Anthony W. Majors

Postictal Alteration of Sodium Content and Apparent Diffusion Coefficient in Epileptic Rat Brain Induced by Kainic Acid

Summary: Purpose: We studied temporal changes of brain sodium and apparent diffusion coefficient (ADC) in a temporal lobe epilepsy (TLE) rat model using kainic acid (KA).

Brain Tissue Sodium Is a Ticking Clock Telling Time After Arterial Occlusion in Rat Focal Cerebral Ischemia

BACKGROUND AND PURPOSE Many patients with acute stroke are excluded from receiving thrombolysis agents within the necessary time limit (3 or 6 hours from stroke onset) because they or their family members are unable provide the time of stroke onset. Brain tissue sodium concentration ([Na(+)]) increases gradually and incessantly during the initial hours of experimental focal cerebral ischemia but only in severely damaged brain regions. We propose that this steady increase in [Na(+)] can be used to estimate the time after arterial occlusion in the rat middle cerebral artery occlusion model of ischemic stroke. METHODS Sixteen anesthetized Sprague-Dawley rats underwent permanent middle cerebral artery occlusion combined with bilateral common artery occlusion. After 100 to 450 minutes, diffusion-weighted MRI was used to generate apparent diffusion coefficient (ADC) maps, cerebral blood flow (CBF) was determined with (14)C-iodoantipyrine (in a subset of 7 animals), and the brain was frozen. Autoradiographic CBF sections and punch samples for Na(+) analysis were obtained from the brain at the same level of the MR image. Severely at risk regions were identified with an ADC of <520 microm(2)/s and, in the subset, with both ADC of <520 microm(2)/s and CBF of <40 mL. 100 g(-1). min(-1). RESULTS Both CBF and the ADC dropped quickly and remained stable in the initial hours after ischemic onset. Linear regression revealed strong linearity between [Na(+)] and time after onset, with a slope of 0.95 or 1.00 (mEq/kg DW)/min, with both ADC and ADC-plus-CBF criteria, respectively. The 95% CIs at 180 and 360 minutes were between 41 and 52 minutes. CONCLUSIONS The time after ischemic onset can be estimated with this 2-step process. First, ADC and CBF are used to identify severely endangered regions. Second, the [Na(+)] in these regions is used to estimate time after onset. The favorable 95% CIs at the time limits for thrombolytic therapy and the availability of measurements of ADC, CBF, and [Na(+)] in humans through the use of MRI suggest that this time-estimation scheme could be used to assess the appropriateness of thrombolysis for patients who do not know when the stroke occurred.

Sensitivity of Magnetic Resonance Diffusion-Weighted Imaging and Regional Relationship Between the Apparent Diffusion Coefficient and Cerebral Blood Flow in Rat Focal Cerebral Ischemia

BACKGROUND AND PURPOSE Magnetic resonance (MR) diffusion-weighted imaging (DWI), a noninvasive procedure, may play an important role in detecting and accurately localizing the extent of evolving infarction within the period immediately following stroke. We evaluated the sensitivity and specificity of DWI in detecting ischemia and compared a quantitative measure derived from the DWI, the apparent diffusion coefficient (ADC), with autoradiographic cerebral blood flow (CBF) in an experimental model of focal cerebral ischemia in rats. METHODS MR imaging data were obtained with a General Electric 4.7-T horizontal bore magnet CSI II system with self-shielded gradients. DWI was acquired within 41 +/- 6 minutes (mean +/- SD) after onset of ischemia and repeated at 169 +/- 14 minutes, followed by CBF determination at 237 +/- 21 minutes. DWI, ADC, and CBF images from each animal were then compared. RESULTS The sensitivities for detecting an abnormality at 1 and 3 hours for DWI were significantly different, and the sensitivity of 3-hour DWI did not differ from the CBF sensitivity of 99%. A mean +/- SD ADC threshold of 460 +/- 95 microns 2/s was defined as 45% higher than the low ADC in the ischemic core compared with the contralateral ADC. Subthreshold ADC area and ischemic area were significantly correlated (r2 = .69, P < .05). In 19 of 48 regions of interest classified as ischemic (< 35 mL.100 g-1.min-1) from both the 3-hour ADC and CBF images, 3-hour ADC correlated significantly with CBF (r2 = .27, n = 19, P < .05), whereas in the nonischemic regions ADC was inversely correlated with CBF. Several ischemic regions showed a sharp drop in ADC to 37% (P < .001, n = 5) compared with all other regions (n = 43) from 1 to 3 hours. CONCLUSIONS Because of the change in the sensitivity of detecting ischemia with DWI, the difference in correlation of CBF with ADC between ischemic and nonischemic cortex, and the presence of several regions in which ADC dropped to 37% from 1 to 3 hours, our data suggest that ADC values potentially can be used to monitor evolving infarction.

Pretransplant assessment of renal viability by phosphorus-31 magnetic resonance spectroscopy. Clinical experience in 40 recipient patients.

