Left: Dr. Abbas Sadikot, Right: Dr. Alain Dagher


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."