Kurt Bockhorst

NMR Imaging of the Apparent Diffusion Coefficient (ADC) for the Evaluation of Metabolic Suppression and Recovery after Prolonged Cerebral Ischemia

Adult normothermic cats were submitted to 1-h complete cerebrocirculatory arrest by intrathoracic occlusion of the internal mammary, the innominate, and the subclavian arteries in combination with pharmacologically induced hypotension. After ischemia, recirculation was initiated at different blood pressure levels to manipulate the postischemia resuscitation conditions. The resulting spectrum of postischemic recovery was studied by combining nuclear magnetic resonance imaging of the apparent diffusion coefficient (ADC) with pictorial assays of brain tissue pH, ATP, glucose, and lactate. Before ischemia, the mean ADC (average of seven coronal slices of five cats) was 713 ± 40 × 10−6 mm2/s. After 10-min ischemia, ADC declined to 68% of control and after 50 min slightly further to 63% of control. During recirculation after 1-h ischemia, recovery of ADC varied depending on the initial reperfusion pressure and other systemic variables. In two animals ADC only transiently increased followed by a secondary decline below the postischemic level. In three other animals ADC returned to near control within 1 h of recirculation. The comparison of ADC changes with previously reported changes in extracellular volume revealed a close relationship, supporting the notion that ADC is a function of the intra/extracellular water compartmentation. Recovery of ADC correlated closely with tissue pH and metabolic recovery, studied 3 h after the initiation of recirculation. Animals without recovery of ADC exhibited global depletion of ATP and glucose and severe lactacidosis, whereas animals with recovery of ADC showed replenishment of ATP and glucose to near control and a substantial reversal of lactacidosis. Our data demonstrate that imaging of ADC provides reliable information about the metabolic state of the brain and can be used to monitor, with high temporal and regional resolution, the manifestation and reversal of ischemic brain injury.

Imaging of the apparent diffusion coefficient for the evaluation of cerebral metabolic recovery after cardiac arrest

The apparent diffusion coefficient (ADC) of water is a sensitive indicator of water and ion homeostasis of brain. Resuscitation of the brain after cardiac arrest, the most frequent reason for global cerebral ischemia under clinical conditions, depends critically on the reversal of disturbances of water and ion homeostasis. We, therefore, investigated whether ADC imaging can be used to monitor the development and reversal of ischemic brain injury during and after cardiac arrest. Ten adult mongrel normothermic cats were anesthetized with alfentanil and midazolam, immobilized with pancuronium, and mechanically ventilated with O2/N2O. Arterial, left ventricular, central venous, and intracranial pressures were monitored throughout the experiment. Magnetic resonance imaging was performed in a 4.7T MR scanner with a shielded gradient system. Diffusion-weighted images (DWI) were obtained by pulsed gradient spin echoes (diffusion weighting factor b: 0, 500, 1000, 1500 s/mm2). Quantitative ADC images were calculated from DWIs by fitting signal intensities against b-factors. Fifteen minute cardiac arrest was induced in the magnet by electrical fibrillation. Resuscitation was also carried out in the magnet, using a pneumatic vest for remotely controlled closed chest cardiac massage. Seven of 10 animals were resuscitated successfully and subsequently monitored for 3 h. During cardiac arrest, ADC declined from 678 +/- 79 x 10(-6) to 430 +/- 128 x 10(-6) mm2/s (63% of baseline). In the successfully resuscitated animals ADC returned to 648 +/- 108 x 10(-6) mm2/s within 30 min and remained at this level throughout the 3 h of recirculation. Regional evaluations of ADC revealed a transient overshoot in brainstem and basal ganglia to 114% of control at 15 min before returning to baseline values after 40 min. Failure of cardiac resuscitation prevented ADC normalization and led to its further decline to below 50% of control. Postcardiac arrest normalization of ADC maps correlated with homogeneous return of ATP, glucose, and lactate to near normal, whereas failure of ADC normalization was associated with depletion of ATP and glucose and severe lactate accumulation. In conclusion, our data indicate, that normalization of ADC is a reliable indicator of cerebral recovery after resuscitation from cardiac arrest.

Proton relaxation enhancement in experimental brain tumors ― in vivo NMR study of manganese(III)TPPS in rat brain gliomas

The effect of manganese(III)tetraphenylporphine sulfonate (MnTPPS) on the relaxation enhancement of NMR images (MRI) was studied in experimental brain tumors in rats. Brains were inoculated with the glioma cell line F98 12 to 19 days before the NMR experiment, and the effect of MnTPPS (0.25 mmol/kg body weight) was investigated 2 and 4 days after intraperitoneal injection. After MnTPPS addition tumors could be clearly distinguished by the brightness from the surrounding brain whereas they were barely visible without contrast enhancement. At SE time of 25 msec and TR time of 3500 msec the ratio of magnetization values of tumor versus normal grey matter increased from 0.98 +/- 0.08 to 1.24 +/- 0.09 (means +/- SD). When TR was shortened to 1100 msec contrast enhancement further increased to 1.77 +/- 0.25. These results demonstrate for the first time that MnTPPS is an efficient agent for contrast enhancement of brain tumors.

