Publications by authors named "Paulo Loureiro de Sousa"

33 Publications

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies.

Neurobiol Aging 2021 May 14;105:252-261. Epub 2021 May 14.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.029DOI Listing
May 2021

Fast Open-Source Toolkit for Water T2 Mapping in the Presence of Fat From Multi-Echo Spin-Echo Acquisitions for Muscle MRI.

Front Neurol 2021 26;12:630387. Epub 2021 Feb 26.

Department of Neurology, Buffalo Neuroimaging Analysis Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States.

Imaging has become a valuable tool in the assessment of neuromuscular diseases, and, specifically, quantitative MR imaging provides robust biomarkers for the monitoring of disease progression. Quantitative evaluation of fat infiltration and quantification of the T2 values of the muscular tissue's water component (wT2) are two of the most essential indicators currently used. As each voxel of the image can contain both water and fat, a two-component model for the estimation of wT2 must be used. In this work, we present a fast method for reconstructing wT2 maps obtained from conventional multi-echo spin-echo (MESE) acquisitions and released as Free Open Source Software. The proposed software is capable of fast reconstruction thanks to extended phase graphs (EPG) simulations and dictionary matching implemented on a general-purpose graphic processing unit. The program can also perform more conventional biexponential least-squares fitting of the data and incorporate information from an external water-fat acquisition to increase the accuracy of the results. The method was applied to the scans of four healthy volunteers and five subjects suffering from facioscapulohumeral muscular dystrophy (FSHD). Conventional multi-slice MESE acquisitions were performed with 17 echoes, and additionally, a 6-echo multi-echo gradient-echo (MEGE) sequence was used for an independent fat fraction calculation. The proposed reconstruction software was applied on the full datasets, and additionally to reduced number of echoes, respectively, to 8, 5, and 3, using EPG and biexponential least-squares fitting, with and without incorporating information from the MEGE acquisition. The incorporation of external fat fraction maps increased the robustness of the fitting with a reduced number of echoes per datasets, whereas with unconstrained fitting, the total of 17 echoes was necessary to retain an independence of wT2 from the level of fat infiltration. In conclusion, the proposed software can successfully be used to calculate wT2 maps from conventional MESE acquisition, allowing the usage of an optimized protocol with similar precision and accuracy as a 17-echo acquisition. As it is freely released to the community, it can be used as a reference for more extensive cohort studies.
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http://dx.doi.org/10.3389/fneur.2021.630387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952742PMC
February 2021

Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models.

Hum Mol Genet 2021 May;30(9):771-788

Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France.

Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype-phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 16 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted six biological cascades centred around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.
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http://dx.doi.org/10.1093/hmg/ddab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161522PMC
May 2021

Non-invasive assessment of skeletal muscle fibrosis in mice using nuclear magnetic resonance imaging and ultrasound shear wave elastography.

Sci Rep 2021 01 11;11(1):284. Epub 2021 Jan 11.

AIM & CEA NMR Laboratory, Neuromuscular Investigation Center, Institute of Myology, Paris, France.

Fibrosis is a key pathological feature in muscle disorders, but its quantification mainly relies on histological and biochemical assays. Muscle fibrosis most frequently is entangled with other pathological processes, as cell membrane lesions, inflammation, necrosis, regeneration, or fatty infiltration, making in vivo assessment difficult. Here, we (1) describe a novel mouse model with variable levels of induced skeletal muscle fibrosis displaying minimal inflammation and no fat infiltration, and (2) report how fibrosis affects non-invasive metrics derived from nuclear magnetic resonance (NMR) and ultrasound shear-wave elastography (SWE) associated with a passive biomechanical assay. Our findings show that collagen fraction correlates with multiple non-invasive metrics. Among them, muscle stiffness as measured by SWE, T, and extracellular volume (ECV) as measured by NMR have the strongest correlations with histology. We also report that combining metrics in a multi-modality index allowed better discrimination between fibrotic and normal skeletal muscles. This study demonstrates that skeletal muscle fibrosis leads to alterations that can be assessed in vivo with multiple imaging parameters. Furthermore, combining NMR and SWE passive biomechanical assay improves the non-invasive evaluation of skeletal muscle fibrosis and may allow disentangling it from co-occurring pathological alterations in more complex scenarios, such as muscular dystrophies.
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http://dx.doi.org/10.1038/s41598-020-78747-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801669PMC
January 2021

The hippocampal region is necessary for text comprehension and memorization: a combined VBM/DTI study in neuropsychological patients.

Brain Imaging Behav 2021 Jan 7. Epub 2021 Jan 7.

ICube Laboratory (UMR 7357), University of Strasbourg and CNRS, Strasbourg, France.

According to the Construction-Integration model (Kintsch 1988; Kintsch 1998), two forms of representation are activated during the reading and the comprehension of a text: 1) the text base, which includes semantic propositions and 2) the situation model, corresponding to the integration of the information contained in the text to the memories and knowledge of the reader. Functional neuroimaging studies in healthy subjects have shown that the text base is underpinned by frontal regions and lateral temporal regions whereas the situation model would rather depend on the posterior cingulate cortex, the precuneus and other regions depending on the dimension studied. However, the brain regions highlighted so far were only involved in comprehension and not necessary for this cognitive ability. For the first time, we explored the brain structures necessary to understand texts using a combined VBM/DTI approach in neuropsychological patients with whom we obtained comprehension scores (text base and situation model) after the reading of narrative texts. To our great surprise and contrary to our hypotheses, which were based on the results of functional neuroimaging studies, our own results show that it is the hippocampal region that is necessary to activate and memorize/remember the text base and the situation model. The highlighting of a link between the integrity of a portion of the uncinate fasciculus which is well known to play a role in semantic processing and the performance scores of the text base suggests that the hippocampal region is necessary not only for the retrieval of the text base and of the situation model thanks to episodic memory, but also for the activation of the text base during the reading and the comprehension of a text.
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http://dx.doi.org/10.1007/s11682-020-00432-1DOI Listing
January 2021

Association of cerebral microbleeds with cerebrospinal fluid Alzheimer-biomarkers and clinical symptoms in early dementia with Lewy bodies.

