Resolution, sensitivity and precision with autoradiography and small animal positron emission tomography: implications for functional brain imaging in animal research

doi:10.1016/j.nucmedbio.2005.04.020

Nuclear Medicine and Biology

Volume 32, Issue 7, October 2005, Pages 719-725

https://doi.org/10.1016/j.nucmedbio.2005.04.020 Get rights and content

Abstract

Quantitative autoradiographic methods for in vivo measurement of regional rates of cerebral blood flow, glucose metabolism, and protein synthesis contribute significantly to our understanding of phsysiological and biochemical responses of the brain to changes in the environment. A disadvantage of these autoradiographic methods is that experimental animals can be studied only once. With the advent of small animal positron emission tomography (PET) and with increases in the sensitivity and spatial resolution of scanners it is now possible to use adaptations of these methods in experimental animals with PET. These developments allow repeated studies of the same animal, including studies of the same animal under different conditions, and longitudinal studies. In this review we summarize the tradeoffs between the use of autoradiography and small animal PET for functional brain imaging studies in animal research.

Introduction

Since the earliest positron emission tomography (PET) scanners made their debut in the 1960s, there have been numerous technological improvements that allow brain imaging with increasing spatial resolution. PET scanners optimized specifically for use with small animals have been designed and reconstruction algorithms advanced such that we can now expect to examine tissues with a spatial resolution less than 2 mm full-width at half maximum (FWHM). Newer detector materials and design configurations are providing increasing sensitivity. Much of the focus to date has been on the development of new tracers and improvements in instrumentation; indeed, current small animal PET imaging technologies have opened up a number of new investigative possibilities. Small animal PET is however, not suitable for all functional brain imaging studies. In the present discussion, we contrast the strengths and intrinsic limitations of PET with those of autoradiographic techniques in order to try to identify applications better suited to each method.

Section snippets

Measuring the rate of a biologic process

It is important to emphasize that the goal of functional brain imaging is not the generation of images per se, but rather to gain greater understanding of the physiology and biochemistry of the brain. Methods are well established for the measurement of regional cerebral blood flow (rCBF) [1], regional cerebral glucose metabolism (rCMR_glc) [2] and regional rates of cerebral protein synthesis (rCPS) [3] with radiolabeled tracers and quantitative autoradiography. Measurement of rCBF [4] and rCMR_glc

Functional brain imaging with quantitative autoradiography

Autoradiography allows measurement of tissue activity with a spatial resolution that is approximately an order of magnitude higher than is possible with PET, on the order of less than a few hundred microns versus a few millimeters with PET. It is also possible to conduct the studies in freely moving, conscious, behaving animals. The major disadvantage is that an animal can only be studied once. Longitudinal studies and kinetic studies require the use of multiple animals, adding interanimal

Functional brain imaging with small animal PET

The primary advantage of PET studies lies in the ability to perform repeat studies in the same animal. Thus, studies can be designed to use an animal as its own control, reducing both the total number of animals required and the effects of interanimal variability. Longitudinal studies are possible. Additionally, with sufficiently sensitive PET scanners, rapid dynamic scanning is feasible and tracer kinetic modeling can be carried out with data from a single animal. The most obvious disadvantage

Animal head immobilization

In vivo brain imaging with PET requires that an animal's head be immobilized during scanning. Until recently, the method of choice has been the use of anesthetic agents. In rats, most general anesthetics have been shown to produce widespread decreases in local cerebral glucose utilization [28]. rCBF either increases or is unchanged under isoflurane anesthesia [29], is slightly reduced under nitrous oxide anesthesia [30] and is substantially reduced under pentobarbital and chloralose anesthesia

Studies suitable for small animal PET

The above considerations suggest that functional brain imaging studies suitable for small animal PET are those in which the animals can be trained to accept head fixation, those in which the process studied is relatively unaffected by anesthesia or those studies with tracers that are effectively trapped, such as [¹⁸F]FDG. The latter case may allow an awake uptake followed by scanning under anesthesia but precludes kinetic studies. Additionally, in order to examine changes in a functional

Use of autoradiographic data in designing small animal PET studies

The effect of object size on quantification with PET has been extensively studied. Various test objects filled with a positron-emitting compound are placed in the scanner and percent recovery of the known activity is measured. For a hot cylinder in a cold background, for example, obtaining a recovery coefficient greater than 80% requires a cylinder greater than 1.5 FWHM in diameter [41]. From these measurements, activity “spilled out” to the surrounding areas can be determined. Since there is

Conclusions

Advances in PET technology have opened up the possibility for performing repeated studies in the same animal and improvements in scanner sensitivity have made single animal kinetic studies achievable. Quantitative autoradiographic data may be useful for making preliminary assessments of whether PET studies are likely to have sufficient power for detecting specific regional changes, but the most formidable challenge remains to devise animal restraint methods that do not mask the effects one is

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Resolution, sensitivity and precision with autoradiography and small animal positron emission tomography: implications for functional brain imaging in animal research

Abstract

Introduction

Section snippets

Measuring the rate of a biologic process

Functional brain imaging with quantitative autoradiography

Functional brain imaging with small animal PET

Animal head immobilization

Studies suitable for small animal PET

Use of autoradiographic data in designing small animal PET studies

Conclusions

Eur Neuropsychopharmacol

NeuroImage

Brain Res

Nucl Med Biol

Nucl Instrum Methods in Phys Res A

NeuroImage

Measurement of local cerebral blood flow with iodo[14C]antipyrine

Am 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

Measurement of local cerebral protein synthesis in vivo: influence of recycling of amino acids derived from protein degradation

Proc Natl Acad Sci U S A

Brain blood flow measured with intravenous H215O: II. Implementation and validation

J Nucl Med

The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man

Circ Res

Measurement of regional rates of cerebral protein synthesis with l-[1-11C]leucine and PET with correction for recycling of tissue amino acids: I. Kinetic modeling approach

J Cereb Blood Flow Metab

Measurement of regional rates of cerebral protein synthesis with l-[1-11C]leucine and PET with correction for recycling of tissue amino acids: II. Validation in rhesus monkeys

J Cereb Blood Flow Metab

Techniques for the measurement of cerebral blood flow

Relationships among local functional activity, energy metabolism, and blood flow in the central nervous system

Fed Proc

Registration and three-dimensional reconstruction of autoradiographic images by the disparity analysis method

IEEE Trans Med Imaging

Localization of activity-associated changes in metabolism of the central nervous system with the deoxyglucose method: prospects for cellular resolution

The local circulation of the living brain: values in the unanesthetized and anesthetized cat

Trans Am Neurol Ass

The theory and applications of the exchange of inert gas at the lungs and tissues

Pharmacol Rev

Measurement of regional cerebral blood flow with antipyrine-14C in awake cats

J Appl Physiol

Measurement of local cerebral blood flow with iodo[¹⁴C]antipyrine

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

Brain blood flow measured with intravenous H₂¹⁵O: II. Implementation and validation

The [¹⁸F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man

Measurement of regional rates of cerebral protein synthesis with l-[1-¹¹C]leucine and PET with correction for recycling of tissue amino acids: I. Kinetic modeling approach

Measurement of regional rates of cerebral protein synthesis with l-[1-¹¹C]leucine and PET with correction for recycling of tissue amino acids: II. Validation in rhesus monkeys