Showing papers by "Paulo Loureiro de Sousa published in 2016"

Skeletal Muscle Quantitative Nuclear Magnetic Resonance Imaging and Spectroscopy as an Outcome Measure for Clinical Trials.

Abstract: Recent years have seen tremendous progress towards therapy of many previously incurable neuromuscular diseases. This new context has acted as a driving force for the development of novel non-invasive outcome measures. These can be organized in three main categories: functional tools, fluid biomarkers and imagery. In the latest category, nuclear magnetic resonance imaging (NMRI) offers a considerable range of possibilities for the characterization of skeletal muscle composition, function and metabolism. Nowadays, three NMR outcome measures are frequently integrated in clinical research protocols. They are: 1/ the muscle cross sectional area or volume, 2/ the percentage of intramuscular fat and 3/ the muscle water T2, which quantity muscle trophicity, chronic fatty degenerative changes and oedema (or more broadly, "disease activity"), respectively. A fourth biomarker, the contractile tissue volume is easily derived from the first two ones. The fat fraction maps most often acquired with Dixon sequences have proven their capability to detect small changes in muscle composition and have repeatedly shown superior sensitivity over standard functional evaluation. This outcome measure will more than likely be the first of the series to be validated as an endpoint by regulatory agencies. The versatility of contrast generated by NMR has opened many additional possibilities for characterization of the skeletal muscle and will result in the proposal of more NMR biomarkers. Ultra-short TE (UTE) sequences, late gadolinium enhancement and NMR elastography are being investigated as candidates to evaluate skeletal muscle interstitial fibrosis. Many options exist to measure muscle perfusion and oxygenation by NMR. Diffusion NMR as well as texture analysis algorithms could generate complementary information on muscle organization at microscopic and mesoscopic scales, respectively. 31P NMR spectroscopy is the reference technique to assess muscle energetics non-invasively during and after exercise. In dystrophic muscle, 31P NMR spectrum at rest is profoundly perturbed, and several resonances inform on cell membrane integrity. Considerable efforts are being directed towards acceleration of image acquisitions using a variety of approaches, from the extraction of fat content and water T2 maps from one single acquisition to partial matrices acquisition schemes. Spectacular decreases in examination time are expected in the near future. They will reinforce the attractiveness of NMR outcome measures and will further facilitate their integration in clinical research trials.

Simultaneous muscle water T2 and fat fraction mapping using transverse relaxometry with stimulated echo compensation.

Abstract: Skeletal muscle inflammation/necrosis and fat infiltration are strong indicators of disease activity and progression in many neuromuscular disorders. They can be assessed by muscle T2 relaxometry and water-fat separation techniques, respectively. In the present work, we exploited differences between water and fat T1 and T2 relaxivities by applying a bi-component extended phase graph (EPG) fitting approach to simultaneously quantify the muscle water T2 and fat fraction from standard multi-slice multi-echo (MSME) acquisitions in the presence of stimulated echoes. Experimental decay curves were adjusted to the theoretical model using either an iterative non-negative least-squares (NNLS) procedure or a pattern recognition approach. Twenty-two patients (age, 49 ± 18 years) were selected to cover a large range of muscle fat infiltration. Four cases of chronic or subchronic juvenile dermatomyositis (age, 8 ± 3 years) were investigated before and 3 months following steroid treatment. For control, five healthy volunteers (age, 25 ± 2 years) were recruited. All subjects underwent the MSME sequence and EPG fitting procedure. The EPG fitting algorithm allowed a precise estimation of water T2 and fat fraction in diseased muscle, even in the presence of large B1(+) inhomogeneities. In the whole cohort of patients, there was no overall correlation between water T2 values obtained with the proposed method and the fat fraction estimated inside muscle tissues (R(2) = 0.02). In the patients with dermatomyositis, there was a significant decrease in water T2 (-4.09 ± 3.7 ms) consequent to steroid treatment. The pattern recognition approach resulted in a 20-fold decrease in processing time relative to the iterative NNLS procedure. The fat fraction derived from the EPG fitting approach correlated well with the fat fraction derived from a standard three-point Dixon method (≈1.5% bias). The bi-component EPG fitting analysis is a precise tool to monitor muscle tissue disease activity and is able to handle bias introduced by fat infiltration and B1(+) inhomogeneities.

