Biomarkers of treatment response in patients with progressive multiple sclerosis treated with high-dose pharmaceutical-grade biotin (MD1003).

BACKGROUND: High-dose pharmaceutical-grade biotin (MD1003) has positive effects on disability in progressive multiple sclerosis (PMS), but its mechanism of action remains unclear. The objective of our study was to quantify the effect of MD1003 in patients with PMS, using clinical response, plasma neurofilament light chain (pNfL) levels, and brain (BV) or cervical spinal cord volume (CSCV). MATERIALS AND METHODS: Forty-eight patients with PMS newly treated with MD1003 were followed during one year. Patients were assessed clinically using the Expanded Disability Status Scale (EDSS), the nine-hole peg test (9HPT), and the 25-foot walk time (25FWT). CSCV was quantified using CORDIAL software and BV using SIENA or SIENAX. We measured pNfL level using SIMOA at several time points. Bayesian linear and logistic regressions were used to evaluate potential prognostic factors. RESULTS: Treatment response, defined as a significant decrease of EDSS, 25FWT, or 9HPT at 1 year, was observed in 13 patients (27%). A gain of volume was noted in 7/24 patients for brain and in 10/19 patients for cervical spinal cord. The strongest predictors of poor treatment response were a high pNfL level at MD1003 onset (OR 0.96; 95% CI [0.91; 1]), high age at MS onset (OR 0.95; 95% CI [0.89; 1.01]), and an increase in brain lesion load during MD1003 treatment (OR 0.81; 95% CI [0.55; 1.05]). CONCLUSIONS: MD1003 treatment was associated with clinical, BV, and CSCV improvement at 1 year. The correlation between the levels of pNfL at baseline, the age at multiple sclerosis onset, and a treatment response at M12 is consistent with a better effect in less disabled patients.

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

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 T1 , B1+ and B0 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 (R1,f T2,f ), the cross-relaxation rate (R) and the bound pool transverse relaxation time (T2,r ). 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 R1,f T2,f  = 0.0129, R = 26.5 s-1 , and T2,r  = 9.1 µs, yielding an overall MPF bias of 10-4 (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.

Signal changes in enhanced T1-weighted images related to gadolinium retention: A three-time-point imaging study.

BACKGROUND AND PURPOSE: Concern has grown about the finding of gadolinium deposits in the brain after administering gadolinium-based contrast agents (GBCAs). The mechanism is unclear, and related questions remain unanswered, including the stability over time. Therefore, we conducted a three-time-point study to explore T1-weighted (W) signal changes in the dentate nucleus (DN) and globus pallidus (GP), after the first, fifth, and tenth injections of either a macrocyclic agent (gadoterate meglumine) or a linear agent (gadobenate dimeglumine). MATERIALS AND METHODS: For this retrospective, multicenter, longitudinal study, two groups of 18 (gadoterate meglumine) and 19 (gadobenate dimeglumine) patients were identified. The evolution of the signal over time was analyzed using DN/pons (DN/P) and GP/thalamus (GP/T) ratios. RESULTS: DN/P and GP/T ratios tended to increase after the fifth administration of gadobenate dimeglumine, following by a downward trend. A trend in a decrease in DN/P and GP/T ratios were found after the fifth and tenth administrations of gadoterate meglumine. CONCLUSION: After exposure to gadobenate dimeglumine, the signal intensity (SI) tended to increase after the fifth injection owing to gadolinium accumulation, however, a SI increase was not found after the tenth administration supporting the hypothesis of a slow elimination of the previously retained gadolinium (wash-out effect) from the brain or of a change in form (by dechelation), causing the signal to fade. No increasing SI was found in the DN and GP after exclusive exposure to gadoterate meglumine, thus confirming its stability. We found, instead, a trend for a significative gadolinium elimination over time.

Brain network remodelling reflects tau-related pathology prior to memory deficits in Thy-Tau22 mice.

In Alzheimer's disease, the tauopathy is known as a major mechanism responsible for the development of cognitive deficits. Early biomarkers of such affectations for diagnosis/stratification are crucial in Alzheimer's disease research, and brain connectome studies increasingly show their potential establishing pathology fingerprints at the network level. In this context, we conducted an in vivo multimodal MRI study on young Thy-Tau22 transgenic mice expressing tauopathy, performing resting state functional MRI and structural brain imaging to identify early connectome signatures of the pathology, relating with histological and behavioural investigations. In the prodromal phase of tauopathy, before the emergence of cognitive impairments, Thy-Tau22 mice displayed selective modifications of brain functional connectivity involving three main centres: hippocampus (HIP), amygdala (AMG) and the isocortical areas, notably the somatosensory (SS) cortex. Each of these regions showed differential histopathological profiles. Disrupted ventral HIP-AMG functional pathway and altered dynamic functional connectivity were consistent with high pathological tau deposition and astrogliosis in both hippocampus and amygdala, and significant microglial reactivity in amygdalar nuclei. These patterns were concurrent with widespread functional hyperconnectivity of memory-related circuits of dorsal hippocampus-encompassing dorsal HIP-SS communication-in the absence of significant cortical histopathological markers. These findings suggest the coexistence of two intermingled mechanisms of response at the functional connectome level in the early phases of pathology: a maladaptive and a likely compensatory response. Captured in the connectivity patterns, such first responses to pathology could further be used in translational investigations as a lead towards an early biomarker of tauopathy as well as new targets for future treatments.

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.

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.

Small Animal Shanoir (SAS) A Cloud-Based Solution for Managing Preclinical MR Brain Imaging Studies.

Clinical multicenter imaging studies are frequent and rely on a wide range of existing tools for sharing data and processing pipelines. This is not the case for preclinical (small animal) studies. Animal population imaging is still in infancy, especially because a complete standardization and control of initial conditions in animal models across labs is still difficult and few studies aim at standardization of acquisition and post-processing techniques. Clearly, there is a need of appropriate tools for the management and sharing of data, post-processing and analysis methods dedicated to small animal imaging. Solutions developed for Human imaging studies cannot be directly applied to this specific domain. In this paper, we present the Small Animal Shanoir (SAS) solution for supporting animal population imaging using tools compatible with open data. The integration of automated workflow tools ensures accessibility and reproducibility of research outputs. By sharing data and imaging processing tools, hosted by SAS, we promote data preparation and tools for reproducibility and reuse, and participation in multicenter or replication "open science" studies contributing to the improvement of quality science in preclinical domain. SAS is a first step for promoting open science for small animal imaging and a contribution to the valorization of data and pipelines of reference.

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

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.

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

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).

Emotional disturbances in multiple sclerosis: A neuropsychological and fMRI study.

BACKGROUND: Emotional disturbances in multiple sclerosis (MS) are often explored in terms of affect recognition, with controversial results that likely reflect the high lesional heterogeneity. Patients' emotional experience, however, has seldom been studied and has never been explored using fMRI. OBJECTIVES: To explore the emotional experience in MS and compare these data with fMRI measurements using for the first time real-life emotional scenes differing in valence and arousal. METHODS: Twenty-five right-handed women with relapsing-remitting MS and 27 right-handed age-, sex-, and education-matched healthy controls visualized during an fMRI session, emotional scenes taken from the international affect picture system (IAPS) and differing in valence (positive, negative, neutral) and arousal (ranging from calm to excited). During a post-scanning debriefing, participants were asked to look again at each image and score it in terms of valence and arousal sensation on a scale of 1-9. RESULTS: Cognitively well-preserved MS subjects presented a significantly more scattered emotional experience compared to controls in response to positive and negative pictures. In fMRI, MS patients also presented a higher variability of response when compared to controls in left inferior orbitofrontal cortex for positive stimulations. For negative condition, no significant results were observed between the two groups. However, a trend was detected in left amygdala, right fusiform gyrus, right caudate nucleus and right pallidum for negative stimulations. CONCLUSION: In response to emotional stimuli, MS subjects presented a scattered emotional experience subtended by a greater variability of brain response, highlighting an emotional pattern not previously reported in MS patients.

Multi-parametric quantitative MRI reveals three different white matter subtypes.

