Impact of follow ups, time interval and study duration in diffusion & myelin MRI clinical study in MS.

It is currently unknown how quantitative diffusion and myelin MRI designs affect the results of a longitudinal study. We used two independent datasets containing 6 monthly MRI measurements from 20 healthy controls and 20 relapsing-remitting multiple sclerosis (RR-MS) patients. Six designs were tested, including 3 MRI acquisitions, either over 6 months or over a shorter study duration, with balanced (same interval) or unbalanced (different interval) time intervals between MRI acquisitions. First, we show that in RR-MS patients, the brain changes over time obtained with 3 MRI acquisitions were similar to those observed with 5 MRI acquisitions and that designs with an unbalanced time interval showed the highest similarity, regardless of study duration. No significant brain changes were found in the healthy controls over the same periods. Second, the study duration affects the sample size in the RR-MS dataset; a longer study requires more subjects and vice versa. Third, the number of follow-up acquisitions and study duration affect the sensitivity and specificity of the associations with clinical parameters, and these depend on the white matter bundle and MRI measure considered. Together, this suggests that the optimal design depends on the assumption of the dynamics of change in the target population and the accuracy required to capture these dynamics. Thus, this work provides a better understanding of key factors to consider in a longitudinal study and provides clues for better strategies in clinical trial design.

High-frequency longitudinal white matter diffusion- and myelin-based MRI database: Reliability and variability.

Assessing the consistency of quantitative MRI measurements is critical for inclusion in longitudinal studies and clinical trials. Intraclass coefficient correlation and coefficient of variation were used to evaluate the different consistency aspects of diffusion- and myelin-based MRI measures. Multi-shell diffusion and inhomogeneous magnetization transfer data sets were collected from 20 healthy adults at a high-frequency of five MRI sessions. The consistency was evaluated across whole bundles and the track-profile along the bundles. The impact of the fiber populations on the consistency was also evaluated using the number of fiber orientations map. For whole and profile bundles, moderate to high reliability of diffusion and myelin measures were observed. We report higher reliability of measures for multiple fiber populations than single. The overall portrait of the most consistent measurements and bundles drawn from a wide range of MRI techniques presented here will be particularly useful for identifying reliable biomarkers capable of detecting, monitoring and predicting white matter changes in clinical applications and has the potential to inform patient-specific treatment strategies.

DORIS: A diffusion MRI-based 10 tissue class deep learning segmentation algorithm tailored to improve anatomically-constrained tractography.

Modern tractography algorithms such as anatomically-constrained tractography (ACT) are based on segmentation maps of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF). These maps are generally estimated from a T1-weighted (T1w) image and then registered in diffusion weighted images (DWI) space. Registration of T1w to diffusion space and partial volume estimation are challenging and rarely voxel-perfect. Diffusion-based segmentation would, thus, potentially allow not to have higher quality anatomical priors injected in the tractography process. On the other hand, even if FA-based tractography is possible without T1 registration, the literature shows that this technique suffers from multiple issues such as holes in the tracking mask and a high proportion of generated broken and anatomically implausible streamlines. Therefore, there is an important need for a tissue segmentation algorithm that works directly in the native diffusion space. We propose DORIS, a DWI-based deep learning segmentation algorithm. DORIS outputs 10 different tissue classes including WM, GM, CSF, ventricles, and 6 other subcortical structures (putamen, pallidum, hippocampus, caudate, amygdala, and thalamus). DORIS was trained and validated on a wide range of subjects, including 1,000 individuals from 22 to 90 years old from clinical and research DWI acquisitions, from 5 public databases. In the absence of a "true" ground truth in diffusion space, DORIS used a silver standard strategy from Freesurfer output registered onto the DWI. This strategy is extensively evaluated and discussed in the current study. Segmentation maps provided by DORIS are quantitatively compared to Freesurfer and FSL-fast and the impacts on tractography are evaluated. Overall, we show that DORIS is fast, accurate, and reproducible and that DORIS-based tractograms produce bundles with a longer mean length and fewer anatomically implausible streamlines.

Tractography of the external capsule and cognition: A diffusion MRI study of cholinergic fibers.

