Perfusion Methods

How is perfusion defined and measured? 

Perfusion refers to the rate of blood flow through the capillary circulation of an organ or tissue. To account for different sized organs, perfusion is commonly normalized as bulk blood flow rate (mL/min) divided by organ mass (per 100 g). Perfusion is thus typically reported in units of mL/min/100g tissue.

Perfusion differs among organs and may change in response to pathology or metabolic needs.  For example, the perfusion of cerebral gray and white matter are about 60 and 20 mL/min/100g respectively. Myocardial perfusion is much greater, ranging between about 100 mL/min/100g at rest to 400 mL/min/100g during maximal exercise. 

Arterial spin labelling (ASL) perfusion map of brain with hypervascular glioma

Measurement of perfusion requires the use of tracers -- molecules, molecular aggregates, or small particles that distribute in tissues commensurate with blood flow and can be detected. Some remain in the intravascular space, but others have a wider distribution.  

1. Intravascular tracers remain confined to blood vessels. MR examples include the (now out-of-production) contrast agent gadofosveset (Ablavar®) which bound to serum albumin and ultra-small superparamagnetic iron oxide (USPIO) particles.
2. Extracellular tracers do not enter cells but freely pass through vessel walls to distribute in the extracellular spaces of tissues. Most gadolinium-based contrast agents are in this category.
3. Diffusible tracers distribute throughout all tissue compartments including the interior of cells. A common example in MRI is magnetically tagged water molecules used for arterial spin labelling (ASL). 

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Intravascular Tracers

Although no method is perfect, the traditional laboratory "gold standard" for measuring tissue perfusion uses ~15 μm diameter microspheres injected intra-arterially. These particles are trapped by capillary beds in proportion to regional blood flow. Anatomic specimens are then harvested, and the particles visually counted by light or electron microscopy. Microspheres can also be radioactively or fluorescently labelled allowing semi-automated counting methods to be used. 

~15 μm diameter injectable microspheres used for laboratory perfusion measurements

Because they require arterial catheterization and tissue harvesting for measurement, laboratory microspheres are not practical for routine clinical perfusion measurements. However, several particulate agents detectable by noninvasive radiologic means have been developed for clinical use. The most commonly recognized ones include radiolabeled blood cells and macroaggregated albumin (for nuclear medicine) and encapsulated microbubbles (for ultrasound). No truly particulate agent is commercially available for MR perfusion imaging, but a close analog might be gadofosveset (Ablavar®), which binds to serum albumin and remains largely confined to the intravascular space for several hours after injection. Ultra-small superparamagnetic iron oxides (USPIO) particles have been used "off-label" in MR for this purpose as well.

Extracellular Tracers

Iodine- and gadolinium-based contrast agents are widely used as tracers to measure perfusion by CT and MRI respectively. These low molecular weight (500-1000 Da) compounds initially distribute in plasma after injection but then rapidly diffuse into the extracellular spaces of most tissues. The only exception is within the central nervous system where tight endothelial junctions along the blood-brain barrier preclude extracellular passage into normal brain and spinal cord. Although some newer specialized MR contrast agents (e.g. gadoxetate/Eovist®) have hepatic uptake, most do not enter normal cells and remain confined to the extracellular space.  

Diffusible Tracers

Cine images from 1st pass myocardial perfusion study using a saturation recovery spoiled-GRE method

Freely diffusible tracers are radioactively or magnetically labeled ions and small molecules that easily move between intracellular and extracellular compartments. These are well known in nuclear medicine/PET and include ¹⁵O-labelled O₂, H₂O, and CO₂; ¹³NH₃; ⁸²Rb; and ²⁰¹Tl. Inhaled Xe gas, another diffusible tracer, achieved minor interest for CT perfusion imaging in the 1990's but has now largely been abandoned. In MRI magnetically tagged water molecules are widely used as diffusible tracers, forming the basis of the arterial spin labelling (ASL) technique.

PET using ¹⁵O-water is generally considered the noninvasive gold standard for measuring perfusion in most organs. However, it is a cumbersome technique requiring on-line tracer production and delivery to the patient with continuous arterial blood sampling. And it is not perfect, being subject to partial volume effects especially around small, convoluted brain structures. Compared to microspheres, ¹⁵O-water PET tends to underestimate perfusion at high flow rates and overestimate perfusion at low flow rates.

¹⁵O-water PET is considered to be the most accurate method for measuring blood flow noninvasively.

Relative few side-by-side comparisons of ¹⁵O-water PET and MR perfusion using dynamic susceptibilty contrast (DSC) or ASL exist. Studies that have been performed do demonstrate MR perfusion methods provide reproducible and reliable qualitative information about blood flow. Accurate quantitative measurements are possible but challenging, being dependent on the MR method (DSC v ASL) and sophistication of the mathematical model used.