May 5, 2012
“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, a researcher at the Gladstone
Institute of Neurological Disease and an
associate professor of neurology 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.