Int J Geriatr Psychiatry 2021 06 26;36(6):851-857. Epub 2020 Dec 26.

IMIS Team and IRIS Plateform, ICube Laboratory, UMR 7357, French National Centre for Scientific Research (CNRS), Strasbourg, France.

Objectives: To determine the prevalence, localization and associations of cerebral microbleeds (CMB) in dementia with Lewy bodies (DLB) with its core clinical symptoms and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). We hypothesize DLB patients with CMB have increased amyloid burden compared to those without CMB, which could also translate into clinical differences.

Methods: Retrospective cross-sectional analysis from the AlphaLewyMA study (https://clinicaltrials.gov/ct2/show/NCT01876459). Patients underwent a standardized protocol of brain MRI including 3D T1, 3D FLAIR and T2* sequences, and CSF analysis of AD biomarkers. CMB and white matter hyperintensities (WMHs) were visually assessed in prodromal and mild demented (DLB, N = 91) and AD (AD, N = 67) patients.

Results: CMB prevalence did not differ among DLB and AD (24.2% vs. 37.3%; p = 0.081). CMB were mainly distributed in lobar topographies in both DLB (74%) and AD (89%). CMB in DLB was not associated with global cognitive performance, executive functioning, speed of information processing, or AD CSF biomarkers. Similarly, there was no difference regarding specific clinical symptoms: fluctuations, psychotic phenomena, sleep behavior disorder and Parkinsonism between DLB patients with and without CMB. AD patients with CMB had increased burden of WMH compared to those without (2.1 ± 0.86 vs. 1.4 ± 0.89; p = 0.005), according to Fazekas scale, whereas no significant difference was observed in DLB patients (1.68 ± 0.95 vs. 1.42 ± 0.91; p = 0.25).

Conclusion: CMB were equally prevalent with similar topographic distribution in both DLB and AD patients. CMB was not associated with CSF AD biomarkers or core clinical symptoms in DLB.
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http://dx.doi.org/10.1002/gps.5485DOI Listing
June 2021

Differential diagnostic value of total alpha-synuclein assay in the cerebrospinal fluid between Alzheimer's disease and dementia with Lewy bodies from the prodromal stage.

Alzheimers Res Ther 2020 09 29;12(1):120. Epub 2020 Sep 29.

CM2R (Research and Resources Memory Centre), Geriatric Day Hospital and Neuropsychology Unit, Geriatrics Department, University Hospitals of Strasbourg, Strasbourg, France.

Background: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage.

Methods: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d), and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer's biomarkers (t-Tau, P-Tau, Aβ42, and Aβ40) were also measured.

Results: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. However, the ROC curves show a moderate discriminating power between AD and DLB (AUC = 0.78) which does not improve the discriminating power of the combination of Alzheimer biomarkers (AUC = 0.95 with or without alpha-synuclein). Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB.

Conclusions: The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. The adding of alpha-synuclein total to the combination of Alzheimer's biomarker does not improve the differential diagnosis between AD and DLB.

Trial Registration: ClinicalTrials.gov, NCT01876459 (AlphaLewyMa).
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http://dx.doi.org/10.1186/s13195-020-00684-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523311PMC
September 2020

Determination of optimal parameters for 3D single-point macromolecular proton fraction mapping at 7T in healthy and demyelinated mouse brain.

Magn Reson Med 2021 01 27;85(1):369-379. Epub 2020 Jul 27.

ICube, Université de Strasbourg, CNRS, Strasbourg, France.

Purpose: To determine optimal constrained tissue parameters and off-resonance sequence parameters for single-point macromolecular proton fraction (SP-MPF) mapping based on a comprehensive quantitative magnetization transfer (qMT) protocol in healthy and demyelinated living mice at 7T.

Methods: Using 3D spoiled gradient echo-based sequences, a comprehensive qMT protocol is performed by sampling the Z-spectrum of mice brains, in vivo. Provided additional T , and B maps allow for the estimation of qMT tissue parameters, among which three will be constrained, namely the longitudinal and transverse relaxation characteristics of the free pool (R T ), the cross-relaxation rate (R) and the bound pool transverse relaxation time (T ). Different sets of constrained parameters are investigated to reduce the bias between the SP-MPF and its reference based on the comprehensive protocol.

Results: Based on a whole-brain histogram analysis about the constrained parameters, the optimal experimental parameters that minimize the global bias between reference and SP-MPF maps consist of a 600° and 6 kHz off-resonance irradiation pulse. Following a Bland-Altman analysis over regions of interest, optimal constrained parameters were R T = 0.0129, R = 26.5 s , and T = 9.1 µs, yielding an overall MPF bias of 10 (limits of agreement [-0.0068;0.0070]) and a relative variation of 0.64% ± 5.95% between the reference and the optimal single-point method across all mice.

