Measurement of input functions in rodents: challenges and solutions

doi:10.1016/j.nucmedbio.2005.06.012

Nuclear Medicine and Biology

Volume 32, Issue 7, October 2005, Pages 679-685

https://doi.org/10.1016/j.nucmedbio.2005.06.012 Get rights and content

Abstract

Introduction

Tracer kinetic modeling used in conjunction with positron emission tomography (PET) is an excellent tool for the noninvasive quantification of physiological, biological and molecular processes and their alterations due to disease. Currently, complex multi-compartment modeling approaches are being applied in a variety of clinical studies to determine myocardial perfusion, viability and glucose utilization as well as fatty acid metabolism and oxidation in the normal and diseased heart. These kinetic models require two key measurements of tracer activity over time, tracer activity in arterial blood (input function) and its corresponding activity in the organ of interest. The alteration in the time course of tracer activity as it travels from blood to the organ of interest describes the kinetics of the tracer. To be able to implement these approaches in rodent models of disease using small-animal PET (microPET), it is imperative that the input function is measured accurately.

Methods

The blood input functions in rodent experiments were obtained by (1) direct blood sampling, (2) direct measurement of blood activity by a beta-detecting probe that counts the activity in the blood, (3) an arterial–venous bypass (A/V shunt), (4) factor analysis of dynamic structures from dynamic PET images and (5) measurement from region-of-interest (ROI) analysis of dynamic PET images. Direct blood sampling was used as the reference standard to which the results of the other techniques were compared.

Results

Beta probes are difficult to operate and may not provide accurate blood input functions unless they are used intravenously, which requires complicated microsurgery. A similar limitation applies to the A/V shunt. Factor analysis successfully extracts the blood input function for mice and rats. The ROI-based method is less accurate due to limited image resolution of the PET system, which results in severe partial volume effect and spillover from myocardium.

Conclusion

The current reference standard, direct blood sampling, is more invasive and has limited temporal resolution. With current imaging technology, image-based extraction of blood input functions is possible by factor analysis, while forthcoming technological developments are likely to allow extraction of input function directly from the images. These techniques will reduce the level of complexity and invasiveness for animal experiments and are likely to be used more widely in the future.

Introduction

Measurement of the blood activity concentration over time forms the basic element for tracer kinetic modeling, and the so-called blood input function is a prerequisite for accurate determination of various biological parameters. For PET applications, this function relates to the influx of a radiopharmaceutical into a multi-compartmental model. In our institution, myocardial metabolism [glucose utilization (MRGlu), fatty acid consumption, oxygen consumption] and myocardial viability (myocardial ischemia, left ventricular hypertrophy and cardiomyopathy) have been studied for many years [1], [2]. Diagnostic imaging of several neurological diseases, such as Alzheimer's, has also been facilitated by FDG-PET where cerebral glucose metabolic rate studies have been performed by several groups for more than 25 years [3], [4], [5]. Recently, these studies have been conducted using small animals, particularly in transgenic mice that have been genetically altered to exhibit certain phenotypes. Therefore, techniques that have been established to serially measure blood activity concentrations in humans need to be carefully revisited for animal experiments because vascular access is more problematic, the blood volume smaller and the heart rate much higher in mice than in larger animals or humans.

Several techniques have been proposed for obtaining the blood input function and applied successfully in human imaging. The techniques reviewed in the current manuscript for measurements of the blood input function are beta-probe measurements, microblood sampling, arterial–venous shunts, factor analysis of dynamic structures and image-based measurement from a left ventricular region of interest (ROI).

Section snippets

Methods

In the following experiments, animals were handled in accordance with the Animal Studies Committee at Washington University, School of Medicine. A complete description of the animal handling procedure, including animal care, anesthesia and monitoring, can be found in Ref. [6].

Results

Fig. 1 presents a measurement from a beta probe inserted along the carotid artery. On this figure, we can see clearly that the beta probe is able to detect the initial peak of the activity in the blood, but, unfortunately, the gamma contamination was not completely removed using the measurement of the second probe, illustrating the inherent difficulty of this technique.

The A/V shunt (Fig. 2) technique was used to measure blood flow. With this system, flow values consistent with normal blood

Conclusion

The different methods for obtaining the blood input function have various practicality and level of invasiveness. The beta-probe technique provides excellent temporal resolution, and when special attention is given to gamma-ray contamination it can yield a very precise measurement. Due to the size of the probe, this technique may be more amenable to studies in rats, which have the benefit of a larger vasculature. Arterial/venous shunts also allow for excellent temporal resolution but are

Acknowledgments

The authors wish to thank Lori Strong, Margaret Morris, Mark Nolte, Jerrel Rutlin and Lynne Jones for technical assistance.

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^☆: This work was supported by NIH Grant (PO1HL13851) and NIH/NCI SAIRP Grant (1 R24 CA83060) with additional support from the Alvin J. Siteman Cancer Center at Washington University.

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Measurement of input functions in rodents: challenges and solutions☆

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Results

Conclusion

Acknowledgments

J Nucl Cardiol

Nucl Med Biol

J Am Coll Cardiol

Comparison of 1-11C-Glucose and 18F-FDG for quantifying myocardial glucose use with PET

J Nucl Med

Error sensitivity of flurorodeoxyglucose method for measurement of cerebral metabolic rate of glucose

J Cereb Blood Flow Metab

Noninvasive determination of local cerebral metabolic rate of glucose

Ann J Physiol

The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat

J Neurochem

Arterial input function measurement without blood sampling using a {beta}-microprobe in rats

J Nucl Med

Development of a phoswich detector for a continuous blood-sampling system

IEEE Trans Nucl Sci

Clinical and clinicopathological assessment of serial phlebotomy is the Sprague Dawley rat

Lab Anim Sci

Handling of dynamic sequence in nuclear medicine

IEEE Trans Nucl Sci

Derivation of input function from FDG-PET studies in small hearts

J Nucl Med

Factor analysis for extraction of blood time–activity curves in dynamic FDG-PET studies

J Nucl Med

Comparison of 1-¹¹C-Glucose and ¹⁸F-FDG for quantifying myocardial glucose use with PET

The [¹⁴C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat