Biomedical subjects

Christian Beaulieu

Publications and source records attributed to Christian Beaulieu.

At least 19 recordsLinked to original sources

PubMed2007

A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.

The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (DeltaPsim) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.

Animals↗

PubMed2006

Voxel based versus region of interest analysis in diffusion tensor imaging of neurodevelopment.

There are two main methods of quantitative analysis in diffusion tensor imaging (DTI) studies: manual region of interest (ROI) and automated voxel based. The purpose of this study is to compare the results of each of these methods applied to the same data set. Linear correlative analysis was performed for mean diffusivity (Trace/3 ADC) and for fractional anisotropy (FA) versus age within 8-12 years (N = 32) and within 21-27 years (N = 28), as well as a group comparison. SPM analysis identified more structures changing with age, partly due to the limited regions measured with ROI analysis. In general, ROI and voxel-based analysis methods produced comparable results for widespread reductions of Trace/3 ADC and increases of FA with age, particularly for group comparison. The discrepancies (i.e., missed regions) were likely related to problems of spatial normalization for SPM analysis, and masking localized changes by averaging all the voxels within a region of interest for ROI analysis. These two analysis methods for DTI offer complementary results, but neither one yields the complete story of neurodevelopment.

Adult↗

PubMed2006

Anisotropic diffusion of metabolites in peripheral nerve using diffusion weighted magnetic resonance spectroscopy at ultra-high field.

Although the diffusivity and anisotropy of water has been investigated thoroughly in ordered axonal systems (i.e., nervous tissue), there have been very few studies on the directional dependence of diffusion of metabolites. In this study, the mean apparent diffusion coefficient (Trace/3 ADC) and fractional anisotropy (FA) values of the intracellular metabolites N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), choline (Cho), taurine (Tau), and glutamate and glutamine (Glx) were measured parallel and perpendicular to the length of excised frog sciatic nerve using a water suppressed, diffusion-weighted, spin-echo pulse sequence at 18.8T. The degree of anisotropy (FA) of NAA (0.41+/-0.09) was determined to be less than tCr (0.59+/-0.07) and Cho (0.61+/-0.11), which is consistent with previously reported human studies of white matter. In contrast, Glx diffusion was found to be almost isotropic with an FA value of 0.20+/-0.06. The differences of FA between the metabolites is most likely due to their differing micro-environments and could be beneficial as an indicator of compartment specific changes with disease, information not readily available with water diffusion.

Animals↗

PubMed2006

Comparison of multislice and single-slice acquisitions for pulsed arterial spin labeling measurements of cerebral perfusion.

Multislice Q2TIPS is a widely used pulsed arterial spin labeling (PASL) technique for efficient and accurate quantification of cerebral blood flow (CBF). Slices are typically acquired inferior to superior from a tagging plane. Superior slices show signal loss greater than the loss expected from blood T1 decay. In order to assess the reasons for this additional signal loss, three single-slice acquisition studies were compared to multislice acquisition (six slices) in healthy volunteers. In Study 1 (n=8), the tagging plane was fixed in location, and the inversion time (TI2) was 1500 ms for each slice. For Study 2 (n=12), the tagging plane was fixed as in Study 1; however, TI2 increased as slices were acquired further from the tagging plane. In Study 3 (n=9), the tagging plane was kept adjacent to the imaging slice, and TI2 was 1500 ms for every slice. Gray matter (GM) and white matter (WM) signal-to-noise ratio (SNR) and CBF were measured per slice. GM SNR from single-slice acquisitions was significantly higher at slices 4-6 in Study 2 and at slices 2-6 in Study 3 compared to multislice acquisitions. Signal loss in distal slices of multislice acquisitions can be attributed to the destruction of tagged bolus in addition to blood T1 decay. If limited brain coverage is acceptable, perfusion images with greater SNR are achievable with limited slices and placement of the tagging region immediately adjacent to the site of interest.

Adult↗

PubMed2006

Diffusion tensor imaging of time-dependent axonal and myelin degradation after corpus callosotomy in epilepsy patients.

