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Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage., Graphical abstract, Highlights • NAWM is investigated in NPSLE and SLE using MTI and DTI. • Differences in DTI and MTR between NPSLE and HC are widespread but only moderately co-localized. • Significant differences in MD between SLE and NPSLE suggest link to onset of NPSLE.

There is a growing interest in identifying neuroimaging-based biomarkers for Parkinson's disease (PD), a progressive neurodegenerative disorder in which the major pathologic substrate is the loss of pigmented dopaminergic neurons in the substantia nigra (SN). Recently, an MRI technique dubbed "neuromelanin-sensitive MRI" (NM-MRI), has been found to provide notable contrast between the SN and surrounding brain tissues with potential applications as biomarker of PD. The contrast in NM-MRI has been associated with magnetization transfer (MT) effects, and thus the goal of this study was to characterize the impact of MT on NM-MRI, and to demonstrate the feasibility of performing quantitative MT (qMT) imaging in human SN. The results of this study demonstrate that high-resolution rapid qMT imaging of the SN can be reliably obtained within reasonable scan times, thereby can be translatable into clinical practice.

Background: Adrenomyeloneuropathy (AMN) is the adult variant of X-linked adrenoleukodystrophy. The disease pathology is usually limited to spinal cord and peripheral nerves, and when this is the case, it is referred to as “pure” AMN. Histopathology shows cerebral involvement even in pure AMN; however, not much is known about the nature, extent, and clinical relevance of these findings. Objective: To investigate brain involvement in AMN patients with normal MRI, employing multislice MR spectroscopic imaging. Methods: Twelve men with pure AMN were compared with 19 age-matched healthy volunteers. Metabolite ratios (N-acetylaspartate [NAA]/choline [Cho], NAA/creatine [Cr], and Cho/Cr) were measured from seven brain regions. Global metabolite ratios were generated as an average of these seven regional ratios. The Expanded Disability Status Scale (EDSS) was used for neurologic evaluation. Results: The patients with AMN showed reduced global NAA/Cho (AMN 1.40 ± 0.16 vs controls 1.75 ± 0.34; p = 0.003)) and global NAA/Cr (AMN 2.32 ± 0.13 vs controls 2.62 ± 0.43; p = 0.03). Regionally, NAA/Cho was lowered in the internal capsule (AMN 1.30 ± 0.20 vs controls 1.69 ± 0.37; p = 0.002) and in parieto-occipital white matter (AMN 1.45 ± 0.19 vs controls 1.78 ± 0.55; p = 0.04). NAA/Cr was lowered in parieto-occipital white matter (AMN 2.34 ± 0.31 vs controls 2.83 ± 0.71; p = 0.04). EDSS demonstrated an inverse association with global NAA/Cr (r = −0.65, p = 0.02) and NAA/Cr in centrum semiovale (r = −0.73, p = 0.006) and in parieto-occipital white matter (r = −0.64, p = 0.02). Cho/Cr was not significantly elevated. Conclusions:1H-MR spectroscopic imaging is able to detect biochemical abnormalities suggestive of axonal damage even in the brains of patients with pure adrenomyeloneuropathy. The axonopathy is most prominent in internal capsule and parieto-occipital white matter and may contribute to clinical disability.

High-magnetic-field (7 T) chemical exchange saturation transfer (CEST) MRI provides information on the tissue biochemical environment. Multiple sclerosis (MS) affects the entire central nervous system, including the spinal cord. Optimal CEST saturation parameters found via simulation were implemented for CEST MRI in 10 healthy controls and 10 patients with MS, and the results were examined using traditional asymmetry analysis and a Lorentzian fitting method. In addition, T1 - and T2 *-weighted images were acquired for lesion localization and the transmitted B1 (+) field was evaluated to guide imaging parameters. Distinct spectral features for all tissue types studied were found both up- and downfield from the water resonance. The z spectra in healthy subjects had the expected z spectral shape with CEST effects apparent from 2.0 to 4.5 ppm. The z spectra from patients with MS demonstrated deviations from this expected normal shape, indicating this method's sensitivity to known pathology as well as to tissues appearing normal on conventional MRI. Examination of the calculated CESTasym revealed increased asymmetry around the amide proton resonance (Δω = 3.5 ppm), but it was apparent that this measure is complicated by detail in the CEST spectrum upfield from water, which is expected to result from the nuclear Overhauser effect. The z spectra upfield (negative ppm range) were also distinct between healthy and diseased tissue, and could not be ignored, particularly when considering the conventional asymmetry analysis used to quantify the CEST effect. For all frequencies greater than +1 ppm, the Lorentzian differences (and z spectra) for lesions and normal-appearing white matter were distinct from those for healthy white matter. The increased frequency separation and signal-to-noise ratio, in concert with prolonged T1 at 7 T, resulted in signal enhancements necessary to detect subtle tissue changes not possible at lower field strengths. This study presents CEST imaging metrics that may be sensitive to the extensive and temporally varying biochemical neuropathology of MS in the spinal cord. Copyright © 2016 John WileySons, Ltd.

BACKGROUND: The high value of the specific absorption rate (SAR) of radio-frequency (RF) energy arising from the series of RF refocusing pulses in T2-weighted (T2-w) turbo spin echo (TSE) MRI hampers its clinical application at 7.0 Tesla (7T). T2-w gradient and spin echo (GRASE) uses the speed from gradient refocusing in combination with the chemical-shift/static magnetic field (B0) inhomogeneity insensitivity from spin-echo refocusing to acquire T2-w images with a limited number of refocusing RF pulses, thus reducing SAR. OBJECTIVES: To investigate whether low SAR T2-w GRASE could replace T2-w TSE in detecting white matter (WM) disease in MS patients imaged at 7T. METHODS: The .7 mm(3) isotropic T2-w TSE and T2-w GRASE images with variable echo times (TEs) and echo planar imaging (EPI) factors were obtained on a 7T scanner from postmortem samples of MS brains. These samples were derived from brains of 3 female MS patients. WM lesions (WM-Ls) and normal-appearing WM (NAWM) signal intensity, WM-Ls/NAWM contrast-to-noise ratio (CNR) and MRI/myelin staining sections comparisons were obtained. RESULTS: GRASE sequences with EPI factor/TE = 3/50 and 3/75 ms were comparable to the SE technique for measures of CNR in WM-Ls and NAWM and for detection of WM-Ls. In all sequences, however, identification of areas with remyelination, Wallerian degeneration, and gray matter demyelination, as depicted by myelin staining, was not possible. CONCLUSIONS: T2-w GRASE images may replace T2-w TSE for clinical use. However, even at 7T, both sequences fail in detecting and characterizing MS disease beyond visible WM-Ls.