A group of 40 cadaveric kidneys was studied just prior to planned transplantation to further assess the applicability of 31P-MRS in the analysis of clinical renal transplant viability. Renal intracellular high-energy phosphorus metabolites (ATP [or NADP], phosphomonoester [PME] and inorganic phosphate [Pi]) and pH were measured noninvasively with MRS surface coils external to cold storage containers. Pretransplant MRS parameters were correlated with subsequent renal function in recipient patients (measured one week postoperatively by the need of dialysis, drop in serum creatinine, urine output, and 123I or 131I Hippuran assessed renal tubular function). ATP and NADP was detected in eleven kidneys and was significantly (P<0.001) associated with the best renal function posttransplantation. These kidneys also had the highest PME/Pi ratios (1.66–0.54), while lower ratios (0.36–0.10) were associated with prolonged acute tubular necrosis. The PME/Pi ratios significantly (P<0.0001) correlated with subsequent clinical renal function, whereas cold storage times (37±10 hr) or intracellular renal pH (6.53–7.91) did not. These preliminary data suggest that MRS is a noninvasive, nondestructive and sterile method for assessing clinical viability during hypothermic storage of human cadaver kidneys and the subsequent recovery of renal function postrenal transplantation.

Response of a non-Hodgkin lymphoma to 60Co therapy monitored by 31P MRS in situ☆

High quality 31P MR spectra (signal to noise ratio (S/N) approximately 18, 15 min acquisition for each spectrum) were consistently obtained with surface coils over a period of 6-week RT. Both transient and steady state alterations in metabolites in response to RT were found in this case. The transient changes occurred during the first 3 hr immediately after the 3rd fractionated RT, these changes include the transient elevation of the PCr resonance, a decrease in PDE and an increase in intracellular pH. The monitoring showed that the metabolites approached steady state approximately 2 hr after the fractionated radiation intervention, suggesting that in vivo MRS can be useful for studying the dynamics of tumor response to RT such as repair of potential lethal damage, growth delay, and reoxygenation etc. The steady-state MR spectra showed the net response to each intervention and can clinically be useful for predicting and measuring the result of the fractionated RT. In this case study, the PDE peak which contains the phospholipid metabolites GPC and GPE, is the most sensitive resonance in response to RT. After the 3rd RT, prior to tumor size reduction, the PDE to ATP ratio decreased 33% and intracellular pH increased to 7.34 +/- 0.05 from 7.27 +/- 0.05. In the subsequent RT interventions, both the tumor size and PDE/ATP ratio continually decreased whereas the pH values remained alkaline and fluctuated around 7.34 to 7.65. The data suggest that the phospholipid metabolite PDE may signal important alterations in membrane metabolism that eventually lead to cell death.

Short echo time proton spectroscopy of human brain using a gradient head coil

Short echo time, single voxel localized proton spectroscopy was accomplished using a stimulated echo (STEAM) sequence running on a Siemens 1.5-T system with a head coil incorporating the Z and Y gradients. Spectra from the temporal lobe, the cerebellum and mid brain were acquired from a group of normal volunteers using the following parameters: voxel size = 8 ml, TE = 22 msec, 512 signal averages and TR = 1.7 sec. STEAM spectra acquired with the small diameter gradients showed significantly fewer artifacts at short TE, allowing the observation of glutamate/glutamine, GABA, taurine, and inositol in addition to the prominent resonance of choline, creatine/phosphocreatine and N-acetylaspartate (NAA). The levels of chlorine, creatine and NAA were found to be significantly different in the three regions of the brain examined.

Phosphorus metabolites and the distribution of cell cycle phase of RIF-1 tumors in response to 14 Gy irradiation

Simultaneous measurements of DNA cell phase cycle distributions and in vivo 31P NMR spectroscopy were performed on 40 RIF‐1 murine tumors irradiated with 14 Gy of X‐radiation. Diploid and tetraploid tumor populations were observed. The cells blocked in G2/M phase were measured as a function of the ratios of tetraploid cell number in G2/ M phase versus total cell population measured. The G2/M population reached a maximum at 32 h post irradiation, dropping to control values by 72 h, while the ratio of inorganic phosphate to β‐nucleotide triphosphate dropped significantly at 32 h and remained significantly lower than control up to 72 h post irradiation. Measurements of PME, PDE, PCr, and pH showed no significant variations at any time point. No significant change in host cell population could be observed. Since the measured G2/M population never increased to more than 3% of the total cell population, the change observed in the 31P NMR spectra were not simply the result of possible differences in NMR profiles of the different cell phase populations but were more likely due to a change in the metabolic characteristics or environment of a majority of the Cells.

In Situ 31P-MRS as a Potential Predictor for Therapeutic Response of Human Neoplasms

Prediction of radiocurability, chemotherapeutic sensitivity or other therapeutic efficacy of cancer by means of laboratory tests has long been searched for. For example, Glucksmann and coworkers tried to correlate histopathological changes to clinical outcome in individual patients (with uterine cervical carcinoma) as early as 1941 (1). Atkin et al. (2) showed (on human cervical cancer cells) that cancers with near-diploid DNA content tended to be more radioresistant than tetraploid tumors. Kolstad (3) correlated the tissue oxygen concentration with the initial response to radiotherapy. Potential lethal damage repair (PLDR) and labeling index depression has been used by Weishselbaum (4) and Tubiana and Malaise (5) respectively to estimate radiocurability. In prediction of tumor response to chemotherapeutic agents, the stem cell assay (6,7) has been employed. Others have studied in vitro radiobiological parameters as potential predictors (8,9). However, all these predictive assays are invasive, time consuming procedures and lack accuracy due to heterogeneity of tumors and limited by biopsying only a very small part of the tumor mass.