Axonal degeneration of white matter fibers is a key consequence of neuronal or axonal injury. It is characterized by a series of time-related events with initial axonal membrane collapse followed by myelin degradation being its major hallmarks. Standard imaging cannot differentiate these phenomena, which would be useful for clinical investigations of degeneration, regeneration and plasticity. Animal models suggest that diffusion tensor magnetic resonance imaging (DTI) is capable of making such distinction. The applicability of this technique in humans would permit inferences on white matter microanatomy using a non-invasive technique. The surgical bisection of the anterior 2/3 of the corpus callosum for the palliative treatment of certain types of epilepsy serves as a unique opportunity to assess this method in humans. DTI was performed on three epilepsy patients before corpus callosotomy and at two time points (1 week and 2-4 months) after surgery. Tractography was used to define voxels of interest for analysis of mean diffusivity, fractional anisotropy and eigenvalues. Diffusion anisotropy was reduced in a spatially dependent manner in the genu and body of the corpus callosum at 1 week and remained low 2-4 months after the surgery. Decreased anisotropy at 1 week was due to a reduction in parallel diffusivity (consistent with axonal fragmentation), whereas at 2-4 months, it was due to an increase in perpendicular diffusivity (consistent with myelin degradation). DTI is capable of non-invasively detecting, staging and following the microstructural degradation of white matter following axonal injury.

Adult↗

PubMed2006

The relationship between diffusion anisotropy and time of onset after stroke.

Diffusion anisotropy changes in stroke lesions less than 24 h after onset have been reported to be elevated, decreased, or both. To address these mixed findings, we sought to characterize temporal changes of diffusion anisotropy by analyzing anatomically distinct ischemic white matter (WM) regions at 3 time phases within the first 34 h of ischemic stroke onset in 26 stroke patients (2 to 5 h, N=7; 7 to 14 h, N=11; 18 to 34 h, N=8). Mean diffusivity (Trace/3 apparent diffusion coefficient (ADC)), fractional anisotropy (FA), and T2-weighted signal intensity were measured for major and subcortical WM in lesions defined by a >or=30% drop in Trace/3 ADC. Major WM tract lesions with mean decreases of approximately 40% in relative (r) Trace/3 ADC showed an increased rFA of 1.11+/-0.18 (P<0.01) during the hyperacute phase (2 to 5 h), whereas rFA declined to 0.90+/-0.20 (P<0.01) and 0.88+/-0.12 (P<0.01) in the acute (7 to 14 h) and subacute (18 to 34 h) phases, respectively. Of those patients with lesions in major WM, 4 of 8 patients <or=7 h showed elevated rFA as opposed to none of the remaining 13 patients after 7 h. A greater proportion of the evaluated WM regions-of-interest (ROI) in the hyperacute phase revealed increases in rFA (60%), whereas conversely large proportions of ROIs (55% and 59%) in the acute and subacute phases showed reduced rFA. Similar anisotropy changes were noted in subcortical WM regions in the gyri.

Adult↗

PubMed2006

Pulsed arterial spin labeling parameter optimization for an elderly population.

PURPOSE: To optimize pulsed arterial spin labeling (PASL) parameters for the elderly to take into account possible perfusion changes that occur in the brain with age. MATERIALS AND METHODS: Healthy young (N = 14, age range = 21-27 years) and elderly (N = 12, age range = 61-67 years) subjects were scanned using Q2TIPS (QUIPSS II with thin-slice TI, periodic saturation) with varying inversion times (TI(2)) at 1.5T. The difference signal (DeltaM), transit time (deltat), and cerebral blood flow (CBF) were calculated in segmented gray matter (GM). RESULTS: The young displayed more perfusion-weighted signal difference than the elderly at all TI(2)'s. The peak DeltaM occurred at TI(2) approximately 1300 msec and 1500 msec in the young and elderly groups, respectively. Qualitatively, intravascular signal was minimal in the younger group by TI(2) = 1500 msec, whereas a longer TI(2) of 1800 msec was needed to minimize this signal in the elderly. The transit time was approximately 100 msec longer in the elderly, and CBF was in the range of literature values. CONCLUSION: For acquiring perfusion-weighted images with minimal intravascular signal and adequate tissue signal for PASL studies of cerebral perfusion in the elderly, a longer inversion time is advantageous.

Adult↗

PubMed2006

Diffusion tensor spectroscopy (DTS) of human brain.

