LEVELAND, Jan. 21 — If Americans develop a disease like the human form of mad cow that worries millions of Europeans, Dr. Pierluigi Gambetti may be the man to find it.
Dr. Gambetti, an Italian neuropathologist whose mild manner and penchant for cardigan sweaters make him look a bit like Mr. Rogers, is director of the National Prion Disease Pathology Surveillance Center at Case Western Reserve University here. For the last five years, he and his staff have been collecting brain tissue from people all over the country who die from mysterious, rapidly progressive neurological disease.
Now that the first case of a cow infected with mad cow disease has been discovered in the United States, Dr. Gambetti's work has taken on new urgency.
Right now, the surveillance center is examining about half of the nation's cases of human Creutzfeldt-Jakob disease, or C.J.D., a rare brain disorder that occurs naturally in a dozen or so subtypes.
The disease is thought to occur worldwide at a rate of one in one million people, meaning some 300 Americans can be expected to develop it each year. But a Swiss surveillance team recently revised that number to three in a million, based on improved recognition of the disease in their country.
That has prompted Dr. Gambetti to increase his efforts to get more suspect brain tissue to his laboratory. "We could be missing unusual cases," he said.
C.J.D. is a reportable disease in 26 states, including New York. As such, physicians are encouraged to let authorities know when they think they have a case. But compliance is not widely enforced, Dr. Gambetti said.
The Centers for Disease Control and Prevention lacks authority to force states to make the disease reportable, unless there is an emergency.
At the federal surveillance center, Dr. Gambetti's assignment is to decide cause of death. He tries to determine whether a person has died from C.J.D., or whether someone has contracted variant C.J.D., a subtype related to eating beef infected with British mad cow disease.
He has also been asked to follow disease outbreaks. For example, he explored whether American hunters were developing something akin to mad deer disease, now that domestic deer and elk have been found to suffer from chronic wasting disease, a brain malady similar to C.J.D.
Dr. Gambetti says he has studied over 1,200 brains using a battery of tests that very accurately diagnose C.J.D., which is believed to be caused by misfolded proteins called prions. So far, he has identified 732 cases. Most are classified as the sporadic form of the disease, arising as a natural consequence of aging.
The rest stem from genetic mutations or from contact with infected human tissue like growth hormone collected from cadavers. Others died from a variety of brain disorders with a different pathology. In the United States, only one person — a Florida woman who lived most of her life in England — has been found to have the variant C.J.D. related to mad cow disease.
There is no evidence based on meticulous autopsies that C.J.D. is occurring in clusters, Dr. Gambetti said. Nor is there good reason to think that most experienced neurologists are misdiagnosing C.J.D. as Alzheimer's disease, he added.
Still, he suspects cases may be missed because many pathologists resist doing autopsies, Dr. Gambetti said, adding that many funeral homes will not touch a body that has been autopsied for C.J.D.
"Prions are like the miasma of the Middle Ages," Dr. Gambetti said. "People are very afraid." Indeed, prions are difficult to destroy and can adhere to medical instruments.
To obtain more brains, Dr. Gambetti set up a network of 20 regional centers willing to do autopsies on suspected C.J.D. patients. The center pays up to $1,500 for the cost of transporting bodies and removing brain tissue. One corpse was recently flown to Washington from Alaska to retrieve the brain, he said. In each case, the brain's right hemisphere is flash frozen, the left hemisphere is put in a preservative, and each is turned over to Federal Express.
In a typical week, the center receives three to five brains. Kay Edmonds, a lead technician, unpacks them, gives them a case number and begins the testing process, which takes weeks.
The left hemisphere is further preserved, sliced, stained and embedded in wax. Dr. Gambetti and other pathologists receive 24 slides covering its major regions. Using powerful microscopes, they look for holes and plaque characteristic of C.J.D. "I know it when I see it," Dr. Gambetti said. Each type of C.J.D. leaves a different pattern.
The frozen right hemisphere goes to a dissecting room on another floor. Ms. Edmonds and a fellow technician, Shigan Liu, step into moon suits, adding extra paper booties, face mask, hair net, plastic face shield and several pairs of latex gloves.
Although there is no evidence to suggest that prions travel through air and are infectious via a respiratory route, they are treated as dangerous particles.
The dissection takes place under a hood with airflow forced up and out of the room into special filters.
Last week, Ms. Liu held a half brain that had been smashed in transit and resembled a rectangular block of red meat. After much deliberation, she took snips from three brain regions. Ms. Edmonds put them in labeled vials, refroze them and sent them to another technician, Dr. Wenquan Zou.
Dr. Zou extracted DNA to learn the sequence of the patient's prion protein. Then he began tests to detect abnormally folded prions. The tests, called Western blots, separate proteins into 3 vertical and 40 horizontal bands that reflect their composition. To a nonscientist, they look like smudges. To an expert, the smudges fall into patterns that can reveal numerous subtypes of C.J.D.
Sporadic C.J.D. is found in six forms. Experts believe it arises in mostly older people whose protein recycling system has broken down, allowing misfolded prions to accumulate and create holes in brain tissue. The same forms are found in patients who contract C.J.D. from infected medical instruments or human tissues.
Mutations in the prion gene produce at least 35 different forms of C.J.D., Dr. Gambetti said. New mutations continue to be discovered.
Variant C.J.D. related to mad cow disease is "absolutely unmistakable" on these tests, Dr. Gambetti said. It has not shown up in residents of the United States.
If a domestic form of mad cow disease existed, unrelated to British beef, it should show up in the surveillance, Dr. Gambetti said. A new pattern or variant would emerge in some number of cases. But with four or five exceptions, every case examined thus far fits one or more known patterns, he said.
If hunters were developing a human form of chronic wasting disease, similar patterns should show up in those diagnosed with C.J.D. "We went to extraordinary lengths to check out 10 hunters," Dr. Gambetti said. "All had different sub-types of known C.J.D."
One, who was 24, had a very rare subtype known to affect younger people. The center obtained pathology reports about three young Europeans who died of the same subtype but were not hunters. The patterns were identical.
Nor has the center found evidence to support claims that C.J.D. has occurred in clusters. Fears that eight New Jersey residents who visited a racetrack in New Jersey and all contracted C.J.D. from having been there are not based on advanced autopsy evidence, Dr. Gambetti said. Two of those brains were examined at the center. One had C.J.D., the other did not. Details about the others are sketchy, and the C.D.C. is investigating.
Another fear, stemming from a recent British study using transgenic mice, is that mad cow disease may be masquerading as sporadic C.J.D. But if that were true, the rates of sporadic C.J.D. should be much higher in Britain, Dr. Gambetti said. The numbers don't show it, at least not yet.
Dr. Gambetti said he hoped to be able to test cattle prions, known as bovine spongiform encephalopathy, in his laboratory alongside human tissues.
But because B.S.E. is on a list of pathogens that terrorists might weaponize, he must satisfy requirements of the Homeland Security Department. "We're waiting for a permanent camera," he said, "that will monitor every person coming and going into the lab."