INTRODUCTION: Magnetic resonance imaging (MRI) shows slight spatial variations in brain white matter (WM). We used quantitative multi-parametric MRI to evaluate in what respect these inhomogeneities could correspond to WM subtypes with specific characteristics and spatial distribution. MATERIALS AND METHODS: Twenty-six controls (12 women, 38 ±9 Y) took part in a 60-min session on a 3T scanner measuring 7 parameters: R1 and R2, diffusion tensor imaging which allowed to measure Axial and Radial Diffusivity (AD, RD), magnetization transfer imaging which enabled to compute the Macromolecular Proton Fraction (MPF), and a susceptibility-weighted sequence which permitted to quantify R2* and magnetic susceptibility (χm). Spatial independent component analysis was used to identify WM subtypes with specific combination of quantitative parameters values. RESULTS: Three subtypes could be identified. t-WM (track) mostly mapped on well-formed projection and commissural tracts and came with high AD values (all p < 10(-18)). The two other subtypes were located in subcortical WM and overlapped with association fibers: f-WM (frontal) was mostly anterior in the frontal lobe whereas c-WM (central) was underneath the central cortex. f-WM and c-WM had higher MPF values, indicating a higher myelin content (all p < 1.7 10(-6)). This was compatible with their larger χm and R2, as iron is essentially stored in oligodendrocytes (all p < 0.01). Although R1 essentially showed the same, its higher value in t-WM relative to c-WM might be related to its higher cholesterol concentration. CONCLUSIONS: Thus, f- and c-WMs were less structured, but more myelinated and probably more metabolically active regarding to their iron content than WM related to fasciculi (t-WM). As known WM bundles passed though different WM subtypes, myelination might not be uniform along the axons but rather follow a spatially consistent regional variability. Future studies might examine the reproducibility of this decomposition and how development and pathology differently affect each subtype.

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

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.

A diffusion-based method for long-T2 suppression in steady state sequences: Validation and application for 3D-UTE imaging.

PURPOSE: To introduce a novel method for long-T2 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-T2 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-T2 component signal cancellation through diffusion effects is addressed, and the condition met for sets of sequence parameters. Simultaneously, the short-T2 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-T2 components, as well as on an ex vivo mouse head. RESULTS: Within equal scan times, the proposed method allowed for an efficient long-T2 signal suppression, and expectedly yielded a higher signal to noise ratio in short-T2 structures compared to the IR-UTE technique, although an intrinsic short-T2 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-T2 suppression results in a less penalizing method to generate a high and selective contrast in short-T2 components. Magn Reson Med 80:548-559, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Which is the most appropriate strategy for conducting multivariate voxel-based group studies on diffusion tensors?

There is a real need in the neuroscience community for efficient tools to compare Diffusion Tensor Magnetic Resonance Imaging across cohorts of subjects. Most studies focus on the comparison of scalar images such as fractional anisotropy or mean diffusivity. Although different statistical frameworks have been proposed to compare the whole diffusion tensor information, they are still seldom used in neuroimaging studies. In this paper, we investigate on both simulated and real data whether there is a real added value of considering the whole tensor information for conducting voxel-based group studies. Then, we compare two statistical tests dedicated to tensor, namely the Cramér test and a tensor-based extension of the General Linear Model (GLM), the latter presenting the advantage to account for covariates. We also evaluate the impact of different metrics (Euclidean, Log-Euclidean and affine-invariant Riemannian metrics) for estimating the GLM parameters. Finally, we address the problem of interpreting the change detection maps obtained by tensor-based methods by proposing a way to characterize each of the detected clusters according to several scalar indices. Our study suggests that if there is no prior assumption about the nature of the expected changes, it is really preferable to use tensor-based rather than scalar-based statistical analysis. The Cramér test can advantageously be used when no confounding variable hampers the group comparison, otherwise the GLM should be considered. Finally, the different metrics show similar performance in the real scenario, with a significant computational overhead for the Riemannian framework.

Cortical Thickness in Dementia with Lewy Bodies and Alzheimer's Disease: A Comparison of Prodromal and Dementia Stages.

