David A. Rudko

Multiple Sclerosis: Improved Identification of Disease-relevant Changes in Gray and White Matter by Using Susceptibility-based MR Imaging

PURPOSE To evaluate the potential of quantitative susceptibility (QS) and R2* mapping as surrogate biomarkers of clinically relevant, age-adjusted demyelination and iron deposition in multiple sclerosis (MS). MATERIALS AND METHODS All study participants gave written informed consent, and the study was approved by the institutional review board. Quantitative maps of the magnetic resonance imaging susceptibility parameters (R2* and QS) were computed for 25 patients with either clinically isolated syndrome (CIS) or relapsing-remitting MS, as well as for 15 age- and sex-matched control subjects imaged at 7 T. The candidate MR imaging biomarkers were correlated with Extended Disability Status Scale (EDSS), time since CIS diagnosis, time since MS diagnosis, and age. RESULTS QS maps aided identification of significant, voxel-level increases in iron deposition in subcortical gray matter (GM) of patients with MS compared with control subjects. These voxel-level increases were not observed on R2* maps. Region-of-interest analysis of mean R2* and QS in subcortical GM demonstrated that R2* (R ≥ 0.39, P < .01) and QS (R ≥ 0.44, P < .01) were strongly correlated with EDSS. In white matter (WM), the volume of total WM damage (defined by a z score of less than -2.0 criterion, indicating demyelination) on QS maps correlated significantly with EDSS (R = 0.46, P = .02). Voxelwise QS also supported a significant contribution of age to demyelination in patients with MS, suggesting that age-adjusted clinical scores may provide more robust measures of MS disease severity compared with non-age-adjusted scores. CONCLUSION Using QS and R2* mapping, evidence of both significant increases in iron deposition in subcortical GM and myelin degeneration along the WM skeleton of patients with MS was identified. Both effects correlated strongly with EDSS.

In vivo normative atlas of the hippocampal subfields using multi-echo susceptibility imaging at 7 Tesla

Objectives: To generate a high‐resolution atlas of the hippocampal subfields using images acquired from 7 T, multi‐echo, gradient‐echo MRI for the evaluation of epilepsy and neurodegenerative disorders as well as investigating R2* (apparent transverse relaxation rate) and quantitative volume magnetic susceptibility (QS) of the subfields. Experimental Design: Healthy control subjects (n = 17) were scanned at 7 T using a multi‐echo gradient‐echo sequence and susceptibility‐weighted magnitude images, R2* and QS maps were reconstructed. We defined a hippocampal subfield labeling protocol for the magnitude image produced from the average of all echoes and assessed reproducibility through volume and shape metrics. A group‐wise diffeomorphic registration procedure was used to generate an average atlas of the subfields for the whole subject cohort. The quantitative MRI maps and subfield labels were then warped to the average atlas space and used to measure mean values of R2* and QS characterizing each subfield. Principal Observations: We were able to reliably label hippocampal subfields on the multi‐echo susceptibility images. The group‐averaged atlas accurately aligns these structures to produce a high‐resolution depiction of the subfields, allowing assessment of both quantitative susceptibility and R2* across subjects. Our analysis of variance demonstrates that there are more apparent differences between the subfields on these quantitative maps than the normalized magnitude images. Conclusion: We constructed a high‐resolution atlas of the hippocampal subfields for use in voxel‐based studies and demonstrated in vivo quantification of susceptibility and R2* in the subfields. This work is the first in vivo quantification of susceptibility values within the hippocampal subfields at 7 T. Hum Brain Mapp 35:3588–3601, 2014.

Origins of R2* orientation dependence in gray and white matter.

