An Open-Source Tool for Anisotropic Radiation Therapy Planning in Neuro-oncology Using DW-MRI Tractography.

There is evidence from histopathological studies that glioma tumor cells migrate preferentially along large white matter bundles. If the peritumoral white matter structures can be used to predict the likely trajectory of migrating tumor cells outside of the surgical margin, then this information could be used to inform the delineation of radiation therapy (RT) targets. In theory, an anisotropic expansion that takes large white matter bundle anatomy into account may maximize the chances of treating migrating cancer cells and minimize the amount of brain tissue exposed to high doses of ionizing radiation. Diffusion-weighted MRI (DW-MRI) can be used in combination with fiber tracking algorithms to model the trajectory of large white matter pathways using the direction and magnitude of water movement in tissue. The method presented here is a tool for translating a DW-MRI fiber tracking (tractography) dataset into a white matter path length (WMPL) map that assigns each voxel the shortest distance along a streamline back to a specified region of interest (ROI). We present an open-source WMPL tool, implemented in the package Diffusion Imaging in Python (DIPY), and code to convert the resulting WMPL map to anisotropic contours for RT in a commercial treatment planning system. This proof-of-concept lays the groundwork for future studies to evaluate the clinical value of incorporating tractography modeling into treatment planning

Quantitative Imaging of Single, Unstained Viruses with Coherent X-rays

Since Perutz, Kendrew and colleagues unveiled the structure of hemoglobin and myoglobin based on X-ray diffraction analysis in the 1950s, X-ray crystallography has become the primary methodology used to determine the 3D structure of macromolecules. However, biological specimens such as cells, organelles, viruses and many important macromolecules are difficult or impossible to crystallize, and hence their structures are not accessible by crystallography. Here we report, for the first time, the recording and reconstruction of X-ray diffraction patterns from single, unstained viruses. The structure of the viral capsid inside a virion was visualized. This work opens the door for quantitative X-ray imaging of a broad range of specimens from protein machineries, viruses and organelles to whole cells. Moreover, our experiment is directly transferable to the use of X-ray free electron lasers, and represents a major experimental milestone towards the X-ray imaging of single macromolecules.Comment: 16 pages, 5 figure

An MRI Study of Symptomatic Adhesive Capsulitis

Background: Appilication of MR imaging to diagnose Adhesive Capsulitis (AC) has previously been described. However, there is insufficient information available for the MRI analysis of AC. This study is to describe and evaluate the pathomorphology of the shoulder in Asian patients with AC compared to healthy volunteers. Methodology/Principal Findings: 60 Asian patients with clinically diagnosed AC and 60 healthy volunteers without frozen shoulder underwent MRI of the shoulder joint. All subjects who were age- and sex-matched control ones underwent routine MRI scans of the affected shoulder, including axial, oblique coronal, oblique sagittal T1WI SE and coronal oblique T2WI FSE sequences. Significant abnormal findings were observed on MRI, especially at the rotator cuff interval. The coracohumeral ligament (CHL), articular capsule thickness in the rotator cuff interval as well as the fat space under coracoid process were evaluated. MRI showed that patients with adhesive capsulitis had a significantly thickened coracohumeral ligament and articular capsule in the rotator cuff interval compared to the control subjects (4.2 vs. 2.4 mm, 7.2 vs. 4.4 mm; p<0.05). Partial or complete obliteration of the subcoracoid fat triangle was significantly more frequent in patients with adhesive capsulitis compared with control subjects (73% vs. 13%, 26% vs. 1.6%; p<0.001). Synovitis-like abnormality around the long biceps tendon was significantly more common in patients with adhesive capsulitis than in control subjects. With regards to the inter-observer variability, two MR radiologists had an excellent kappa value of 0.86. Conclusions/Significance: MRI can be used to show characteristic findings in diagnosing AC. Thickening of the CHL and the capsule at the rotator cuff interval and complete obliteration of the fat triangle under the coracoid process have been shown to be the most characteristic MR findings seen with AC

Frontal white matter tracts sustaining speech production in primary progressive aphasia

In primary progressive aphasia (PPA), speech and language difficulties are caused by neurodegeneration of specific brain networks. In the nonfluent/agrammatic variant (nfvPPA), motor speech and grammatical deficits are associated with atrophy in a left fronto-insular-striatal network previously implicated in speech production. In vivo dissection of the crossing white matter (WM) tracts within this "speech production network" is complex and has rarely been performed in health or in PPA. We hypothesized that damage to these tracts would be specific to nfvPPA and would correlate with differential aspects of the patients' fluency abilities. We prospectively studied 25 PPA and 21 healthy individuals who underwent extensive cognitive testing and 3 T MRI. Using residual bootstrap Q-ball probabilistic tractography on high angular resolution diffusion-weighted imaging (HARDI), we reconstructed pathways connecting posterior inferior frontal, inferior premotor, insula, supplementary motor area (SMA) complex, striatum, and standard ventral and dorsal language pathways. We extracted tract-specific diffusion tensor imaging (DTI) metrics to assess changes across PPA variants and perform brain-behavioral correlations. Significant WM changes in the left intrafrontal and frontostriatal pathways were found in nfvPPA, but not in the semantic or logopenic variants. Correlations between tract-specific DTI metrics with cognitive scores confirmed the specific involvement of this anterior-dorsal network in fluency and suggested a preferential role of a posterior premotor-SMA pathway in motor speech. This study shows that left WM pathways connecting the speech production network are selectively damaged in nfvPPA and suggests that different tracts within this system are involved in subcomponents of fluency. These findings emphasize the emerging role of diffusion imaging in the differential diagnosis of neurodegenerative diseases

