Lynda McKenzie was in her early 30s when she started noticing some odd physical symptoms. She was a single mother of two who owned a small crafts shop in Milton, Ontario, and everyday tasks at home and work were becoming more challenging. My right leg was dragging, I had a slight tremor and my voice was getting softer, says McKenzie. Also, my writing was getting smaller it seemed like messages werent going from my brain to my hands.

Dr. Claire Henchcliffe

As time went on, her symptoms became more intense, and in 1987 McKenzie went to a doctor who diagnosed her with Parkinsons disease. At age 34, the news came as a shock, but it was helpful because she could finally seek treatments that might help. One included a double-blind placebo surgical study led by Dr. Curt Freed of the University of Colorado. Half the patients enrolled in the study received a transplantation of fetal brain tissue cells meant to change the brains chemistry and alleviate Parkinsons symptoms. One of those patients was McKenzie.Two decades later, Weill Cornell Medicine physician-scientist Dr. Claire Henchcliffe, decided to revisit Dr. Freeds study which, at the time it was conducted, was considered groundbreaking and potentially game-changing. As a clinician-scientist focused on studying the pathology of Parkinsons disease for decades, she wondered how the surviving patients were doing today, and what implications that might have for contemporary research into stem cell-based transplants for Parkinsons patients. No one had systematically gone back to see how effective the tissue injections had been over the long term, says Dr. Henchcliffe, an associate professor in the Department of Neurology and the Feil Family Brain and Mind Research Institute. Knowing how these patients are doing could provide insight and direction for future research.

BRAIN SCANS: PET images of a healthy volunteer (box A) and of a man whos had Parkinsons for eight years (box B). Photo Provided.

During the transplant study, which ran from May 1995 to January 1998, Dr. Freed and his colleagues surgically implanted fetal brain tissue into patients brains in the hope of replenishing their levels of dopamine a chemical that helps coordinate the bodys movements, but which is depleted by Parkinsons. Overall, within a year of the procedure, the patients dopamine levels did increase. Unfortunately, though, the transplants didnt offer the cure that McKenzie and her fellow patients had wished for: their symptoms relented for a while, but ultimately returned. Their disease continued to progress, albeit more slowly than it might have otherwise.

The patients Dr. Henchcliffe met with had been diagnosed at an early age and had been living with Parkinsons for a long time at least 28 years and as long as 36 which is unusual among patients with early Parkinsons diagnoses, who usually have a decreased life expectancy compared to those diagnosed later in life. In the three who received PET scans, her team found that the implanted fetal tissue had survived in its intended location in the brain. Whats more, she says, the patients levels of dopamine were a lot more robust than what youd expect at this late stage of Parkinsons disease. That increased dopamine had had a generally helpful effect: their symptoms, while serious, were markedly less severe than what doctors would have anticipatedinthe normal course of Parkinsons. They were functioning at a higher-than- expected level, Dr. Henchcliffe says, which was a big surprise. They took comparatively few medications, and two were walking without walkers and living independently.

While Dr. Freeds study did not ultimately revolutionize Parkinsons treatment, Dr. Henchcliffe says, it offers valuable insights into how todays neuroscientists may design cell transplant therapies, and suggests that tissue transplants that deliver dopamine into the brain could provide a durable, long-lasting treatment for Parkinsons disease. Building on the promise of the long-term results of Dr. Freeds study, Dr. Henchcliffe is eager to explore with a team of collaborators at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center how human embryonic stem cells could improve the lives of Parkinsons patients: Dr. Henchcliffe believes that dopamine neurons derived from the stem cells would more accurately and effectively promote the brains production of dopamine. Pharmaceutical treatments can add dopamine to the brain, but they arent perfect: they require people to take medication for life, and they have limitations over the long term, says Dr. Henchcliffe. A transplant approach, on the other hand, could get to the root of the problem.The added dopamine did not appear to help alleviate all symptoms of Parkinsons, however, just some of the lost motor skills; some patients still experienced the depression, dizziness on standing and drooling commonly seen in the disease. And Dr. Henchcliffe also found that the added tissue had caused some adverse effects normally only associated with very late stages of Parkinsons and with overdoses of some Parkinsons medications. Three patients were suffering from involuntary jerking movements, called dyskinesia, and one developed oral-facial dystonia a lack of control over the mouth, tongue and jaw muscles that caused grimacing.

- Erica Cirino

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