Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of molecular changes involved in demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K+ channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K+ channel PET tracer [ 18 F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [ 18 F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [ 18 F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [ 18 F]3F4AP for the focal brain injury was higher than [ 18 F]FDG, [ 11 C]PiB, and [ 11 C]PBR28, and compared favorably to currently used MRI methods.

SUMMARY This report describes the statistical relationship of several whole blood viscosity parameters and cerebral blood flow (CBF) in 53 consecutive patients and normal controls. Significant correlations were present between CBF and serum fibrinogen (P = .05), hematocrit (P < .05), and a relationship involving both fibrinogen and hematocrit (P < .01).We conclude that heightened whole blood viscosity does correlate with decreased cerebral blood flow in the ranges measured in our patients, that both fibrinogen and hematocrit must be taken into consideration in viscosity determinations, and that changes in viscosity may have an important effect on CBF in regions of low flow.

We used the noninvasive 133-xenon inhalation technique to determine cerebral hemodynamics in 55 normal volunteers aged 18 to 88. Values for cerebral blood flow and cerebrovascular CO2 reactivity in fast-clearing tissue (flow gray) and slow-clearing tissue (flow white) were examined as functions of age and in relation to hematocrit, blood pressure, and evidence of extracranial vascular disease. Flow gray declined linearly with age, but no corresponding change was found in flow white or in CO2 reactivity. The data suggest that the progressive fall in flow gray is due to a physiologic aging process.

This report describes a strategy for measurement of regional CBF that rigorously accounts for differing tracer partition coefficients and recirculation, and is convenient for use with positron emission tomography. Based on the Kety model, the measured tissue concentration can be expressed in terms of the arterial concentration, the rate constant K, and the blood flow f. The local partition coefficient may be computed as p = f/K. In our approach, maps of K and f are computed from two transverse section reconstructions. The reconstructions are based on weighted sums of projection data measured frequently during the observation period. Theoretical studies of noise propagation in the estimates of K and f were carried out as a function of tomographic count rate, total measurement time, and tracer half-life for varying input functions. These calculations predict that statistical errors in f of between 5 and 10% at a resolution of 1 cm full width at half maximum can be obtained with existing tomographs following i.v. injection. To compare theory and experiment, a series of flow studies were carried out in phantoms using a positron tomograph. These measurements demonstrate close agreement between computed flow and noise estimates and those measured in a controlled situation. This close agreement between theory and experiment as well as the low statistical errors observed suggest that this approach may be a useful tool in clinical investigation.

The distribution of fluconazole in tissue of human volunteers was determined by positron emission tomographic scanning over a 2-h period following the infusion of a tracer dose of 18F-fluconazole (5 to 7 mCi) plus 400 mg of unlabeled drug (the standard daily dose of fluconazole). Previous studies have validated this approach for animals. From serial positron emission tomographic imaging and blood sampling, pharmacokinetics of fluconazole in tissue were determined. There was significant distribution of the radiolabeled drug in all organs studied, with nearly constant levels achieved by 1 h. Since levels of fluconazole of >6 ,ug/g are needed to treat infection with most strains of Candida and levels of > 10 ,ug/g are needed for Cryptococcus neoformans, Coccidioides immitis, and Histoplasma capsulatum, the following predictions can be made. The current standard dose of 400 mg/day should be more than adequate in the treatment of urinary tract and hepatosplenic candidiasis but problematic in the treatment of candidal osteomyelitis, even with the higher levels that develop after multiple doses. Similarly, higher doses should be considered, particularly in immunocompromised patients, with infection with C. neoformans, H. capsulatum, and C. immitis that involves the central nervous and musculoskeletal systems.

A simple modification of the filtered backprojection algorithm is presented for the computation of the local statistical noise in emission computed tomography. The technique is general in that any distribution of radioactivity may be accommodated. When applied to positron emission tomography, it is shown that the effects of photon absorption, random coincidences, radioactive decay, and detector nonuniformity may be included. Calculations have shown the effects of resolution, object size, and photon absorption on the statistical noise of disk-shaped emitters. Comparison of calculation and experiment show close agreement both in magnitude and spatial variation. Measurements of the noise level in tomograms of the brain obtained during continuous inhalation of 150-CO2 demonstrate that estimates of radioactivity concentration with a precision of a few percent are readily attainable.

'8F-labeled fleroxacin was used to measure the pharmacokinetics of fieroxacin in healthy and infected animals by positron emission tomography (PET) and tissue radioactivity measurements. In all experiments, a pharmacological dose of unlabeled drug (10 mJkg) was coinjected with the tracer. The pharmacokinetics of [18FJfleroxacin was measured in groups of healthy mice (n = six per group) at 10, 30, 60, and 120 min after inijection and in groups of rats with Escherchia coli thigh infections (n = six per group) at 60 and 120 min after injection by radioactivity measurements in excised tissues. In healthy rabbits (n = 4) and in rabbits with E. coli thigh infections (n = 4), tissue concentrations of drug were determined by serial PET imaging over 2 h; after the final image was acquired, animals were sacrificed and concentrations measured by PET were compared with the results of tissue radioactivity measureinents. In all three species, there was rapid equilibration of[18F]fleroxacin to significant concentratiobs in most peripheral organs; low concentrations of drug were detected in the brain. Accumulations of radiolabeled drug in infected and healthy thigh muscles were similar. Peak concentrations of drug of more than three times the MIC for 90% of members of the family Enterobacteriaceae (>100-fold for most organisms) were achieved in all tissues except brain and remained above this level for more than 2 h. Especially high peak concentrations were achieved in the kidney (>75 ,ug/g), liver (>50 ,ug/g), blood (>25 ,g/g), and bone and lung (>10 Fg/g). Since the MICs for 90% of all Enterobacteriaceae are <2 ,ug/ml, fleroxacin should be particularly useful in treating gram-negative infections affecting these tissues. In contrast, the low concentration of drug delivered to the brain should limit the toxicity of the drug for the central nervous systens.

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