Conclusion: The necessity of estimating animal model- and field-dependent constrained parameters was demonstrated. The single-point MPF method can be reliably applied at 7T, as part of routine preclinical in vivo imaging protocol in mice.
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http://dx.doi.org/10.1002/mrm.28397DOI Listing
January 2021

The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial.

Trials 2020 Jun 29;21(1):591. Epub 2020 Jun 29.

Centre d᾿Investigation Clinique INSERM 1434, Strasbourg, France.

Background: Central nervous system damage in multiple sclerosis (MS) is responsible for serious deficiencies. Current therapies are focused on the treatment of inflammation; however, there is an urgent need for innovative therapies promoting neuroregeneration, particularly myelin repair. It is demonstrated that testosterone can act through neural androgen receptors and several clinical observations stimulated an interest in the potential protective effects of testosterone treatment for MS. Here, we sought to demonstrate the effects of a testosterone supplementation in testosterone-deficient men with relapsing-remitting MS.

Methods/design: This report presents the rationale and methodology of TOTEM RRMS, a French, phase 2, multicenter, randomized, placebo-controlled, and double-blind trial, which aims to prevent the progression of MS in men with low testosterone levels by administration of testosterone undecanoate, who were kept under natalizumab (Tysabri®) to overcome the anti-inflammatory effect of testosterone. Forty patients will be randomized into two groups receiving either a testosterone treatment (Nebido®) or a matching placebo. The intervention period for each group will last 66 weeks (treatment will be injected at baseline, week 6, and then every 12 weeks). The main objective is to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging techniques and thalamic atrophy analyses. As secondary objectives, impacts of the testosterone supplementation will be studied using other conventional and unconventional MRI parameters and with clinical outcomes.

Discussion: The action of testosterone is observed in different experimental autoimmune encephalomyelitis models and epidemiological studies in humans. However, despite several preclinical data and some small clinical trials in MS, clear evidence for a therapeutic effect of hormone therapy is still missing. Therefore, our goal is to demonstrate the effects of testosterone therapies in MS. As there is no effective treatment currently available on fatigue in MS, careful attention should also be paid to secondary endpoints: fatigue, cognitive functions, and other symptoms that may improve life quality. Assuming a positive outcome of the trial, this treatment could be considered as a new neuroprotective and remyelinating therapy in relapsing-remitting MS and could be applicable to other demyelinating diseases.

Trial Registration: ClinicalTrials.gov NCT03910738. Registered on 10 April 2019.
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http://dx.doi.org/10.1186/s13063-020-04517-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322908PMC
June 2020

Changes in gray matter volume and functional connectivity in dementia with Lewy bodies compared to Alzheimer's disease and normal aging: implications for fluctuations.

Alzheimers Res Ther 2020 01 6;12(1). Epub 2020 Jan 6.

ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS, University of Strasbourg and CNRS, Strasbourg, France.

Background: Fluctuations are one of the core clinical features characterizing dementia with Lewy bodies (DLB). They represent a determining factor for its diagnosis and strongly impact the quality of life of patients and their caregivers. However, the neural correlates of this complex symptom remain poorly understood. This study aimed to investigate the structural and functional changes in DLB patients, compared to Alzheimer's disease (AD) patients and healthy elderly subjects, and their potential links with fluctuations.

Methods: Structural and resting-state functional MRI data were collected from 92 DLB patients, 70 AD patients, and 22 control subjects, who also underwent a detailed clinical examination including the Mayo Clinic Fluctuation Scale. Gray matter volume changes were analyzed using whole-brain voxel-based morphometry, and resting-state functional connectivity was investigated using a seed-based analysis, with regions of interest corresponding to the main nodes of the salience network (SN), frontoparietal network (FPN), dorsal attention network (DAN), and default mode network (DMN).

Results: At the structural level, fluctuation scores in DLB patients did not relate to the atrophy of insular, temporal, and frontal regions typically found in this pathology, but instead showed a weak correlation with more subtle volume reductions in different regions of the cholinergic system. At the functional level, the DLB group was characterized by a decreased connectivity within the SN and attentional networks, while the AD group showed decreases within the SN and DMN. In addition, higher fluctuation scores in DLB patients were correlated to a greater connectivity of the SN with the DAN and left thalamus, along with a decreased connectivity between the SN and DMN, and between the right thalamus and both the FPN and DMN.

Conclusions: Functional connectivity changes, rather than significant gray matter loss, could play an important role in the emergence of fluctuations in DLB. Notably, fluctuations in DLB patients appeared to be related to a disturbed external functional connectivity of the SN, which may lead to less relevant transitions between different cognitive states in response to internal and environmental stimuli. Our results also suggest that the thalamus could be a key region for the occurrence of this symptom.
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http://dx.doi.org/10.1186/s13195-019-0575-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945518PMC
January 2020

Pay attention to the basal ganglia: a volumetric study in early dementia with Lewy bodies.

Alzheimers Res Ther 2019 12 21;11(1):108. Epub 2019 Dec 21.

Geriatrics and Neurology Departments, Research and Resources Memory Center (CM2R), Strasbourg University Hospital, Strasbourg, France.

Background: Cortical and subcortical cognitive impairments are usually found in dementia with Lewy bodies (DLB). Roughly, they comprise visuo-constructive/executive function and attention/processing speed impairments, whereas memory would remain relatively spared. In this study, we focused on the neuro-anatomical substrates of attention and processing speed, which is still poorly understood. For the purpose of the study, we examined the correlations between behavioral scores measuring the speed of processing and the degree of cerebral atrophy in patients with prodromal to moderate DLB.