A diffusion-weighted multishot echo-planar imaging approach combined with SENSE and a two-dimensional (2D) navigated motion correction was investigated as an alternative to conventional single-shot counterpart to obtain optic nerve images at higher spatial resolution with reduced artifacts.Fifteen healthy subjects were enrolled in the study. Six of these subjects underwent a repeated acquisition at least 2 weeks after the initial scan session to address reproducibility. Both single-shot and multishot diffusion tensor imaging studies of the human optic nerve were performed with matched scan time. Effect of subject motions were corrected using 2D phase navigator during multishot image reconstruction. Tensor-derived indices from proposed multishot were compared against conventional single-shot approach. Image resolution difference, right-left optic nerve asymmetry, and test-retest reproducibility were also assessed.In vivo results of acquired multishot images and quantitative maps of diffusion properties of the optic nerve showed significantly reduced image artifacts (e.g., distortions and blurring), and the derived diffusion indices were comparable to those from other studies. Single-shot scans presented larger variability between right and left optic nerves than multishot scans. Multishot scans also presented smaller variations across scans at different time points when compared with single-shot counterparts.The multishot technique has considerable potential for providing improved information on optic nerve pathology and may also be translated to higher fields.

New magnetic resonance imaging (MRI) sequences are enabling clinical study of the in vivo spinal cord’s internal structure. Yet, low contrast-to-noise ratio, artifacts, and imaging distortions have limited the applicability of tissue segmentation techniques pioneered elsewhere in the central nervous system. Recently, methods have been presented for cord/non-cord segmentation on MRI and the feasibility of gray matter/white matter tissue segmentation has been evaluated. To date, no automated algorithms have been presented. Herein, we present a non-local multi-atlas framework that robustly identifies the spinal cord and segments its internal structure with submillimetric accuracy. The proposed algorithm couples non-local fusion with a large number of slice-based atlases (as opposed to typical volumetric ones). To improve performance, the fusion process is interwoven with registration so that segmentation information guides registration and vice versa. We demonstrate statistically significant improvement over state-of-the-art benchmarks in a study of 67 patients. The primary contributions of this work are (1) innovation in non-volumetric atlas information, (2) advancement of label fusion theory to include iterative registration/segmentation, and (3) the first fully automated segmentation algorithm for spinal cord internal structure on MRI.

The spinal cord is an essential and vulnerable component of the central nervous system. Differentiating and localizing the spinal cord internal structure (i.e., gray matter vs. white matter) is critical for assessment of therapeutic impacts and determining prognosis of relevant conditions. Fortunately, new magnetic resonance imaging (MRI) sequences enable clinical study of the in vivo spinal cord's internal structure. Yet, low contrast-to-noise ratio, artifacts, and imaging distortions have limited the applicability of tissue segmentation techniques pioneered elsewhere in the central nervous system. Additionally, due to the inter-subject variability exhibited on cervical MRI, typical deformable volumetric registrations perform poorly, limiting the applicability of a typical multi-atlas segmentation framework. Thus, to date, no automated algorithms have been presented for the spinal cord's internal structure. Herein, we present a novel slice-based groupwise registration framework for robustly segmenting cervical spinal cord MRI. Specifically, we provide a method for (1) pre-aligning the slice-based atlases into a groupwise-consistent space, (2) constructing a model of spinal cord variability, (3) projecting the target slice into the low-dimensional space using a model-specific registration cost function, and (4) estimating robust segmentation susing geodesically appropriate atlas information. Moreover, the proposed framework provides a natural mechanism for performing atlas selection and initializing the free model parameters in an informed manner. In a cross-validation experiment using 67 MR volumes of the cervical spinal cord, we demonstrate sub-millimetric accuracy, significant quantitative and qualitative improvement over comparable multi-atlas frameworks, and provide insight into the sensitivity of the associated model parameters.

Magnetic resonance imaging (MRI) of the human spinal cord in vivo suffers from multiple practical limitations: low signal-to-noise ratio, the need for high resolution, and the detrimental influence of various motions, both voluntary and involuntary. While the latter are problematic at any field strength, the former can be to some degree addressed using higher field strengths. The increased signal-to-noise ratio at higher field strengths can be harnessed for higher spatial resolution or faster exam times. However, MRI at ultra-high fields currently suffers from significantly more inhomogenous transmit fields and larger susceptibility effects. In this chapter, we demonstrate some advantages of ultra-high field MRI for the anatomical and quantitative characterization of the human spinal cord in vivo, discuss the relevant impediments faced at higher field strength, and propose strategies for overcoming these shortcomings.

Summary The mechanisms underlying the pathogenesis of multiple sclerosis induce the changes that underpin relapse-associated and progressive disability. Disease mechanisms can be investigated in preclinical models and patients with multiple sclerosis by molecular and metabolic imaging techniques. Many insights have been gained from such imaging studies: persisting inflammation in the absence of a damaged blood–brain barrier, activated microglia within and beyond lesions, increased mitochondrial activity after acute lesions, raised sodium concentrations in the brain, increased glutamate in acute lesions and normal-appearing white matter, different degrees of demyelination in different patients and lesions, early neuronal damage in grey matter, and early astrocytic proliferation and activation in lesions and white matter. Clinical translation of molecular and metabolic imaging and extension of these techniques will enable the assessment of novel drugs targeted at these disease mechanisms, and have the potential to improve health outcomes through the stratification of patients for treatments.

