Incorporating dixon multi-echo fat water separation for novel quantitative magnetization transfer of the human optic nerve in vivo.

PURPOSE: The optic nerve (ON) represents the sole pathway between the eyes and brain; consequently, diseases of the ON can have dramatic effects on vision. However, quantitative magnetization transfer (qMT) applications in the ON have been limited to ex vivo studies, in part because of the fatty connective tissue that surrounds the ON, confounding the magnetization transfer (MT) experiment. Therefore, the aim of this study was to implement a multi-echo Dixon fat-water separation approach to remove the fat component from MT images. METHODS: MT measurements were taken in a single slice of the ON and frontal lobe using a three-echo Dixon readout, and the water and out-of-phase images were applied to a two-pool model in ON tissue and brain white matter to evaluate the effectiveness of using Dixon fat-water separation to remove fatty tissue from MT images. RESULTS: White matter data showed no significant differences between image types; however, there was a significant increase (p < 0.05) in variation in the out-of-phase images in the ON relative to the water images. CONCLUSIONS: The results of this study demonstrate that Dixon fat-water separation can be robustly used for accurate MT quantification of anatomies susceptible to partial volume effects resulting from fat. Magn Reson Med 77:707-716, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Disambiguating the optic nerve from the surrounding cerebrospinal fluid: Application to MS-related atrophy.

PURPOSE: Our goal is to develop an accurate, automated tool to characterize the optic nerve (ON) and cerebrospinal fluid (CSF) to better understand ON changes in disease. METHODS: Multi-atlas segmentation is used to localize the ON and sheath on T2-weighted MRI (0.6 mm(3) resolution). A sum of Gaussian distributions is fit to coronal slice-wise intensities to extract six descriptive parameters, and a regression forest is used to map the model space to radii. The model is validated for consistency using tenfold cross-validation and for accuracy using a high resolution (0.4 mm(2) reconstructed to 0.15 mm(2)) in vivo sequence. We evaluated this model on 6 controls and 6 patients with multiple sclerosis (MS) and a history of optic neuritis. RESULTS: In simulation, the model was found to have an explanatory R-squared for both ON and sheath radii greater than 0.95. The accuracy of the method was within the measurement error on the highest possible in vivo resolution. Comparing healthy controls and patients with MS, significant structural differences were found near the ON head and the chiasm, and structural trends agreed with the literature. CONCLUSION: This is a first demonstration that the ON can be exclusively, quantitatively measured and separated from the surrounding CSF using MRI.

Chemical exchange saturation transfer of the cervical spinal cord at 7 T.

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 Wiley & Sons, Ltd.

Quantifying the impact of underlying measurement error on cervical spinal cord diffusion tensor imaging at 3T.

PURPOSE: To empirically characterize and quantify the impact of gradient weighting schemes on the appearance and fidelity of diffusion tensor imaging of the human spinal cord in vivo in clinically relevant scan time equivalents (STE). MATERIALS AND METHODS: In five healthy controls at 3T, we evaluated test-retest reproducibility and performed voxelwise analysis of diffusion tensor imaging (DTI)-derived indices (fractional anisotropy [FA], mean [MD], axial [AD], and radial [RD] diffusivity) in the cervical spinal cord to assess spatial dependencies of measurement error and differences across three different sampling schemes (6, 15, and 32 directions) at STE of 4.5, 9, and 18 minutes. A subjective assessment was also performed. RESULTS: With six directions, column-specific errors are highest (effect size = 2.9%, 4.4%, 7.2% for FA in dorsal column, lateral column, and gray matter) and different than the 15-direction scheme (P < 0.05). STE sequences with 15 and 32 directions exhibited small differences in error (P > 0.05). For FA and AD, measurement errors are prevalent in gray matter, while partial volume effects with cerebrospinal fluid heavily influence RD. Measurement errors decreased with increasing scan time (P < 0.01), albeit with diminishing returns at scan times longer than 9 minutes (P < 0.05). CONCLUSION: A 15-direction scheme of 9 minutes yields measurements of the cervical spinal cord with low error. J. Magn. Reson. Imaging 2016;44:1608-1618.

Magnetic resonance imaging of the cervical spinal cord in multiple sclerosis at 7T.

BACKGROUND: The clinical course of multiple sclerosis (MS) is mainly attributable to cervical and upper thoracic spinal cord dysfunction. High-resolution, 7T anatomical imaging of the cervical spinal cord is presented. Image contrast between gray/white matter and lesions surpasses conventional, clinical T1- and T2-weighted sequences at lower field strengths. OBJECTIVE: To study the spinal cord of healthy controls and patients with MS using magnetic resonance imaging at 7T. METHODS: Axial (C2-C5) T1- and T2*-weighted and sagittal T2*-/spin-density-weighted images were acquired at 7T in 13 healthy volunteers (age 22-40 years), and 15 clinically diagnosed MS patients (age 19-53 years, Extended Disability Status Scale, (EDSS) 0-3) in addition to clinical 3T scans. In healthy volunteers, a high-resolution multi-echo gradient echo scan was obtained over the same geometry at 3T. Evaluation included signal and contrast to noise ratios and lesion counts for healthy and patient volunteers, respectively. RESULTS/CONCLUSION: High-resolution images at 7T exceeded resolutions reported at lower field strengths. Gray and white matter were sharply demarcated and MS lesions were more readily visualized at 7T compared to clinical acquisitions, with lesions apparent at both fields. Nerve roots were clearly visualized. White matter lesion counts averaged 4.7 vs 3.1 (52% increase) per patient at 7T vs 3T, respectively (p=0.05).