Methods: Ninety-three prodromal to moderate DLB patients (mean MMSE = 25.5) were selected to participate in the study as well as 28 healthy elderly subjects (mean MMSE = 28.9), matched in terms of age and educational level. The Trail Making Test A (TMTA) and the Digit Symbol Substitution Test (DSST) were used to assess attention and processing speed. Behavioral performances were compared between patients and healthy control subjects. Three-dimensional MRI images were acquired for all participants, and correlational analyses were performed in the patient group using voxel-based morphometry (VBM).

Results: The behavioral results on both the TMTA (p = .026) and the DSST (p < .001) showed significantly impaired performances in patients in comparison with control subjects. In addition, correlational analyses using VBM revealed for the TMTA negative correlations in the caudate nucleus (left cluster peak significant at .05 FWE corrected), the putamen, the left thalamus, and the subthalamic nuclei (p < .05 FDR corrected). Some positive correlations associated with the DSST were found in the right inferior frontal gyrus, the left thalamus, and the left cerebellum (p < .001 uncorrected).

Conclusions: The behavioral results are in line with the literature on the DLB cognitive profile and confirm the existence of attention and processing speed impairment. Interestingly, VBM analysis revealed the involvement of the basal ganglia, in particular, the left caudate nucleus, which is part of the attention cerebral network, suggesting an important role of this structure for attentional processing speed. This also suggests the clinical implication of damage in this region relatively early in the course of the disease.
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http://dx.doi.org/10.1186/s13195-019-0568-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925479PMC
December 2019

A Brain Imaging-Based Diagnostic Biomarker for Periodic Catatonia: Preliminary Evidence Using a Bayesian Approach.

Neuropsychobiology 2020 10;79(4-5):352-365. Epub 2019 Sep 10.

Pôle de Psychiatrie, Santé Mentale et Addictologie, University Hospital Strasbourg, Strasbourg, France.

Periodic catatonia (PC) is a psychomotor phenotype with a progressive-remitting course. While it can fit any disorder diagnosis of the schizoaffective spectrum, its core features consist of a mix of hypo- and hyperkinesias resulting in distortions of expressive movements such as grimacing and parakinesias. The replication of cerebral blood flow (CBF) increases in the left supplementary motor area (L-SMA) and lateral premotor cortex (L-LPM) in acute and remitting PC patients indicates that these increases could be used as diagnostic biomarkers. In this proof-of-concept study, 2 different MRI sequences were repeated on 3 separate days to get reliable measurement values of CBF in 9 PC and 26 non-PC patients during different cognitive tasks. Each patient was compared to 37 controls. In L-SMA [-9; +10; +60] and L-LPM [-46; -12; +43], a test was positive if the t value was >2.02 (α < 0.05; two tailed). The measurements had good analytical performance. Regarding the tests, their sensitivities and specificities were significantly different from the chance level on both measures, except for L-SMA sensitivities. When combining all the tests, among regions and methods, sensitivity was 98% (95% credible interval [CI] 76-100%) and specificity 88% (72-97%). Bayesian inferences of its negative predictive values for PC were >95% regardless of the context, while its positive predictive values reached 94% but only when used in combination with clinical criteria. The case-by-case analysis suggests that non-PC patients with neurological motor deficits are at risk to be false positive.
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http://dx.doi.org/10.1159/000501830DOI Listing
April 2021

Correlations of quantitative MRI metrics with myelin basic protein (MBP) staining in a murine model of demyelination.

NMR Biomed 2019 09 21;32(9):e4116. Epub 2019 Jun 21.

Université de Strasbourg, CNRS, ICube, FMTS, Strasbourg, France.

Myelin imaging in the central nervous system is essential for monitoring pathologies involving white matter alterations. Various quantitative MRI protocols relying on the modeling of the interactions of water protons with myelinated tissues have shown sensitivities in case of myelin disruption. Some extracted model parameters are more sensitive to demyelination, such as the bound pool fraction (f) in quantitative magnetization transfer imaging (qMTI), the radial diffusivity in diffusion tensor imaging (DTI), and the myelin water fraction (MWF) in myelin water imaging (MWI). A 3D ultrashort echo time (UTE) sequence within an appropriate water suppression condition (Diff-UTE) is also considered for the direct visualization of the myelin semi-solid matrix (Diff-UTE normalized signal; rSPF). In this paper, we aimed at assessing the sensitivities and correlations of the parameters mentioned above to an immuno-histological study of the myelin basic protein (MBP) in a murine model of demyelination at 7 T. We demonstrated a high sensitivity of the MRI metrics to demyelination, and strong Spearman correlations in the corpus callosum between histology, macromolecular proton fraction (ρ>0.87) and Diff-UTE signal (ρ>0.76), but moderate ones with radial diffusivity and MWF (|ρ|<0.70).
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http://dx.doi.org/10.1002/nbm.4116DOI Listing
September 2019

A double dissociation between two psychotic phenotypes: Periodic catatonia and cataphasia.

Prog Neuropsychopharmacol Biol Psychiatry 2018 08 17;86:363-369. Epub 2018 Mar 17.

Physiopathologie et Psychopathologie Cognitive de la Schizophrénie - INSERM 1114, FMTS, University of Strasbourg, France; Pôle de Psychiatrie, Santé Mentale et Addictologie, University Hospital Strasbourg, France.