Dipy, a library for the analysis of diffusion MRI data

Diffusion Imaging in Python (Dipy) is a free and open source software projectfor the analysis of data from diffusion magnetic resonance imaging (dMRI)experiments. dMRI is an application of MRI that can be used to measurestructural features of brain white matter. Many methods have been developed touse dMRI data to model the local configuration of white matter nerve fiberbundles and infer the trajectory of bundles connecting different parts of thebrain.Dipy gathers implementations of many different methods in dMRI, including:diffusion signal pre-processing; reconstruction of diffusion distributions inindividual voxels; fiber tractography and fiber track post-processing, analysisand visualization. Dipy aims to provide transparent implementations forall the different steps of dMRI analysis with a uniform programming interface.We have implemented classical signal reconstruction techniques, such as thediffusion tensor model and deterministic fiber tractography. In addition,cutting edge novel reconstruction techniques are implemented, such asconstrained spherical deconvolution and diffusion spectrum imaging withdeconvolution, as well as methods for probabilistic tracking and originalmethods for tractography clustering. Many additional utility functions areprovided to calculate various statistics, informative visualizations, as wellas file-handling routines to assist in the development and use of noveltechniques.In contrast to many other scientific software projects, Dipy is not beingdeveloped by a single research group. Rather, it is an open project thatencourages contributions from any scientist/developer through GitHub and opendiscussions on the project mailing list. Consequently, Dipy today has aninternational team of contributors, spanning seven different academic institutionsin five countries and three continents, which is still growing

FeCo/Graphite Nanocrystals for Multi-Modality Imaging of Experimental Vascular Inflammation

BACKGROUND: FeCo/graphitic-carbon nanocrystals (FeCo/GC) are biocompatible, high-relaxivity, multi-functional nanoparticles. Macrophages represent important cellular imaging targets for assessing vascular inflammation. We evaluated FeCo/GC for vascular macrophage uptake and imaging in vivo using fluorescence and MRI. METHODS AND RESULTS: Hyperlipidemic and diabetic mice underwent carotid ligation to produce a macrophage-rich vascular lesion. In situ and ex vivo fluorescence imaging were performed at 48 hours after intravenous injection of FeCo/GC conjugated to Cy5.5 (n = 8, 8 nmol of Cy5.5/mouse). Significant fluorescence signal from FeCo/GC-Cy5.5 was present in the ligated left carotid arteries, but not in the control (non-ligated) right carotid arteries or sham-operated carotid arteries (p = 0.03 for ligated vs. non-ligated). Serial in vivo 3T MRI was performed at 48 and 72 hours after intravenous FeCo/GC (n = 6, 270 µg Fe/mouse). Significant T2* signal loss from FeCo/GC was seen in ligated left carotid arteries, not in non-ligated controls (p = 0.03). Immunofluorescence staining showed colocalization of FeCo/GC and macrophages in ligated carotid arteries. CONCLUSIONS: FeCo/GC accumulates in vascular macrophages in vivo, allowing fluorescence and MR imaging. This multi-functional high-relaxivity nanoparticle platform provides a promising approach for cellular imaging of vascular inflammation

Imaging of the unstable plaque: how far have we got?

Rupture of unstable plaques may lead to myocardial infarction or stroke and is the leading cause of morbidity and mortality in western countries. Thus, there is a clear need for identifying these vulnerable plaques before the rupture occurs. Atherosclerotic plaques are a challenging imaging target as they are small and move rapidly, especially in the coronary tree. Many of the currently available imaging tools for clinical use still provide minimal information about the biological characteristics of plaques, because they are limited with respect to spatial and temporal resolution. Moreover, many of these imaging tools are invasive. The new generation of imaging modalities such as magnetic resonance imaging, nuclear imaging such as positron emission tomography and single photon emission computed tomography, computed tomography, fluorescence imaging, intravascular ultrasound, and optical coherence tomography offer opportunities to overcome some of these limitations. This review discusses the potential of these techniques for imaging the unstable plaque

Molecular MRI of Inflammation in Atherosclerosis

Inflammatory activity in atherosclerotic plaque is a risk factor for plaque rupture and atherothrombosis and may direct interventional therapy. Inflammatory activity can be evaluated at the (sub)cellular level using in vivo molecular MRI. This paper reviews recent progress in contrast-enhanced molecular MRI to visualize atherosclerotic plaque inflammation. Various MRI contrast agents, among others ultra-small particles of iron oxide, low-molecular-weight Gd-chelates, micelles, liposomes, and perfluorocarbon emulsions, have been used for in vivo visualization of various inflammation-related targets, such as macrophages, oxidized LDL, endothelial cell expression, plaque neovasculature, MMPs, apoptosis, and activated platelets/thrombus. An enzyme-activatable magnetic resonance contrast agent has been developed to study myeloperoxidase activity in inflamed plaques. Agents creating contrast based on the chemical exchange saturation transfer mechanism were used for thrombus imaging. Transfer of these molecular MRI techniques to the clinic will critically depend on the safety profiles of these newly developed magnetic resonance contrast agents