A pharmacokinetic model for quantitative evaluation of spinal cord injury with dynamic contrast‐enhanced magnetic resonance imaging

Abstract

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows in vivo measurement of many physiological parameters of clinical interest (1-3). Following intravenous administration, the exogenous paramagnetic contrast agent gadopentetate-dimeglumine (Gd) is distributed throughout the body, except in the central nervous system (CNS) tissue because of the blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB). In the presence of CNS pathology, the barrier is regionally disrupted; Gd no longer remains intravascular and leaks into the interstitial tissue spaces. Measuring the rate of this leakage facilitates quantitative evaluation of barrier permeability. For example, the BBB in brain tumors or injuries was successfully characterized in vivo using Gd concentration data obtained from DCE-MRI (4). This technique has not yet been applied to evaluate the status of BSCB following traumatic spinal cord injury (SCI) or disease. Quantitative measurements of changes in BSCB permeability in vivo can be used to assess the severity of injury, monitor the evolution of cord pathology, identify the effective time interval for delivering drugs to the cord tissue across the compromised barriers, and observe the endogeneous repair processes (5).In this paper, we report results from in vivo DCE-MRI experiments performed on rats in the acute phase of SCI with Gd administered intravenously as a bolus. The time course and distribution of Gd concentration in injured spinal cord (SC) tissue and cerebrospinal fluid (CSF) were determined from intensity enhancements on the postcontrast T 1 -weighted images that were acquired sequentially. To represent the concentration data, a pharmacokinetic model was developed under limited permeability conditions for BSCB (6). This model consists of three compartments for plasma, injured cord, and CSF. Inclusion of a separate compartment for CSF was necessary because even though in humans CSF intensity remains nearly unchanged after Gd delivery in normal subjects, intensity enhances almost immediately in the CSF of normal rats (see the Discussion section). In this model, Gd transport between compartments was represented by different transfer rate constants. A window-based simulation analysis and modeling software was used to estimate the transfer parameters from the concentration data in plasma, CSF, and injured cord. The estimates associated with injured cord were ultimately used to evaluate the status of BSCB. Unlike the two-compartment pharmacokinetic models suggested specifically for studying BBB (4), the proposed model with three compartments takes into account the exchange of Gd between plasma and CSF. The utility of the model is discussed in the context of primary and secondary pathobiological processes that take place in the acute phase of SCI and the time window of opportunity for any therapeutic intervention. MATERIALS AND METHODS Animals and SCIA total of 11 (eight injured, two laminectomy controls, and one naïve control) male Sprague-Dawley rats weighing 350 -400 g were used...

Shutter‐speed analysis of contrast reagent bolus‐tracking data: Preliminary observations in benign and malignant breast disease

“…One of these is a specific temporal mismatch of the bestfitted standard model curve and the B-T data shape: the model lags behind during the tissue CR wash-in, then oscillates during wash-out, initially overshooting and later undershooting (7). This signature has been experimentally observed for fittings of rodent data conducted by ourselves (7,12) and others (13,14). The second signature, K trans and v e underestimations increasing with CR dose (7), has also been observed in mouse tumor model data (12).…”

Evidence for shutter-speed variation in CR bolus-tracking studies of human pathology

“…6 This signature has been reported for fittings of experimental rodent data conducted by ourselves, 6,11 and by others. 12,13 A second tell-tale inadequacy is that the K trans and v e values returned by the standard model decrease with increasing CR dose. 6 Of course, these are defined as tissue parameters that should not be dose-dependent.…”

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“…Magnetic resonance imaging (MRI) has shown promise as a useful and powerful tool for detection and characterization of spinal cord pathology in animal models (Berens et al, 2005;Bilgen et al, 2000Bilgen et al, , 2001bBilgen and Narayana, 2001;Chakeres et al, 1987;Deo et al, 2006;Falconer et al, 1994;Narayana et al, 1999Narayana et al, , 2004Ohta et al, 1999;Schwartz and Hackney, 2003;Weber et al, 2006). The noninvasive nature of MRI offers the possibility of following pathological changes over time in the same animal, avoids inter-subject variability, and decreases the number of animals that need to be used to attain statistical significance.…”

“…Damage to this barrier directly affects pathophysiological processes of lesion development and penetration of potential therapeutic agents from the systemic circulation into the central nervous system. Although MRI characteristics of BSCB disruption after SCI have been extensively studied by others (Berens et al, 2005;Bilgen et al, 2002;Bilgen and Narayana, 2001;Runge et al, 1997;Schwartz, 2005;Whetstone et al, 2003), no longitudinal studies have compared integrity of BSCB between two injury severities. Our results indicate a significant difference between the two study groups at 7 days post-injury, with contrast enhancement of the lesion being much stronger in the severely injured animals than in the mildly injured ones.…”

“…Older reports were performed at lower field strengths between 1.5-2T with or without implantable RF coils. These studies examined acute changes in vivo in one lesion severity (Bilgen and Narayana, 2001;Duncan et al, 1992) and temporal changes ex vivo (Hackney et al, 1994) or in vivo (Bilgen et al, 2001aFalconer et al, 1994;Narayana et al, 1999;Runge et al, 1997) in thoracic SCI. Just one study used in vivo MRI to examine two cervical lesion severities imaged at two time points and compared that with histopathology and behavioral tests (Ohta et al, 1999).…”