Predicting clinical scores from magnetic resonance scans in Alzheimer's disease.

Machine learning and pattern recognition methods have been used to diagnose Alzheimer's disease (AD) and mild cognitive impairment (MCI) from individual MRI scans. Another application of such methods is to predict clinical scores from individual scans. Using relevance vector regression (RVR), we predicted individuals' performances on established tests from their MRI T1 weighted image in two independent data sets. From Mayo Clinic, 73 probable AD patients and 91 cognitively normal (CN) controls completed the Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), and Auditory Verbal Learning Test (AVLT) within 3months of their scan. Baseline MRI's from the Alzheimer's disease Neuroimaging Initiative (ADNI) comprised the other data set; 113 AD, 351 MCI, and 122 CN subjects completed the MMSE and Alzheimer's Disease Assessment Scale-Cognitive subtest (ADAS-cog) and 39 AD, 92 MCI, and 32 CN ADNI subjects completed MMSE, ADAS-cog, and AVLT. Predicted and actual clinical scores were highly correlated for the MMSE, DRS, and ADAS-cog tests (P<0.0001). Training with one data set and testing with another demonstrated stability between data sets. DRS, MMSE, and ADAS-Cog correlated better than AVLT with whole brain grey matter changes associated with AD. This result underscores their utility for screening and tracking disease. RVR offers a novel way to measure interactions between structural changes and neuropsychological tests beyond that of univariate methods. In clinical practice, we envision using RVR to aid in diagnosis and predict clinical outcome.

Increased plasma levels of N-terminal brain natriuretic peptide (NT-proBNP) in type 2 diabetic patients with vascular complications

Résumé : Les concentrations plasmatiques du peptide natriurétique de type B sont augmentées chez les diabétiques de type 2 atteints de complications vasculaires. But : Les concentrations plasmatiques du peptide natriurétique de type B (NT-proBNP) sont augmentées chez les diabétiques de type 2 atteints de complications vasculaires. Les concentrations plasmatiques du peptide natriurétique de type B (BNP), ou de sa pro-hormone (NT-proBNP), sont reconnues depuis peu comme marqueur de choix de la dysfonction cardiaque. Les diabétiques de type 2 sont à haut risque de développer des complications cardiovasculaires. L'objectif de cette étude a été de déterminer si les concentrations plasmatiques de NT-proBNP étaient comparables chez des diabétiques de type 2 avec ou sans complications vasculaires. Méthodes : Nous avons mesuré le NT-proBNP plasmatique chez 54 diabétiques de type 2, 27 sans complications micro- ou macrovasculaires et 27 présentant des complications soit micro- soit macrovasculaires, soit les deux. Le même dosage a été effectué chez 38 témoins sains, appariés pour l'âge et le sexe avec les diabétiques. Résultat : Le NT-proBNP plasmatique était plus élevé chez les diabétiques avec complications (médiane 121 pg/ml, intervalle interquartile 50-240 pg/ml) que chez ceux sans complications (37 pg/ml, 21-54 pg/ml, P < 0,01). Comparés au groupe témoin (55 pg/ml, 40-79 pg/ml), seuls les diabétiques avec complications vasculaires avaient un NT-proBNP plasmatique significativement augmenté (P < 0,001). Chez les diabétiques la maladie coronarienne et la néphropathie (définie selon l'excrétion urinaire d'albumine) étaient chacune associée de façon indépendante avec une augmentation des concentrations plasmatiques de NT-proBNP. Conclusion : Chez les diabétiques de type 2 souffrant de complications micro- ou macrovasculaires, les concentrations plasmatiques de NT-proBNP sont augmentées par rapport à celles des malades indemnes de complications vasculaires. L'augmentation de sécrétion de ce peptide est associée de façon indépendante avec la maladie coronarienne et la néphropathie. La mesure du NT-proBNP plasmatique pourrait donc être utile pour dépister la présence de complications micro- ou macrovasculaires.

Breathhold three-dimensional coronary magnetic resonance angiography using real-time navigator technology.