Schizophrenia as a single liability model was confronted to the multiple psychotic phenotypes model proposed by the Wernicke-Kleist-Leonhard school, focusing on two: periodic catatonia (PC) and cataphasia (C). Both are stable and heritable psychotic phenotypes with no crossed liability and are coming with the buildup of specific residual symptoms: impairment of psychomotricity for PC and a specific disorganization of thought and language in C. Regional cerebral blood flow (rCBF) was used as a biomarker. We attempted to refute the single phenotype model by looking at relevant and specific rCBF anomalies for PC and C, that would exceed anomalies in common relative to controls (CTR), i.e. looking for a double dissociation. Twenty subjects with PC, 9 subjects with C and 27 matched controls had two MRI QUIPSS-II arterial spin labeling sequences converted in rCBF. One SPM analysis was performed for each rCBF measurement and the results were given as the conjunction of both analysis. There was a clear double dissociation of rCBF correlates between PC and C, both being meaningful relative to their residual symptomatology. In PC: rCBF was increased in the left motor and premotor areas. In C: rCBF was decreased bilaterally in the temporo-parietal junctions. Conversely, in both (schizophrenia): rCBF was increased in the left striatum which is known to be an anti-psychotics' effect. This evidence refuts the single schizophrenia model and suggests better natural foundations for PC and C phenotypes. This pleads for further research on them and further research on naturally founded psychotic phenotypes.

Clinical Trial: Name of the registry: ClinicalTrials.gov Identification: NCT02868879.
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http://dx.doi.org/10.1016/j.pnpbp.2018.03.008DOI Listing
August 2018

A diffusion-based method for long-T suppression in steady state sequences: Validation and application for 3D-UTE imaging.

Magn Reson Med 2018 08 19;80(2):548-559. Epub 2017 Dec 19.

Université de Strasbourg, CNRS, ICube, FMTS, Strasbourg, France.

Purpose: To introduce a novel method for long-T signal physical suppression in steady-state based on configuration states combination and modulation using diffusion weighting. Its efficiency in yielding a high contrast in short-T structures using an ultrashort echo time acquisition module (Diff-UTE) is compared to the adiabatically prepared Inversion-Recovery-UTE sequence (IR-UTE).

Theory And Methods: Using a rectangular-pulse prepared 3D-UTE sequence, the possibility of long-T component signal cancellation through diffusion effects is addressed, and the condition met for sets of sequence parameters. Simultaneously, the short-T component signal is maximized using a Bloch equation-based optimization process. The method is evaluated from simulations, and experiments are conducted on a phantom composed of short and long-T components, as well as on an ex vivo mouse head.

Results: Within equal scan times, the proposed method allowed for an efficient long-T signal suppression, and expectedly yielded a higher signal to noise ratio in short-T structures compared to the IR-UTE technique, although an intrinsic short-T signal loss is expected through the preparation module.

Conclusion: The Diff-UTE method represents an interesting alternative to the IR-UTE technique. Diffusion weighting allowing for a long-T suppression results in a less penalizing method to generate a high and selective contrast in short-T components. Magn Reson Med 80:548-559, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.27057DOI Listing
August 2018

Insular atrophy at the prodromal stage of dementia with Lewy bodies: a VBM DARTEL study.

Sci Rep 2017 08 25;7(1):9437. Epub 2017 Aug 25.

ICube, UMR 7357, CNRS, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.

Diffuse atrophy including the insula was previously demonstrated in dementia with Lewy bodies (DLB) patients but little is known about the prodromal stage of DLB (pro-DLB). In this prospective study, we used SPM8-DARTEL to measure gray matter (GM) and white matter (WM) atrophy in pro-DLB patients (n = 54), prodromal Alzheimer's disease (pro-AD) patients (n = 16), DLB patients at the stage of dementia (mild-DLB) (n = 15), and Alzheimer's disease patients at the stage of dementia (mild-AD) (n = 28), and compared them with healthy elderly controls (HC, n = 22). Diminished GM volumes were found in bilateral insula in pro-DLB patients, a trend to significance in right hippocampus and parahippocampal gyrus in pro-AD patients, in left insula in mild-DLB patients, and in medial temporal lobes and insula in mild-AD patients. The comparison between prodromal groups did not showed any differences. The comparison between groups with dementia revealed atrophy around the left middle temporal gyrus in mild-AD patients. Reduced WM volume was observed in mild-DLB in the pons. The insula seems to be a key region in DLB as early as the prodromal stage. MRI studies looking at perfusion, and functional and anatomical connectivity are now needed to better understand the role of this region in DLB.
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http://dx.doi.org/10.1038/s41598-017-08667-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573371PMC
August 2017

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

J Neuromuscul Dis 2016 03;3(1):1-28

N.I. Prirogov Russian National Medical Research University, Clinical Research Institute of Pediatrics, Moscow, Russian Federation.

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.
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http://dx.doi.org/10.3233/JND-160145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271435PMC
March 2016

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

Alzheimers Res Ther 2016 07 20;8:31. Epub 2016 Jul 20.

Institute of Neuroscience, Campus for Aging and Vitality, Newcastle University, Newcastle upon Tyne, UK.

Background: Little is known about the patterns of brain atrophy in prodromal dementia with Lewy bodies (pro-DLB).

Methods: 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).

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1186/s13195-016-0198-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970221PMC
July 2016

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

Inorg Chem 2016 05 13;55(9):4545-54. Epub 2016 Apr 13.

