Metabolic voxel-based analysis of the complete human brain using fast 3D-MRSI: Proof of concept in multiple sclerosis.
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ABSTRACT:
SUBMITTER: Donadieu M
PROVIDER: S-EPMC4940345 | biostudies-literature | 2016 Aug
REPOSITORIES: biostudies-literature
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Metabolic voxel-based analysis of the complete human brain using fast 3D-MRSI: Proof of concept in multiple sclerosis.
Donadieu Maxime M Le Fur Yann Y Lecocq Angèle A Maudsley Andrew A AA Gherib Soraya S Soulier Elisabeth E Confort-Gouny Sylviane S Pariollaud Fanelly F Ranjeva Marie-Pierre MP Pelletier Jean J Guye Maxime M Zaaraoui Wafaa W Audoin Bertrand B Ranjeva Jean-Philippe JP
Journal of magnetic resonance imaging : JMRI 20160112 2
<h4>Purpose</h4>To detect local metabolic abnormalities over the complete human brain in multiple sclerosis (MS) patients, we used optimized fast volumic echo planar spectroscopic imaging (3D-EPSI).<h4>Materials and methods</h4>Weighted mean combination of two 3D-EPSI covering the whole brain acquired at 3T in AC-PC and AC-PC+15° axial planes was performed to obtain high-quality metabolite maps for five metabolites: N-acetyl aspartate (NAA), glutamate+glutamine (Glx), choline (Cho), myo-inositol ...[more]
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Project description:BACKGROUND:Over the past decades, positron emission tomography (PET) imaging has become an increasingly useful research modality in the field of multiple sclerosis (MS) research, as PET can visualise molecular processes, such as neuroinflammation, in vivo. The second generation PET radioligand [18F]DPA714 binds with high affinity to the 18-kDa translocator-protein (TSPO), which is mainly expressed on activated microglia. The aim of this proof of concept study was to evaluate this in vivo marker of neuroinflammation in primary and secondary progressive MS. METHODS:All subjects were genotyped for the rs6971 polymorphism within the TSPO gene, and low-affinity binders were excluded from participation in this study. Eight patients with progressive MS and seven age and genetic binding status matched healthy controls underwent a 60 min dynamic PET scan using [18F]DPA714, including both continuous on-line and manual arterial blood sampling to obtain metabolite-corrected arterial plasma input functions. RESULTS:The optimal model for quantification of [18F]DPA714 kinetics was a reversible two-tissue compartment model with additional blood volume parameter. For genetic high-affinity binders, a clear increase in binding potential was observed in patients with MS compared with age-matched controls. For both high and medium affinity binders, a further increase in binding potential was observed in T2 white matter lesions compared with non-lesional white matter. Volume of distribution, however, did not differentiate patients from healthy controls, as the large non-displaceable compartment of [18F]DPA714 masks its relatively small specific signal. CONCLUSION:The TSPO radioligand [18F]DPA714 can reliably identify increased focal and diffuse neuroinflammation in progressive MS when using plasma input-derived binding potential, but observed differences were predominantly visible in high-affinity binders.
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Project description:ObjectiveThe concept of coping with disease appears frequently in the literature; however, there is no precise definition of coping. The aim of this study is to clarify coping concept, and to identify its attributes, antecedents, and consequences in patients with multiple sclerosis.MethodsRodgers' evolutionary method of concept analysis was used to clarify the concept of coping. A literature review was conducted with key terms 'multiple sclerosis', 'coping', 'adjustment', and 'deal with'. After searching databases, 1370 papers were found for the period 1995-2017. Finally, 55 articles and texts were selected for analysis. Data analysis was carried out using thematic analysis. An independent researcher checked the process to ensure credibility and reduce personal bias.ResultsCoping with multiple sclerosis is a multidimensional concept with three main attributes: maintenance of emotional balance, acceptance of the disease, and self-regulation. Social support, awareness toward the disease, attitude toward the disease, and religious-spiritual beliefs were found as antecedents. Health promotion, adherence to treatment regimen, independence in personal life and social relationships, and improvement of family relationships were found as consequences of these attributes.ConclusionThese findings not only add to the body of knowledge in health science, but also serve as an important motivation for further theory development and research in this context. Nurses and health professions can also benefit from a deeper understanding of coping concept in providing and planning healthcare for these patients.
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Project description:BackgroundAxonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS.MethodsThe ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume.DiscussionWe hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest.Trial registrationClinical Trials Register, EudraCT 2017-001253-13 . Registered on 15 February 2018.
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Project description:INTRODUCTION:Progressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%-70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing-remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol-treated compared to placebo-treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes. METHODS:Sixty-two estriol- and forty-nine placebo-treated RRMS patients underwent clinical evaluations and brain MRI. Voxel-based morphometry (VBM) was used to evaluate voxelwise GM sparing from high-resolution T1-weighted scans. RESULTS:A region of treatment-induced sparing (TIS) was defined as the areas where GM was spared in estriol- as compared to placebo-treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability-specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol-treated subjects that was associated with better performance on the PASAT. CONCLUSIONS:Discovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.