The diffusion tensor of N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), and choline (Cho) was measured at 3T using a diffusion weighted STEAM (1)H-MRS sequence in the healthy human brain in 6 distinct regions (4 white matter and 2 cortical gray matter). The Trace/3 apparent diffusion coefficient (ADC) of each metabolite was significantly greater in white matter than gray matter. The Trace/3 ADC values of tCr and Cho were found to be significantly greater than NAA in white matter, whereas all 3 metabolites had similar Trace/3 ADC in cortical gray matter. Fractional anisotropy (FA) values for all 3 metabolites were consistent with water FA values in the 4 white matter regions; however, metabolite FA values were found to be higher than expected in the cortical gray matter. The principal diffusion direction derived for NAA was in good agreement with expected anatomic tract directions in the white matter.

Adolescent↗

PubMed2006

Extratemporal white matter abnormalities in mesial temporal lobe epilepsy demonstrated with diffusion tensor imaging.

PURPOSE: Recent studies have demonstrated bilateral white matter abnormalities in temporal lobe epilepsy (TLE) patients with unilateral mesial temporal sclerosis (MTS). The purpose of this project was to determine whether abnormalities of water diffusion are seen in extratemporal white matter of patients with TLE and pathologically confirmed MTS and to determine whether these findings are associated with worse surgical outcome. METHODS: Eleven patients with TLE and unilateral MTS confirmed in surgical specimens and 14 controls were studied by using cerebrospinal fluid-suppressed diffusion tensor imaging (DTI) and T2 relaxometry. RESULTS: Hippocampal T2 signal for patients was significantly elevated both ipsilateral (p<0.001) and contralateral (p=0.006) to MTS. DTI demonstrated reduced fractional anisotropy of the genu of the corpus callosum (p=0.003) and external capsule (p=0.02) and elevated mean diffusivity of the genu (p=0.005), splenium (p=0.03), and external capsule (p<0.001). For both the genu and external capsule, parallel diffusion of patients was not different from that of controls (genu, p=0.81; external capsule, p=0.45), whereas perpendicular diffusion was elevated (genu, p=0.001; external capsule, p<0.001). With mean postsurgical follow-up of 18.5 months, eight of 11 patients were entirely seizure free and the remaining three had all experienced a worthwhile reduction in seizure frequency. CONCLUSIONS: Our findings suggest that although patients with TLE and MTS have extensive bilateral and extratemporal pathology, these findings may not be associated with a worse postsurgical outcome.

Adult↗

PubMed2005

Diffusion tensor imaging of neurodevelopment in children and young adults.

Diffusion tensor magnetic resonance imaging (DTI) was used to study regional changes in the brain's development from childhood (8-12 years, mean 11.1 +/- 1.3, N = 32) to young adulthood (21-27 years, mean 24.4 +/- 1.8, N = 28). Mean diffusivity (Trace/3 apparent diffusion coefficient, ADC) and fractional anisotropy (FA) were measured in 30 regions of interest (ROIs) in 13 distinct brain structures. Correlational analysis was performed to detect changes within 8-12 years and within 21-27 years, and group analysis to compare childhood diffusion properties with young adult values. Increases of fractional anisotropy were seen in the genu of the corpus callosum, splenium of the corpus callosum, corona radiata, putamen, and head of the caudate nucleus within 8-12 years, and also between childhood and young adulthood. Reductions in Trace/3 ADC were observed in 9 of 13 structures within 8-12 years and into young adulthood as well. DTI demonstrates more widespread changes in the brain's microstructure with maturation than previous reports using conventional T1-weighted MRI scans. These findings suggest a continuation of the brain's microstructural development through adolescence.

Adult↗

PubMed2005

Imaging brain connectivity in children with diverse reading ability.

Reading is a complex cognitive skill that requires the coordination of multiple brain regions. Although functional neuroimaging studies highlight the cortical brain regions associated with a specific cognitive task like reading, they do not directly address the underlying neural connections necessary for efficient performance of this task. Adults with reading disability have demonstrated lower regional white matter connectivity, but it is not known whether this relationship between neuronal wiring and reading performance also holds in younger readers. Using diffusion tensor magnetic resonance imaging (DTI) that highlights the structural integrity of the brain wiring, we show that regional brain connectivity in the left temporo-parietal white matter correlates with a wide range of reading ability in children as young as 8-12 years old. Diffusion tensor tractography suggests that the posterior limb of the internal capsule is consistent with the location of the largest cluster of correlation between reading ability (Word Identification subtest) and fractional anisotropy. The maturation of the white matter may play a key role in the development of cognitive processes such as reading.