Istituto ISOF-CNR , via P. Gobetti 101, 40129 Bologna, Italy.

A molecular theranostic agent for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) consisting of four [GdDTTA](-) complexes (DTTA(4-) = 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 micromolar concentration and moderate light irradiation (21 J cm(-2)) induced 50% of cell death. Altogether, these results demonstrate the high potential of this conjugate as a theranostic agent for MRI and PDT.
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http://dx.doi.org/10.1021/acs.inorgchem.6b00381DOI Listing
May 2016

BLOCH equations-based reconstruction of myocardium t1 maps from modified look-locker inversion recovery sequence.

PLoS One 2015 11;10(5):e0126766. Epub 2015 May 11.

Institute of Myology, NMR Laboratory, Paris, France; CEA, DSV, I2BM, MIRCen, IdM NMR Laboratory, Paris, France; UPMC University Paris 06, Paris, France.

Modified Look-Locker Inversion recovery (MOLLI) sequence is increasingly performed for myocardial T1 mapping but is known to underestimate T1 values. The aim of the study was to quantitatively analyze several sources of errors when T1 maps are derived using standard post-processing of the sequence and to propose a reconstruction approach that takes into account inversion efficacy (η), T2 relaxation during balanced steady-state free-precession readouts and B1+ inhomogeneities. Contributions of the different sources of error were analyzed using Bloch equations simulations of MOLLI sequence. Bloch simulations were then combined with the acquisition of fast B1+ and T2 maps to derive more accurate T1 maps. This novel approach was evaluated on phantoms and on five healthy volunteers. Simulations show that T2 variations, B1+ heterogeneities and inversion efficiency represent major confounders for T1 mapping when MOLLI is processed with standard 3-parameters fitting. In vitro data indicate that T1 values are accurately derived with the simulation approach and in vivo data suggest that myocardium T1 are 15% underestimated when processed with the standard 3-parameters fitting. At the cost of additional acquisitions, this method might be suitable in clinical research protocols for precise tissue characterization as it decorrelates T1 and T2 effects on parametric maps provided by MOLLI sequence and avoids inaccuracies when B1+ is not homogenous throughout the myocardium.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126766PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427396PMC
February 2016

Skeletal muscle quantitative nuclear magnetic resonance imaging follow-up of adult Pompe patients.

J Inherit Metab Dis 2015 May 7;38(3):565-72. Epub 2015 Mar 7.

Institut de Myologie and CEA, DSV, IBM, MIRCen, Laboratoire de RMN, Pitie-Salpetriere University Hospital, Bd de l'Hôpital, 75651, Paris Cedex 13, France,

Adult late-onset Pompe disease is most often a slowly progressive limb-girdle and spine extensor muscle dystrophy, due to defective lysosomal acid maltase. With the exception of the few patients who present with a dramatically accelerated clinical course, standard diagnostic imaging fail to detect and evaluate disease progression between two successive visits. In muscle dystrophy of very rapid evolution, like the Duchenne disease, quantitative NMR imaging has successfully demonstrated its capacity to objectivate both disease activity and degenerative changes progression over short follow-up periods. The purpose of this retrospective monocentric open-label study was to investigate whether quantitative NMR imaging can monitor disease progression in adult Pompe patients despite its very slow nature. Quantitative imaging of Pompe patients succeeded in demonstrating that muscle fatty infiltration increased on average by 0.9%/year, with the hamstring and adductor muscles showing the fastest degradation. Muscle water T2 mapping revealed that 32% of all muscles had abnormally high T2 in at least one of two successive examinations. When muscle water T2 was abnormal, fatty degenerative changes were further increased by 0.61%/year. Enzyme replacement therapy resulted in 0.68%/year slowdown of the muscle fatty infiltration, in both muscles with normal and high T2s.
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http://dx.doi.org/10.1007/s10545-015-9825-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432102PMC
May 2015

Quantitative T2 combined with texture analysis of nuclear magnetic resonance images identify different degrees of muscle involvement in three mouse models of muscle dystrophy: mdx, Largemyd and mdx/Largemyd.

PLoS One 2015 24;10(2):e0117835. Epub 2015 Feb 24.

Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo-IB-USP, São Paulo, São Paulo, Brazil.

Quantitative nuclear magnetic resonance imaging (MRI) has been considered a promising non-invasive tool for monitoring therapeutic essays in small size mouse models of muscular dystrophies. Here, we combined MRI (anatomical images and transverse relaxation time constant-T2-measurements) to texture analyses in the study of four mouse strains covering a wide range of dystrophic phenotypes. Two still unexplored mouse models of muscular dystrophies were analyzed: The severely affected Largemyd mouse and the recently generated and worst double mutant mdx/Largemyd mouse, as compared to the mildly affected mdx and normal mice. The results were compared to histopathological findings. MRI showed increased intermuscular fat and higher muscle T2 in the three dystrophic mouse models when compared to the wild-type mice (T2: mdx/Largemyd: 37.6±2.8 ms; mdx: 35.2±4.5 ms; Largemyd: 36.6±4.0 ms; wild-type: 29.1±1.8 ms, p<0.05), in addition to higher muscle T2 in the mdx/Largemyd mice when compared to mdx (p<0.05). The areas with increased muscle T2 in the MRI correlated spatially with the identified histopathological alterations such as necrosis, inflammation, degeneration and regeneration foci. Nevertheless, muscle T2 values were not correlated with the severity of the phenotype in the 3 dystrophic mouse strains, since the severely affected Largemyd showed similar values than both the mild mdx and worst mdx/Largemyd lineages. On the other hand, all studied mouse strains could be unambiguously identified with texture analysis, which reflected the observed differences in the distribution of signals in muscle MRI. Thus, combined T2 intensity maps and texture analysis is a powerful approach for the characterization and differentiation of dystrophic muscles with diverse genotypes and phenotypes. These new findings provide important noninvasive tools in the evaluation of the efficacy of new therapies, and most importantly, can be directly applied in human translational research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117835PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339395PMC
November 2015

Validation of a generic approach to muscle water T2 determination at 3T in fat-infiltrated skeletal muscle.