Significance Differences in the apparent transverse relaxation rate () between tissues are exploited in numerous magnetic resonance imaging (MRI) techniques from functional MRI to susceptibility weighted imaging. Recent results show a surprising dependence of tissue on orientation. This study demonstrates that the orientation dependence of in both white and cortical gray matter has a sinusoidal dependence on tissue orientation and a linear dependence on the perturber volume fraction (measured by quantitative histology). A biophysical model is used to relate the observed orientation dependence to the local Larmor frequency shift and volume magnetic susceptibility of the tissue. Estimates of the apparent transverse relaxation rate () can be used to quantify important properties of biological tissue. Surprisingly, the mechanism of dependence on tissue orientation is not well understood. The primary goal of this paper was to characterize orientation dependence of in gray and white matter and relate it to independent measurements of two other susceptibility based parameters: the local Larmor frequency shift (fL) and quantitative volume magnetic susceptibility (Δχ). Through this comparative analysis we calculated scaling relations quantifying (reversible contribution to the transverse relaxation rate from local field inhomogeneities) in a voxel given measurements of the local Larmor frequency shift. is a measure of both perturber geometry and density and is related to tissue microstructure. Additionally, two methods (the Generalized Lorentzian model and iterative dipole inversion) for calculating Δχ were compared in gray and white matter. The value of Δχ derived from fitting the Generalized Lorentzian model was then connected to the observed orientation dependence using image-registered optical density measurements from histochemical staining. Our results demonstrate that the and fL of white and cortical gray matter are well described by a sinusoidal dependence on the orientation of the tissue and a linear dependence on the volume fraction of myelin in the tissue. In deep brain gray matter structures, where there is no obvious symmetry axis, and fL have no orientation dependence but retain a linear dependence on tissue iron concentration and hence Δχ.In many neurological diseases such as multiple sclerosis, Alzheimer’s, and Parkinson, and in conditions following traumatic brain injury, microstructural changes occur in gray and white matter (1–4). One method for quantifying these microstructural changes is the mapping of the effective transverse relaxation rate (). Along with the longitudinal relaxation rate (R1) and transverse relaxation rate (R2), has been viewed as a fundamental MRI tissue parameter, affected by several factors including myelin content (5, 6), endogenous ferritin-based (Fe3+) iron (7, 8), tissue microstructure (6), and paramagnetic, blood deoxyhemoglobin (9). However, a number of recent studies have reported a somewhat surprising dependence of on tissue orientation, at least in white matter (10–12). The purpose of this paper was to investigate the mechanisms that could contribute to this orientation dependence of in both gray and white matter. Because is influenced by magnetic field perturbations, we examined the role of local Larmor frequency shift (fL) and quantitative magnetic susceptibility (Δχ), parameters that relate field and frequency. Through this analysis we identified unique scaling relations that relate to the local Larmor frequency shift calculated after removal of macroscopic field inhomogeneities. Additionally, we compared two methods for computing Δχ in gray and white matter: (i) fitting the Generalized Lorentzian (GL) model of field perturbers (13) to fL measured at multiple brain orientations and (ii) magnitude-regularized dipole inversion (14). The difference between these two estimates represents the local frequency shift due to a cylindrical, axon geometry and is a marker of axonal integrity. Having modeled the orientation dependence, we next examined the effect of myelin and iron on both and Δχ. We demonstrated a linear correlation between these quantities and optical density (OD) derived from diaminobenzidine (DAB)-enhanced Perls stain (sensitive to ferritin-based iron) for cortical gray matter. Similarly, using OD derived from solochrome cyanine-R (ScR)–stained slides in rat brain major white matter fiber regions, we showed strong positive correlations between the transverse relaxation constants, R2 and , and myelin density. Taken together, our results demonstrate that observed values in ex vivo brains can be explained by a sinusoidal dependence on tissue microstructure orientation in conjunction with a linear dependence on the myelin concentration in cortical gray and white matter. In deeper gray matter structures with no preferred symmetry axis, does not have an orientation dependence but retains a linear dependence on iron concentration.