Anisotropy↗

PubMed2005

Identification of a potent and selective synthetic agonist at the CRTH2 receptor.

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor whose function in vivo has been incompletely characterized. One of the reasons is that its current known ligands, prostaglandin D(2) and some of its metabolites, have either poor selectivity for CRTH2 or are metabolically unstable in vivo. In this study, we describe the biological and pharmacological properties of L-888,607, the first synthetic potent and selective CRTH2 agonist. We show that L-888,607 exhibits 1) subnanomolar affinity for the human CRTH2 receptor, 2) high selectivity over all other prostanoid receptors and other receptors tested, 3) agonistic activity on recombinant and endogenously expressed CRTH2 receptor, and 4) relative stability in vivo. L-888,607 thus represents a suitable tool to investigate the in vivo function of CRTH2.

Acetates↗

PubMed2005

Bilateral limbic diffusion abnormalities in unilateral temporal lobe epilepsy.

Diffusion tensor magnetic resonance imaging can acquire quantitative information on the microstructural integrity of white matter structures and depict brain connectivity in vivo based on the behavior of water diffusion. Diffusion tensor imaging-derived tractography has been used for virtual dissection of the fornix and cingulum in healthy subjects, but not in patients with temporal lobe epilepsy (TLE). Eight patients with medically intractable TLE and unilateral mesial temporal sclerosis and nine healthy control subjects were imaged using diffusion tensor imaging. Fiber tracking was performed to delineate the fornix and cingulum, which were quantitatively analyzed. Bilateral symmetrical reduction in fractional anisotropy was observed in the fornix of patients with TLE, together with an increase in water mobility perpendicular to the axis of the fibers. The findings in the cingulum are similar to those of the fornix with the exception of significantly increased bulk diffusivity in the latter. We observed strikingly symmetrical bilateral abnormalities of axonal integrity in the fornix and cingulum in a series of patients with unilateral mesial temporal sclerosis. Our findings suggest that TLE with unilateral mesial temporal sclerosis is associated with bilateral limbic system pathology.

Adult↗

PubMed2005

Trace apparent diffusion coefficients of metabolites in human brain using diffusion weighted magnetic resonance spectroscopy.

The rotationally invariant trace/3 apparent diffusion coefficients (ADC) of N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), and choline (Cho) were determined using a diffusion-weighted stimulated echo acquisition mode sequence at 3 T in three separate human brain regions, namely the subcortical white matter, occipital gray matter, and frontal gray matter. The measurement of the mean diffusivity eliminates the dependence of the measured ADC on the direction of the diffusion gradient relative to the tissue microstructure (i.e., anisotropy). Macroscopic brain motions induce phase errors that were compensated for by phasing (zero and first order) on the single average spectrum (zero order on the NAA peak) prior to summing the individual spectra. This method yielded reproducible trace/3 ADC values in the expected range without the use of cardiac gating. The mean diffusivity of NAA (0.14 +/- 0.03 x 10(-3) mm(2)/s) appears to be less than that of tCr (0.17 +/- 0.04 x 10(-3) mm(2)/s) and Cho (0.18 +/- 0.05 x 10(-3) mm(2)/s) in human brain.

Anisotropy↗

PubMed2005

In vivo sodium magnetic resonance imaging of the human brain using soft inversion recovery fluid attenuation.

Sodium imaging with soft inversion recovery fluid attenuation, which may be advantageous for intracellular weighting, was demonstrated with cerebrospinal fluid (CSF) suppression in five healthy volunteers at 4.7 T. Long rectangular inversion pulses reduce the average power deposition in an inversion recovery sequence, allowing repetition time to be shortened and more averages acquired for a given scan length. Longer pulses also significantly reduce the "depth" of Mz inversion in environments with rapid T1 and T2 relaxation (i.e., brain relative to CSF). Phantom experiments and simulation show a marked SNR increase when using a 10-ms, rather than a 1-ms, rectangular inversion pulse. Images were acquired in 11.1 min with a voxel size of 0.25 cm3 and the SNR in CSF, which is typically approximately 3 times larger than in brain, was reduced to 23% of that in the brain tissue, which had an average SNR of 17.