Grey matter atrophy in prodromal stage of dementia with Lewy bodies and Alzheimer’s disease

Abstract: Little is known about the patterns of brain atrophy in prodromal dementia with Lewy bodies (pro-DLB). In this study, we used SPM8 with diffeomorphic anatomical registration through exponentiated lie algebra to measure grey matter (GM) volume and investigate patterns of GM atrophy in pro-DLB (n = 28) and prodromal Alzheimer’s disease (pro-AD) (n = 27) and compared and contrasted them with those in elderly control subjects (n = 33) (P ≤ 0.05 corrected for family-wise error). Patients with pro-DLB showed diminished GM volumes of bilateral insulae and right anterior cingulate cortex compared with control subjects. Comparison of GM volume between patients with pro-AD and control subjects showed a more extensive pattern, with volume reductions in temporal (hippocampi and superior and middle gyri), parietal and frontal structures in the former. Direct comparison of prodromal groups suggested that more atrophy was evident in the parietal lobes of patients with pro-AD than patients with pro-DLB. In patients with pro-DLB, we found that visual hallucinations were associated with relative atrophy of the left cuneus. Atrophy in pro-DLB involves the insulae and anterior cingulate cortex, regions rich in von Economo neurons, which we speculate may contribute to the early clinical phenotype of pro-DLB.

Four Gadolinium(III) Complexes Appended to a Porphyrin: A Water-Soluble Molecular Theranostic Agent with Remarkable Relaxivity Suited for MRI Tracking of the Photosensitizer.

Abstract: A molecular theranostic agent for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) consisting of four [GdDTTA]− complexes (DTTA4− = diethylenetriamine-N,N,N″,N″-tetraacetate) linked to a meso-tetraphenylporphyrin core, as well as its yttrium(III) analogue, was synthesized. A variety of physicochemical methods were used to characterize the gadolinium(III) conjugate 1 both as an MRI contrast agent and as a photosensitizer. The proton relaxivity measured in H2O at 20 MHz and 25 °C, r1 = 43.7 mmol–1 s–1 per gadolinium center, is the highest reported for a bishydrated gadolinium(III)-based contrast agent of medium size and can be related to the rigidity of the molecule. The complex displays also a remarkable singlet oxygen quantum yield of ϕΔ = 0.45 in H2O, similar to that of a meso-tetrasulfonated porphyrin. We also evidenced the ability of the gadolinium(III) conjugate to penetrate in cancer cells with low cytotoxicity. Its phototoxicity on Hela cells was evaluated following incubation at low ...

Inner speech and clarity of self-concept in thought disorder and auditory-verbal hallucinations

Abstract: Eighty patients and thirty controls were interviewed using one interview that promoted personal disclosure and another about everyday topics. Speech was scored using the Thought, Language and Communication scale (TLC). All participants completed the Self-Concept Clarity Scale (SCCS) and the Varieties of Inner Speech Questionnaire (VISQ). Patients scored lower than comparisons on the SCCS. Low scores were associated the disorganized dimension of TD. Patients also scored significantly higher on condensed and other people in inner speech, but not on dialogical or evaluative inner speech. The poverty of speech dimension of TD was associated with less dialogical inner speech, other people in inner speech, and less evaluative inner speech. Hallucinations were significantly associated with more other people in inner speech and evaluative inner speech. Clarity of self-concept and qualities of inner speech are differentially associated with dimensions of TD. The findings also support inner speech models of hallucinations.

Imagerie et spectroscopie par résonance magnétique nucléaire du muscle strié squelettique - Utilisation comme outil d’évaluation pour les essais cliniques