A prototype fan-beam optical CT scanner for 3D dosimetry

PURPOSE The objective of this work is to introduce a prototype fan-beam optical computed tomography scanner for three-dimensional (3D) radiation dosimetry. METHODS Two techniques of fan-beam creation were evaluated: a helium-neon laser (HeNe, λ = 543 nm) with line-generating lens, and a laser diode module (LDM, λ = 635 nm) with line-creating head module. Two physical collimator designs were assessed: a single-slot collimator and a multihole collimator. Optimal collimator depth was determined by observing the signal of a single photodiode with varying collimator depths. A method of extending the dynamic range of the system is presented. Two sample types were used for evaluations: nondosimetric absorbent solutions and irradiated polymer gel dosimeters, each housed in 1 liter cylindrical plastic flasks. Imaging protocol investigations were performed to address ring artefacts and image noise. Two image artefact removal techniques were performed in sinogram space. Collimator efficacy was evaluated by imaging highly opaque samples of scatter-based and absorption-based solutions. A noise-based flask registration technique was developed. Two protocols for gel manufacture were examined. RESULTS The LDM proved advantageous over the HeNe laser due to its reduced noise. Also, the LDM uses a wavelength more suitable for the PRESAGE(TM) dosimeter. Collimator depth of 1.5 cm was found to be an optimal balance between scatter rejection, signal strength, and manufacture ease. The multihole collimator is capable of maintaining accurate scatter-rejection to high levels of opacity with scatter-based solutions (T < 0.015%). Imaging protocol investigations support the need for preirradiation and postirradiation scanning to reduce reflection-based ring artefacts and to accommodate flask imperfections and gel inhomogeneities. Artefact removal techniques in sinogram space eliminate streaking artefacts and reduce ring artefacts of up to ∼40% in magnitude. The flask registration technique was shown to achieve submillimetre and subdegree placement accuracy. Dosimetry protocol investigations emphasize the need to allow gel dosimeters to cool gradually and to be scanned while at room temperature. Preliminary tests show that considerable noise reduction can be achieved with sinogram filtering and by binning image pixels into more clinically relevant grid sizes. CONCLUSIONS This paper describes a new optical CT scanner for 3D radiation dosimetry. Tests demonstrate that it is capable of imaging both absorption-based and scatter-based samples of high opacities. Imaging protocol and gel dosimeter manufacture techniques have been adapted to produce optimal reconstruction results. These optimal results will require suitable filtering and binning techniques for noise reduction purposes.PURPOSE The objective of this work is to introduce a prototype fan-beam optical computed tomography scanner for three-dimensional (3D) radiation dosimetry. METHODS Two techniques of fan-beam creation were evaluated: a helium-neon laser (HeNe, λ = 543 nm) with line-generating lens, and a laser diode module (LDM, λ = 635 nm) with line-creating head module. Two physical collimator designs were assessed: a single-slot collimator and a multihole collimator. Optimal collimator depth was determined by observing the signal of a single photodiode with varying collimator depths. A method of extending the dynamic range of the system is presented. Two sample types were used for evaluations: nondosimetric absorbent solutions and irradiated polymer gel dosimeters, each housed in 1 liter cylindrical plastic flasks. Imaging protocol investigations were performed to address ring artefacts and image noise. Two image artefact removal techniques were performed in sinogram space. Collimator efficacy was evaluated by imaging highly opaque samples of scatter-based and absorption-based solutions. A noise-based flask registration technique was developed. Two protocols for gel manufacture were examined. RESULTS The LDM proved advantageous over the HeNe laser due to its reduced noise. Also, the LDM uses a wavelength more suitable for the PRESAGETM dosimeter. Collimator depth of 1.5 cm was found to be an optimal balance between scatter rejection, signal strength, and manufacture ease. The multihole collimator is capable of maintaining accurate scatter-rejection to high levels of opacity with scatter-based solutions (T < 0.015%). Imaging protocol investigations support the need for preirradiation and postirradiation scanning to reduce reflection-based ring artefacts and to accommodate flask imperfections and gel inhomogeneities. Artefact removal techniques in sinogram space eliminate streaking artefacts and reduce ring artefacts of up to ∼40% in magnitude. The flask registration technique was shown to achieve submillimetre and subdegree placement accuracy. Dosimetry protocol investigations emphasize the need to allow gel dosimeters to cool gradually and to be scanned while at room temperature. Preliminary tests show that considerable noise reduction can be achieved with sinogram filtering and by binning image pixels into more clinically relevant grid sizes. CONCLUSIONS This paper describes a new optical CT scanner for 3D radiation dosimetry. Tests demonstrate that it is capable of imaging both absorption-based and scatter-based samples of high opacities. Imaging protocol and gel dosimeter manufacture techniques have been adapted to produce optimal reconstruction results. These optimal results will require suitable filtering and binning techniques for noise reduction purposes.

Manual Segmentation of MS Cortical Lesions Using MRI: A Comparison of 3 MRI Reading Protocols

BACKGROUND AND PURPOSE: Double inversion recovery has been suggested as the MR imaging contrast of choice for segmenting cortical lesions in patients with multiple sclerosis. In this study, we sought to determine the utility of double inversion recovery for cortical lesion identification by comparing 3 MR imaging reading protocols that combine different MR imaging contrasts. MATERIALS AND METHODS: Twenty-five patients with relapsing-remitting MS and 3 with secondary-progressive MS were imaged with 3T MR imaging by using double inversion recovery, dual fast spin-echo proton-density/T2-weighted, 3D FLAIR, and 3D T1-weighted imaging sequences. Lesions affecting the cortex were manually segmented by using the following 3 MR imaging reading protocols: Protocol 1 (P1) used all available MR imaging contrasts; protocol 2 (P2) used all the available contrasts except for double inversion recovery; and protocol 3(P3) used only double inversion recovery. RESULTS: Six hundred forty-three cortical lesions were identified with P1 (mean = 22.96); 633, with P2 (mean = 22.6); and 280, with P3 (mean = 10). The counts obtained by using P1 and P2 were not significantly different (P = .93). The counts obtained by using P3 were significantly smaller than those obtained by using either P1 (P < .001) or P2 (P < .001). The intraclass correlation coefficients were P1 versus P2 = 0.989, P1 versus P3 = 0.615, and P2 versus P3 = 0.588. CONCLUSIONS: MR imaging cortical lesion segmentation can be performed by using 3D T1-weighted and 3D FLAIR images acquired with a 1-mm isotropic voxel size, supported by conventional T2-weighted and proton-density images with 3-mm-thick sections. Inclusion of double inversion recovery in this multimodal reading protocol did not significantly improve the cortical lesion identification rate. A multimodal approach is superior to using double inversion recovery alone.

