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

Highlights

• Applied the single-point qMT method to cervical spinal cord in vivo.

• Evaluated assumption validity in single-point model in disease and healthy tissue.

• SC qMT can provide MPF maps in vivo with excellent grey/white matter contrast.

• Observed MPF values were higher in healthy WM and GM than in MS lesions.

• This technique may provide a reliable outcome for evaluating spinal cord disease.

Abstract

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 T 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 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.

Introduction

The spinal cord is responsible for mediating neurological function between the brain and the peripheral nervous system and is somatotopically organized — sensory information is conveyed through the dorsal columns, while the lateral columns convey a significant fraction of motor function. The integrity of these organized columns is vital to preserving specific neurological function; therefore, even small spinal cord lesions (e.g. multiple sclerosis (MS)) can result in severe neurological impairment. While the absolute mechanism of the pathophysiology of MS and nervous system tissue deterioration remains challenging to unravel, there is a body of evidence that suggests that axonal loss resulting in spinal cord atrophy may relate to clinical impairment (Cohen et al., 2012, Rocca et al., 2011). Conventional MRI (i.e. spin-density, T₁- and T₂-weighted) can be used to measure atrophy or determine the location of inflammatory lesions in the spinal cord, but the relationship between conventional MRI indices (e.g. atrophy, lesion burden) and nervous system function and disease progression over time tends to be poor (Stankiewicz et al., 2009).

More quantitative MRI measurements, such as magnetization transfer (MT) and diffusion tensor imaging (DTI) metrics have been applied to the cervical spinal cord to investigate the relationship between neurological function and spinal cord microstructure (Cohen-Adad et al., 2011, Ellingson et al., 2008, Filippi and Agosta, 2010, Freund et al., 2010, Nair et al., 2010, Naismith et al., 2013, Oh et al., 2013, Poloni et al., 2011, Smith et al., 2009, Zackowski et al., 2009). Importantly, as these measurements report on microstructural changes that may precede atrophy, they potentially offer greater prediction of spinal cord function than conventional methods. While quantitative MRI methods have shown promise for characterizing spinal cord damage in diseases such as MS (Stroman et al., 2014, Wheeler-Kingshott et al., 2014), widespread adoption has been challenged by the low signal to noise ratio (SNR), long acquisition times, and sensitivity to motion.

The focus of this work is on magnetization transfer (MT) imaging. Briefly, in addition to free water protons observed with conventional MRI, there are protons residing on immobile macromolecules in tissue (Wolff and Balaban, 1989). Conventional MRI cannot image these protons directly because their T₂ relaxation times are too short (≈ 10 μs) to be captured by typical readout schemes. However, these macromolecular protons communicate with the surrounding water and, thus, can be indirectly imaged by exploiting this exchange, which is referred to as the MT effect. Importantly, MT imaging can serve as a surrogate marker for white matter myelin density in nervous system tissue (Koenig, 1991, Kucharczyk et al., 1994, Schmierer et al., 2007) and, therefore, may be a more specific biomarker of disease evolution. Despite this promise, MT imaging has faced significant challenges in the spinal cord.

The contrast in an MT experiment is generated via application of a radiofrequency (RF) irradiation pulse at an offset frequency with respect to water (Δω) to selectively saturate the spectrally broad macromolecular protons. This saturation is then transferred to the free water pool via MT, resulting in an observed signal attenuation. The MT effect is often semi-quantitatively characterized via the MTR, which has been shown to correlate with myelin content (Schmierer et al., 2007). Unfortunately MTR is also sensitive to pulse sequence design, B₁ and B₀ inhomogeneities (Berry et al., 1999), as well as tissue relaxation times and other non-MT-specific NMR parameters (Henkelman et al., 1993, Stanisz et al., 2005). This limits the ability of researchers and clinicians to create a standard MTR metric to define pathology. To overcome some of these limitations and to derive indices that are directly reflective of MT phenomena, quantitative MT (qMT) has been developed and implemented in the brain, but rarely in the spinal cord (Levesque et al., 2010b, Samson et al., 2013, Sled and Pike, 2001, Smith et al., 2009, Stanisz et al., 2005). qMT typically requires images to be acquired at multiple RF irradiation powers and/or offsets, generating a so-called MT z-spectrum for each voxel (Hinton and Bryant, 1996). The resulting z-spectrum can then be fit to a two (or more)-pool model to estimate quantitative indices, such as the macromolecular proton fraction (MPF) – defined as the macromolecular pool size divided by the sum of the macromolecular and free pool sizes, or f, as reported by Yarnykh (2012) – the MT exchange rate from the macromolecular pool to the free pool (k_mf), and the transverse and longitudinal relaxation times for each pool (Stanisz et al., 2005). Often, the focus is on the MPF as it has been shown to correlate well with white matter myelin density (Odrobina et al., 2005, Ou et al., 2009, Schmierer et al., 2007, Underhill et al., 2011), and may offer a biomarker of demyelination and axonal loss in white matter pathologies.

While qMT offers indices reflective of tissue physiology, translation of this methodology into the spinal cord within a clinically feasible scan time has proven to be a challenge. Even in the brain, collection of multi-power, multi-offset, high SNR, voxel-wise MT z-spectra can result in scan times as long as 30–45 min for whole-brain coverage at low resolution (Yarnykh, 2012). As the cord is small (only 1.5 cm in diameter at the cervical levels), with its component white and grey matter groups on the order of millimeters, even higher resolution is necessary, exacerbating the scan time problem. Additionally, at these high-resolutions, transverse spinal cord motion resulting from cardiac and respiratory cycles, as well as cerebrospinal fluid pulsation, can lead to substantial artifacts. Lastly, the spinal cord is surrounded by large bones that create spatially varying susceptibility gradients. Importantly for qMT, these susceptibility gradients can alter the effective B₁ and B₀ fields, leading to spatially dependent RF powers and offset frequencies. Fortunately, when performing qMT in the spinal cord, the model incorporates both B₁ and B₀ corrections, which can minimize the impact of spatially varying B₁ and B₀ errors in the estimated MPF value.

A new method to perform a qMT analysis using only a single MT-weighted acquisition and a reference measurement (no RF saturation) has been recently proposed for the brain (Yarnykh, 2012). This method imposes constraints on the two-pool model in order to derive quantitative maps of the MPF in tissue from a single offset measurement (n.b., additional T₁, B₁, and B₀ measurements are also performed). Using this model, improved resolution or reduced sensitivity to motion can potentially be realized in clinically relevant scan times, making it a viable approach for the spinal cord. Thus, the goal of this study was to determine the feasibility of translating this single-point approach to the cervical spinal cord as a means of performing high resolution, rapid qMT imaging. Towards this end, we performed in vivo qMT in the cervical spinal cord of healthy controls and MS patients using (i) a low-resolution, multi-offset and power MT acquisition with a full model fit (the gold-standard); and (ii) high-resolution, single-point fits using the optimal offset and power from numerical simulations (c.f. Materials and methods section). We evaluated the robustness of the single-point methods and sensitivity for disease in patients with MS. Additional numerical studies were performed to assess the affect of the constraints on the single-point qMT parameters. Lastly, the reproducibility of the acquisition and analysis methods was experimentally studied.