Chemical exchange saturation transfer (CEST)-derived, pH-weighted, amide proton transfer (APT) MRI has shown promise in animal studies for the prediction of infarction risk in ischemic tissue. Here, APT MRI was translated to patients with acute stroke (1-24 h post-symptom onset), and assessments of APT contrast, perfusion, diffusion, disability and final infarct volume (23-92 days post-stroke) are reported. Healthy volunteers (n = 5) and patients (n = 10) with acute onset of symptoms (0-4 h, n = 7; uncertain onset24 h, n = 3) were scanned with diffusion- and perfusion-weighted MRI, fluid-attenuated inversion recovery (FLAIR) and CEST. Traditional asymmetry and a Lorentzian-based APT index were calculated in the infarct core, at-risk tissue (time-to-peak, TTP; lengthening) and final infarct volume. On average (mean ± standard deviation), control white matter APT values (asymmetry, 0.019 ± 0.005; Lorentzian, 0.045 ± 0.006) were not significantly different (p 0.05) from APT values in normal-appearing white matter (NAWM) of patients (asymmetry, 0.022 ± 0.003; Lorentzian, 0.048 ± 0.003); however, ischemic regions in patients showed reduced (p = 0.03) APT effects compared with NAWM. Representative cases are presented, whereby the APT contrast is compared quantitatively with contrast from other imaging modalities. The findings vary between patients; in some patients, a trend for a reduction in the APT signal in the final infarct region compared with at-risk tissue was observed, consistent with tissue acidosis. However, in other patients, no relationship was observed in the infarct core and final infarct volume. Larger clinical studies, in combination with focused efforts on sequence development at clinically available field strengths (e.g. 3.0 T), are necessary to fully understand the potential of APT imaging for guiding the hyperacute management of patients.

The clinicoradiologic paradox, or disconnect between clinical and radiologic findings, is frequently encountered in multiple sclerosis (MS), particularly in the spinal cord (SC), where lesions are expected to cause clinical impairment. We aimed to assess whether quantitative diffusion tensor and magnetization transfer imaging measures in the SC can distinguish MS cases of comparable lesion burdens with high and low disability.One hundred twenty-four patients with MS underwent 3-T cervical SC MRI and were categorized into 4 subgroups according to SC lesion count and disability level. Regions of interest circumscribed the SC cross-section axially between C3 and C4. Cross-sectional area, fractional anisotropy (FA), mean diffusivity (MD), perpendicular diffusivity (λ(⊥)), parallel diffusivity (λ(‖)), and magnetization transfer ratio (MTR) were calculated. Differences between patient subgroups were assessed using t tests and linear regression.FA, MD, λ(⊥), λ(‖), MTR, and SC cross-sectional area were more abnormal in the high- vs low-disability subgroup of patients with low lesion counts (p0.05). MRI measures (except λ(‖) and MTR) were more abnormal in the high- vs low-disability subgroup of patients with high lesion counts (p0.05). In age- and sex-adjusted comparisons of high- vs low-disability subgroups, all MRI measures retained differences in the low-lesion subgroup, except λ(‖), whereas only FA, MD, and λ(⊥) retained differences in the high-lesion subgroup.In this cross-sectional study of patients with MS, quantitative MRI reflects clinically relevant differences beyond what can be detected by conventional MRI. Our findings support the utility of quantitative MRI in clinical settings, where accurate measurement of disease burden is becoming increasingly critical for assessing treatment efficacy.

Quantitative magnetization transfer (qMT) imaging yields indices describing the interactions between free water protons and immobile macromolecular protons. These indices include the macromolecular to free pool size ratio ( PSR ), which has been shown to be correlated with myelin content in white matter. Because of the long scan times required for whole-brain imaging (≈ 20–30 min), qMT studies of the human brain have not found widespread application. Herein, we investigated whether the increased signal-to-noise ratio available at 7.0 T could be used to reduce qMT scan times. More specifically, we developed a selective inversion recovery (SIR) qMT imaging protocol with a i ) novel transmit radiofrequency ( B 1 + ) and static field ( B 0 ) insensitive inversion pulse, ii ) turbo field-echo readout, and iii ) reduced TR. In vivo qMT data were obtained in the brains of healthy volunteers at 7.0 T using the resulting protocol (scan time ≈ 40 s/slice, resolution = 2 × 2 × 3 mm 3 ). Reliability was also assessed in repeated acquisitions. The results of this study demonstrate that SIR qMT imaging can be reliably performed within the radiofrequency power restrictions present at 7.0 T, even in the presence of large B 1 + and B 0 inhomogeneities. Consistent with qMT studies at lower field strengths, the observed PSR values were higher in white matter (mean ± SD = 17.6 ± 1.3%) relative to gray matter (10.3 ± 1.6%) at 7.0 T. In addition, regional variations in PSR were observed in white matter. Together, these results suggest that qMT measurements are feasible at 7.0 T and may eventually allow for the high-resolution assessment of changes in composition throughout the normal and diseased human brain in vivo.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) indirectly images exchangeable solute protons resonating at frequencies different than bulk water. These solute protons are selectively saturated using low bandwidth RF irradiation and saturation is transferred to bulk water protons via chemical exchange, resulting in an attenuation of the measured water proton signal. CEST MRI is an advanced MRI technique with wide application potential due to the ability to examine complex molecular contributions. CEST MRI at high field (7 Tesla [7 T]) will improve the overall results due to increase in signal, T1 relaxation time, and chemical shift dispersion. Increased field strength translates to enhanced quantification of the metabolite of interest, allowing more fundamental studies on underlying pathophysiology. CEST contrast is affected by several tissue properties, such as the concentrations of exchange partners and their rate of proton exchange, whose effects have been examined and explored in this review. We have highlighted the background of CEST MRI, typical implementation strategy, and complications at 7 T.