The acquisition duration of most three-dimensional (3D) coronary magnetic resonance angiography (MRA) techniques is considerably prolonged, thereby precluding breathholding as a mechanism to suppress respiratory motion artifacts. Splitting the acquired 3D volume into multiple subvolumes or slabs serves to shorten individual breathhold duration. Still, problems associated with misregistration due to inconsistent depths of expiration and diaphragmatic drift during sustained respiration remain to be resolved. We propose the combination of an ultrafast 3D coronary MRA imaging sequence with prospective real-time navigator technology, which allows correction of the measured volume position. 3D volume splitting using prospective real-time navigator technology, was successfully applied for 3D coronary MRA in five healthy individuals. An ultrafast 3D interleaved hybrid gradient-echoplanar imaging sequence, including T2Prep for contrast enhancement, was used with the navigator localized at the basal anterior wall of the left ventricle. A 9-cm-thick volume, with in-plane spatial resolution of 1.1 x 2.2 mm, was acquired during five breathholds of 15-sec duration each. Consistently, no evidence of misregistration was observed in the images. Extensive contiguous segments of the left anterior descending coronary artery (48 +/- 18 mm) and the right coronary artery (75 +/- 5 mm) could be visualized. This technique has the potential for screening for anomalous coronary arteries, making it well suited as part of a larger clinical MR examination. In addition, this technique may also be applied as a scout scan, which allows an accurate definition of imaging planes for subsequent high-resolution coronary MRA.

In-vivo magnetic resonance imaging of the structural core of the Papez circuit in humans.

Papez circuit is one of the major pathways of the limbic system, and it is involved in the control of memory and emotion. Structural and functional alterations have been reported in psychiatric, neurodegenerative, and epileptic diseases. Despite the clinical interest, however, in-vivo imaging of the entire circuit remains a technological challenge. We used magnetic resonance diffusion spectrum imaging to comprehensively picture the Papez circuit in healthy humans: (i) the hippocampus-mammillary body pathway, (ii) the connections between the lateral subiculum and the cingulate cortex, and (iii) the mammillo-thalamic tract. The diagnostic and therapeutic implications of these results are discussed in the context of recent findings reporting the involvement of the Papez circuit in neurological and psychiatric diseases.

Usefulness of methadone plasma concentration measurement in patients receiving nevirapine or efavirenz.

Objective: To determine methadone plasma trough and peak concentrations in patients presenting opiate withdrawal symptoms after introduction of nevirapine or efavirenz. To describe the disappearance of these symptoms after methadone titration based on plasma concentrations rather than on the symptoms. Methods: Nine patients undergoing highly active antiretroviral therapy (HAART) and either nevirapine or efavirenz treatment were monitored daily for opiate withdrawal in a specialized drug addiction center. Methadone dose was titrated daily, and plasma concentrations were measured. The data are retrospective (case series). Results: Several patients complained of symptoms such as nausea, vomiting, accelerated intestinal transit, or insomnia. Even after methadone titration based on clinical symptoms, patients and health-care providers trained in infectious disease did not classify these as withdrawal symptoms and considered them as the side effects of HAART or anxiety. Methadone plasma trough concentration showed low levels of (R)- and (R,S)-methadone. Further methadone dose adjustment according to plasma level resulted in the disappearance of these withdrawal symptoms. The daily methadone dose was split when the peak/trough (R)-methadone ratio was more than 2. Conclusions: When introducing efavirenz or nevirapine to patients undergoing methadone treatment, withdrawal symptoms should be monitored, especially those such as insomnia, vomiting, or nausea. Methadone plasma trough and peak measurements can be of value in preventing unnecessary side effects of HAART.

The GTPase RalA regulates different steps of the secretory process in pancreatic beta-cells.

