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 5 10), CMT type 2A (CMT2A, n 5 3), hereditary neuropathy with liability to pressure palsies (n 5 3), and healthy controls (n 5 21). Additional patients without a genetically confirmed subtype (n 5 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 6 3.3 percent units) and CMT2A (31.5 6 1.9 percent units) relative to controls (37.2 6 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p 5 0.01 for genetically confirmed patients only, p 5 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. Charcot-Marie-Tooth (CMT) diseases are a group of inherited neuropathies that affect motor and sensory nerves. A majority of CMT phenotypes can be classified as primary demyelination/dysmyelinating (CMT1) or primary axonal (CMT2) neuropathies.1,2 CMT type 1A (CMT1A z 80% of CMT1 cases 3,4 ) arises from duplication of the peripheral myelin protein 22 (PMP22) gene 5,6 and results in dysmyelination and secondary axonal loss. 7 CMT type 2A (CMT2A z 35% of CMT2 cases 8 ) is caused by missense mutations in the gene that encodes for mitofusin 2 9 and leads to primary axonal degeneration. 8 Although the pathologic features of CMT1A/CMT2A are different, length-dependent axonal loss occurs in both and is predictive of outcomes.

Background and Purpose A promising method for identifying hemodynamic impairment that may serve as a biomarker for stroke risk in patients with intracranial (IC) stenosis is cerebrovascular reactivity (CVR) mapping using non-invasive 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 (BOLD) carbogen-induced CVR scans were performed in patients with symptomatic IC stenosis (n=92) and control (n=10) volunteers, with a subgroup of patients (n=57) undergoing cerebral blood flow-weighted (CBFw) pseudo-continuous arterial spin labeling (pCASL) CVR. Subjects were stratified for four sub-studies: to evaluate relationships between (i) carbogen and hyercarbic normoxic (HN) CVR in healthy tissue (n=10), (ii) carbogen CBF CVR and BOLD CVR in IC stenosis patients (n=57), (iii) carbogen CVR and clinical measures of disease in patients with asymmetric IC atherosclerotic (n=31) and moyamoya (n=29) disease, and (iv) the CVR scan and immediate and longer-term complications (n=92). Results Non-invasive BOLD carbogen-induced CVR values correlate with (i) lobar HN gas stimuli in healthy tissue (R=0.92; P<0.001), (ii) carbogen-induced CBF CVR in IC stenosis patients (R=0.30–0.33; P<0.012), and (iii) 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 IC vasculopathy.

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.

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 3.0 tesla in the spinal cords of healthy volunteers and patients with relapsing remitting multiple sclerosis (MS). Low- and high-resolution acquisitions (low/high resolution = 1×1×5 mm3/0.65×0.65×5 mm3) with clinically acceptable scan times (12 min/7 min) 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 tissue. 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.

Background The clinical course of 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, 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 both fields. 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).

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.

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 mm3 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 mm2 reconstructed to 0.15 mm2) 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.

High-magnetic field (7T) chemical exchange saturation transfer (CEST) MRI provides information regarding 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 ten healthy controls and ten MS patients and results were examined using traditional asymmetry analysis and Lorentzian fit method. Additionally, 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 down-field from the water resonance. The z-spectra in healthy subjects had the expected z-spectra shape with CEST effects apparent from 2.0 ppm – 4.5 ppm. The z-spectra from MS patients demonstrated deviations from this expected, normal shape indicating this method’s sensitivity to known pathology as well as those tissues appearing normal on conventional MRI. Examination of the calculated CESTasym reveals increased asymmetry around the amide proton resonance (Δω = 3.5 ppm) but it is apparent that this measure is complicated by detail in the CEST spectrum up-field from water, which is expected to result from Nuclear Overhauser effect. The z-spectra up field (negative ppm range) are also distinct between healthy and diseased tissue and cannot be ignored, particularly when considering the conventional asymmetry analysis used to quantify the CEST effect. For all frequencies greater than +1 ppm, the Lorentzian difference (and z-spectra) for lesions and normal appearing white matter are distinct from healthy white matter. The increased frequency separation and signal to noise (SNR) in concert with prolonged T1 at 7T result 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.