Chemical exchange saturation transfer imaging can generate contrast that is sensitive to amide protons associated with proteins and peptides (termed amide proton transfer, APT). In breast cancer, APT contrast may report on underlying changes in microstructural tissue composition. However, to date, there have been no developments or applications of APT chemical exchange saturation transfer to breast cancer. As a result, the aims of this study were to (i) experimentally explore optimal scan parameters for breast chemical exchange saturation transfer near the amide resonance at 3 T, (ii) establish the reliability of APT imaging of healthy fibroglandular tissue, and (iii) demonstrate preliminary results on APT changes in locally advanced breast cancer observed during the course of neoadjuvant chemotherapy. Chemical exchange saturation transfer measurements were experimentally optimized on cross-linked bovine serum albumin phantoms, and the reliability of APT imaging was assessed in 10 women with no history of breast disease. The mean difference between test-retest APT values was not significantly different from zero, and the individual difference values were not dependent on the average APT value. The 95% confidence interval limits were ±0.70% (α = 0.05), and the repeatability was 1.91. APT measurements were also performed in three women before and after one cycle of chemotherapy. Following therapy, APT increased in the one patient with progressive disease and decreased in the two patients with a partial or complete response. Together, these results suggest that APT imaging may report on treatment response in these patients.

Advanced magnetic resonance (MR) approaches permit the noninvasive quantification of macromolecular, functional, and physiological properties of biological tissues. In this chapter, we review the application of advanced MR techniques to the spinal cord. Macromolecular properties of the spinal cord can be studied using magnetization transfer (MT) MR, diffusion tensor imaging (DTI), Q-space diffusion spectroscopy, and selective detection of myelin water. The functional and metabolic status of the spinal cord can be studied using functional MRI (fMRI), perfusion imaging, and magnetic resonance spectroscopy (MRS). Finally, we consider the outlook for advanced MR studies in persons in whom metal hardware has been implanted to stabilize the cord. In spite of the spinal cord's diminutive size, its location deep within the body, and constant motion, recent work shows that the spinal cord can be studied using these advanced MR approaches.

The use of advanced MRI modalities to study brain disease has provided new insights into the understanding of the pathophysiologic mechanisms of several neurologic disorders. It is notable that many of these modalities have not been widely applied to the spinal cord (SC), mainly because of the technical hurdles in performing high-confidence MRI acquisitions in this long, yet thin structure located deep to other structures with high magnetic susceptibility.1 More recently, however, technical developments have improved MRI of the SC. Optimization of specific sequences (e.g., diffusion tensor imaging [DTI]) for SC anatomy,2 higher field strength, and new coil technology have helped conventional and quantitative MRI of the SC to become more sensitive, specific, and accurate.1

To measure longitudinal (T(1)) and multi-echo transverse (T(2)) relaxation times of healthy breast tissue at 3 Tesla (T).High-resolution relaxation time measurements were made in six healthy female subjects. Inversion recovery images were acquired at 10 inversion times between 100 ms and 4000 ms, and multiple spin echo images were acquired at 16 echo times between 10 ms and 160 ms.Longitudinal relaxation times T(1) were measured as 423 ± 12 ms for adipose tissue and 1680 ± 180 ms for fibroglandular tissue. Multi-echo transverse relaxation times T(2) were measured as 154 ± 9 ms for adipose tissue and 71 ± 6 ms for fibroglandular tissue. Histograms of the voxel-wise relaxation times and quantitative relaxation time maps are also presented.T(1) and multi-echo T(2) relaxation times in normal human breast tissue are reported. These values are useful for pulse sequence design and optimization for 3T breast MRI. Compared with the literature, T(1) values are significantly longer at 3T, suggesting that longer repetition time and inversion time values should be used for similar image contrast.

Quantitative magnetization transfer imaging yields indices describing the interactions between free water protons and immobile, macromolecular protons-including the macromolecular to free pool size ratio (PSR) and the rate of magnetization transfer between pools k(mf) . This study describes the first implementation of the selective inversion recovery quantitative magnetization transfer method on a clinical 3.0-T scanner in human brain in vivo. Selective inversion recovery data were acquired at 16 different inversion times in nine healthy subjects and two patients with relapsing remitting multiple sclerosis. Data were collected using a fast spin-echo readout and reduced repetition time, resulting in an acquisition time of 4 min for a single slice. In healthy subjects, excellent intersubject and intrasubject reproducibilities (assessed via repeated measures) were demonstrated. Furthermore, PSR values in white (mean ± SD = 11.4 ± 1.2%) and gray matter (7.5 ± 0.7%) were consistent with previously reported values, while k(mf) values were approximately 2-fold slower in both white (11 ± 2 s(-1) ) and gray matter (15 ± 6 s(-1) ). In relapsing remitting multiple sclerosis patients, quantitative magnetization transfer indices were sensitive to pathological changes in lesions and in normal appearing white matter.

Inflammatory demyelination and axon damage in the corpus callosum are prominent features of multiple sclerosis (MS) and may partially account for impaired performance on complex tasks. The objective of this article was to characterize quantitative callosal MRI abnormalities and their association with disability. In 69 participants with MS and 29 healthy volunteers, lesional and extralesional callosal MRI indices were estimated via diffusion tensor tractography. expanded disability status scale (EDSS) and MS functional composite (MSFC) scores were recorded in 53 of the participants with MS. All tested callosal MRI indices were diffusely abnormal in MS. EDSS score was correlated only with age (r = 0.51). Scores on the overall MSFC and its paced serial auditory addition test (PASAT) and 9-hole peg test components were correlated with callosal fractional anisotropy (r = 0.27, 0.35, and 0.31, respectively) and perpendicular diffusivity (r = —0.29, —0.30, and —0.31) but not with overall callosal volume or callosal lesion volume; the PASAT score was more weakly correlated with callosal magnetization-transfer ratio (r = 0.21). Anterior callosal abnormalities were associated with impaired PASAT performance and posterior abnormalities with slow performance on the 9-hole peg test. In conclusion, abnormalities in the corpus callosum can be assessed with quantitative MRI and are associated with cognitive and complex upper-extremity dysfunction in MS.

Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)- and magnetization transfer (MT)-derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column-specific parallel (lambda(||)) and perpendicular (lambda(perpendicular)) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT-weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time-points separated by more than 1 week. Cross-sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: lambda(||): 2.13 +/- 0.14 and 2.14 +/- 0.11 microm(2)/ms; lambda(perpendicular): 0.67 +/- 0.16 and 0.61 +/- 0.09 microm(2)/ms; MD: 1.15 +/- 0.15 and 1.12 +/- 0.08 microm(2)/ms; FA: 0.68 +/- 0.06 and 0.68 +/- 0.05; MTCSF: 0.52 +/- 0.05 and 0.50 +/- 0.05. We examined the variability and interrater and test-retest reliability for each metric. These column-specific MR measurements are expected to enhance understanding of the intimate structure-function relationship in the cervical spinal cord and may be useful for the assessment of disease progression.

Which aspects of tissue microstructure affect diffusion weighted MRI signals? Prior models, many of which use Monte-Carlo simulations, have focused on relatively simple models of the cellular microenvironment and have not considered important anatomic details. With the advent of higher-order analysis models for diffusion imaging, such as high-angular-resolution diffusion imaging (HARDI), more realistic models are necessary. This paper presents and evaluates the reproducibility of simulations of diffusion in complex geometries. Our framework is quantitative, does not require specialized hardware, is easily implemented with little programming experience, and is freely available as open-source software. Models may include compartments with different diffusivities, permeabilities, and T2 time constants using both parametric (e.g., spheres and cylinders) and arbitrary (e.g., mesh-based) geometries. Three-dimensional diffusion displacement-probability functions are mapped with high reproducibility, and thus can be readily used to assess reproducibility of diffusion-derived contrasts.

To determine whether damage to the optic radiation (OR) in multiple sclerosis (MS) is associated with optic nerve injury and visual dysfunction.Case-control study.Referral center.Ninety referred patients with MS and 29 healthy volunteers.Magnetic resonance imaging indices along the OR were reconstructed with diffusion tensor tractography. Retinal nerve fiber layer thickness and visual acuity at high and low contrast were measured in a subset of the MS group (n = 36).All tested magnetic resonance imaging indices (fractional anisotropy [FA]; mean, parallel, and perpendicular [lambda( perpendicular)] diffusivity; T2 relaxation time; and magnetization transfer ratio) were significantly abnormal in patients with MS. Mean retinal nerve fiber layer thickness was significantly correlated with FA (r = 0.55; P.001) and lambda( perpendicular) (r = -0.37; P = .001). The retinal nerve fiber layer thickness in the nasal retinal quadrant was also specifically correlated with FA and lambda( perpendicular) in the synaptically connected contralateral OR. In individuals with less severely damaged optic nerves (mean retinal nerve fiber layer thickness80 mum), letter acuity scores at 2.5% contrast were correlated with OR-specific FA (r = 0.55; P = .004), lambda( perpendicular) (r = -0.40; P = .04), and magnetization transfer ratio (r = 0.54; P = .01), as well as the fraction of OR volume made up of lesions (r = -0.69; P.001).Fractional anisotropy and lambda( perpendicular) are potentially useful quantitative magnetic resonance imaging biomarkers of OR-specific damage in MS. Such damage is associated with retinal injury and visual disability.

Consideration of spatially variable noise fields is becoming increasing necessary in magnetic resonance imaging given recent innovations in artifact identification and statistically-driven image processing. Fast imaging methods enable study of difficult anatomical targets and improve image quality but also increase the spatial variability in the noise field. Traditional analysis techniques have either assumed that the noise is constant across the field of view (or region of interest) or have relied on separate magnetic resonance image acquisitions to measure the noise field. These methods are either inappropriate for many modern scanning protocols or are overly time-consuming for already lengthy scanning sessions. We propose a new, general framework for estimating spatially variable noise fields from related, but independent magnetic resonance scans which we call noise field equivalent scans. These heuristic analyses enable robust noise field estimation in the presence of artifacts. Generalization of noise estimators based on uniform regions, difference images, and maximum likelihood are presented and compared with the estimators derived from the proposed framework. Simulations of diffusion tensor imaging and T2-relaxometry demonstrate a ten-fold reduction in mean squared error in noise field estimation, and these improvements are shown to be robust to artifact contamination. In vivo studies show that spatially variable noise fields can be readily estimated with typical data acquired at 1.5T.

When applying RF saturation to tissue, MRI signal reductions occur due to magnetization transfer (MT) and direct saturation (DS) effects on water protons. It is shown that the direct effects, often considered a nuisance, can be used to distinguish gray matter regions with different iron content. Direct saturation effects were selected by reducing the magnitude and duration of RF irradiation to minimize confounding MT effects. Contrary to MT saturation spectra, direct water saturation spectra are characterized by a symmetric Lorentzian-shaped frequency dependence that can be described by an exact analytical solution of the Bloch equations. The effect of increased transverse relaxation, e.g. due to the presence of iron, will broaden this saturation spectrum. As a first application, direct saturation ratio (DSR) images were acquired to visualize gray matter structures in the human brain. Similar to T2*w images, the quality of DSR images was affected by local field inhomogeneity, but this could be easily corrected for by centering the saturation spectrum on a voxel-by-voxel basis. The results show that, contrary to commonly used T2*-weighted and absolute R2 images, the DSR images visualize all gray matter structures, including cortex. A direct correlation between DSR and iron content was confirmed for these structures.