BACKGROUND: RalA and RalB are multifuntional GTPases involved in a variety of cellular processes including proliferation, oncogenic transformation and membrane trafficking. Here we investigated the mechanisms leading to activation of Ral proteins in pancreatic beta-cells and analyzed the impact on different steps of the insulin-secretory process. METHODOLOGY/PRINCIPAL FINDINGS: We found that RalA is the predominant isoform expressed in pancreatic islets and insulin-secreting cell lines. Silencing of this GTPase in INS-1E cells by RNA interference led to a decrease in secretagogue-induced insulin release. Real-time measurements by fluorescence resonance energy transfer revealed that RalA activation in response to secretagogues occurs within 3-5 min and reaches a plateau after 10-15 min. The activation of the GTPase is triggered by increases in intracellular Ca2+ and cAMP and is prevented by the L-type voltage-gated Ca2+ channel blocker Nifedipine and by the protein kinase A inhibitor H89. Defective insulin release in cells lacking RalA is associated with a decrease in the secretory granules docked at the plasma membrane detected by Total Internal Reflection Fluorescence microscopy and with a strong impairment in Phospholipase D1 activation in response to secretagogues. RalA was found to be activated by RalGDS and to be severely hampered upon silencing of this GDP/GTP exchange factor. Accordingly, INS-1E cells lacking RalGDS displayed a reduction in hormone secretion induced by secretagogues and in the number of insulin-containing granules docked at the plasma membrane. CONCLUSIONS/SIGNIFICANCE: Taken together, our data indicate that RalA activation elicited by the exchange factor RalGDS in response to a rise in intracellular Ca2+ and cAMP controls hormone release from pancreatic beta-cell by coordinating the execution of different events in the secretory pathway.

EuroCMR (European Cardiovascular Magnetic Resonance) registry: results of the German pilot phase.

OBJECTIVES: During its German pilot phase, the EuroCMR (European Cardiovascular Magnetic Resonance) registry sought to evaluate indications, image quality, safety, and impact on patient management of routine CMR. BACKGROUND: CMR has a broad range of applications and is increasingly used in clinical practice. METHODS: This was a multicenter registry with consecutive enrollment of patients in 20 German centers. RESULTS: A total of 11,040 consecutive patients were enrolled. Eighty-eight percent of patients received gadolinium-based contrast agents. Twenty-one percent underwent adenosine perfusion, and 11% high-dose dobutamine-stress CMR. The most important indications were workup of myocarditis/cardiomyopathies (32%), risk stratification in suspected coronary artery disease/ischemia (31%), as well as assessment of viability (15%). Image quality was good in 90.1%, moderate in 8.1%, and inadequate in 1.8% of cases. Severe complications occurred in 0.05%, and were all associated with stress testing. No patient died during or due to CMR. In nearly two-thirds of patients, CMR findings impacted patient management. Importantly, in 16% of cases the final diagnosis based on CMR was different from the diagnosis before CMR, leading to a complete change in management. In more than 86% of cases, CMR was capable of satisfying all imaging needs so that no further imaging was required. CONCLUSIONS: CMR is frequently performed in clinical practice in many participating centers. The most important indications are workup of myocarditis/cardiomyopathies, risk stratification in suspected coronary artery disease/ischemia, and assessment of viability. CMR imaging as used in the centers of the pilot registry is a safe procedure, has diagnostic image quality in 98% of cases, and its results have strong impact on patient management.

Effect of sodium loading/depletion on renal oxygenation in young normotensive and hypertensive men.

The goal of this study was to investigate the effect of sodium intake on renal tissue oxygenation in humans. To this purpose, we measured renal hemodynamics, renal sodium handling, and renal oxygenation in normotensive (NT) and hypertensive (HT) subjects after 1 week of a high-sodium and 1 week of a low-sodium diet. Renal oxygenation was measured using blood oxygen level-dependent magnetic resonance. Tissue oxygenation was determined by the measurement of R2* maps on 4 coronal slices covering both kidneys. The mean R2* values in the medulla and cortex were calculated, with a low R2* indicating a high tissue oxygenation. Ten male NT (mean age: 26.5+/-7.4 years) and 8 matched HT subjects (mean age: 28.8+/-5.7 years) were studied. Cortical R2* was not different under the 2 conditions of salt intake. Medullary R2* was significantly lower under low sodium than high sodium in both NT and HT subjects (28.1+/-0.8 versus 31.3+/-0.6 s(-1); P<0.05 in NT; and 27.9+/-1.5 versus 30.3+/-0.8 s(-1); P<0.05, in HT), indicating higher medullary oxygenation under low-sodium conditions. In NT subjects, medullary oxygenation was positively correlated with proximal reabsorption of sodium and negatively with absolute distal sodium reabsorption, but not with renal plasma flow. In HT subjects, medullary oxygenation correlated with the 24-hour sodium excretion but not with proximal or with the distal handling of sodium. These data demonstrate that dietary sodium intake influences renal tissue oxygenation, low sodium intake leading to an increased renal medullary oxygenation both in normotensive and young hypertensive subjects.

