Although it will continue to be important, anatomical imaging alone isn’t enough anymore. These advances have prepared radiology and nuclear medicine for the next stage of medical imaging—molecular imaging diagnostics of the biology of disease.

—Michael E. Phelps, Ph.D.

Radiologists are increasingly using PET scans to accurately diagnose diseases such as Alzheimer disease (AD). As revolutionary new technologies are developed, including microfluidic chip technology, it is hoped that improved molecular diagnosis of the biology of disease will lead to better disease management and possibly cure.

PET/CT scanning with fluorodeoxyglucose (FDG) is in widespread use to confirm and document activity of many diseases. These scans can enable an early positive diagnosis of AD and differentiation of AD from other causes of dementia.

“The right way to use FDG PET is choosing the correct clinical setting,” said Mark A. Mintun, M.D., a professor of radiology at Washington University Medical School in St. Louis, who taught a mini-course on PET at RSNA 2005. “An FDG PET study helps clarify and confirm diagnosis when a patient has comorbidities, such as depression, or other neurological disorders that make an evaluation more complex.”

The published sensitivity for AD diagnosis by FDG PET is between 85 percent and 90 percent.

Hybrid PET/CT

With PET/CT, radiologists can see the metabolic function of the brain and detect AD before it is clinically evident—up to eight years in some cases.

“PET/CT is the best diagnostic tool to evaluate brain function in the diagnosis of AD,” said Michael Kinzer, M.D., clinical director of PET Fusion Imaging, a partnership of Fort Wayne Radiology and Parkview Health in Fort Wayne, Ind. “As in the evaluation of cancer, the earlier and more accurately AD can be detected, the better it can be treated.”

Dr. Kinzer and his colleagues have experience with a hybrid PET/CT scanner, the only one available in northeast Indiana. “The metabolic changes the PET scan detects are much earlier than the anatomical changes seen by CT,” he explained. “For example, if I see an abnormality on the PET images that could be due to a stroke or AD, I can look at the CT component of the image that shows the same anatomic slice of brain. The hybrid scanner fuses both images together enabling the differentiation between the sequella of stroke from the functional decline of AD.”

A study in the February 2006 issue of Radiology shows that combined PET/CT is more sensitive and specific than either of its constituent imaging methods alone and probably more so than images obtained from separate PET and CT systems and viewed side by side. See page xx for more details.

Benefits of Early Diagnosis

A variety of conditions that mimic AD dementia, such as frontotemporal dementia, multiple mini strokes, chronic depression of the aged (“pseudo dementia”) or other neuropsychiatric disorders, are prevalent in the age group in which AD is most prevalent. All of these conditions have specific characteristics that can be detected with PET and with CT. Dr. Kinzer said after looking at a brain’s functional patterns, he can reliably differentiate AD from other disease processes.

Although there is no cure, AD patients who have access to newer treatments early in the disease process realize more benefits than those who start therapy later. Early treatment benefits include delaying progression of symptoms and postponing the need for nursing home care.

“From an emotional standpoint, it is useful for patients and families to have another reliable tool to aid in the diagnosis of AD so they can get their lives in order and prepare for the future,” commented Dr. Kinzer. “PET/CT helps us provide helpful information to the clinicians that we serve, their patients and the patients’ families. Our hope is that early diagnosis will allow for early treatment, impede dementia and possibly, one day, offer a cure.”

Molecular Therapeutics and the Future of AD

Dr. Kinzer said that imaging has a very exciting role to play in the future of AD diagnosis and treatment. “Biomolecular imaging research may allow a specific antibody to be sent to the destructive plaques of AD. In the future, I can see that instead of merely diagnosing AD, radiologists will be able to send antibodies that are tagged with a nuclear agent to destroy the plaques that are causing AD,” he explained.

Dr. Mintun said he believes that future AD imaging will include the regular use of molecular imaging probes to view the actual amyloid plaques of AD rather than just the metabolic consequences.

“That is very different from imaging the metabolism of the brain with FDG,” he explained. “FDG imaging is very useful, but imaging the plaques opens up a whole new way of diagnosing, understanding and potentially managing the treatment of AD.”

The co-inventor of the PET scanner sees myriad possibilities in the future treatment of AD and other diseases. “The defining issues for the future of molecular imaging will not come from molecular imaging but rather from molecular therapeutics,” said Michael E. Phelps, Ph.D., the Norton Simon Professor and chairman of the department of molecular and medical pharmacology at the UCLA School of Medicine, and director of the UCLA-DOE Institute for Molecular Medicine. “Radiologists should look toward the revolutionary advances occurring in the biology of disease and molecular therapeutics to see the future.”

Dr. Phelps said that the numerous pre-clinical molecular imaging centers funded by the National Institutes of Health have brought together radiologists, medical physicists, chemists and biologists to build the scientific foundation of molecular imaging and to merge many imaging technologies together to efficiently present their combined information regarding disease. Within this pre-clinical environment there are microscanners for PET, MR, CT and ultrasound and optical imaging that are being used to build a new knowledge and procedure base for future clinical practice.

“Young radiologists are now learning more about the biology of disease and pharmaceutical sciences,” Dr. Phelps said. “Although it will continue to be important, anatomical imaging alone isn’t enough anymore. These advances have prepared radiology and nuclear medicine for the next stage of medical imaging—molecular imaging diagnostics of the biology of disease.”

New Microchip Technology

A new technology using integrated microfluidics chips is being developed to simplify, lower the cost and diversify the types of molecules used to image the biology of disease, such as AD.

In an article in the December 15 issue of Science, Dr. Phelps and his colleagues demonstrated that FDG could be synthesized on a "stamp-size" digital chip. These chips have a design similar to integrated electronic circuits, except they are made up of fluid channels, chambers and values. The chips can execute the chemical operations required to synthesize and label molecules for PET imaging. All of the chip’s operations are controlled and executed by a PC.

The commercial version of these chips could be shipped to users—universities, pharmaceutical companies and medical centers—to produce molecules of their choosing for molecular imaging with PET. These chips will fuel growth in the number and diversity of imaging molecules and applications of PET in biology, pharmaceutical research and patient care.

“The value of all this is to move toward an open environment with chips as an enabling technology,” explained Dr. Phelps.

“There is a vast array of PET radiopharmacies throughout the world today. In America, there is a PET radiopharmacy within 100 miles of most hospital beds. While these radiopharmacies ship FDG for clinical service and experimental imaging probes and labeled drugs to commercial research labs, they could also ship the radioisotope so users could make whatever imaging probes or labeled drugs they choose,” he said. “This open system would allow academic labs and pharmaceutical companies to make many different molecules for PET for their use. Some of the labeled molecules would come back to radiology and nuclear medicine for molecular imaging diagnostics.”

To view the abstract of the Science article, Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics,” go to www.sciencemag.org/cgi/content/abstract/310/5755/1793.

Mild AD as demonstrated by CT (upper left), PET (upper right) and fused image (lower left).
Images courtesy of Michael Kinzer, M.D., PET Fusion Imaging

Microchip for production of FDG.
Image courtesy of Hsian-Rong Tseng, Ph.D., UCLA