INTRODUCTION: White matter changes (WMC) in the cholinergic tracts contribute to executive dysfunction in the context of cognitive aging. WMC in the external capsule have been associated with executive dysfunction. The objectives of this study were to: 1) Characterize the lateral cholinergic tracts (LCT) and the superior longitudinal fasciculus (SLF). 2) Evaluate the association between diffusion measures within those tracts and cognitive performance. METHODS: Neuropsychological testing and high angular resolution diffusion imaging (HARDI) of 34 healthy elderly participants was done, followed by anatomically constrained probabilistic tractography reconstruction robust to crossing fibers. The external capsule was manually segmented on a mean T1 image then merged with an atlas, allowing extraction of the LCT. Diffusion tensor imaging (DTI) and HARDI-based measures were obtained. RESULTS: Correlations between diffusion measures in the LCT and the time of completion of Stroop (left LCT radial and medial diffusivity), the Symbol Search score (right LCT apparent fiber density) and the motor part of Trail-B (left LCT axial and radial diffusivity) were observed. Correlations were also found with diffusion measures in the SLF. WMC burden was low, and no correlation was found with diffusion measures or cognitive performance. DISCUSSION: DTI and HARDI, with isolation of strategic white matter tracts for cognitive functions, represent complimentary tools to better understand the complex process of brain aging.

Free Water in White Matter Differentiates MCI and AD From Control Subjects.

Recent evidence shows that neuroinflammation plays a role in many neurological diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD), and that free water (FW) modeling from clinically acquired diffusion MRI (DTI-like acquisitions) can be sensitive to this phenomenon. This FW index measures the fraction of the diffusion signal explained by isotropically unconstrained water, as estimated from a bi-tensor model. In this study, we developed a simple but powerful whole-brain FW measure designed for easy translation to clinical settings and potential use as a priori outcome measure in clinical trials. These simple FW measures use a "safe" white matter (WM) mask without gray matter (GM)/CSF partial volume contamination (WM safe) near ventricles and sulci. We investigated if FW inside the WM safe mask, including and excluding areas of white matter damage such as white matter hyperintensities (WMHs) as shown on T2 FLAIR, computed across the whole white matter could be indicative of diagnostic grouping along the AD continuum. After careful quality control, 81 cognitively normal controls (NC), 103 subjects with MCI and 42 with AD were selected from the ADNIGO and ADNI2 databases. We show that MCI and AD have significantly higher FW measures even after removing all partial volume contamination. We also show, for the first time, that when WMHs are removed from the masks, the significant results are maintained, which demonstrates that the FW measures are not just a byproduct of WMHs. Our new and simple FW measures can be used to increase our understanding of the role of inflammation-associated edema in AD and may aid in the differentiation of healthy subjects from MCI and AD patients.

Diffusion MRI monitoring of specific structures in the irradiated rat brain.

PURPOSE: The analysis of biological and mesoscopic structures properties by diffusion MRI (dMRI) in brain after radiation therapy remains challenging. In our study, we described the consequences associated with an unwanted dose to healthy tissue, assessing radiation-induced brain alterations of living rats with dMRI compared to histopathology and behavioral assays. METHODS: The right primary motor cortex M1 of the rat brain was targeted by stereotactic radiosurgery with a mean radiation dose of 41 Gy. Multidirectional single b-value dMRI data of the whole brain were acquired with a 7T small-animal scanner before irradiation until 110 days post-irradiation. Diffusion tensor imaging metrics, such as fractional anisotropy (FA), mean diffusivity (MD), axial (AD), and radial diffusivity (RD) were compared to brain alterations detected by immunohistochemistry and motor performances measured by a behavioral test. RESULTS: Between days 90 and 110, radiation necrosis was observed into the white matter spreading into M1 . Results showed a reduction of FA in the corpus callosum and in the striatum, which was driven by an increase in RD from 90 to 110 days post-irradiation, whereas only RD increased in M1 . Values of RD and AD increased in the irradiated hippocampus, while FA remained constant. Moreover, an increased MD, AD and RD was observed in the hippocampus that was probably related to inflammation as well as reactive astrogliosis after 110 days post-irradiation. Finally, rats did not exhibit locomotor deficits. CONCLUSIONS: dMRI metrics can assess brain damage; the sensitivity of dMRI metrics depends on the brain region.

Improving the evaluation of cardiac function in rats at 7T with denoising filters: a comparison study.

