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Biomedical subjects

D A Rottenberg

Publications and source records attributed to D A Rottenberg.

At least 55 records · Page 3Linked to original sources
PubMed1987

Scaled subprofile model: a statistical approach to the analysis of functional patterns in positron emission tomographic data.

The data obtained from measurements of regional rCMRglu using [18F]fluorodeoxyglucose (FDG)/positron emission tomographic (PET) data contain more structure than can be identified with group mean rCMRglu profiles or regional correlation coefficients. This additional structure is revealed by a novel mathematical-statistical model of regional metabolic interactions that explicitly represents rCMRglu profiles as a combination of region-independent global effects, a group mean pattern and a mosaic of interacting networks. In its application to FDG/PET data, this model removes global subject effects [global scaling factors (GSFs)] and a group mean pattern (profile) so as to maximize statistical power for the detection and simultaneous discovery of all networks of two or more regions that form a significant and consistent linearly covarying pattern. The model approach presented here was applied to the combined rCMRglu data from 12 demented AIDS patients and 18 normal controls: Two significant metabolic covariance pattern descriptors that together accounted for 71 to 96% of the rCMRglu/GSF variation across subjects for 22/28 regions in the AIDS group were extracted. Each descriptor was found to be highly correlated with performance on several neuropsychological tests, providing independent validation of the analysis technique as a means of discovering and describing behaviorally related components of group rCMRglu profiles.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Synthesis and evaluation of fluorine-18 21-fluoroprednisone as a potential ligand for neuro-PET studies.

No-carrier-added fluorine-18-labeled fluoroprednisone ([18F]21-fluoroprednisone) was synthesized by tosylate displacement in 2%-8% radiochemical yield in 80 min end of cyclotron bombardment (EOB), and its metabolism and distribution were investigated. After intravenous administration to rats, [18F]21-fluoroprednisone was rapidly cleared from the blood and biotransformed into [18F]20-dihydro-21-fluoroprednisone. The suitability of [18F]21-fluorocorticoids for receptor imaging in humans with positron emitting tomography will depend on the synthesis of compounds with high binding affinity and low rate of carbonyl reduction at C-20.

Animals↗
PubMed1987

[13N]cisplatin PET to assess pharmacokinetics of intra-arterial versus intravenous chemotherapy for malignant brain tumors.

The biodistribution, blood clearance, and in vivo transformation of cisplatin (cisdiaminedichloroplatinum, DDP) were studied in rats using 13N-labeled and unlabeled DDP. Following the i.v. injection of [13N]DDP, virtually no 13N activity was detected in brain tissue, and no measurable amount of the 13N label was displaced from [13N]DDP. Based on these results, [13N]DDP/positron emission tomographic (PET) scans were performed in two glioblastoma patients undergoing Phase II intra-arterial (i.a.) DDP chemotherapy: [13N]DDP was infused i.v. over 13-15 min, during which time serial PET scans were obtained. One hour later, [13N]DDP mixed with cold DDP (100 mg/m2 therapeutic dose) was infused at the same rate i.a., and a second sequence of PET scans was acquired. The pharmacologic advantage of i.a. administration was calculated as the ratio of integrated tumor/brain count ratios for the i.a. and i.v. studies. Our preliminary results demonstrate the feasibility of quantifying the pharmacologic advantage of i.a. DDP chemotherapy in individual brain tumor patients using [13N]DDP and PET.

Animals↗
PubMed1986

Acute high-dose methotrexate neurotoxicity in the rat.

Intravenous high-dose methotrexate chemotherapy may produce acute, subacute, or chronic neurotoxicity in patients with cancer. Acute encephalopathies following high-dose methotrexate treatment are recognized with increasing frequency. This study describes a model of acute high-dose methotrexate neurotoxicity in the rat characterized by a profound dose-dependent depression of cerebral glucose metabolism in association with behavioral and electroencephalographic abnormalities. Alterations in the amino acid profile, similar to those described in cancer patients after high-dose methotrexate treatment, were observed in the absence of biochemical evidence of systemic organ toxicity. This model facilitates the study of the biochemical mechanisms of antifolate neurotoxicity in humans and permits the evaluation of potential therapeutic interventions.