Activity assays and immunoassays for plasma Renin and prorenin: information provided and precautions necessary for accurate measurement.

BACKGROUND: Measurement of plasma renin is important for the clinical assessment of hypertensive patients. The most common methods for measuring plasma renin are the plasma renin activity (PRA) assay and the renin immunoassay. The clinical application of renin inhibitor therapy has thrown into focus the differences in information provided by activity assays and immunoassays for renin and prorenin measurement and has drawn attention to the need for precautions to ensure their accurate measurement. CONTENT: Renin activity assays and immunoassays provide related but different information. Whereas activity assays measure only active renin, immunoassays measure both active and inhibited renin. Particular care must be taken in the collection and processing of blood samples and in the performance of these assays to avoid errors in renin measurement. Both activity assays and immunoassays are susceptible to renin overestimation due to prorenin activation. In addition, activity assays performed with peptidase inhibitors may overestimate the degree of inhibition of PRA by renin inhibitor therapy. Moreover, immunoassays may overestimate the reactive increase in plasma renin concentration in response to renin inhibitor therapy, owing to the inhibitor promoting conversion of prorenin to an open conformation that is recognized by renin immunoassays. CONCLUSIONS: The successful application of renin assays to patient care requires that the clinician and the clinical chemist understand the information provided by these assays and of the precautions necessary to ensure their accuracy.

Simultaneous determination of plasma levels of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric method is presented which allows the simultaneous determination of the plasma concentrations of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine after derivatization with the chiral reagent, (S)-(-)-N-trifluoroacetylprolyl chloride. No interference was observed from endogenous compounds following the extraction of plasma samples from six different human subjects. The standard curves were linear over a working range of 10 to 750 ng/ml for racemic fluoxetine and norfluoxetine and of 50 to 500 ng/ml for fluvoxamine. Recoveries ranged from 50 to 66% for the three compounds. Intra- and inter-day coefficients of variation ranged from 4 to 10% for fluvoxamine and from 4 to 13% for fluoxetine and norfluoxetine. The limits of quantitation of the method were found to be 2 ng/ml for fluvoxamine and 1 ng/ml for the (R)- and (S)-enantiomers of fluoxetine and norfluoxetine, hence allowing its use for single dose pharmacokinetics. Finally, by using a steeper gradient of temperature, much shorter analysis times are obtained if one is interested in the concentrations of fluvoxamine alone.

Clinical consequences of imatinib plasma concentrations variability in hemato-oncologic patients

Background: Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Considering the large inter-individual differences in the function of the systems involved in its disposition, exposure to imatinib can be expected to vary widely among patients. This observational study aimed at describing imatinib pharmacokinetic variability and its relationship with various biological covariates, especially plasma alpha1-acid glycoprotein (AGP), and at exploring the concentration-response relationship in patients. Methods: A population pharmacokinetic model (NONMEM) including 321 plasma samples from 59 patients was built up and used to derive individual post-hoc Bayesian estimates of drug exposure (AUC; area under curve). Associations between AUC and therapeutic response or tolerability were explored by ordered logistic regression. Influence of the target genotype (i.e. KIT mutation profile) on response was also assessed in GIST patients. Results: A one-compartment model with first-order absorption appropriately described the data, with an average oral clearance of 14.3 L/h (CL) and volume of distribution of 347 L (Vd). A large inter-individual variability remained unexplained, both on CL (36%) and Vd (63%), but AGP levels proved to have a marked impact on total imatinib disposition. Moreover, both total and free AUC correlated with the occurrence and number of side effects (e.g. OR 2.9±0.6 for a 2-fold free AUC increase; p<0.001). Furthermore, in GIST patients, higher free AUC predicted a higher probability of therapeutic response (OR 1.9±0.5; p<0.05), notably in patients with tumor harboring an exon 9 mutation or wild-type KIT, known to decrease tumor sensitivity towards imatinib. Conclusion: The large pharmacokinetic variability, associated to the pharmacokinetic-pharmacodynamic relationship uncovered are arguments to further investigate the usefulness of individualizing imatinib prescription based on TDM. For this type of drug, it should ideally take into consideration either circulating AGP concentrations or free drug levels, as well as KIT genotype for GIST.