Dual echo vessel-encoded ASL for simultaneous BOLD and CBF reactivity assessment in patients with ischemic cerebrovascular disease.

PURPOSE: Blood oxygenation level-dependent (BOLD)-weighted and vessel-encoded arterial spin labeling (VE-ASL) MRI provide complementary information and can be used in sequence to gauge hemodynamic contributions to cerebrovascular reactivity. Here, cerebrovascular reactivity is assessed using dual echo VE-ASL MRI to understand how VE labeling preparations influence BOLD and ASL contrast in flow-limited and healthy perfusion territories. METHODS: Patients (n = 12; age = 55 +/- 14 years; 6F/6M) presenting with ischemic steno-occlusive cerebrovascular disease underwent 3.0T angiographic imaging, T1 -weighted structural, and planning-free dual echo hypercarbic hyperoxic (i.e., carbogen) VE-ASL MRI. Vasculopathy extent, timecourses, and cerebrovascular reactivity (signal change and Z-statistic) for different VE-ASL images were contrasted across flow territories and Bonferroni-corrected P-values reported. RESULTS: BOLD cerebrovascular reactivity (i.e., long-TE VE-ASL) Z-statistics were similarly sensitive to asymmetric disease (P ≤ 0.002) regardless of labeling scenario. Cerebral blood flow reactivity correlated significantly with BOLD reactivity (Z-statistic). However, BOLD signal changes did not differ significantly between labeling scenarios (P > 0.003) or across territories (P > 0.002), indicating BOLD signal changes in response to carbogen offer low sensitivity to lateralizing disease. CONCLUSION: Dual echo VE-ASL can provide simultaneous cerebral blood flow and qualitative BOLD contrast consistent with lateralizing disease severity in patients with asymmetric steno-occlusive disease. The methodological strengths and limitations of composite BOLD and VE-ASL measurements in the clinic are discussed.

Routine clinical evaluation of cerebrovascular reserve capacity using carbogen in patients with intracranial stenosis.

BACKGROUND AND PURPOSE: A promising method for identifying hemodynamic impairment that may serve as a biomarker for stroke risk in patients with intracranial stenosis is cerebrovascular reactivity (CVR) mapping using noninvasive MRI. Here, abilities to measure CVR safely in the clinic using hypercarbic hyperoxic (carbogen) gas challenges, which increase oxygen delivery to tissue, are investigated. METHODS: In sequence with structural and angiographic imaging, blood oxygenation level-dependent carbogen-induced CVR scans were performed in patients with symptomatic intracranial stenosis (n=92) and control (n=10) volunteers, with a subgroup of patients (n=57) undergoing cerebral blood flow-weighted pseudocontinuous arterial spin labeling CVR. Subjects were stratified for 4 substudies to evaluate relationships between (1) carbogen and hypercarbic normoxic CVR in healthy tissue (n=10), (2) carbogen cerebral blood flow CVR and blood oxygenation level-dependent CVR in intracranial stenosis patients (n=57), (3) carbogen CVR and clinical measures of disease in patients with asymmetrical intracranial atherosclerotic (n=31) and moyamoya (n=29) disease, and (4) the CVR scan and immediate and longer-term complications (n=92). RESULTS: Noninvasive blood oxygenation level-dependent carbogen-induced CVR values correlate with (1) lobar hypercarbic normoxic gas stimuli in healthy tissue (R=0.92; P<0.001), (2) carbogen-induced cerebral blood flow CVR in patients with intracranial stenosis (R=0.30-0.33; P<0.012), and (3) angiographic measures of disease severity both in atherosclerotic and moyamoya patients after appropriate processing. No immediate stroke-related complications were reported in response to carbogen administration; longer-term neurological events fell within the range for expected events in this patient population. CONCLUSIONS: Carbogen-induced CVR elicited no added adverse events and provided a surrogate marker of cerebrovascular reserve consistent with intracranial vasculopathy.

Rapid, high-resolution quantitative magnetization transfer MRI of the human spinal cord.