In vivo NMR T2 relaxation of experimental brain tumors in the cat: A multiparameter tissue characterization

Experimental gliomas (F98) were inoculated in cat brain for the systematic study of their in vivo T2 relaxation time behavior. With a CPMG multi-echo imaging sequence, a train of 16 echoes was evaluated to obtain the transverse relaxation time and the magnetization M(0) at time t = 0. The magnetization decay curves were analyzed for biexponentiality. All tissues showed monoexponential T2, only that of the ventricular fluid and part of the vital tumor tissue were biexponential. Based on these NMR relaxation parameters the tissues were characterized, their correct assignment being assured by comparison with histological slices. T2 of normal grey and white matter was 74 +/- 6 and 72 +/- 6 msec, respectively. These two tissue types were distinguished through M(0) which for white matter was only 0.88 of the intensity of grey matter in full agreement with water content, determined from tissue specimens. At the time of maximal tumor growth and edema spread a tissue differentiation was possible in NMR relaxation parameter images. Separation of the three tissue groups of normal tissue, tumor and edema was based on T2 with T2(normal) < T2(tumor) < T2(edema). Using M(0) as a second parameter the differentiation was supported, in particular between white matter and tumor or edema. Animals were studied at 1-4 wk after tumor implantation to study tumor development. The magnetization M(0) of both tumor and peritumoral edema went through a maximum between the second and third week of tumor growth. T2 of edema was maximal at the same time with 133 +/- 4 msec, while the relaxation time of tumor continued to increase during the whole growth period, reaching values of 114 +/- 12 msec at the fourth week. Thus, a complete characterization of pathological tissues with NMR relaxometry must include a detailed study of the developmental changes of these tissues to assure correct experimental conditions for the goal of optimal contrast between normal and pathological regions in the NMR images.

Quantitative magnetic resonance imaging of rat brain tumors: In vivo NMR relaxometry for the discrimination of normal and pathological tissues

The in vivo relaxation times T1 and T2 were quantitatively determined in rat brain. Animals with implanted experimental brain tumors were investigated for discrimination of pathological regions from normal brain structures based on relaxation time differences. The different cerebral tumors (glioma, schwannoma, neuroblastoma) showed no difference in relaxation times, but all tumors had T1(1301 +/- 167 ms) and T2(91 +/- 9 ms) times distinctly longer than normal brain (T1: 1057 +/- 77 ms; T2: 77 +/- 6 ms). T1 can be used for distinction of tumor and edema from normal brain, while T2 is the better parameter for discrimination between tumor and edema. Furthermore, the effect of MRI contrast agents (GdDTPA, MnTPPS, GdTPPS) on the relaxation times of these experimental brain tumors was measured. The enhancement of tumors produced by GdDTPA disappeared within ten minutes after i.p. application. At later times, central cysts and peritumoral edema became the most enhanced structures. The enhancement of tumor following MnTPPS application remained unchanged in T1-weighted images during the whole observation period of four days. A significant reduction of enhancement was not observed during this time. The effect of MnTPPS on T2 was weak. Replacement of manganese with gadolinium as the central ion of the porphyrin TPPS led to a contrast agent with enhancement effects on both, T1- and T2-weighted images.

Resuscitation from cardiac arrest in cats: influence of epinephrine dosage on brain recovery☆

The quality of brain recovery after cardiac arrest depends crucially on the speed of cardiac resuscitation because the low cerebral perfusion pressure during the resuscitation procedure facilitates the development of no-reflow. To accelerate return of spontaneous circulation, high dose epinephrine has been recommended but the effect on the dynamics of early brain recovery is still unknown. We, therefore, studied the dynamics of brain resuscitation after cardiopulmonary resuscitation (CPR) with standard and high dose epinephrine using non-invasive NMR techniques. Fifteen min cardiac arrest was induced in normothermic cats by ventricular fibrillation. CPR was performed using an inflatable pneumatic vest for cyclic chest compression. With the beginning of CPR the standard dose group received 0.02 mg/kg epinephrine (n = 6) and the high dose group received 0.2 mg/kg (n = 8). Brain recovery was monitored by magnetic resonance imaging of the apparent diffusion coefficient (ADC) of water for 3 h. Although high dose epinephrine treatment led to a significantly higher blood pressure during early reperfusion, rapidly changing heterogeneities of early brain recovery were observed in both groups. High dose epinephrine thus does not improve the quality of post-cardiac arrest brain recovery during the first 3 h of reperfusion.