A prototype fan-beam optical CT scanner for polymer gel dosimetry

A prototype optical CT scanner has been developed for scanning polymer gel dosimeters used in 3D radiation therapy dose verification. The scanner is based on a 3rd generation, fan-beam CT design and employs a 543 nm laser fanned through a 60° line-generating lens. A series of 5 detector arrays or 64 elements each collects light on the distal side of the water tank. Pre-detector collimators are employed to reject light scattered away from incident ray trajectory. Results of scanner characterisation studies, as well as preliminary data acquired on irradiated polymer gels, are discussed.

Inter-echo variance as a weighting factor for multi-channel combination in multi-echo acquisition for local frequency shift mapping

To develop and evaluate a local frequency shift (LFS) mapping method specifically designed for multi‐echo acquisitions and multi‐channel receive coils.

MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis.

Objective: To identify gadolinium-enhancing lesions affecting the cortex of patients with early multiple sclerosis (MS) and to describe the frequency and evolution of these lesions. Methods: We performed a retrospective, observational, longitudinal analysis of MRI scans collected as part of the Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3T MRI Endpoints (BECOME) study. Seventy-five patients with early-stage MS were scanned monthly, over a period of 12–24 months, using 3T MRI after administration of triple-dose gadolinium. A total of 1,188 scans were included in the analysis. A total of 139 were selected using an image pipeline algorithm that integrated the image information from cortical gray matter masks and gadolinium-enhancing lesion masks. These scans were evaluated to identify gadolinium-enhancing lesions affecting the cortex. Results: The total number of gadolinium-enhancing lesions was 2,044. The number of gadolinium-enhancing lesions affecting the cortex was 120 (6%), 95% of which were leukocortical. The number of patients who showed gadolinium-enhancing lesions affecting the cortex was 27 (36%). The number of gadolinium-enhancing lesions affecting the cortex at baseline was 25 (21%) and the number of new lesions that developed in follow-up scans was 49 (41%). The number of persistent lesions was 46 (38%). Conclusions: The presence of enhancing lesions affecting the cortex and adjacent white matter, although transient and not frequent, suggests that at least some cortical lesions are related to blood–brain barrier disruption. Our data support the concept that there may be an acute inflammatory phase in the development of leukocortical MS lesions. Clinicaltrials.gov identifier: NCT00176592.

Delineation of cortical pathology in multiple sclerosis using multi-surface magnetization transfer ratio imaging

The purpose of our study was to evaluate the utility of measurements of cortical surface magnetization transfer ratio (csMTR) on the inner, mid and outer cortical boundaries as clinically accessible biomarkers of cortical gray matter pathology in multiple sclerosis (MS). Twenty-five MS patients and 12 matched controls were recruited from the MS Clinic of the Montreal Neurological Institute. Anatomical and magnetization transfer ratio (MTR) images were acquired using 3 Tesla MRI at baseline and two-year time-points. MTR maps were smoothed along meshes representing the inner, mid and outer neocortical boundaries. To evaluate csMTR reductions suggestive of sub-pial demyelination in MS patients, a mixed model analysis was carried out at both the individual vertex level and in anatomically parcellated brain regions. Our results demonstrate that focal areas of csMTR reduction are most prevalent along the outer cortical surface in the superior temporal and posterior cingulate cortices, as well as in the cuneus and precentral gyrus. Additionally, age regression analysis identified that reductions of csMTR in MS patients increase with age but appear to hit a plateau in the outer caudal anterior cingulate, as well as in the precentral and postcentral cortex. After correction for the naturally occurring gradient in cortical MTR, the difference in csMTR between the inner and outer cortex in focal areas in the brains of MS patients correlated with clinical disability. Overall, our findings support multi-surface analysis of csMTR as a sensitive marker of cortical sub-pial abnormality indicative of demyelination in MS patients.

An Open Resource for Non-human Primate Imaging

Summary Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.