January 27, 2009 - By Bruce Goldman
STANFORD, Calif. - You come into a doctor's office with severe knee pain. The physician orders an MRI, which reveals substantial loss of cartilage - osteoarthritis, that is - in your knee joint. At this point, not much can be done beyond gulping down palliatives and trying to keep your weight off the joint. But the damage may have started building as much as 20 years earlier, possibly due to a traumatic injury to the affected joint.
Just ask Garry Gold, MD, an associate professor of radiology at the Stanford University School of Medicine. Now 45, Gold sustained a knee injury 20 years ago while playing in a pickup basketball game. These days, he's starting to wish his house, currently being remodeled, didn't have any stairs.
Gold, who has been diagnosed with osteoarthritis, is working with an imaging technology called sodium MRI to diagnose osteoarthritis as long as decades before the onset of physical symptoms. That may spawn new therapies that could possibly have blocked his disease before it put an end to his basketball days.
Gold is collecting young athletes who've suffered damage to the anterior cruciate ligament, or ACL, in their knee - an injury afflicting several hundred thousand people annually in the United States alone. This knee insult is especially common among female athletes. "A good fraction of the Stanford women's basketball and soccer teams either have torn their ACL sometime in the past or will tear it while they're still at Stanford," Gold said. Even when the initial ligament lesion is repaired surgically, victims remain at almost doubled risk for symptomatic osteoarthritis in the injured knee a decade or two down the road, compared with uninjured people.
Using the new imaging technology, Gold and colleagues have been able to spot, soon after such an injury, telltale signs of cartilage deterioration consistent with the development of osteoarthritis.
MRI now in routine use works by pulsing the area to be observed with electromagnetic energy, at a frequency that preferentially excites the protons in water molecules. As the protons settle back to a relaxed state, they send out an electromagnetic burst of their own, which can be picked up by sensors in the apparatus. Because cartilage has lots of water compared with nearby bone, it shows up on a computer-generated image of the region.
But while standard MRI gives a reasonable display of overall cartilage structure, it doesn't tell a diagnostician much about the quality of that cartilage.
"If you look into a big house and you see that it's standing up," Gold said, "you may assume it's going to be safe in the event of an earthquake. But without closer inspection, you don't know much about the integrity of the structure."
If standard MRI is akin to a view of standing timber in the house, the version Gold is using, called sodium MRI, enables the visualization of dry rot infecting and weakening the wood.
Garry Gold, MD, explains how sodium MRI has the potential to detect osteoarthritis before it develops and shows what sodium MRI scans look like. Video length: 3 min.
A key structural material in cartilage, called glycosaminoglycan, occurs in a complex with sodium, an elemental metal that has its own set of excitation and relaxation frequencies and is more restricted to cartilage than water is.
Sodium MRI has been around for years, but until recently it couldn't be used in clinical settings. For one thing, the magnets employed to excite sodium atoms were too puny, making crisp resolution possible only with tiny creatures such as mice. Gold and his colleague Brian Hargreaves, PhD, assistant professor of radiology, have designed improved magnets and software to scale up the technology for human application.
They're on the right track, said Ari Borthakur, a University of Pennsylvania scientist who is not involved in Gold's research but has done pioneering work with sodium MRI since writing his PhD thesis on it some years ago. "Everything his lab has developed is going to be applicable in the clinics," said Borthakur. "As America ages, we're expecting to see a huge increase in osteoarthritis, and any technique that could be used for its early diagnosis, or that could help developing therapies for curing it, or even slowing the progression of cartilage loss, would be tremendous."
Gold and Hargreaves' project is being conducted with funding from the National Institutes of Health and GlaxoSmithKline, an international pharmaceutical company. Neither researcher owns stock in, or receives consulting fees from, the company.
Working with Hargreaves, Gold has imaged the knees of about a dozen volunteers who have suffered a recent ACL injury. In every case so far, significant losses of glycosaminoglycan can be glimpsed under sodium MRI scanning, despite the absence of any sign of damage to cartilage observed with standard MRI. Almost invariably, sodium MRI scans of the injured knee - but not of the other, uninjured one - reveal glycosaminoglycan deficits within three years of the injury, potentially enabling a vastly accelerated diagnosis.
This ought to speed the development of new therapies, and radically lower the cost of doing so, Gold said. The idea is to be able to use glycosaminoglycan loss as a "surrogate marker" of impending osteoarthritis, much as high LDL levels are used to flag people at risk of heart disease - perhaps years before actual symptoms of heart disease manifest. While not everybody with elevated LDL develops cardiovascular disease, this marker has been sufficiently predictive of that condition that regulatory authorities routinely approve drugs based on their ability to lower LDL.
Catching osteoarthritis during its stealth phase may spur clinical trials that would be prohibitively time-consuming and costly if standard MRI were employed, because of the huge lag from the time of an ACL injury until the time cartilage deterioration can be detected by that old method.
With sodium MRI, cohorts of treated vs. untreated at-risk patients could be imaged over time to see if, within a few years of the injury, a drug or a lifestyle change is reducing or arresting the loss of glycosaminoglycan from the ligament. Once promising drugs or lifestyle changes are identified, they could then be administered to at-risk patients long before symptoms surface, Gold said.
As for Gold himself, he has yet to see what his own damaged knee looks like under sodium MRI. The 6-foot-6 once-avid amateur basketball center's knee is too big for even his improved new experimental apparatus to fit. It's probably too late for any kind of imaging to do Gold much good now, anyway. He already knows he's got arthritis. "I don't even want to look," he said.
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