Spatially selective implementation of the adiabatic T2 prep sequence for magnetic resonance angiography of the coronary arteries.

In coronary magnetic resonance angiography, a magnetization-preparation scheme for T2 -weighting (T2 Prep) is widely used to enhance contrast between the coronary blood-pool and the myocardium. This prepulse is commonly applied without spatial selection to minimize flow sensitivity, but the nonselective implementation results in a reduced magnetization of the in-flowing blood and a related penalty in signal-to-noise ratio. It is hypothesized that a spatially selective T2 Prep would leave the magnetization of blood outside the T2 Prep volume unaffected and thereby lower the signal-to-noise ratio penalty. To test this hypothesis, a spatially selective T2 Prep was implemented where the user could freely adjust angulation and position of the T2 Prep slab to avoid covering the ventricular blood-pool and saturating the in-flowing spins. A time gap of 150 ms was further added between the T2 Prep and other prepulses to allow for in-flow of a larger volume of unsaturated spins. Consistent with numerical simulation, the spatially selective T2 Prep increased in vivo human coronary artery signal-to-noise ratio (42.3 ± 2.9 vs. 31.4 ± 2.2, n = 22, P < 0.0001) and contrast-to-noise-ratio (18.6 ± 1.5 vs. 13.9 ± 1.2, P = 0.009) as compared to those of the nonselective T2 Prep. Additionally, a segmental analysis demonstrated that the spatially selective T2 Prep was most beneficial in proximal and mid segments where the in-flowing blood volume was largest compared to the distal segments. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Early detection of idiopathic Parkinson's disease based on magnetic resonance imaging

The diagnosis of idiopathic Parkinson's disease (IPD) is entirely clinical. The fact that neuronal damage begins 5-10 years before occurrence of sub-clinical signs, underlines the importance of preclinical diagnosis. A new approach for in-vivo pathophysiological assessment of IPD-related neurodegeneration was implemented based on recently developed neuroimaging methods. It is based on non- invasive magnetic resonance data sensitive to brain tissue property changes that precede macroscopic atrophy in the early stages of IPD. This research aims to determine the brain tissue property changes induced by neurodegeneration that can be linked to clinical phenotypes which will allow us to create a predictive model for early diagnosis in IPD. We hypothesized that the degree of disease progression in IPD patients will have a differential and specific impact on brain tissue properties used to create a predictive model of motor and non-motor impairment in IPD. We studied the potential of in-vivo quantitative imaging sensitive to neurodegeneration- related brain tissue characteristics to detect changes in patients with IPD. We carried out methodological work within the well established SPM8 framework to estimate the sensitivity of tissue probability maps for automated tissue classification for detection of early IPD. We performed whole-brain multi parameter mapping at high resolution followed by voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) comparing healthy subjects to IPD patients. We found a trend demonstrating non-significant tissue property changes in the olfactory bulb area using the MT and R1 parameter with p<0.001. Comparing to the IPD patients, the healthy group presented a bilateral higher MT and R1 intensity in this specific functional region. These results did not correlate with age, severity or duration of disease. We failed to demonstrate any changes with the R2* parameter. We interpreted our findings as demyelination of the olfactory tract, which is clinically represented as anosmia. However, the lack of correlation with duration or severity complicates its implications in the creation of a predictive model of impairment in IPD.