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.

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.

Commentary and opinion: I. Principal component analysis, variance partitioning, and "functional connectivity".

We briefly review the need for careful study of "variance partitioning" and "optimal model selection" in functional positron emission tomography (PET) data analysis, emphasizing the use of principal component analysis (PCA) and the importance of data analytic techniques that allow for heterogeneous spatial covariance structures. Using an [15O]water dataset, we demonstrate that--even after data processing--the intrasubject signal component of primary interest in baseline activation studies constitutes a very small fraction of the intersubject variance. This small intrasubject variance component is subtly but significantly changed by using analysis of covariance instead of scaled subprofile model processing before applying PCA. Finally, we argue that the concept of "functional connectivity" should be interpreted very generally until the relative roles of inter- and intrasubject variability in both disease and normal PET datasets are better understood.

The in vivo autoradiographic measurement of regional cerebral blood flow using stable xenon and computerized tomography: the effect of tissue heterogeneity and computerized tomography noise.

We have studied the effect of brain tissue (gray matter-white matter) heterogeneity and computerized tomography (CT) noise on the accuracy of xenon CT measurements of regional cerebral blood flow (rCBF) based upon "autoradiographic" and multiple-scan washin protocols. The results of our mathematical analysis indicate that both protocols are associated with a variety of measurement errors that lead to unacceptable and, to a large extent, unpredictable uncertainties in calculated values of rCBF. Brain tissue heterogeneity and high volumetric flow rates may--even in the absence of movement artifact and CT noise--lead to measurement errors in excess of 20%. Moreover, CT noise is additive in regard to these errors, and constitutes the most confounding variable of all.

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.

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.

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.

Repeated least squares analysis of simulated xenon computed tomographic measurements of regional cerebral blood flow.

Computer simulations were done as a feasibility study of xenon computed tomographic measurements of regional cerebral blood flow. Accuracy of initial least squares estimates of gray matter and white matter rate constants from a two-compartment model depended very little on the number and timing of scans, but did depend significantly on the enhancement-to-noise ratio as well as on the true values of the rate constants and gray/white ratio. Nonlinear least squares gives an optimal fit of the predicted wash-in--wash-out curve to the data rather than optimal estimates of the rate constants. A polynomial correction factor was obtained by regressing initial estimates on the true values used to generate the simulations. The correction factor substantially reduced error in the estimates and, in particular, eliminated large outliers.

Effects of percent thresholding on the extraction of [18F]fluorodeoxyglucose positron emission tomographic region-of-interest data.

Although we and others have employed a thresholding strategy to extract "peak" values from positron emission tomographic (PET) regions of interest (ROIs), the effects of peak picking on fitted fluorodeoxyglucose rate constants, regional metabolic rate for glucose (rCMRglc) profiles, patterns of regional metabolic covariation, and PET-neurobehavioral correlations have not been systematically investigated. Our results suggest that under some commonly encountered imaging conditions percent thresholding may increase sensitivity to regional activation; however, the effect of thresholding is determined by a number of factors, including the relative magnitude of regional activation, ROI size, and the specific threshold selected. The difference-annulus concept is proposed as a means to study the effects of different region drawing and thresholding strategies, and to determine if a given ROI contains one and only one source of covarying metabolic activity.

Principal component analysis and the scaled subprofile model compared to intersubject averaging and statistical parametric mapping: I. "Functional connectivity" of the human motor system studied with [15O]water PET.

Using [15O]water PET and a previously well studied motor activation task, repetitive finger-to-thumb opposition, we compared the spatial activation patterns produced by (1) global normalization and intersubject averaging of paired-image subtractions, (2) the mean differences of ANCOVA-adjusted voxels in Statistical Parametric Mapping, (3) ANCOVA-adjusted voxels followed by principal component analysis (PCA), (4) ANCOVA-adjustment of mean image volumes (mean over subjects at each time point) followed by F-masking and PCA, and (5) PCA with Scaled Subprofile Model pre- and postprocessing. All data analysis techniques identified large positive focal activations in the contralateral sensorimotor cortex and ipsilateral cerebellar cortex, with varying levels of activation in other parts of the motor system, e.g., supplementary motor area, thalamus, putamen; techniques 1-4 also produced extensive negative areas. The activation signal of interest constitutes a very small fraction of the total nonrandom signal in the original dataset, and the exact choice of data preprocessing steps together with a particular analysis procedure have a significant impact on the identification and relative levels of activated regions. The challenge for the future is to identify those preprocessing algorithms and data analysis models that reproducibly optimize the identification and quantification of higher-order sensorimotor and cognitive responses.