OBJECTIVES: To assess and compare cortical thickness (CTh) of patients with prodromal Dementia with Lewy bodies (pro-DLB), prodromal Alzheimer's disease (pro-AD), DLB dementia (DLB-d), AD dementia (AD-d) and normal ageing. METHODS: Study participants(28 pro-DLB, 27 pro-AD, 31 DLB-d, 54 AD-d and 33 elderly controls) underwent 3Tesla T1 3D MRI and detailed clinical and cognitive assessments. We used FreeSurfer analysis package to measure CTh and investigate patterns of cortical thinning across groups. RESULTS: Comparison of CTh between pro-DLB and pro-AD (p<0.05, FDR corrected) showed more right anterior insula thinning in pro-DLB, and more bilateral parietal lobe and left parahippocampal gyri thinning in pro-AD. Comparison of prodromal patients to healthy elderly controls showed the involvement of the same regions. In DLB-d (p<0.05, FDR corrected) cortical thinning was found predominantly in the right temporo-parietal junction, and insula, cingulate, orbitofrontal and lateral occipital cortices. In AD-d(p<0.05, FDR corrected),the most significant areas affected included the entorhinal cortices, parahippocampal gyri and parietal lobes. The comparison of AD-d and DLB-d demonstrated more CTh in AD-d in the left entorhinal cortex (p<0.05, FDR corrected). CONCLUSION: Cortical thickness is a sensitive measure for characterising patterns of grey matter atrophy in early stages of DLB distinct from AD. Right anterior insula involvement may be a key region at the prodromal stage of DLB and needs further investigation.

Evaluation of an albumin-binding gadolinium contrast agent in multiple sclerosis.

OBJECTIVE: The first goal of this study is to compare gadofosveset trisodium--a gadolinium agent that reversibly binds to albumin--to an extracellular contrast agent (Gd-DOTA) for the detection of multiple sclerosis lesions. The second goal is to determine the best postinjection time for the detection of contrast-enhanced lesions. METHODS: Nine patients underwent 2 MRI examinations, respectively, after Gd-DOTA (0.1 mmol/kg) and gadofosveset trisodium (0.03 mmol/kg) administration. Axial T1 spin-echo-weighted images were acquired at several time points after injection (4 minutes for Gd-DOTA, and 4, 8, 12, 16, 20 minutes, 1 hour, and 4 hours for gadofosveset trisodium). Images were analyzed by 4 neuroradiologists who marked the contrast-enhanced lesions and, for each marked lesion, chose the acquisition they preferred and segmented the lesion on their preferred acquisition. RESULTS: The 4-hour gadofosveset trisodium acquisition was ranked best for the 3 tasks: contrast-enhanced lesions were seen by more readers, they preferred this acquisition, and improvements of the signal enhancement (125%) and of the contrast-to-noise ratio (73%) vs Gd-DOTA at 4 minutes were observed (p < 0.05). CONCLUSION: Gadofosveset trisodium after 4 hours significantly improves the number of detected contrast-enhanced multiple sclerosis lesions as compared to Gd-DOTA after 4 minutes, even though the injected dose of gadolinium was two-thirds lower.

Integrating digital topology in image-processing libraries.

This paper describes a method to integrate digital topology informations in image-processing libraries. This additional information allows a library user to write algorithms respecting topological constraints, for example, a seed fill or a skeletonization algorithm. As digital topology is absent from most image-processing libraries, such constraints cannot be fulfilled. We describe and give code samples for all the structures necessary for this integration, and show a use case in the form of a homotopic thinning filter inside ITK. The obtained filter can be up to a hundred times as fast as ITK's thinning filter and works for any image dimension. This paper mainly deals of integration within ITK, but can be adapted with only minor modifications to other image-processing libraries.

An efficient and generic extension to ITK to process arbitrary shaped regions of interest.

The paper describes a software method to extend ITK (Insight ToolKit, supported by the National Library of Medicine), leading to ITK++. This method, which is based on the extension of the iterator design pattern, allows the processing of regions of interest with arbitrary shapes, without modifying the existing ITK code. We experimentally evaluate this work by considering the practical case of the liver vessel segmentation from CT-scan images, where it is pertinent to constrain processings to the liver area. Experimental results clearly prove the interest of this work: for instance, the anisotropic filtering of this area is performed in only 16 s with our proposed solution, while it takes 52 s using the native ITK framework. A major advantage of this method is that only add-ons are performed: this facilitates the further evaluation of ITK++ while preserving the native ITK framework.