Amino Acids↗
PubMed1986

In vivo measurement of regional brain and tumor pH using [14C]dimethyloxazolidinedione and quantitative autoradiography. II: Characterization of the extracellular fluid compartment using pH-sensitive microelectrodes and [14C]sucrose.

We measured the extracellular (interstitial) pH (pHe) of RG-2 rat gliomas using H+-sensitive microelectrodes and estimated the volume of tumor extracellular space based on the tissue-plasma ratio of [14C]sucrose. The average RG-2 pHe was 7.63 +/- 0.15 (mean +/- SD, n = 6), whereas the average pHe of contralateral brain tissue was 7.34 +/- 0.10 (n = 3) and arterial pH was 7.36 +/- 0.02. RG-2 extracellular space water volume was estimated to be 0.3 ml water/g tissue. In separate experiments in normal, nontumored rats, intracellular pH (pHi) was calculated for nine gray and white matter regions based on measurements of tissue and plasma [14C]dimethyloxazolidinedione concentration. pHi values ranged from 6.80 to 6.94, and no consistent gray-white differences were observed. Our data suggest that tumor pHi is not more acidic than that of normal brain tissue and that the observed alkalinity of primary brain tumors is due to the presence of a large alkaline extracellular space.

Animals↗
PubMed1986

Accuracy of PET RCBF measurements: effect of time shift between blood and brain radioactivity curves.

Analytic expressions were derived for estimating the error in PET RCBF measurements associated with the time lag between brain and blood radioactivity following bolus H2(15)O injection and during non-steady-state CO15O inhalation. This lag time reflects the physiological difference in arrival times of 15O activity at brain and radial arterial sampling site as well as the experimentally introduced resistance to flow offered by the arterial catheter/stopcock assembly. Multiple measurements of this time lag ranged between 1 and 10 s. For non-steady-state CO15O PET measurements, estimated errors in RCBF ranged from 0.02 to 30% for delays of 2-8 s and scan lengths of 30-180 s. In the range 20-100 ml min-1 per 100 g, variations in RCBF only marginally affected these errors. Errors increased with longer delays but decreased sharply with scan durations greater than 60 s. For 30-180 s scans, even larger errors are associated with the H2(15)O injection technique (peak blood activity at 10 s): 1-60% for delays of 2-8 s. A 'slow' bolus peaking at 20 s decreased the error by 40%. For the H2(15)O method it is essential to estimate the time shift to within 2 s if accurate flow measurements (error less than 5%) are to be obtained from 40-60 s scans.

Brain↗
PubMed1985

In vivo measurement of brain tumor pH using [11C]DMO and positron emission tomography.

In vivo measurements of regional brain tissue/tumor pH (rpH) have been accomplished in 9 patients with primary or metastatic brain tumors using [11C]dimethyloxazolidinedione [( 11C]DMO) and positron emission tomography. Tumor rpH values ranged from 6.88 to 7.26, whereas gray matter and white matter rpH values ranged from 6.74 to 7.09 and from 6.77 to 7.03, respectively. Our results, which are consistent with reported [14C]DMO autoradiographic measurements of brain and tumor pH, suggest that the pH microenvironment of brain tumors is not more "acidic" than that of normal gray or white matter.

Adult↗
PubMed1985

Positron emission tomographic measurement of blood-to-brain and blood-to-tumor transport of 82Rb: the effect of dexamethasone and whole-brain radiation therapy.

Unidirectional blood-to-brain and blood-to-tumor transport rate constants for rubidium 82 were determined using dynamic positron emission tomography in patients with primary or metastatic brain tumors. Regional influx rate constants (K1) and plasma water volume (Vp) were estimated from the time course of blood and brain radioactivity following a bolus injection of tracer. Eight patients were studied before and 24 to 72 hours after treatment using pharmacological doses of dexamethasone, and 6 additional patients with metastatic brain tumors were studied before and within 60 to 90 minutes after 200- to 600-rad whole-brain radiation therapy. Steroid treatment was associated with a 9 to 48% decrease in tumor K1 and a 21% mean decrease in tumor Vp. No consistent changes in K1 or Vp were observed in control brain regions. Tumor K1 and Vp did not increase in patients undergoing whole-brain radiation therapy, all of whom were taking dexamethasone at the time of study. These data suggest that corticosteroids decrease the permeability of tumor capillaries to small hydrophilic molecules (including those of some chemotherapeutic agents) and that steroid pretreatment prevents acute, and potentially dangerous, increases in tumor capillary permeability following cranial irradiation.