BACKGROUND: We investigate the use of different denoising filters on low signal-to-noise ratio cardiac images of the rat heart acquired with a birdcage volume coil at 7T. Accuracy and variability of cardiac function parameters were measured from manual segmentation of rat heart images with and without filtering. METHODS: Ten rats were studied using a 7T Varian system. End-diastolic and end-systolic volumes, ejection fraction and left ventricle mass (LVM) were calculated from manual segmentation by two experts on cine-FLASH short-axis slices covering the left ventricle. Series were denoised with an anisotropic diffusion filter, a whole variation regularization or an optimized Rician non-local means (ORNLM) filtering technique. The effect of the different filters was evaluated by the calculation of signal-to-noise (SNR) and contrast-to-noise (CNR) ratios, followed by a study of intra- and inter-expert variability of the measurement of physiological parameters. The calculated LVM was compared to the LVM obtained by weighing the heart ex vivo. RESULTS: The SNR and the CNR increased after application of the different filters. The performance of the ORNLM filter was superior for all the parameters of the cardiac function, as judged from the inter- and intra-observer variabilities. Moreover, this filtering technique resulted in the lowest variability in the LVM evaluation. CONCLUSIONS: In cardiac MRI of rats, filtering is an interesting alternative that yields better contrast between myocardium and surrounding tissues and the ORNLM filter provided the largest improvements.

"On-command" dissolvable tympanostomy tube in the chinchilla model: A proof of concept.

OBJECTIVES: To prove the concept that a dissolvable "on-command" tympanostomy tube placed into the tympanic membrane of a chinchilla can dissolve when a benign solution is applied and result in a well healed tympanic membrane without histologic evidence of injury. STUDY DESIGN: Prospective Randomized Single-Subject Controlled Trial. METHODS: Prototype tympanostomy tubes were fabricated from poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co- methyl methacrylate) (PBM). "In vitro" dissolution studies were performed with applications of the benign chemical, hydrogen peroxide (HP). PBM tubes were placed into ten chinchilla tympanic membranes matched with standard plastic tubes placed into the contralateral side. All 20 tubes were exposed to HP for 21 days with serial endoscopic examinations. In vitro PBM tubes were weighed before and after interventions and compared to control tubes. In vivo photo documentation was used to show progression of dissolution and histologic slides were obtained to show the effect of the PBM on surrounding tissues. RESULTS: Compared to control tubes, all those exposed to hydrogen peroxide had a statistically significant reduction in weight (p < 0.01). After placement into the tympanic membrane of chinchillas, all PBM tubes dissolved within 21 days of hydrogen peroxide treatment leaving behind histologically normal, intact tympanic membranes. CONCLUSION: Our PBM tubes dissolve "on-command" in a chinchilla model when exposed to treatment with a benign chemical. Dissolvable "on-command" tympanostomy tubes may reduce significant complications related to pediatric tympanostomy tube use.

Biocompatibility of "On-command" dissolvable tympanostomy tube in the rat model.

OBJECTIVES/HYPOTHESIS: A prototype tympanostomy tube, composed of polybutyl/methyl methacrylate-co-dimethyl amino ethyl methacrylate (PBM), was tested to 1) evaluate the effect of PBM tubes on rat dermis as a corollary for biocompatibility and (2) to observe the efficacy of dissolution with isopropyl alcohol (iPrOH) and ethanol (EtOH). STUDY DESIGN: Original animal experiment and bench testing. METHODS: A two-part study was conducted to assess biocompatible substance with inducible dissolvability as a critical characteristic for a newly engineered tympanostomy tube. First, tympanostomy tubes were inserted subcutaneously in 10 rats, which served as an animal model for biosafety, and compared to traditional tubes with respect to histologic reaction. Tissue surrounding the PBM prototype tubes was submitted for histopathology and demonstrated no tissue reactivity or signs of major inflammation. In the second part, we evaluated the dissolvability of the tube with either isopropyl alcohol, ethanol, ofloxacin, ciprodex, water, and soapy water. PBM tubes were exposed to decreasing concentrations of iPrOH and EtOH with interval qualitative assessment of dissolution. RESULTS: Histologic examination did not reveal pathology with PBM tubes. Concentrations of at least 50% iPrOH and EtOH dissolve PBM tubes within 48 hours, whereas concentrations of at least 75% iPrOH and EtOH were required for dissolution when exposure was limited to four 20-minute intervals. CONCLUSIONS: PBM is biocompatible in the rat model. Additionally, PBM demonstrates rapid dissolution upon alcohol-based stimuli, validating the proof-of-concept of dissolvable on-command or biocommandible ear tubes. Further testing of PBM is needed with a less ototoxic dissolver and in a better simulated middle ear environment before testing can be performed in humans. LEVEL OF EVIDENCE: NA Laryngoscope, 127:956-961, 2017.