The human spinal cord contains segregated sensory and motor pathways that have been difficult to quantify using conventional magnetic resonance imaging (MRI) techniques. Multiple sclerosis is characterized by both focal and spatially diffuse spinal cord lesions with heterogeneous pathologies that have limited attempts at linking MRI and behaviour. We used a novel magnetization-transfer-weighted imaging approach to quantify damage to spinal white matter columns and tested its association with sensorimotor impairment. We studied 42 participants with multiple sclerosis who each underwent MRI at 3 Tesla and quantitative tests of sensorimotor function. We measured cerebrospinal-fluid-normalized magnetization-transfer signals in the dorsal and lateral columns and grey matter of the cervical cord. We also measured brain lesion volume, cervical spinal cord lesion number and cross-sectional area, vibration sensation, strength, walking velocity and standing balance. We used linear regression to assess the relationship between sensorimotor impairment and MRI abnormalities. We found that the dorsal column cerebrospinal-fluid-normalized magnetization-transfer signal specifically correlated with vibration sensation (R = 0.58, P < 0.001) and the lateral column signal with strength (R = −0.45, P = 0.003). Spinal cord signal measures also correlated with walking and balance dysfunction. A stepwise multiple regression showed that the dorsal column signal and diagnosis subtype alone explained a significant portion of the variance in sensation (R2 = 0.54, P < 0.001), whereas the lateral column signal and diagnosis subtype explained a significant portion of the variance in strength (R2 = 0.30, P < 0.001). These results help to understand the anatomic basis of sensorimotor disability in multiple sclerosis and have implications for testing the effects of neuroprotective and reparative interventions.

Magnetization transfer (MT) imaging has assessed myelin integrity in the brain and spinal cord; however, quantitative MT (qMT) has been confined to the brain or excised tissue. We characterized spinal cord tissue with qMT in vivo, and as a first application, qMT-derived metrics were examined in adults with the genetic disorder Adrenomyeloneuropathy (AMN). AMN is a progressive disease marked by demyelination of the white matter tracts of the cervical spinal cord, and a disease in which conventional MRI has been limited. MT data were acquired at 1.5 Tesla using 10 radiofrequency offsets at one power in the cervical cord at C2 in 6 healthy volunteers and 9 AMN patients. The data were fit to a two-pool MT model and the macromolecular fraction (M(ob)), macromolecular transverse relaxation time (T(2b)) and the rate of MT exchange (R) for lateral and dorsal column white matter and gray matter were calculated. M(ob) for healthy volunteers was: WM = 13.9 +/- 2.3%, GM = 7.9 +/- 1.5%. In AMN, dorsal column M(ob) was significantly decreased (P0.03). T(2b) for volunteers was: 9 +/- 2 micros and the rate of MT exchange (R) was: WM = 56 +/- 11 Hz, GM = 67 +/- 12 Hz. Neither T(2b) nor R showed significant differences between healthy and diseased cords. Comparisons are made between qMT, and conventional MT acquisitions.

Q-space imaging is an emerging diffusion weighted MR imaging technique to estimate molecular diffusion probability density functions (PDF's) without the need to assume a Gaussian distribution. We present a robust M-estimator, Q-space Estimation by Maximizing Rician Likelihood (QEMRL), for diffusion PDF's based on maximum likelihood. PDF's are modeled by constrained Gaussian mixtures. In QEMRL, robust likelihood measures mitigate the impacts of imaging artifacts. In simulation and in vivo human spinal cord, the method improves reliability of estimated PDF's and increases tissue contrast. QEMRL enables more detailed exploration of the PDF properties than prior approaches and may allow acquisitions at higher spatial resolution.

Q-space analysis is an alternative analysis technique for diffusion-weighted imaging (DWI) data in which the probability density function (PDF) for molecular diffusion is estimated without the need to assume a Gaussian shape. Although used in the human brain, q-space DWI has not yet been applied to study the human spinal cord in vivo. Here we demonstrate the feasibility of performing q-space imaging in the cervical spinal cord of eight healthy volunteers and four patients with multiple sclerosis. The PDF was computed and water displacement and zero-displacement probability maps were calculated from the width and height of the PDF, respectively. In the dorsal column white matter, q-space contrasts showed a significant (P < 0.01) increase in the width and a decrease in the height of the PDF in lesions, the result of increased diffusion. These q-space contrasts, which are sensitive to the slow diffusion component, exhibited improved detection of abnormal diffusion compared to perpendicular apparent diffusion constant measurements. The conspicuity of lesions compared favorably with magnetization transfer (MT)-weighted images and quantitative CSF-normalized MT measurements. Thus, q-space DWI can be used to study water diffusion in the human spinal cord in vivo and is well suited to assess white matter damage.

BACKGROUND AND PURPOSE: The association of MR imaging abnormalities with clinical disability in multiple sclerosis (MS) has been disappointing. This association might be improved by imaging specific functional systems in the central nervous system—for example, the motor system in a patient with weakness. Our aim was to assess the relationship between muscle strength in MS and corticospinal tract (CST) abnormalities detected with multimodality MR imaging of the brain. MATERIALS AND METHODS: In 47 individuals with MS, diffusion tensor imaging (DTI) at 3T was used to reconstruct the intracranial CSTs. Tract profiles depicted the variation in T2 relaxation time, magnetization transfer ratio (MTR), and DTI-derived indices (fractional anisotropy and diffusivity) as a function of normalized position along the tract. Brain parenchymal fraction was calculated as a normalized measure of brain volume. Stepwise linear regression modeling was used to determine the MR imaging indices most closely related to ankle dorsiflexion and hip flexion strength assessed with quantitative dynamometry. RESULTS: Individuals with MS were significantly weak: Average ankle strength fell 1.7 SDs below the age-, handedness-, and sex-corrected healthy mean. Brain parenchymal fraction was not associated with weakness. A parsimonious model that includes MTR in the brain stem and MS clinical subtype explained 30%–45% of the variance in ankle and hip strength. The model was successfully applied to scans and strength data from the same individuals at an earlier time point. CONCLUSION: MR imaging abnormalities specific to the motor tract are associated with clinical dysfunction related to that tract. The relevant abnormalities are found in the brain stem, distant from the periventricular inflammatory lesions that are common in MS. This suggests that neurodegeneration, rather than primary inflammation, at least partially explains the findings.