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Project description:Multiple sclerosis (MS) pathology progressively affects multiple central nervous system (CNS) areas. Due to this fact, MS produces a wide array of symptoms. Symptomatic therapy of one MS symptom can cause or worsen other unwanted symptoms (anticholinergics used for bladder dysfunction produce impairment of cognition, many MS drugs produce erectile dysfunction, etc.). Appropriate symptomatic therapy is an unmet need. Several important functions/symptoms (muscle tone, sleep, bladder, pain) are mediated, in great part, in the brainstem. Cannabinoid receptors are distributed throughout the CNS irregularly: There is an accumulation of CB1 and CB2 receptors in the brainstem. Nabiximols (a combination of THC and CBD oromucosal spray) interact with both CB1 and CB2 receptors. In several clinical trials with Nabiximols for MS spasticity, the investigators report improvement not only in spasticity itself, but also in several functions/symptoms mentioned before (spasms, cramps, pain, gait, sleep, bladder function, fatigue, and possibly tremor). We can conceptualize and, therefore, hypothesize, through this indirect information, that it could be considered the existence of a broad "Spasticity-Plus Syndrome" that involves, a cluster of symptoms apart from spasticity itself, the rest of the mentioned functions/symptoms, probably because they are interlinked after the increase of muscle tone and mediated, at least in part, in the same or close areas of the brainstem. If this holds true, there exists the possibility to treat several spasticity-related symptoms induced by MS pathology with a single therapy, which would permit to avoid the unnecessary adverse effects produced by polytherapy. This would result in an important advance in the symptomatic management of MS.
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Project description:BackgroundMore than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis.MethodsPatients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200.FindingsWe isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio.InterpretationAutologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection.FundingMedical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.
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Project description:ObjectiveTo retrospectively evaluate if texture-based radiomics features are able to detect interstitial lung disease (ILD) and to distinguish between the different disease stages in patients with systemic sclerosis (SSc) in comparison with mere visual analysis of high-resolution computed tomography (HRCT).MethodsSixty patients (46 females, median age 56 years) with SSc who underwent HRCT of the thorax were retrospectively analyzed. Visual analysis was performed by two radiologists for the presence of ILD features. Gender, age, and pulmonary function (GAP) stage was calculated from clinical data (gender, age, pulmonary function test). Data augmentation was performed and the balanced dataset was split into a training (70%) and a testing dataset (30%). For selecting variables that allow classification of the GAP stage, single and multiple logistic regression models were fitted and compared by using the Akaike information criterion (AIC). Diagnostic accuracy was evaluated from the area under the curve (AUC) from receiver operating characteristic (ROC) analyses, and diagnostic sensitivity and specificity were calculated.ResultsValues for some radiomics features were significantly lower (p < 0.05) and those of other radiomics features were significantly higher (p = 0.001) in patients with GAP2 compared with those in patients with GAP1. The combination of two specific radiomics features in a multivariable model resulted in the lowest AIC of 10.73 with an AUC of 0.96, 84% sensitivity, and 99% specificity. Visual assessment of fibrosis was inferior in predicting individual GAP stages (AUC 0.86; 83% sensitivity; 74% specificity).ConclusionThe correlation of radiomics with GAP stage, but not with the visually defined features of ILD-HRCT, implies that radiomics might capture features indicating severity of SSc-ILD on HRCT, which are not recognized by visual analysis.Key points• Radiomics features can predict GAP stage with a sensitivity of 84% and a specificity of almost 100%. • Extent of fibrosis on HRCT and a combined model of different visual HRCT-ILD features perform worse in predicting GAP stage. • The correlation of radiomics with GAP stage, but not with the visually defined features of ILD-HRCT, implies that radiomics might capture features on HRCT, which are not recognized by visual analysis.
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Project description:BackgroundThermal assessment of the plantar surface of the foot using spot thermometers and thermal imaging has been proven effective in diabetic foot ulcer prevention. However, with traditional cameras this is limited to single spots or a two-dimensional (2D) view of the plantar side of foot, where only 50% of the ulcers occur. To improve ulcer detection, the view has to be extended beyond 2D. Our aim is to explore for proof of concept the combination of three-dimensional (3D) models with thermal imaging for inflammation detection in diabetic foot disease.MethodFrom eight participants with a current diabetic foot ulcer we simultaneously acquired a 3D foot model and three thermal infrared images using a high-resolution medical 3D imaging system aligned with three smartphone-based thermal infrared cameras. Using spatial transformations, we aimed to map thermal images onto the 3D model, to create the 3D visualizations. Expert clinicians assessed these for quality and face validity as +, +/-, -.ResultsWe could replace the texture maps (color definitions) of the 3D model with the thermal infrared images and created the first-ever 3D thermographs of the diabetic foot. We then converted these models to 3D PDF-files compatible with the hospital IT environment. Face validity was assessed as + in six and +/- in two cases.ConclusionsWe have provided a proof of concept for the creation of clinically useful 3D thermal foot images to assess the diabetic foot skin temperature in 3D in a hospital IT environment. Future developments are expected to improve the image-processing techniques to result in easier, handheld applications and driving further research.
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