http://www.mcgill.ca/uro/Rep/r3114/neural.html

New hope in neural transplants

TIM HORNYAK | Muriel White's hands shake as she sets tea
cups on her coffee table. Even though she takes eight pills a
day to fight the effects of Parkinson's disease, the china in
her tea service rattles as if the ground were quaking.

"You can hear me coming from a long way away," laughs
White, 84. Two years ago, she was diagnosed with
Parkinson's at the Montreal Neurological Institute (MNI).
While White is still in the early stages of the degenerative
neural disorder, many patients are diagnosed at a much
earlier age, including 37-year-old actor Michael J. Fox,
who revealed he had Parkinson's last November. There is
still no cure, but a wave of recent research at the MNI and
other McGill centres could yield treatments for Canada's
100,000 Parkinson's patients that are better than ever.

The British surgeon James Parkinson first described
"paralysis agitans" in 1817. Researchers -- including
McGill's own Theodore Sourkes -- have since linked the
chronic, nonfatal disease to the death of
dopamine-producing cells in the substantia nigra area of the
brain. Eighty per cent of those cells have usually died by the
time primary signs appear: tremor, rigidity, poor
coordination and a shuffling gait.

The cause of Parkinson's is still largely unknown, but
researchers are focusing on environmental and genetic
reasons. Dr. Michel Panisset, director of the Movement
Disorders Clinic at McGill's Douglas Hospital, has found a
correlation between Parkinsonian symptoms and areas in
southern Quebec with high levels of manganese, an element
found in MMT, now a common fuel additive. Panisset is
also involved in a study with the U.S. National Institutes of
Health that will examine genetic predisposition to
Parkinson's in 500 pairs of relatives.

"Research in Parkinson's has gone absolutely crazy," said
Panisset in a Parkinson's talk given last month as part of
Brain Awareness Week at the MNI.

Existing drugs, said Panisset, are good at controlling the
symptoms of the disease, but none can halt the death of
dopamine-producing neurons.

Furthermore, drugs such as levodopa, introduced in the
1960s and still a cornerstone in treatment, tend to be less
effective over time. Neurologists must then look to
alternative treatments to regain control over symptoms.

"I think the surgeries are a major contributor to a better
quality of life in patients," said Panisset. "These are really
patients that would not be able to be controlled any more
with medication. Before these surgeries, we had nothing to
offer them."

Attempted as early as 1900, surgery for Parkinson's has
recently had a resurgence thanks to improvements in brain
imaging, neurosurgery and our knowledge of brain
physiology. MNI neurosurgeon Dr. Abbas Sadikot uses a
computerized, three-dimensional stereotactic brain atlas to
precisely target brain tissues with an instrument called a
leukotome. Inserted into an awake patient's skull, the
leukotome is guided into the globus pallidus or the thalamus
and produces lesions that dull overactive neural pathways.
Although there is a two per cent risk of brain bleeding in
such procedures, studies have shown lesions often rid
patients of tremor and the jerky movements associated with
prolonged drug treatment. Results are immediate, and some
televised reports have portrayed nearly immobile patients
suddenly moving about quickly after surgery.

Sadikot is also working with MNI microbiologist Dr. Freda
Miller on an experimental surgical treatment for Parkinson's
-- neural transplantation. A controversial source of graft
cells has been neurons from aborted human fetuses, but
emerging sources include cells from the carotid arteries that
supply blood to the head, porcine cells and skin cells
genetically engineered to make dopamine. Miller, however,
is looking at the olfactory epithelium -- cellular membranes
covering nasal pathways -- a source that has been literally
under her nose since she began research into neuronal
survival five years ago.

One of Miller's former postdoctoral researchers recently
made an important discovery in her lab. Dr. Andrew
Gloster found that stem cells -- basic cells that develop in
the fetus and later become specific cell types -- could be
extracted from the olfactory epithelium of adult rats. When
cultured in a dish, the stem cells could differentiate into the
types of cells lost in Parkinson's disease. Transplantation
experiments performed in adult mice, says Miller, have so
far shown promising results.

"We definitely get the right kind of neurons in the right
place," says Miller. "The question is: Do we have enough
for any kind of functional recovery? That's part of
optimizing the transplantation process." Miller will now
focus on obtaining olfactory stem cells from humans,
manipulating them into the cells killed by Parkinson's and
transplanting them into the brain.

Monitoring the work of those cells will be possible with a
new brain-imaging technique partly developed at the MNI
by Dr. Alain Dagher.

Until recently, it was impossible to measure the release of
neurotransmitters such as dopamine in the human brain. By
refining an established positron-emission tomography (PET)
technique that assesses the survival of dopamine neurons via
a radioactive dye injected into the patient, Dagher is now
able to gauge the actual function of those neurons with a
chemical that labels dopamine receptors.

"With this method where we can measure dopamine
release," says Dagher, "if you put in a graft, you can prove
that it's actually working, that it's actually synthesizing
dopamine."

Since dopamine is involved in higher-order brain functions
like motivation, Dagher will use the new PET technique to
study the role of dopamine in drug addiction, gambling and
playing video games. But the technique could be developed
into both a more sensitive diagnostic test for Parkinson's
and a better way of measuring the effectiveness of drugs
like levodopa.

That may become a key innovation as demand for the drug
grows. Due to Canada's aging population, experts expect
the number of Parkinson's patients to rise at least 30
per cent by 2020. As for the future of research into
Parkinson's, McGill investigators are cautious but very
optimistic.

"As far as talking about a cure for a disease, that's always
risky," says Panisset. "But if it continues like this, I think
we're going to make some very significant progress in the
near future."

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