Magnetization transfer (MT) imaging provides a unique method of tissue characterization by capitalizing on the interaction between solid-like tissue components and bulk water. We used a continuous-wave (CW) MT pulse sequence with low irradiation power to study healthy human brains in vivo at 3 T and quantified the asymmetry of the MT effects with respect to the water proton frequency. This asymmetry was found to be a difference of approximately a few percent from the water signal intensity, depending on both the RF irradiation power and the frequency offset. The experimental results could be quantitatively described by a modified two-pool MT model extended with a shift contribution for the semisolid pool with respect to water. For white matter, this shift was fitted to be 2.34 +/- 0.17 ppm (N = 5) upfield from the water signal.

To develop an experimental protocol to calculate the precision and accuracy of fractional anisotropy (FA), mean diffusivity (MD), and the orientation of the principal eigenvector (PEV) as a function of the signal-to-noise ratio (SNR) in vivo.A healthy male volunteer was scanned in three separate scanning sessions, yielding a total of 45 diffusion tensor imaging (DTI) scans. To provide FA, MD, and PEV as a function of SNR, sequential scans from a scan session were grouped into nonintersecting sets. Analysis of the accuracy and precision of the DTI-derived contrasts was done in both a voxel-wise and region of interest (ROI)-based manner.An upward bias of FA and no significant bias in MD were present as SNR decreased, confirming results from simulation-based studies. Notably, while the precision of the PEV became worse at low SNR, no bias in the PEV orientation was observed. Overall, an accurate and precise quantification of FA values in GM requires substantially more SNR than the quantification of white matter (WM) FA valuesThis study provides guidance for FA, MD, and PEV quantification and a means to investigate the minimal detectable differences within and across scan sessions as a function of SNR.

The optic nerve (ON) plays a critical role in many devastating pathological conditions. Segmentation of the ON has the ability to provide understanding of anatomical development and progression of diseases of the ON. Recently, methods have been proposed to segment the ON but progress toward full automation has been limited. We optimize registration and fusion methods for a new multi-atlas framework for automated segmentation of the ONs, eye globes, and muscles on clinically acquired computed tomography (CT) data. Briefly, the multi-atlas approach consists of determining a region of interest within each scan using affine registration, followed by nonrigid registration on reduced field of view atlases, and performing statistical fusion on the results. We evaluate the robustness of the approach by segmenting the ON structure in 501 clinically acquired CT scan volumes obtained from 183 subjects from a thyroid eye disease patient population. A subset of 30 scan volumes was manually labeled to assess accuracy and guide method choice. Of the 18 compared methods, the ANTS Symmetric Normalization registration and nonlocal spatial simultaneous truth and performance level estimation statistical fusion resulted in the best overall performance, resulting in a median Dice similarity coefficient of 0.77, which is comparable with inter-rater (human) reproducibility at 0.73.

The magnetization transfer ratio (MTR) is a reliable measure of MT effects because it employs an internal standard that allows quantitative comparison between subjects, independent of other contrasts, coil loading, and coil sensitivity profiles. However, at very high spatial resolution in the spinal cord at 1.5 T, the use of MTR quantification has been hampered by low signal-to-noise ratio (SNR) and acute sensitivity to motion. Here, the suitability of cerebrospinal fluid (CSF) as an alternative inter-subject MT signal intensity reference for the spine is evaluated. Contrary to MTR, this so-called MTCSF internal standard does not remove interfering T(1), T(2), and spin density contrast and is not expected to be able to discriminate between myelination and inflammation effects. However, it can detect initial changes in myelination when signal alterations are not yet detectable by conventional MRI. As a first example, this is demonstrated for the noninflammatory spinal cord white matter disease adrenomyeloneuropathy.

Background: In adrenomyeloneuropathy (AMN) conventional MRI detects only spinal cord atrophy in the late stages. Objective: To apply a magnetization transfer-weighted (MTw) imaging to patients with AMN and AMN-like syndrome in order to visualize and quantitatively assess the pathology of white matter tracts in the cervical spinal cord. Methods: MTw studies were conducted in nine men with AMN, eight symptomatic heterozygous women, and 10 age- and sex-matched controls and compared to the Expanded Disability Status Scale (EDSS) and quantitative tests of vibratory sense and postural sway. MTw data sets were obtained at the level of C1 to C3 using a three-dimensional gradient echo acquisition technique, these images were then standardized between subjects by using the in-slice CSF signal as a normalization reference, allowing a quantitative assessment of the MTw signal. Results: In contrast to conventional MRI, MTw images showed signal hyperintensities in the lateral and dorsal columns of all patients. The MT signal quantified in the dorsal column showed significant differences between patients with AMN, X-linked adrenoleukodystrophy heterozygotes, and controls. MT hyperintensity in the dorsal column correlated with EDSS, vibratory sense, and postural sway. Conclusion: Magnetization transfer-weighted imaging is a sensitive modality for the visual and quantitative assessment of spinal cord pathology in adrenomyeloneuropathy, and is a potential tool for evaluation of new therapies.

Recently a 13-interval magic asymmetrical gradient stimulated echo (MAGSTE) sequence has been proposed for accurate displacement measurements in the presence of spatially varying background gradients. In this paper, the commonly used trapezoidal and sine shaped gradients are studied for the MAGSTE sequence, and the magic asymmetrical gradient ratio and b-factor are provided. The derivation enables the MAGSTE sequence to be implemented on systems with non-negligible gradient rise times.

