a high variability between subjects. However, the most frequent activation regions were located in frontal areas and in regions comprising the middle temporal and medial superior temporal areas. Our study allowed the characterization of the most frequently involved foci in optokinetic stimulation, pursuit and saccadic eye movement tasks. The combination of these tasks constitutes a suitable tool for mapping major areas involved in the oculomotor system.

Evaluation of different magnetic resonance imaging contrast materials to be used as dummy markers in image-guided brachytherapy for gynecologic malignancies

Objective To identify a contrast material that could be used as a dummy marker for magnetic resonance imaging. Materials and Methods Magnetic resonance images were acquired with six different catheter-filling materials-water, glucose 50%, saline, olive oil, glycerin, and copper sulfate (CuSO4) water solution (2.08 g/L)-inserted into compatible computed tomography/magnetic resonance imaging ring applicators placed in a phantom made of gelatin and CuSO4. The best contrast media were tested in four patients with the applicators in place. Results In T2-weighted sequences, the best contrast was achieved with the CuSO4-filled catheters, followed by saline- and glycerin-filled catheters, which presented poor visualization. In addition (also in T2-weighted sequences), CuSO4 presented better contrast when tested in the phantom than when tested in the patients, in which it provided some contrast but with poor identification of the first dwell position, mainly in the ring. Conclusion We found CuSO4 to be the best solution for visualization of the applicator channels, mainly in T2-weighted images in vitro, although the materials tested presented low signal intensity in the images obtained in vivo, as well as poor precision in determining the first dwell position.

Myoinositol reduction in medial prefrontal cortex of obsessive compulsive disorder: a proton magnetic resonance spectroscopy study

Background: Late Onset Alzheimer’s Disease (LOAD) is one of the most common debilitating causes of dementia worldwide with heritability estimates ranging from 50 – 70%. Genome-wide association studies (GWAS) have identified more than 20 genetic loci in addition to APOEe4 that are associated with increased risk for LOAD. While most of these genes have weak effects, using a polygenic risk profile score (RPS) approach – a method that allows exploration of the influence of the cumulative effect of risk alleles we and others have shown the negative influence of LOAD risk genes on brain structure (Chauhan et al., 2015) and function (Xiao et al., 2015 HBM) even in healthy volunteers. Identifying mechanisms, particularly genetic mechanisms that confer resilience to the detrimental effect of LOAD related risk genes on brain structure and function could provide a viable avenue to identify novel therapeutic targets for LOAD. To that end, in the current study, we explored the role of polymorphisms in the gene encoding Reelin (RELN), a glycoprotein that has been shown to be critical for neuronal development and synaptic plasticity (Kramer et al. 2011), on the detrimental effect of LOAD RPS on hippocampal function. Studies have shown that normal RELN levels are necessary to prevent abnormal phosphorylation of tau (Ohkubo et al., 2003) and beta-amyloidinduced suppression of long term potentiation and NMDA receptors (Durakoglugil et al., 2009). Methods: BOLD functional MRI images (GE 3 T MRI scanner, TR/TE 1⁄4 2000/28ms, flip angle 1⁄4 90 deg, FOV 1⁄4 64x64, 24 axial slices, 170 volumes) were collected for 265 right-handed Caucasian healthy volunteers (116 male, 149 female) from the age of 18 to 86 years (SD 1⁄4 14.17) while they performed a simple declarative memory task (SDMT). Images were motion-corrected, normalized to MNI space, and spatially smoothed (8mm FWHM) using SPM5. Odd’s ratios of 22 independent SNPs, with Po1 10-5 in Hollingworth’s metaanalysis1 comprising four Alzheimer’s disease GWAS datasets (GERAD1, EADI1, TGEN1, ADNI), spanning the regions of ABCA7, APOC4, APOE, BCAM, BCL3, BIN1, C16orf88, CDK1, CEACAM1E, CLPTMI, CLU, CNTN5, CR1, CR2, CUX2, EXOC3L2, IQCK, LRRC68, MS4A4A, MS4A4E, MS4A6A, PICALM, PVR, PVRL2, and TOMM40 genes, were used to calculate the RPS for each individual subject using the approach described by Purcell et al.3. Association between RPS and hippocampal activation during the neutral encoding phase of the SDMT was tested using SPM12. To control for population stratification, 5 MDS components based on 8M SNP genotypes from a GWAS analysis extracted with EIGENSOFT5.01 were included in the analysis as covariates along with age, gender, SNAV, and genotyping batch labels. A region of interest analysis was performed using bilateral hippo-parahippocampal masks from the Anatomical Automatic Labeling Atlas. Influence of RELN on association between LOAD related AD RPS and hippocampal activation was examined separately for five independent Reelin polymorphisms (rs736707, rs362691, rs7341475, rs6943822, and rs4298437.) previously implicated in Alzheimer’s disease or Autism Spectrum Disease using flexible factorial analysis in SPM12. Results: fMRI analysis showed a significant negative correlation between LOAD RPS and hippocampal activation (left: PFWE_corrected 1⁄4 0.005, MNI coordinates x 1⁄4 -39, y 1⁄4 -24, z 1⁄4 -12, right: PFWE_corrected 1⁄4 0.139, Puncorrectedo0.001, MNI coordinates x 1⁄4 39, y 1⁄4 -18, z 1⁄4 -18) during the neutral encoding phase of SDMT. There were no significant positive correlations. In addition, there was a significant interactive effect (left: PFWE_corrected 1⁄4 0.076, MNI coordinates x 1⁄4 -30, y 1⁄4 -30, z 1⁄4 -6, right: PFWE_corrected 1⁄4 0.368, Puncorrected1⁄4 0.002, MNI coordinates x 1⁄4 27, y 1⁄4 -33, z 1⁄4 -9) of rs362691 genotype (a G-C missense variant) and LOAD RPS on activation. Furthermore, in the left hippocampus, minor allele C carriers (N1⁄4 56) showed a significant negative relationship (r1⁄4 -0.47, p1⁄4 0.0002, post-hoc analysis in R) between RPS and hippocampal activation, while the major allele G homozygotes (N1⁄4 208) showed no such relationship (r1⁄4 0.0071, p1⁄4 0.9186). None of the other RELN polymorphisms tested showed a significant effect. Conclusions: Our results, while showing a cumulative deleterious effect of several LOAD related risk genes on hippocampal function in healthy volunteers, also illustrate that this relationship is modulated by a missense SNP (rs362691) in the RELN gene. In particular, only the minor allele C carriers show a significant negative relationship between RPS and hippocampal function suggesting that homozygosity for the G allele in this polymorphism could potentially confer a protective effect.