Algorithms↗

PubMed2005

Diffusion tensor imaging abnormalities in focal cortical dysplasia.

PURPOSE: Focal cortical dysplasia (FCD) is one of the most common underlying pathologic substrates in patients with medically intractable epilepsy. While magnetic resonance imaging (MRI) evidence of FCD is an important predictor of good surgical outcome, conventional MRI is not sensitive enough to detect all lesions. Previous reports of diffusion tensor imaging (DTI) abnormalities in FCD suggest the potential of DTI in the detection of FCD. The purpose of this study was to study subcortical white matter underlying small lesions of FCD using DTI. METHODS: Five patients with medically intractable epilepsy and FCD were investigated. Diffusion tensor imaging images were acquired (20 contiguous 3 mm thick axial slices) with maps of fractional anisotropy (FA), trace apparent diffusion coefficient (trace/3 ADC), and principal eigenvalues (ADC parallel and ADC perpendicular to white matter tracts) being calculated for each slice. Region of interest analysis was used to compare subcortical white matter ipsilateral and contralateral to the lesion. RESULTS: Three subjects with FCD associated with underlying white matter hyperintensities on T2 weighted MRI were observed to have increased trace/3 ADC, reduced fractional anisotropy and increased perpendicular water diffusivity which was greater than the relative increase in the parallel diffusivity. No DTI abnormalities were identified in two patients with FCD without white matter hyperintensities on conventional T2-weighted MRI. CONCLUSIONS: While DTI abnormalities in FCD with obvious white matter involvement are consistent with micro-structural degradation of the underlying subcortical white matter, DTI changes were not identified in FCD lesions with normal appearing white matter.

Adolescent↗

PubMed2005

Diffusion tensor tractography of the limbic system.

BACKGROUND AND PURPOSE: The limbic system, relevant to memory and emotion, is an interesting subject of study in healthy and diseased individuals. It consists of a network of gray matter structures interconnected by white matter fibers. Although gray matter components of this system have been studied by using MR imaging, the connecting fibers have not been analyzed to the same degree. Cerebrospinal fluid (CSF) signal intensity contamination of the fornix and cingulum, the 2 major white matter tracts of the limbic system, can alter diffusion-tensor imaging (DTI) measurements and affect tractography. We investigated the effect of CSF signal intensity suppression on fiber tracking of the limbic connections and characterized the diffusion properties of these structures in healthy volunteers. METHODS: Nine healthy individuals were scanned with standard and CSF-suppressed DTI. Tractography of the fornix and cingulum was performed for both acquisition methods. We report mean diffusivity and fractional anisotropy measurements of the crus, body, and columns of the fornix, and descending, superior, and anterior portions of the cingulum. RESULTS: Diffusion measurements were improved and tractography was facilitated by using CSF-suppressed DTI. In particular, tract volume increased, whereas decreases of the mean diffusivity and increases of diffusion anisotropy more accurately represented the underlying tissue by minimizing deleterious partial volume averaging from CSF. This was particularly true for the fornix because it is in closest contact to CSF. Diffusion measurements throughout the limbic connections were consistent in healthy volunteers. CONCLUSION: We recommend the use of CSF suppression when performing diffusion-tensor tractography of the limbic system.

Adult↗

PubMed2004

p-Menthane-3-carboxaldehyde: a useful chiral auxiliary for the synthesis of chiral quaternary carbons of high enantiomeric purity.

(+)- or (-)-p-Menthane-3-carboxaldehyde is made in two easy steps from (+)- or (-)-menthone, respectively. This auxiliary allows for the synthesis of carbonyl compounds bearing a alpha-chiral quaternary carbon. The flexibility, efficiency, and ease of use of the method are demonstrated in a series of examples, which include the total synthesis of (+)-cuparenone as well as a partial synthesis of (-)-cassiol.

Aldehydes↗