Biofunctionalized prussian blue nanoparticles for multimodal molecular imaging applications.

Multimodal, molecular imaging allows the visualization of biological processes at cellular, subcellular, and molecular-level resolutions using multiple, complementary imaging techniques. These imaging agents facilitate the real-time assessment of pathways and mechanisms in vivo, which enhance both diagnostic and therapeutic efficacy. This article presents the protocol for the synthesis of biofunctionalized Prussian blue nanoparticles (PB NPs)--a novel class of agents for use in multimodal, molecular imaging applications. The imaging modalities incorporated in the nanoparticles, fluorescence imaging and magnetic resonance imaging (MRI), have complementary features. The PB NPs possess a core-shell design where gadolinium and manganese ions incorporated within the interstitial spaces of the PB lattice generate MRI contrast, both in T1 and T2-weighted sequences. The PB NPs are coated with fluorescent avidin using electrostatic self-assembly, which enables fluorescence imaging. The avidin-coated nanoparticles are modified with biotinylated ligands that confer molecular targeting capabilities to the nanoparticles. The stability and toxicity of the nanoparticles are measured, as well as their MRI relaxivities. The multimodal, molecular imaging capabilities of these biofunctionalized PB NPs are then demonstrated by using them for fluorescence imaging and molecular MRI in vitro.

Manganese-containing Prussian blue nanoparticles for imaging of pediatric brain tumors.

Pediatric brain tumors (PBTs) are a leading cause of death in children. For an improved prognosis in patients with PBTs, there is a critical need to develop molecularly-specific imaging agents to monitor disease progression and response to treatment. In this paper, we describe manganese-containing Prussian blue nanoparticles as agents for molecular magnetic resonance imaging (MRI) and fluorescence-based imaging of PBTs. Our core-shell nanoparticles consist of a core lattice structure that incorporates and retains paramagnetic Mn(2+) ions, and generates MRI contrast (both negative and positive). The biofunctionalized shell is comprised of fluorescent avidin, which serves the dual purpose of enabling fluorescence imaging and functioning as a platform for the attachment of biotinylated ligands that target PBTs. The surfaces of our nanoparticles are modified with biotinylated antibodies targeting neuron-glial antigen 2 or biotinylated transferrin. Both neuron-glial antigen 2 and the transferrin receptor are protein markers overexpressed in PBTs. We describe the synthesis, biofunctionalization, and characterization of these multimodal nanoparticles. Further, we demonstrate the MRI and fluorescence imaging capabilities of manganese-containing Prussian blue nanoparticles in vitro. Finally, we demonstrate the potential of these nanoparticles as PBT imaging agents by measuring their organ and brain biodistribution in an orthotopic mouse model of PBTs using ex vivo fluorescence imaging.

Biofunctionalized gadolinium-containing prussian blue nanoparticles as multimodal molecular imaging agents.

Molecular imaging agents enable the visualization of phenomena with cellular and subcellular level resolutions and therefore have enormous potential in improving disease diagnosis and therapy assessment. In this article, we describe the synthesis, characterization, and demonstration of core-shell, biofunctionalized, gadolinium-containing Prussian blue nanoparticles as multimodal molecular imaging agents. Our multimodal nanoparticles combine the advantages of MRI and fluorescence. The core of our nanoparticles consists of a Prussian blue lattice with gadolinium ions located within the lattice interstices that confer high relaxivity to the nanoparticles providing MRI contrast. The relaxivities of our nanoparticles are nearly nine times those observed for the clinically used Magnevist. The nanoparticle MRI core is biofunctionalized with a layer of fluorescently labeled avidin that enables fluorescence imaging. Biotinylated antibodies are attached to the surface avidin and confer molecular specificity to the nanoparticles by targeting cell-specific biomarkers. We demonstrate our nanoparticles as multimodal molecular imaging agents in an in vitro model consisting of a mixture of eosinophilic cells and squamous epithelial cells. Our nanoparticles specifically detect eosinophilic cells and not squamous epithelial cells, via both fluorescence imaging and MRI in vitro. These results suggest the potential of our biofunctionalized Prussian blue nanoparticles as multimodal molecular imaging agents in vivo.