Quantitative magnetization transfer (qMT) imaging can provide indices describing the interactions between free water protons and immobile macromolecular protons. These indices include the macromolecular proton fraction (MPF), which has been shown to correlate with myelin content in white matter. Because of the long scan times required for high-resolution spinal cord imaging, qMT studies of the human spinal cord have not found wide-spread application. Herein, we investigated whether these limitations could be overcome by utilizing only a single MT-weighted acquisition and a reference measurement, as was recently proposed in the brain. High-resolution, in vivo qMT data were obtained at 3.0T in the spinal cords of healthy volunteers and patients with relapsing remitting multiple sclerosis (MS). Low- and high-resolution acquisitions (low/high resolution=1×1×5mm(3)/0.65×0.65×5mm(3)) with clinically acceptable scan times (12min/7min) were evaluated. We also evaluated the reliability over time and the sensitivity of the model to the assumptions made in the single-point method, both in disease and healthy tissues. Our findings suggest that the single point qMT technique can provide maps of the MPF in the spinal cord in vivo with excellent grey/white matter contrast, can be reliably obtained within reasonable scan times, and are sensitive to MS pathology. Consistent with previous qMT studies in the brain, the observed MPF values were higher in healthy white matter (0.16±0.01) than in grey matter (0.13±0.01) and in MS lesions (0.09±0.01). The single point qMT technique applied at high resolution provides an improved method for obtaining qMT in the human spinal cord and may offer a reliable outcome measure for evaluating spinal cord disease.

Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases.

OBJECTIVE: The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases. METHODS: MTR was measured in the SN of patients with CMT type 1A (CMT1A, n = 10), CMT type 2A (CMT2A, n = 3), hereditary neuropathy with liability to pressure palsies (n = 3), and healthy controls (n = 21). Additional patients without a genetically confirmed subtype (n = 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated. RESULTS: Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 ± 3.3 percent units) and CMT2A (31.5 ± 1.9 percent units) relative to controls (37.2 ± 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p = 0.01 for genetically confirmed patients only, p = 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels. CONCLUSIONS: MTR measurements may be a viable biomarker of proximal nerve pathology in patients with CMT.

Bolus arrival time and cerebral blood flow responses to hypercarbia.

The purpose of this study was to evaluate how cerebral blood flow and bolus arrival time (BAT) measures derived from arterial spin labeling (ASL) MRI data change for different hypercarbic gas stimuli. Pseudocontinuous ASL (pCASL) was applied (3.0T; spatial resolution=4 × 4 × 7 mm(3); repetition time/echo time (TR/TE)=3,600/11 ms) sequentially in healthy volunteers (n=12; age=30±4 years) for separate experiments in which (i) normocarbic normoxia (i.e., room air), hypercarbic normoxia (i.e., 5% CO2/21% O2/74% N2), and hypercarbic hyperoxia (i.e., carbogen: 5% CO2/95% O2) gas was administered (12 L/minute). Cerebral blood flow and BAT changes were quantified using models that account for macrovascular signal and partial volume effects in all gray matter and regionally in cerebellar, temporal, occipital, frontal, and parietal lobes. Regional reductions in BAT of 4.6% to 7.7% and 3.3% to 6.6% were found in response to hypercarbic normoxia and hypercarbic hyperoxia, respectively. Cerebral blood flow increased by 8.2% to 27.8% and 3.5% to 19.8% for hypercarbic normoxia and hypercarbic hyperoxia, respectively. These findings indicate that changes in BAT values may bias functional ASL data and thus should be considered when choosing appropriate experimental parameters in calibrated functional magnetic resonance imaging or ASL cerebrovascular reactivity experiments that use hypercarbic gas stimuli.

The vascular steal phenomenon is an incomplete contributor to negative cerebrovascular reactivity in patients with symptomatic intracranial stenosis.

'Vascular steal' has been proposed as a compensatory mechanism in hemodynamically compromised ischemic parenchyma. Here, independent measures of cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) responses to a vascular stimulus in patients with ischemic cerebrovascular disease are recorded. Symptomatic intracranial stenosis patients (n=40) underwent a multimodal 3.0T MRI protocol including structural (T1-weighted and T2-weighted fluid-attenuated inversion recovery) and hemodynamic (BOLD and CBF-weighted arterial spin labeling) functional MRI during room air and hypercarbic gas administration. CBF changes in regions demonstrating negative BOLD reactivity were recorded, as well as clinical correlates including symptomatic hemisphere by infarct and lateralizing symptoms. Fifteen out of forty participants exhibited negative BOLD reactivity. Of these, a positive relationship was found between BOLD and CBF reactivity in unaffected (stenosis degree<50%) cortex. In negative BOLD cerebrovascular reactivity regions, three patients exhibited significant (P<0.01) reductions in CBF consistent with vascular steal; six exhibited increases in CBF; and the remaining exhibited no statistical change in CBF. Secondary findings were that negative BOLD reactivity correlated with symptomatic hemisphere by lateralizing clinical symptoms and prior infarcts(s). These data support the conclusion that negative hypercarbia-induced BOLD responses, frequently assigned to vascular steal, are heterogeneous in origin with possible contributions from autoregulation and/or metabolism.