Absolute quantitation in neurological PET: do we need it?

This article addresses the question posed in the title by examining the effects of parameters traditionally associated with improved absolute quantitation, on the analysis of 12 acquired immune deficiency syndrome dementia complex (ADC) patients compared to a normal control group. Results are discussed within the framework of the subprofile scaling model (SSM) for analyzing patterns of regional covariation. It is demonstrated that the ability to extract measures of group discrimination and disease progression are unaffected by (1) limited improvements in image resolution, (2) the use of transmission scan smoothing, (3) the application of a scatter deconvolution correction, and (4) converting region-of-interest measurements of counts per voxel to measurements of regional CMRglc. This "robustness" of the SSM approach is partly due to the extraction of disease-related subject weights, independent of any subject's global scaling effects. It is argued that other analysis techniques that initially reduce intersubject variation (e.g., using regional ratios or normalizing by global metabolic rates before applying traditional multivariate procedures) lack analytic features that may be important to identify multidimensional, disease-related image patterns. Based on the ADC patient data, it is concluded that measures of group discrimination and disease progression will not necessarily benefit from the organization of parameters traditionally associated with improved absolute quantitation.

Akinetic mutism in a bone marrow transplant recipient following total-body irradiation and amphotericin B chemoprophylaxis. A positron emission tomographic and neuropathologic study.

We describe a case of akinetic mutism associated with diffuse cerebral leukoencephalopathy, which developed in a bone marrow transplant recipient following total-body irradiation and amphotericin B chemoprophylaxis. A trial of high-dose bromocriptine did not stimulate purposeful verbal or motor activity. Fluorine 18-fluorodeoxyglucose/positron emission tomographic studies, performed before and during bromocriptine therapy, demonstrated cerebral hypometabolism and treatment-related decreases in regional cerebral blood volume. We conclude that whole-brain or total-body irradiation may increase blood-brain barrier permeability to polyene antibiotics, and that high-dose therapy with dopamine agonists is unlikely to benefit patients with akinetic mutism due to diffuse white-matter lesions.

Transplantation of human fetal dopamine cells for Parkinson's disease. Results at 1 year.

In an effort to improve the clinical signs of Parkinson's disease, we have implanted mesencephalic dopamine cells from a 7-week human embryo into the caudate and putamen of a 52-year-old man with Parkinson's disease. Fetal tissue was obtained from elective abortion. The woman and the patient with Parkinson's disease were unknown to each other. The woman gave specific consent and was not paid. The patient had a 20-year history of parkinsonism treated with multiple drug therapies including levodopa/carbidopa (Sinemet) every 2 1/2 hours. His symptoms were worse on the left side. For 5 months prior to transplantation, the patient underwent clinical evaluations by both a neurologist and a computer system installed in his home for daily measurement of walking and hand movements. Preoperative positron emission tomographic scanning with 6-L[18F]fluorodopa (fluorodopa) demonstrated severe dopamine depletion bilaterally. Fetal tissue was matched to the patient for ABO blood antigens, and maternal serum was screened for hepatitis B and human immunodeficiency virus type 1 prior to surgery. Fetal tissue was implanted stereotactically throughout the caudate and putamen on the right side of the brain via 10 needle tracks. The patient was not immunosuppressed. Results 12 months after surgery showed 42% improvement in left-hand speed before the first morning dose of drug and 40% greater response to drug therapy. Right-hand speed increased 15% before drug therapy and 23% after drug therapy. Reaction time was unaffected. Walking speed increased 33% after drug administration, although walking speed before the first morning dose of drugs declined 40%. Walking speed on an all-day basis improved 17%.(ABSTRACT TRUNCATED AT 250 WORDS)

Lateral and third-ventricular CSF formation after metrizamide CT ventriculography.