Synthesis and size control of iron(II) hexacyanochromate(III) nanoparticles and the effect of particle size on linkage isomerism.

The controlled synthesis of monodisperse nanoparticles of the cubic Prussian blue analogue iron(II) hexacyanochromate(III) is reported along with a kinetic study, using cyanide stretching frequencies, showing the variations of the activation energy (E(a)) of the linkage isomerism as a function of the particle size. Highly reproducible, cubic-shaped iron(II) hexacyanochromate(III) nanocrystals, with sizes ranging from 2 to 50 nm, are synthesized using a microemulsion technique, whereas a bulk synthesis yields nonuniform less monodisperse particles with sizes greater than 100 nm. Monitoring the cyanide stretching frequency with FTIR spectroscopy shows that the rate of isomerization is faster for smaller particles. Moreover, a kinetic analysis at different temperatures (255 K ≤ T ≤ 321 K) gives insight into the evolution of E(a) with the particle size. Finally, time-dependent powder X-ray diffraction and net magnetization confirm the FTIR observations. The data are interpreted within the concept of a simple two-component model with different activation energies for structures near the surface of the solid and within the bulk.

Synthesis and characterization of a tris(2-hydroxyphenyl)methane-based cryptand and its triiron(III) complex.

Reaction of tris(5-amino-2-ethoxy-3-isopropylphenyl)methane and pyridine-2,6-dicarbonyl-dichloride affords a multi-dentate cryptand in 48% yield. Metallation with iron(III) chloride results in a substantial conformational change of this ligand to give a trianionic triiron(III) complex. Ferric cations line the periphery of the internal cavity with each adopting a square pyramidal N(3)Cl(2) coordination environment.

DNA surface modified gadolinium phosphate nanoparticles as MRI contrast agents.

Oligonucleotide modified gadolinium phosphate nanoparticles have been prepared and their magnetic resonance relaxivity properties measured. Nanoparticles of GdPO4·H2O were synthesized in a water/oil microemulsion using IGEPAL CO-520 as surfactant, resulting in 50 to 100 nm particles that are highly dispersible and stable in water. Using surface modification chemistry previously established for zirconium phosphonate surfaces, the particles are directly modified with 5'-phosphate terminated oligonucleotides, and the specific interaction of the divalent phosphate with Gd(3+) sites at the surface is demonstrated. The ability of the modified nanoparticles to act as MRI contrast agents was determined by performing MR relaxivity measurements at 14.1 T. Solutions of nanopure water, Feridex, and Omniscan (FDA approved contrast agents) in 0.25% agarose were used for comparison and control purposes. MRI data confirm that GdPO4·H2O nanoparticles have relaxivities (r1, r2) comparable to those of commercially available contrast agents. In addition, the data suggest that biofunctionalization of the surface of the nanoparticles does not prevent their function as MRI contrast agents.

Photoinduced magnetism in core/shell Prussian blue analogue heterostructures of K(j)Ni(k)[Cr(CN)6]l·nH2O with Rb(a)Co(b)[Fe(CN)6]c·mH2O.

Core/shell and core/shell/shell particles comprised of the Prussian blue analogues K(j)Ni(k)[Cr(CN)(6)](l)·nH(2)O (A) and Rb(a)Co(b)[Fe(CN)(6)](c)·mH(2)O (B) have been prepared for the purpose of studying persistent photoinduced magnetization in the heterostructures. Synthetic procedures have been refined to allow controlled growth of relatively thick (50-100 nm) consecutive layers of the Prussian blue analogues while minimizing the mixing of materials at the interfaces. Through changes in the order in which the two components are added, particles with AB, ABA, BA, and BAB sequences have been prepared. The two Prussian blue analogues were chosen because B is photoswitchable, and A is ferromagnetic with a relatively high magnetic ordering temperature, ~70 K, although it is not known to exhibit photoinduced changes in its magnetic properties. Magnetization measurements on the heterostructured particles performed prior to irradiation show behavior characteristic of the individual components. On the other hand, after irradiation with visible light, the heterostructures undergo persistent photoinduced changes in magnetization associated with both the B and A analogues. The results suggest that structural changes in the photoactive B component distort the normally photoinactive A component, leading to a change in its magnetization.