Adult↗
PubMed1985

Effects of xenon and krypton on regional cerebral blood flow in the rat.

The effects of high inspired concentrations of xenon and krypton on regional CBF (rCBF) were assessed in the rat using [14C]iodoantipyrine and quantitative autoradiography. Inhalation of 80% xenon for 1 or 2 min and inhalation of 40% xenon for 2 min were found to have significant effects on rCBF, including average increases of 75-96% in cerebral neocortical regions. Inhalation of 40% xenon for 1 min and of 80% krypton for 2 min had no significant effect on rCBF in most brain regions studied. If xenon inhalation produces effects on rCBF in humans similar to those observed in the rat, such effects could be an important source of error in xenon computed tomography rCBF studies.

Animals↗
PubMed1985

In vivo measurement of regional brain and tumor pH using [14C]dimethyloxazolidinedione and quantitative autoradiography.

Using [14C]dimethyloxazolidinedione ([14C]-DMO) and quantitative autoradiography, we estimated tissue pH (pHt) and intracellular pH (pHi) in nine regions of the normal rat brain and in intracerebrally implanted RG-2 gliomas. Calculations of regional pHt, based on equilibrium tissue and arterial plasma [14C]DMO concentration, ranged from 6.83 to 6.94; pHi, calculated assuming an extracellular water volume of 0.15 ml/g for gray matter and 0.11 ml/g for white matter, ranged from 6.61 to 6.78. No consistent difference was found in pHt or pHi between white and gray matter regions. Tumor tissue water content was determined by drying to constant weight, and extracellular space water volume (Ve) was estimated with [14C]sucrose in nephrectomized rats using quantitative autoradiography. Tumor pHt ranged from 7.08 to 7.18. For Ve = 0.17 (measured), pHi was 6.94-7.06; for Ve = 0.30 (assumed), the corresponding range for pHi was 6.63-6.90. Thus, the RG-2 glioma is not more "acidic" than adjacent brain tissue and its "alkaline" pHt probably reflects a large extracellular water content and plasma-like extracellular pH.

Animals↗
PubMed1984

In vivo measurement of regional brain tissue pH using positron emission tomography.

Carbon-11-labeled dimethyloxazolidinedione ([11C]DMO) was injected intravenously into human subjects, and serial positron emission tomographic (PET) scans were obtained until brain-blood equilibration was achieved or could be accurately predicted from dynamic PET and 11C blood data. Knowledge of regional brain-blood partition coefficients for DMO, together with measurements of arterial blood hematocrit and pH, permitted the calculation of regional brain tissue and tumor pH (rpH). [11C]DMO PET rpH values were similar to rpH values derived from quantitative autoradiographic measurements of [14C]DMO concentrations in rat brain slices.

Brain↗
PubMed1984

A new headholder for PET, CT, and NMR imaging.

A new headholder was developed for patient restraint and repositioning during positron emission tomography (PET), CT, and nuclear magnetic resonance (NMR) imaging procedures. A customized form was produced for each patient by pouring polyurethane resin and catalyst between an injection-molded polystyrene shell and a protective latex sheet and placing the patient's head in the form while the resin set. Excellent head restraint and repositioning was achieved when the headholder was used with a crossed-laser system. Repositioning accuracy was demonstrated by comparing transmission scans of the same patient obtained on different days and by comparing PET transmission scans with coplanar CT scans. No artifacts due to the headholder were apparent in CT, PET, and NMR images.

Evaluation Studies as Topic↗
PubMed1984

Accuracy of stable xenon/CT measurements of regional cerebral blood flow: effect of extrapolated estimates of brain-blood partition coefficients.