We calculated the rates of lateral and third-ventricular (LTV) cerebrospinal fluid (CSF) formation in three patients undergoing metrizamide computed tomography (CT) ventriculography with reference to Ct estimates of ventricular volume and the time course of LTV metrizamide washout (elimination). Elimination rate constants for metrizamide were derived from measurements of LTV metrizamide concentration on serial postventriculography CT scans, and LTV volumes were estimated by partial volume analysis. CSF formation in the combined lateral ventricles averaged 0.14 ml per minute, and third-ventricular CSF formation averaged 0.014 ml per minute. Thus, the third ventricle accounted for approximately 10% of total LTV CSF production, which accords with relative weights of choroid plexus tissue in the lateral and third ventricles.

Pituitary metastasis: incidence in cancer patients and clinical differentiation from pituitary adenoma.

Symptomatic pituitary metastases are uncommon and may be difficult to differentiate from pituitary adenomas. In order to ascertain the incidence of pituitary tumors in cancer patients and to characterize the clinical presentation of pituitary metastases, we reviewed the clinical experience with these tumors at Memorial Sloan-Kettering Cancer Center (MSKCC) during the period 1976-1979 and a recent series of 500 consecutive autopsies in which the pituitary fossa and gland were examined. In the clinical series, a histologic diagnosis was made in three of five patients. Radiologic evaluation, including polytomography and computed tomography, did not reliably distinguish metastasis from adenoma, but the clinical syndromes were distinctive. In the autopsy series, pituitary metastases were found in 3.6% of cases, pituitary adenomas in 1.8%.

The effect of oral glycerol on intraventricular pressure in man.

Oral glycerol was administered to eight patients with meningeal carcinomatosis or acute leukemia in whom ventricular catheters and Ommaya reservoirs had been implanted for the purpose of intrathecal chemotherapy or chemoprophylaxis. Intraventricular pressure was monitored continuously via the Ommaya reservoirs before and after single doses of 0.5, 1.0 or l.5 gm per kilogram of body weight. The interrelationship between initial pressure, change in pressure, serum osmolarity, and duration of action was investigated, and the ratio of CSF-to-plasma osmolarity was determined 4 to 5 hours after glycerol administration. The effects of chronic 6-hourly and 4-hourly 1 gm per kilogram glycerol doses were studied in a patient with meningeal carcinomatosis and increased intracranial pressure. Our data suggest that as a cerebral dehydrating agent oral glycerol is most effective in patients with markedly increased intracranial pressure. A single 1 gm per kilogram dose is adequate to lower raised intraventricular pressure acutely, but its effect is short-lived. Continuous oral administration must be carefully monitored to avoid the establishment or a reverse osmotic gradient, secondarily increased intracranial pressure, and clinical deterioration.

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.

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.

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.

Improved resolution for PET volume imaging through three-dimensional iterative reconstruction.

UNLABELLED: It has been demonstrated that in two-dimensional iterative reconstruction, a resolution model can improve image resolution while controlling noise. With the lower noise levels of three-dimensional PET volume imaging, these iterative reconstruction advantages may be extended to three dimensions to further improve the reconstructed image resolution. METHODS: We have implemented three-dimensional versions of iterative filtered backprojection (IFBP) and the maximum likelihood by expectation maximization (ML-EM) reconstruction algorithms and applied them to three-dimensional PET volume datasets. The results were compared to images obtained using the standard three-dimensional reprojection reconstruction (3DRP) algorithm. RESULTS: For IFBP with 15 iterations and no regularization compared to 3DRP, both using a ramp filter, the transaxial resolution improved 52%, and the axial resolution improved 39%. With a strong regularization, the transaxial and axial resolution improvements were reduced to 6% and 5%, respectively. If a Hanning roll-off is applied to the ramp filter in the transaxial direction, the transaxial resolution for IFBP without regularization improved 35% compared to 3DRP; with regularization the improvement dropped to 19%. The axial resolution for IFBP and 3DRP was unaffected by this transaxial smoothing in the reconstruction filter. With the same Hanning roll-off, the noise for IFBP without regularization increased by a factor of 6 compared to 3DRP; with regularization the noise was increased only by a factor of 3. Compared to IFBP, the three-dimensional ML-EM reconstruction produced similar resolution improvements with a much smaller increase in noise and slower convergence. Resolution improvements from both IFBP and ML-EM reconstructions are visually apparent in three-dimensional FDG brain images and result in increased activation signals in a three-dimensional [15O]water functional activation study. CONCLUSION: Our results demonstrate that resolution improvement is possible for IFBP and ML-EM compared to 3DRP with or without noise increase.