J Magn Reson Imaging 2015 Mar 3;41(3):645-53. Epub 2014 Mar 3.

Institute of Myology, NMR Laboratory, Paris, France; CEA, I2BM MIRCen IdM NMR Laboratory, Paris, France.

Purpose: To introduce a novel method for skeletal muscle water T2 determination in fat-infiltrated tissues, using a tri-exponential fit of the global muscle signal decay.

Materials And Methods: In all, 48 patients with various neuromuscular diseases were retrospectively selected and their thigh muscles analyzed. Each patient was imaged using a multispin-echo (MSME) sequence with a 17-echo train. The transmit field (B1+) inhomogeneities were evaluated using the actual flip angle imaging method toward voxel sorting. Muscle water T2 was quantified using a tri-exponential signal decay model. The difference between water T2 of voxels within the same muscle but having different fat ratio was analyzed using nonparametric statistical tests. In addition, we evaluated the correlation between fat ratio and T2 values obtained using both a mono- and tri-exponential approach.

Results: The results showed that muscle water T2 values obtained using a tri-exponential approach combined with B1+ map-based voxel sorting were independent of the fat infiltration degree inside the muscle (R(2) < 0.03). This was not the case using the mono-exponential model, which measured different T2s between voxels of the same muscle but with various fat ratio (R(2) > 0.67; P < 10e(-4) ).

Conclusion: The tri-exponential model is an accurate tool to monitor muscle tissue disease activity devoid of bias introduced by fat infiltration.
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http://dx.doi.org/10.1002/jmri.24613DOI Listing
March 2015

Quantitative magnetic resonance imaging in limb-girdle muscular dystrophy 2I: a multinational cross-sectional study.

PLoS One 2014 28;9(2):e90377. Epub 2014 Feb 28.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p<0.005). MRI is non-invasive, objective and does not rely on patient effort compared to clinical and physical measures that are currently employed. We demonstrated (i) that the quantitative Dixon technique is an objective quantitative marker of disease and (ii) new observations of gender specific patterns of muscle involvement in LGMD2I.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090377PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938727PMC
October 2014

Factors controlling T2 mapping from partially spoiled SSFP sequence: optimization for skeletal muscle characterization.

Magn Reson Med 2012 May 16;67(5):1379-90. Epub 2011 Aug 16.

Institute of Myology, NMR Laboratory, Paris, France.

A fast and robust methodology for in vivo T(2) mapping is presented. The approach is based on the partially spoiled steady state free precession technique recently proposed by Bieri et al. (Magn Reson Med 2011). The accuracy of this method was demonstrated in simulations and phantom experiments. Variations in skeletal muscle T(2) relaxation time have been correlated with cell damage and inflammatory response. Nonetheless, the lack of easily implementable, fast, accurate and reproducible methods has hampered the adoption of T(2) measurement as a noninvasive tool for skeletal muscle characterization. The applicability of the partially spoiled steady state free precession method for tissue characterization in muscle disease is illustrated in this work by several examples. Quantitative MRI, in particular T(2) mapping based on partially spoiled steady state free precession acquisitions, might provide objective markers of muscle damage and degenerative changes, and an alternative to serial muscle biopsies.
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http://dx.doi.org/10.1002/mrm.23131DOI Listing
May 2012

Fast monitoring of T(1) , T(2) , and relative proton density (M(0) ) changes in skeletal muscles using an IR-TrueFISP sequence.

J Magn Reson Imaging 2011 Apr;33(4):921-30

Institute of Myology, Paris, France.

Purpose: To investigate the feasibility of fast and simultaneous assessment of T(1) , T(2) , and M(0) (relative proton density) changes in skeletal muscle studies using an inversion recovery true fast imaging with steady-state precession (TrueFISP) sequence.

Materials And Methods: NMR signal dynamics in calf muscles were analyzed under four different conditions: intravenous injection of a low-molecular weight Gd contrast agent (CA), postarterial occlusion reactive hyperemia, local cooling, and an exercise bout. Experiments were conducted on a clinical 3T whole-body scanner.

Results: At rest, average muscle T(1) and T(2) values obtained from the IR-TrueFISP experiments were 1.34 ± 0.13 seconds and 45 ± 5 msec, respectively (median ± standard deviation). 1) Noticeable T(1) decreases (ΔT(1) max ≈-30%) were measured in the calf muscles after CA injection, while no significant changes were observed for T(2) and M(0) . 2) T(2) increased rapidly during reactive hyperemia and reached a peak value (+6%) at about 1 minute postischemia. During ischemia, a significant decrease was observed only in the soleus muscle. No significant paradigm-related changes in M(0) and T(1) were noted in all muscle groups, except in the m. soleus (ΔT(1) ≈+1% during reactive hyperemia). 3) Opposite variations in muscle T(1) (ΔT(1) max ≈-30%) and M(0) (ΔM(0) max ≈+25%) associated with local cooling were detected. 4) Concomitant changes in T(1) (ΔT(1) max ≈+15%), T(2) (ΔT(2) max ≈+35%), and M(0) (ΔM(0) max ≈+16%) were observed in the activated muscles following the exercise bout.