Stable xenon/computed tomographic (Xe/CT) measurements of regional brain-blood partition coefficients for xenon (lambda) and of regional cerebral blood flow (rCBF) have been reported for animal models of stroke and for patients with a variety of neurological diseases. We estimated the uncertainty in reported measurements of lambda and rCBF using computer simulations based on Kety's blood flow equation. Anesthetized baboons were scanned repeatedly for 30-60 min while inhaling an 80:20% xenon-oxygen mixture, and the resulting CT enhancement values for user-defined regions of interest were used to define a mathematical function with which to fit simulated CT enhancement data. In computer simulation studies, extrapolated and fit values of lambda for the same dataset were used to calculate rCBF, and the calculated flow values were compared. Computer simulations for heterogeneous (gray-white matter) regions indicate that better estimates of flow are obtained by fitting lambda than by using extrapolated values of lambda to calculate flow, although, paradoxically, better estimates of lambda are obtained by extrapolation than by fitting lambda.

Animals↗
PubMed1983

Design of steady-state positron emission tomography protocols for neurobehavioral studies: CO15O and 19Ne.

Although the [18F]-2-fluoro-2-deoxyglucose positron emission tomographic technique for measuring regional glucose metabolic rate has been successfully employed for neurobehavioral studies, the long (greater than 30 min) equilibration time required may complicate the interpretation of experimental results. Positron emission tomography neurobehavioral protocols employing the continuous inhalation of CO15O and 19Ne were developed for measuring regional cerebral blood flow during multiple control and stimulation periods. Timing, lung absorbed dose, statistical accuracy, and resolution were considered. Studies with 19Ne require shorter equilibration and stimulation times than do CO15O studies but entail higher absorbed doses and yield poorer imaging statistics.

Absorption↗
PubMed1983

Quantitative CT assessment of furosemide- and mannitol-induced changes in brain water content.

We studied the effects of two commonly employed antiedema agents, mannitol and furosemide, on CT brain density in eight patients with primary and metastatic brain tumors. Noncontrast CTs were performed before and after IV furosemide or IV mannitol, and serial blood samples were analyzed for osmolality. Computer-generated frequency histograms of CT numbers from "before-and-after" brain slices were using quantile-quantile (QQ) plots and the Kruskal-Wallis statistic. After IV mannitol, there was a progressive increase in CT brain density, which corresponded to an upward shift in the QQ plot over the range 0 to 70 Hounsfield units. The differences between baseline and posttreatment histograms for mannitol patients were significantly different from controls, and maximum differences coincided with peak serum osmolality. No statistically significant effects were observed in the furosemide group despite maximal diuresis. The relative magnitude of the quantitative changes observed after mannitol and furosemide administration are consistent with anticipated changes in brain water content.

Brain Edema↗
PubMed1983

C-11 dimethyloxazolidinedione (DMO): biodistribution, radiation absorbed dose, and potential for PET measurement of regional brain pH: concise communication.

An improved radiochemical synthesis for C-11 dimethyloxazolidinedione (C-11 DMO) makes this agent attractive for the measurement of regional brain tissue pH (rpH) using positron emission tomography (PET). Toward this end, biodistribution data for C-14 DMO in rats at various times after an intravenous bolus injection are reported, together with estimates of radiation absorbed dose for C-11 DMO in man. An error analysis of C-11 DMO PET measurement of rpH indicates that rpH can be determined to within +/- 0.1 pH unit for pH greater than 6.5 with a 20-mCi injected bolus of C-11 DMO, a 30- 45-min equilibration time, and a 15-min PET imaging period.

Animals↗
PubMed1982

Quantitative autoradiographic mapping of herpes simplex virus encephalitis with a radiolabeled antiviral drug.

2'-Fluoro-5-methyl-l-beta-D-arabinosyluracil (FMAU) labeled with carbon-14 was used to image herpes simplex virus type 1-infected regions of rat brain by quantitative autoradiography. FMAU is a potent antiviral pyrimidine nucleoside which is selectively phosphorylated by virus-coded thymidine kinase. When the labeled FMAU was administered 6 hours before the rats were killed, the selective uptake and concentration of the drug and its metabolites by infected cells (defined by immunoperoxidase staining of viral antigens) allowed quantitative definition and mapping of HSV-1-infected structures in autoradiograms of brain sections. These results show that quantitative autoradiography can be used to characterize the local metabolism of antiviral drugs by infected cells in vivo. They also suggest that the selective uptake of drugs that exploit viral thymidine kinase for their antiviral effect can, by appropriate labeling, be used in conjunction with clinical neuroimaging techniques to define infected regions of human brain, thereby providing a new approach to the diagnosis of herpes encephalitis in man.

Animals↗