Some cases of a fatal neurodegenerative disorder linked last fall to "mad cow disease" may not be triggered by the agent that most scientists have suspected. That provocative claim, from animal findings described in tomorrow's issue of Science,* implies that health officials may have to revise their surveillance of variant Creutzfeldt-Jakob disease (vCJD), a condition characterized by tremors, memory loss, and dementia that tends to strike people under 40.
The classic form of CJD is a rare disease that strikes people in old age. The variant form, vCJD, is thought to arise from exposure to products derived from cattle infected with bovine spongiform encephalopathy (BSE). Hallmark signs of vCJD are severe lesions in the cerebellum, a brain region involved in movement control, and the presence of large protein aggregations, called plaques, throughout the brain. Many scientists believe that an altered version of the brain prion protein 'PrP' is responsible for the disease.
Neuropathologist Laura Manuelidis, a longtime skeptic of the idea that altered proteins cause BSE, reasoned that a virus or other agent might be responsible for vCJD. Her team at Yale Medical School injected human brain tissue from people diagnosed with the classic form of CJD into hamsters. The hamsters developed spongiform brain lesions, but not damage in the cerebellum or plaques. The researchers set out to test whether this strain might convert into a plaque-producing strain in a different species. They injected brain tissue from the hamsters into the brains of six rats; but after 700 days, only two had developed spongy brain lesions, and they also lacked changes in the cerebellum typical of vCJD. Moreover, they had no detectable levels of misfolded PrP. They did, however, appear to have brain inflammation: an accumulation of microglial cells, the brain's version of macrophages.
One rat had obvious clinical signs of illness, such as a hunched posture. When brain material from it was injected into a second group of seven rats, all developed a fatal disease that looked a lot like vCJD: They developed spongy lesions in the cerebellum and eventually plaques containing misfolded prion protein. Subsequent groups of rats injected with the infected brain material had more pronounced symptoms of cerebellar dysfunction (problems with posture and movement), more extensive plaques with misfolded PrP, and cerebellar lesions.
According to Manuelidis, if a CJD strain can become more virulent as it passes from one rat to another, a similar evolution might be occurring in BSE jumping from cows to people--if the same agent causes vCJD. Therefore, she says, when pathologists examine autopsied brain tissue to chart the incidence of vCJD and other disease variations in people, they might be overlooking cases that exhibit inflammation without misfolded prions. "The bottom line for public health is that [some CJD cases] may not fit into the classification that's currently used," says Manuelidis, who argues that an agent other than misfolded prion proteins may be responsible for vCJD.
Other experts agree that identifying vCJD cases is a challenge. But Manuelidis is overreaching the evidence in suggesting that prions are not to blame, says pathologist Steve DeArmond of the University of California, San Francisco: "In our experience, there is [misfolded PrP] in all CJD cases, if you look hard enough." DeArmond says Manuelidis's results could be explained by insufficient detection methods, rather than by the host organism's response evolving from inflammation into disease.