WCN 2013 No: 1574 Topic: 3 — Stroke Application of chemical exchange saturation transfer (CEST) MRI in acute stroke to visualize tissue acidosis and infarction risk J. Blicher, A. Tietze, I.K. Mikkelsen, L. Ostergaard, M. Strother, S. Smith, M. Donahue. CFIN, Neuroradiology, Aarhus University Hospital, Aarhus, Denmark; Neuroradiology, Aarhus University Hospital, Aarhus, Denmark; Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA Background: In stroke patients with uncertain symptom onset or patients beyond the current time window for ivTPA there is a need for better imaging modalities to guide clinical decision making. Currently, MRI (perfusion weighted imaging) can be used to assess acute cerebral hypoperfusion. However, the technique is invasive, limited to some patients, and distinguishing penumbra from benign oligemia remains difficult. Amide Proton Transfer (APT) MRI is a non-invasive technique sensitive to the exchange of protons between amide-groups and water. The exchange rate is base-catalyzed and thus pH-sensitive. Objective: To investigate the potential for APT imaging, which is sensitive to lactate formation and reduced pH in tissue at risk for infarction, in human acute stroke patients. Patients and methods: 10 patients with acute stroke were scanned on a Phillips 3 T system using our standard acute MRI protocol (including DWI and PWI) as well as a 3-minute APT-sequence. Patients were offered a follow-up scan and a clinical evaluation one month post-stroke. Results: We found a large variation in APT effect between patients. However, in patients with penumbra, based on DWI/PWI missmatch, we found a lower APT effect compared to the ischemic core pointing to early lowering of pH in the penumbra, and possibly changes in protein and water content in the ischemic core. Conclusions: These first results of APT in human acute stroke patients show that the technique could serve as a tool to show early tissue acidosis, and thus guide clinical decision making in stroke care. doi:10.1016/j.jns.2013.07.817 Abstract — WCN 2013 No: 1575 Topic: 3 — Stroke Clinical factors related to severity of post stroke dementia (A retrospective review from 50 geriatric hospitals in Korea) WCN 2013 No: 1575 Topic: 3 — Stroke Clinical factors related to severity of post stroke dementia (A retrospective review from 50 geriatric hospitals in Korea) J.H. Lee, J.H. Park, S.H. Hwang. Neurology, National Health Insurance Service Ilsan Hospital, Goyang-si, Republic of Korea; Neurology, Sanggye Paik Hospital, Inje University College of Medicine, Republic of Korea; Neurology, Hallym University Sacred Heart Hospital, Seoul, Republic of Korea Background and purpose: The results of clinical studies about the severity of post-stroke dementia patients are limited in Korea. We investigate clinical factors related to severity of dementia and to inspect the clinical factors related to the progression of dementia severity. Methods: The patients who visited the hospital by first time between March 2010 and February 2012, among the patients with post-stroke dementia admitted to 50 geriatric hospitals spread all over Korea, formed the analysis cohorts. Retrospective review of medical records was performed. Results:A total of 2965 patients were included. The average duration of illness is 24.61 ± 28.18 months. By the severity of illness, mild cases were 1032 patients (34.81%), moderate 1278 (43.10%), severe 655 (22.09%), and mean score of MMSE was 14.82 ± 6.24. The severity of dementia is higher in patients with overweight by 3.10 times (p= 0.017) existence of inmate by 5.92 times (p= 0.0002), past history of aphasia symptom by 0.18 times (p= 0.0004). Among the clinical factors related to the progression of dementia severity, female patients showed longer duration of illness by 2.89 times comparedwith average, by the results of univariate analysis of 120 severe dementia patients. Conclusions: Among the clinical factors related to severity of poststroke dementia in inpatients of 50 geriatric hospitals in Korea, severity of dementia is higher in patients with overweight, existence of inmate, and past history of aphasia symptom. The progression speed of dementia is suggested to be slow in female, regarding longer duration of illness in severe dementia patients. doi:10.1016/j.jns.2013.07.818 Abstract — WCN 2013 No: 1557 Topic: 3 — Stroke Clinical and radiologic characteristics of RCVS (Reversible Cerebral Vasoconstriction Syndromes) in 23 patients WCN 2013 No: 1557 Topic: 3 — Stroke Clinical and radiologic characteristics of RCVS (Reversible Cerebral Vasoconstriction Syndromes) in 23 patients Y. Ito, H. Moriyoshi, A. Ogura, N. Nakai, S. Nishida, T. Yasuda. Stroke Center, Department of Neurology, TOYOTA Memorial Hospital

Reliable early assessment of breast cancer response to neoadjuvant therapy (NAT) would provide considerable benefit to patient care and ongoing research efforts, and demand for accurate and noninvasive early-response biomarkers is likely to increase. Response assessment techniques derived from quantitative magnetic resonance imaging (MRI) hold great potential for integration into treatment algorithms and clinical trials. Quantitative MRI techniques already available for assessing breast cancer response to neoadjuvant therapy include lesion size measurement, dynamic contrast-enhanced MRI, diffusion-weighted MRI, and proton magnetic resonance spectroscopy. Emerging yet promising techniques include magnetization transfer MRI, chemical exchange saturation transfer MRI, magnetic resonance elastography, and hyperpolarized MR. Translating and incorporating these techniques into the clinical setting will require close attention to statistical validation methods, standardization and reproducibility of technique, and scanning protocol design.

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.

• A series of 1,381 initial biliary tract operations for calculous disease has been analyzed with respect to stones that escape detection during operation or form de novo after operation. The two kinds are often indistinguishable, and both are referred to as "retained stone." After 224 cholecystectomies with choledocholithotomy there were 14 cases of retained stone; after 1,156 cholecystectomies without choledochotomy there were only 9 cases of retained stone. Once the diagnosis of retained stone is established with reasonable certainty, reexploration is generally indicated. In this series, 22 patients under-went a second operation and four underwent a third. The unfortunate occurrence of retained stone is thus more frequently encountered after previous choledocholithotomy and the presence of a biliary duct stone indicates a possible source of serious difficulty.