Entrance of Physiological Imaging and Highly Sensitive Structural Imaging

October, 2011

Physiological imaging techniques measure changes in cerebral blood flow (CBF) and brain metabolism. These measurements complement structural imaging studies by providing information on regional brain function either at rest or in response to specific perturbations and how it is altered by brain disorders.

Positron Emission Tomography (PET) was the first major technology to measure physiological functioning in the brain. In PET scanning, the regional distribution of exogenously administered positron emitting tracers is measured using tomographic imaging.  The first PET tracer to be used in humans was 18F-deoxyglucose, which distributes according to regional glucose utilization. Because water is freely diffusible from the blood to the brain, 15O-H2O provides a PET tracer for measuring cerebral blood flow, and was another early tracer used for measuring regional brain function.

When introduced clinically in the 1970s, PET provided a fundamentally new opportunity to explore the parts of the brain that were activated in undertaking specific tasks, a role it dominated for more than a decade.  This application of PET is predicated on the observation that changes in regional neural activity are coupled to changes in regional cerebral blood flow and metabolism.  More recently the main functions for PET are focused on the study of neurotransmitters (electrochemical signals passed from one brain cell to another to communicate), the actions of pharmaceutical drugs, and the expression of specific genes in the brain.

Additionally, in recent years a few PET tracers have been developed that attach solely to the protein beta amyloid, which builds up in the brains of patients with mild cognitive impairment (MCI) and Alzheimer’s disease. PET imaging with these agents has the potential, along with cognitive tests, to diagnose Alzheimer’s disease in patients, and to identify patterns that may predict which patients with MCI will develop Alzheimer’s disease.  

Due to PET’s ability to measure tiny concentrations of the radioisotope tracer used, its measurements are exquisitely sensitive. But its utility—especially clinically—compared to its use in research, is compromised to some extent by the non-specific nature of the changes in CBF and metabolism and the need to actually make the radioisotopes at the clinical site.

Radioisotopes, produced by huge and expensive cyclotrons, need to be made at the site because they decay quickly and so must be used soon after they are made. This rapid decay is referred to as having a short “half-life,” which is the time it takes for 50 percent of the radioactivity to decay. Because of the tiny amount of radioisotope used and its rapid decay, PET tracers generally produce no adverse effects in patients. The tracer is injected into a patient’s vein and travels to the brain. The positrons rapidly collide with electrons and release gamma rays oriented in opposite directions along exactly the same line. These gamma rays are detected by two sensors simultaneously, enabling computers to precisely pinpoint the brain locations of interest.    

Due to the need for the expensive cyclotron at the clinical site and the subsequent development of alternative physiological imaging techniques, PET is not used extensively to study brain areas that are activated when undertaking a specific cognitive or motor task (“task activation” studies), Instead, one of its current major uses is in research on excitatory and inhibitory neurotransmitters (electrochemical messages passed from one brain cell to another to communicate). Each neurotransmitter, such as dopamine, GABA, serotonin and others, attaches to a specialized receptor on a brain cell that receives the message. In this way, PET identifies brain cell networks using a specific neurotransmitter to communicate, and also helps to see whether abnormally high or low transmitter levels are associated with specific brain conditions.

As an example, Parkinson’s disease is characterized by low levels of the neurotransmitter dopamine. PET is used in Parkinson’s disease research primarily to assess the effects of experimental treatments on dopamine and to determine exactly how they work.     Also, though not often used for this purpose, PET imaging of the dopamine network (dopaminergic system) can help to differentiate early stage Parkinson’s disease from other “parkinsonian” disorders (multiple system atrophy, progressive supranuclear palsy or Huntington’s disease).

In the case of PET exploration of dopamine (as for other neurotransmitters), a radioisotope is attached to molecules that look like dopamine and, when introduced intravenously into a person, are taken up by the same cells that take up dopamine. The radioisotopes make their way to the brain and concentrate there. PET then images the amount of the labeled molecules that has been taken up by brain cells to measure dopamine levels.

Because PET tracers bind to many of the same receptors that pharmaceutical drugs bind to, PET is also widely used to study how pharmaceuticals act in the brain. Additionally, PET can repeatedly and quantitatively image gene expression (proteins produced by genes) in the brain, to provide new insights into the contributions of specific genes to brain disorders and diseases.  

More recently, a few specific PET tracers, such as PIB-PET (Pittsburgh Compound B”) and “florbetapir -F18 PET” have been developed that bind solely to beta amyloid proteins, which accumulate in the brains of people with presymptomatic mild cognitive impairment (MCI), overt MCI, and those with Alzheimer’s disease, but not in the brains of cognitively healthy adults.  Importantly, not all people with presymptomatic or overt MCI go on to develop Alzheimer’s disease. Scientists may be able to identify the patterns that indicate which people with presymtomatic or overt MCI will go on to develop Alzheimer’s disease and which will not, by imaging all three groups of patients serially over several years. 

Because PIB-PET has an extremely short half-life of only 20 minutes, it is used for research only at academic centers. A Food and Drug administration (FDA) advisory committee in early 2011 recommended that Florbetapir F-18, which has a relatively longer half-life than PIB-PET, be considered for FDA approval as the first generally available physiological diagnostic tool for Alzheimer’s disease, to be used in conjunction with cognitive tests. The committee advised that approval be contingent upon the manufacturer developing a training program for clinicians that successfully teaches them how to consistently read the scans accurately.

An imaging technology that is similar to PET is Single Photon Emission Computed Tomography (SPECT). It is used for most of the same purposes as PET, but is less expensive and more convenient for clinical use. SPECT began to be widely employed clinically in the 1980s because, unlike PET, it detects directly emitted gamma-rays from commercially available stable radioisotopes. These isotopes are larger and have a longer half-life than those used in PET, but the imaging is less precise. So, patients who are seen in clinics other than at academic research institutions are far more likely to receive SPECT rather than PET scans. Like PET, however, many of its clinical functions have been taken over by other physiological imaging techniques, most notably Magnetic Resonance Imaging (MRI).