Abstract: Au cours des dernieres annees, les traitements de nombreuses maladies neuromusculaires, jusqu’ici incurables, ont beneficie d’importants progres. Ce bouleversement contextuel a eu pour consequence de stimuler le developpement de nouveaux outils d’evaluation atraumatiques. Ceux-ci peuvent etre classes en trois grandes categories : les explorations fonctionnelles musculaires, les marqueurs des fluides biologiques et l’imagerie musculaire. Au sein de cette derniere, l’imagerie par resonance magnetique nucleaire (IRMN) offre un tres large eventail de possibilites pour caracteriser la composition, la fonction et le metabolisme du muscle strie squelettique. Aujourd’hui, trois indicateurs RMN sont couramment integres dans les protocoles de recherche clinique : 1) le volume musculaire ou l’aire d’une section musculaire transversale ciblee, 2) le pourcentage de graisse intramusculaire et 3) le T2 de l’eau musculaire. Ils permettent de quantifier respectivement la trophicite du muscle, les degenerescences graisseuses chroniques et l’oedeme tissulaire (ou plus generalement « l’activite de la maladie »). Un quatrieme indicateur, le volume de tissu contractile est facilement derivable des deux premiers. Les cartographies de fraction graisseuse, souvent issues de sequences Dixon, ont fait la preuve de leur utilite pour detecter de subtils changements de composition musculaire et se sont, a plusieurs reprises, revelees plus sensibles que les evaluations fonctionnelles standards. Cet indicateur sera probablement le premier parmi ceux proposes a etre valide comme parametre principal par les organismes de regulation. La diversite des contrastes obtenus par RMN permet d’explorer de nombreuses autres pistes de caracterisation du muscle squelettique et de nouveaux biomarqueurs RMN sont a attendre dans un avenir plus ou moins proche. Des sequences a TE ultra-courts (UTE), le rehaussement tardif post-injection de gadolinium et l’elastographie par RMN sont en cours d’etude pour l’evaluation de la fibrose interstitielle du muscle squelettique. De nombreuses options existent pour mesurer la perfusion et l’oxygenation du muscle par RMN. La RMN de diffusion ainsi que l’utilisation d’algorithmes d’analyse de texture pourraient apporter des informations supplementaires sur l’organisation musculaire aux echelles respectivement microscopiques et mesoscopiques. La spectroscopie RMN du phosphore 31 P est la technique de reference pour l’evaluation atraumatique de l’energetique musculaire pendant et apres exercice. Le spectre 31 P du muscle dystrophique au repos est notablement altere, et plusieurs de ses resonances informent sur l’integrite de la membrane cellulaire. D’importants efforts sont consacres a l’acceleration de l’acquisition des images au travers plusieurs approches, allant de l’extraction du contenu en graisse et des cartographies T2 au depart d’une unique sequence, jusqu’a l’utilisation de scenarios d’acquisition partielle des matrices. Dans un avenir proche, une diminution spectaculaire du temps d’acquisition est attendue. Cela renforcera l’attractivite des indicateurs RMN et facilitera leur integration aux essais de recherche clinique.

Prodromal and non-prodromal dementia with lewy bodies and alzheimer's disease: a multimodal mri approach

Abstract: 2011); 17/41 (41%) had onset after and 24/41 (59%) before 65 years. We compared clinical, radiological, and CSF data at the initial valuation. Results: Late-onset bvFTLD (mean age at onset: 7063 years; probable bvFTLD1⁄459%) and presenile-onset bvFTLD (mean age at onset 5965 years; probable bvFTLD1⁄471%) had comparable mean disease duration at initial examination (363 years) and mean follow up duration (563 vs 564 years). MRI examination confirmed more frequent hippocampal atrophy (47% vs 21%) and less lobar atrophy (18% vs 58%) in late-onset bvFTLD; this was clinically correlated to more frequent hippocampal memory deficit (53% vs 12.5%). TEP-FDG or SPECT-HMPAO imaging detected focal hypometabolism/hypoperfusion in 53% vs 62.5% of the patients. Unexpectedly, no differences were found in CSF abeta1-42 (10976276 vs 10346236), T-tau (2896214 vs 2316100), P-tau (40617 vs 37615), and IATI index (260.6 vs 260.6); the ratio T-tau/abeta1-42 (0.2660.16 vs 0.2360.10) and P-tau/abeta1-42 (0.0460.01 vs 0.0460.01) were not different, either. In each group three subjects had high T-tau or P-Tau and one subject low abeta1-42. Conclusions:Late-onset bvFTLD is not rare in clinical practice; we confirmed more hippocampal and global atrophy compared to presenile-onset bvFTLD, clinically correlated to more frequent hippocampal memory loss. TEP-FDG and SPECT-HMPAO focal alterations were equally represented. Since no differences were found in CSF biomarkers, the differences between lateand presenile-onset bvFTLD could not be explained by co-existing AD pathology in older patients. They could instead be due to hippocampal sclerosis, known to be associated to FTLD. These data suggest the potential interest of CSF and metabolic markers in the differential diagnosis of late-onset bv-FTLD vs AD.