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Multiparametric MRI reveals dynamic changes in molecular signatures of injured spinal cord in monkeys.

ABSTRACT: PURPOSE:To monitor the spontaneous recovery of cervical spinal cord injury (SCI) using longitudinal multiparametric MRI methods. METHODS:Quantitative MRI imaging including diffusion tensor imaging, magnetization transfer (MT), and chemical exchange saturation transfer (CEST) were conducted in anesthetized squirrel monkeys at 9.4T. The structural, cellular, and molecular features of the spinal cord were examined before and at different time points after a dorsal column lesion in each monkey. RESULTS:Images with MT contrast enhanced visualization of the gray and white matter boundaries and the lesion and permitted differentiation of core and rim compartments within an abnormal volume (AV). In the early weeks after SCI, both core and rim exhibited low cellular density and low protein content, with high levels of exchanging hydroxyl, amine, and amide protons, as evidenced by increased apparent diffusion coefficient, decreased fractional anisotropy, decreased MT ratio, decreased nuclear Overhauser effect, and large CEST effects. Over time, cellular density and fiber density increased, whereas amide, amine, and hydroxyl levels dropped significantly, but at differing rates. Histology confirmed the nature of the AV to be a cyst. CONCLUSION:Multiparametric MRI offers a novel method to quantify the spontaneous changes in structure and cellular and molecular compositions of SC during spontaneous recovery from injury.

SUBMITTER: Wang F

PROVIDER: S-EPMC4405405 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Multiparametric MRI reveals dynamic changes in molecular signatures of injured spinal cord in monkeys.

Wang Feng F Qi Hui-Xin HX Zu Zhongliang Z Mishra Arabinda A Tang Chaohui C Gore John C JC Chen Li Min LM

Magnetic resonance in medicine 20141021 4

<h4>Purpose</h4>To monitor the spontaneous recovery of cervical spinal cord injury (SCI) using longitudinal multiparametric MRI methods.<h4>Methods</h4>Quantitative MRI imaging including diffusion tensor imaging, magnetization transfer (MT), and chemical exchange saturation transfer (CEST) were conducted in anesthetized squirrel monkeys at 9.4T. The structural, cellular, and molecular features of the spinal cord were examined before and at different time points after a dorsal column lesion in ea ...[more]

PMID: 25334025

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Project description:PurposeThe sensitivity and accuracy of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects for assessing injury-associated changes in cervical spinal cords were evaluated in squirrel monkeys. Multiple interacting pools of protons, including one identified by an NOE at -1.6 ppm relative to water (NOE(-1.6)), were derived and quantified from fitting proton Z-spectra. The effects of down-sampled data acquisitions and corrections for non-specific factors including T1, semi-solid magnetization transfer, and direct saturation of free water (DS), were investigated. The overall goal is to develop a protocol for rapid data acquisition for assessing the molecular signatures of the injured spinal cord and its surrounding regions.MethodsMRI scans were recorded of anesthetized squirrel monkeys at 9.4 T, before and after a unilateral dorsal column sectioning of the cervical spinal cord. Z-spectral images at 51 different RF offsets were acquired. The amplitudes of CEST and NOE effects from multiple proton pools were quantified using a six-pool Lorenzian fitting of each Z-spectrum (MTRmfit). In addition, down-sampled data using reduced selections of RF offsets were analyzed and compared. An apparent exchange-dependent relaxation (AREXmfit) method was also used to correct for non-specific factors in quantifying regional spectra around lesion sites.ResultsThe parametric maps from multi-pool fitting using the complete sampling data (P51e) detected unilateral changes at and around the injury. The maps derived from selected twofold down-sampled data with appropriate interpolation (P26sI51) revealed quite similar spatial distributions of different pools as those obtained using P51e at each resonance shift. Across 10 subjects, both data acquisition schemes detected significant decreases in NOE(-3.5) and NOE(-1.6) and increases in DS(0.0) and CEST(3.5) at the lesion site relative to measures of the normal tissues before injury. AREXmfit of cysts and other abnormal tissues at and around the lesion site also exhibited significant changes, especially at 3.5, -1.6 and -3.5 ppm RF offsets.ConclusionThese results confirm that a reduced set of RF offsets and down sampling are adequate for CEST imaging of injured spinal cord and allow shorter imaging times and/or permit additional signal averaging. AREXmfit correction improved the accuracy of CEST and NOE measures. The results provide a rapid (~13 mins), sensitive, and accurate protocol for deriving multiple NOE and CEST effects simultaneously in spinal cord imaging at high field.

Project description:Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently, patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons below the injury level may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15 g for 1 min. Alterations in gene expression produce long-term sensory changes, therefore, we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescence-activated cell sorting (FACS). RNA was extracted from sorted sensory neurons of naïve, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed, we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain.

Project description:BACKGROUND:Spinal cord (SC) pathology is a major contributor to clinical disability in multiple sclerosis (MS). Conventional magnetic resonance imaging (MRI), specifically SC-MRI lesion load measures that include lesion count and volume, demonstrate only a modest relationship with the clinical status of MS patients. Although SC cross-sectional area (CSA) correlates better with clinical dysfunction than MRI lesion count, SC atrophy likely signifies irreversible tissue loss. Using quantitative MRI indices sensitive to early and late microstructural changes in the spinal cord, we searched for the presence of better correlations between MRI measures and clinical status in MS. OBJECTIVES:We investigated whether diffusion-tensor imaging indices and the magnetization-transfer ratio (MTR) were better associated with the clinical status of MS patients than conventional SC-MRI measures. METHODS:A total of 129 MS patients underwent 3-tesla cervical SC-MRI and quantitative sensorimotor function testing, using the Vibratron-II and dynamometer. Regions-of-interest circumscribed the SC on axial slices between C3-C4. We calculated SC-CSA, fractional anisotropy (FA), mean diffusivity (MD), perpendicular diffusivity (? perpendicular), parallel diffusivity (?||) and MTR. We used multivariable linear regression to determine if there were any associations between MRI indices and clinical measures of dysfunction. RESULTS:All MRI indices were significantly different in subjects with MS versus healthy controls, and between the progressive versus relapsing MS subtypes, with the exception of ?||. In multivariable regression models that were adjusted for age, sex, brain parenchymal fraction, and SC-CSA, the MRI indices independently explained variability in hip flexion strength (p-values: MD, ? perpendicular, ?|| < 0.001; FA = 0.07), vibration sensation threshold (p-values: FA = 0.04; MTR = 0.05; ? perpendicular = 0.06), and Expanded Disability Status Scale scores (p-values: FA = 0.003; MD = 0.03; ? perpendicular = 0.005; MTR = 0.02). CONCLUSIONS:In a large, heterogeneous MS sample, quantitative SC-MRI indices demonstrated independent associations with system-specific and global clinical dysfunction. Our findings suggest that the indices studied may provide important information about microstructural SC changes and the substrates of limb disability in MS. The identified structure-function relationships underpin the potential utility of these measures in assessments of therapeutic efficacy.

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Multiparametric MRI reveals dynamic changes in molecular signatures of injured spinal cord in monkeys.

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Multiparametric MRI reveals dynamic changes in molecular signatures of injured spinal cord in monkeys.

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