NMR-contrast enhancement of experimental brain tumors with MnTPPS: Qualitative evaluation by in vivo relaxometry

The applicability of the synthetic manganese porphyrin MnTPPS as tumor-selective MRI-contrast agent for brain tumors was investigated quantitatively by in vivo relaxometry. To exclude toxic effects of side products, the purification method for MnTPPS was improved. As a result, MnTPPS+Cl- (free acid) with a purity of more than 99.8% was obtained. For the in vivo quantification of the contrast effect the magnetization M(0) and the transversal relaxation time T2 were evaluated in different regions of rat brains with or without implanted gliomas and in temporal muscle. Measurements were performed before and after the application of MnTPPS. The ratio of the magnetization M(0) (TR = 3.5 sec) of the tissue under investigation and the contralateral striatum was defined as contrast ratio Rc(0). Without MnTPPS Rc(0) of edema (0.93 +/- 0.08) and tumor (0.91 +/- 0.07) did not differ from normal brain tissue (corpus callosum: 0.96 +/- 0.07; cortex: 0.98 +/- 0.05). T2 of edema (110 +/- 12 msec) and intracranial tumor (93 +/- 7 msec) were significantly longer than in normal tissue (corpus callosum: 73 +/- 8 msec; parietal cortex: 75 +/- 6 msec; striate nucleus: 78 +/- 7 msec, p < .01). Two hours after the injection of MnTPPS, magnetization of neoplastic tissue was selectively enhanced (TR = 3.5 sec), and T2 was reduced. The smallest dose of 0.06 mmol/kg body weight (bw) increased Rc(0) to 1.12 +/- 0.04, and 0.38 mmol/kg to 1.30 +/- 0.13 (p < .01). T2 of tumor decreased to 85 +/- 6 msec after 0.06 mmol/kg and to 65 +/- 6 msec after 0.38 mmol/kg bw.(ABSTRACT TRUNCATED AT 250 WORDS)

An optimized synthesis of manganese meso-tetra(4-sulfonatophenyl)porphine: A tumor-selective MRI contrast agent

Abstract The preparation of the potential magnetic resonance imaging (MRI) tumor-selective contrast agent manganese meso-tetra(4-sulfonatophenyl)porphine (MnTPPS4) was optimized to yield a product with high purity (⩾-98%) in large amounts (> 1 g). The presented simplified purification method may contribute to the application of MnTPPS4 in clinical trials.

Localization of Experimental Brain Tumors in MRI by Gadolinium Porphyrin

The contrast between edema and F98 glioma in rat brain was distinctly enhanced in T2-weighted MRI (TE 130 ms, TR 3 s) by intraperitoneal injection of the synthetic gadolinium-porphyrin complex, GdTPPS. The T1 relaxation time of the gliomas was selectively shortened by about 50% from 1339 +/- 109 ms to 628 +/- 106 ms, and the T2 relaxation time was shortened by about 35% from 86 +/- 6 ms to 57 +/- 5 ms. The relaxation times of normal tissues under investigation (cortex, corpus callosum, temporal muscle, ventricles) were unaltered. Therefore, GdTPPS-application causes F98 gliomas to appear hyperintense in T1-weighted MRI and hypointense in T2-weighted MRI.

Nmr contrast enhancement of brain tumours: comparison of the blood brain barrier tracer GdDTPA and the tumour-selective contrast agent MnTPPS

Contrast enhancement of two different NMR contrast agents, GdDTPA and MnTPPS, was compared. Sequential recording ofT1-weighted images at 50s intervals allowed the observation of the temporal and spatial evolution of the contrast effect in rats with glioma implanted into the right brain hemisphere. The maximum signal intensity ratio of tumour over contralateral striatum was 1.80±0.10 for GdDTPA and 1.61±0.15 for MnTPPS. The enhancement was maximal 3min after application of GdDTPA and fell rapidly to reach half maximum after 24 min. MnTPPS led to maximum tumour enhancement within 11 min and did not return to control level within the observation period (150 min). In the peritumoural edema, an enhancement effect was absent for MnTPPS, but GdDTPA spread out from the tumour resulting in a delayed but strong enhancement outside the tumour. Thus, GdDTPA, as a blood-brain-barrier tracer, led only to a transient contrast enhancement between tumour and surrounding tissue and no unambiguous demarcation of the tumour against peritumoural edema. Application of MnTPPS resulted in a long-lasting strong tumour enhancement and reliable delineation from peritumoural edema.