Published on: May 6, 2012
by Denise Grady for The New York Times
“If there’s something to be done, I want to be in on the ground floor,” said Elizabeth, 67, a woman participating in studies of frontotemporal degeneration at the University of California, San Francisco.
She asked to be identified by only her middle name to protect her privacy. She is healthy, but she has tested positive for a rare gene that makes the brain disease virtually inevitable; her father, her grandmother, two of her three brothers and other relatives have been affected.
Scientists think that abnormal protein deposits inside brain cells cause frontotemporal degeneration. The proteins vary, but they do not include amyloid, the substance found in Alzheimer’s patients.
In about 40 percent of patients, the deposits are an abnormal form of a protein called tau, which normally gives structural support to brain cells. (Tau is also one of the proteins found in Alzheimer’s patients.)
Two other types of deposits are abnormal versions of proteins involved in other cell functions. In about half of all patients with frontotemporal dementia, the protein is one known as TDP-43, and in about 10 percent it is a substance called FUS.
But why do these protein deposits form? Often, the underlying reason is not known.
At least half of all cases are sporadic, in people with no family history of the disease and no known genetic disorder. About 40 percent of patients do have a family history, and some may have an identifiable genetic mutation.
In the remaining 10 percent — families like Elizabeth’s — the disease is definitely inherited: a dominant gene makes the symptoms inevitable, sometimes as early in life as the 30s or 40s, in anyone who inherits a copy from an affected parent. And each child of an affected parent has a 50-50 chance of inheriting the bad gene.
So far, most inherited cases have been linked to mutations in two genes, both on the same chromosome, number 17. One gene codes for tau. The other gene codes for a protein called progranulin and causes a deficiency of it, which appears linked to the buildup of TDP-43. Three other genes are involved in some cases, and researchers are looking for still more.
Drugs that increase progranulin or prevent tau buildup may also help people with Alzheimer’s disease, said Dr. Bruce L. Miller, a professor of neurology and psychiatry at the University of California, San Francisco.
Tests in mice suggest that a drug called nimodipine, already approved to treat another condition, may increase progranulin in the brain.
Li Gan, another researcher at U.C.S.F., who is studying the drug in animals, said, “The attractiveness of this approach, if it proves effective, is that it is relatively safe and has been used for quite a few years in people.”
But increasing progranulin is not without risk: in animal experiments, high levels increase the risk of cancer.
“Here, we’re talking about stabilizing something that’s deficient,” Dr. Miller said. “We’re optimistic that it won’t be a major stumbling block.”
However, animal studies indicate that the nimodipine dose needed may be dangerously high. Dr. Gan said it was not quite ready for tests in people yet.
Dr. Miller said another drug, one not yet approved, would probably be tested first, maybe as soon as early next year. The first test subjects will be patients of Dr. Miller’s who already have symptoms. Later, the drugs might be offered to people at risk but not yet affected.
“What is so fascinating about this is, what do you define as ‘affected’ in somebody who carries a gene that is going to cause a slow, subtle social decline? What are good markers for someone who is starting to get sick?” Dr. Miller asked. “Addictive behaviors — drugs, alcohol, gambling — bad decision-making, alienation of other people around them. These are things that we never realized could represent the first symptoms of a degenerative disease.”
Among his patients are people who have the dominant gene and whose children are therefore at risk. One is a woman with five children, ranging from their 20s to 40s.
“These families have become my passion and interest,” Dr. Miller said. “These are social genes.”
Elizabeth’s progranulin levels are already low. If a drug could raise them, would she take it?
“Absolutely,” she said.
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