Conclusion: IR-TrueFISP was sufficiently fast and sensitive to detect small and transient T(1) , T(2) , and M(0) changes in the calf muscles under different experimental conditions. The sequence offers a time-resolution adequate to track rapid physiological adaptations in skeletal muscle.
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http://dx.doi.org/10.1002/jmri.22511DOI Listing
April 2011

Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.

PLoS One 2008 Jul 9;3(7):e2608. Epub 2008 Jul 9.

University of Orléans and CNRS, Molecular Immunology and Embryology UMR6218, Orleans, France.

Background: TNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.

Methodology/principal Findings: LTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+) CD8(+) T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM.

Conclusions/significance: LTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2442868PMC
July 2008

Quantitative, dynamic and noninvasive determination of skeletal muscle perfusion in mouse leg by NMR arterial spin-labeled imaging.

Magn Reson Imaging 2008 Nov 21;26(9):1259-65. Epub 2008 May 21.

AIM - CEA NMR Laboratory, Institute of Myology, Pitie-Salpetriere University Hospital, 75651 Paris cedex 13, France.

Because mouse may relatively easily be genetically tailored to develop equivalent of human muscular diseases or to present controlled alterations of mechanisms involved in vasoregulation, it has become the prevalent species to explore such questions. However, the very small size of the animals represents a serious limitation when evaluating the functional consequences of these genetic manipulations. In this context, the recourse to arterial spin labeling (ASL) nuclear magnetic resonance (NMR) methods in which arterial water spins act as an endogenous and freely diffusible tracer of perfusion is tempting but challenging. This article shows that despite the small size of the animal, mouse muscle perfusion may be measured, at rest and in conditions of reactive hyperemia, using saturation inversion recovery sequence, a pulsed ASL variant, combined with NMR imaging. Baseline perfusion values in the mouse leg were 17+/-11 ml.min(-1).100 g(-1) (n=11) and were comparable to microsphere data from the literature. Under ischemia, leg perfusion was 1.2+/-9.3 ml.min(-1).100 g(-1) (n=11). The difference observed between basal and ischemic measurements was statistically different (P=.0001). The temporal pattern of hyperemia in mouse muscle was coherent with previously published measurements in humans and in rats. The mean peak perfusion was 62+/-24 ml.min(-1).100 g(-1) (n=6) occurring 48+/-27 s after the end of occlusion. In conclusion, this study demonstrated the ability of ASL combined to NMR imaging to quantify skeletal muscle perfusion in mice legs, both at rest and dynamically.
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http://dx.doi.org/10.1016/j.mri.2008.02.012DOI Listing
November 2008

In vivo MRI assessment of a novel GdIII-based contrast agent designed for high magnetic field applications.

Contrast Media Mol Imaging 2008 Mar-Apr;3(2):78-85

Centre de Biophysique Moléculaire, CNRS, rue Charles Sadron, 45071 Orléans, France.

Gd(3)L is a trinuclear Gd(3+) complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H(12)L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N'',N''-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd(3)L has remarkable proton relaxivities at high magnetic field (r(1) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd(3)L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd(3)L injection than after GdDOTA injection at an identical dose. The relaxation rates, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(1) for various tissues was similar for Gd(3)L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd(3)L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd(3)L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd(3)L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are also indicative of a fast elimination via the kidneys.
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http://dx.doi.org/10.1002/cmmi.233DOI Listing
June 2008

Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging.

J Neurosci Res 2006 Feb;83(3):392-402

UMR 7004 CNRS/ULP, Institut de Physique Biologique, Faculté de Médecine,Université Louis Pasteur, Strasbourg, France.

Diffusion tensor magnetic resonance imaging (DT-MRI) was applied for in vivo quantification of myelin loss and regeneration. A transgenic mouse line (Oligo-TTK) expressing a truncated form of the herpes simplex virus 1 thymidine kinase gene (hsv1-tk) in oligodendrocytes was studied along with two induced phenotypes of myelin pathology. Myelin loss and axonal abnormalities differentially affect values of DT-MRI parameters in the brain of transgenic mice. Changes in the anisotropy of the white matter were assessed by calculating and mapping the radial (D perpendicular) and axial (D parallel) water diffusion to axonal tracts and fractional anisotropy (FA). A significant increase in D perpendicular attributed to the lack of myelin was observed in all selected brain white matter tracts in dysmyelinated mice. Lower D parallel values were consistent with the histological observation of axonal modifications, including reduced axonal caliber and overexpression of neurofilaments and III beta-tubulin. We show clearly that myelination and axonal changes play a role in the degree of diffusion anisotropy, because FA was significantly decreased in dysmyelinated brain. Importantly, myelin reparation during brain postnatal development induced a decrease in the magnitude of D( perpendicular) and an increase in FA compared with the same brain before recovery. The progressive increase in D parallel values was attributed to the gain in normal axonal morphology. This regeneration was confirmed by the detection of enlarged oligodendrocyte population, newly formed myelin sheaths around additional axons, and a gradual increase in axonal caliber.
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http://dx.doi.org/10.1002/jnr.20742DOI Listing
February 2006
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