PET scans can pick up a useful biomarker for Parkinson's disease and can even help predict who will benefit most from treatment with transplanted fetal neural tissue, according to a controversial, almost two-decade study.
As reported in the January issue of the Journal of Nuclear Medicine, doctors found that good uptake of 18F-fluorodopa (18F-FDOPA), a radiotracer analogue of dopamine, and a neurotransmitter known to be depleted in Parkinson's, was associated with improvement of disease symptoms.
But the study, which tracked many of the patients of the original experiment conducted over a decade ago for up to four years following their surgery, found the success of engrafting dopamine-producing brain tissue from fetuses into the deteriorating brains brought mixed results.
Clinical improvements on the Unified Parkinson's Disease Rating Scale (UPDRS), a common measure of disease severity, climbed about 25 percent. But the results were short-lived, peaking at about two years following engraftment, with the modest gains starting to vanish after four years.
"The 25 percent benefit is usually more than a placebo effect. We generally think of placebo as being 20 percent or lower, so 25 percent seemed to be meaningful or significant," says David Eidelberg, MD, the study's lead author and a neurologist and director of the Center for Neuroscience at the Feinstein Institute for Medical Research on Long Island, NY.
But he adds, "For a late-stage patient, 25 percent improvement did not necessarily mean their lifestyles were radically impacted by the therapy."
Still, the follow-up study did dispel fears called up by the initial experiment, begun in the early 1990s, where a condition known as graft-induced dyskinesia (GID) that causes uncontrolled muscle spasms afflicted about five of the original patients. Dr. Eidelberg said the side effects, thought to be caused by excess dopamine production, discouraged doctors who worried that extensive transplants would result in a swarm of such cases.
But no new cases emerged in a subsequent trial, and Dr. Eidelberg says they now know why: grafts on the putamen, the part of the brain where dopamine signaling helps control voluntary movement, probably only lead to GID if the brain region is producing higher levels of dopamine.
"We learned that putting the graft in areas that are less depleted of dopamine may not give you a great response," he says. "If it's not terribly depleted, you'd get an imbalance; the graft would produce an abnormal amount of dopamine."
"It's almost like an overdose," he adds, "even though dopamine levels don't reach supernormal levels, but still the balance is artificially asymmetric."
And identifying good candidates for the procedure was something PET was good at, according to Dr. Eidelberg.
Patients whose FDOPA scans indicated they had relatively stronger dopamine activity (but not so much as to provoke a GID reaction) in the putamen were vastly more likely to improve after the operation.
"You didn't have to do the graft and wait," says Dr. Eidelberg. "We were able to identify based on amount of dopamine they lost."
And it did all this because FDOPA proved to be an excellent biomarker of the disease, he says. Uptake of the radiotracer shot up to 55 percent of normal signal ratio after transplantation, with higher levels of uptake associated with better outcomes.
"[This] lends credence to clinical assessment and gives objective measure to gauge improvements," Dr. Eidelberg notes.
The study, which followed 33 of the original 39 subjects for two years after surgery, and 15 after four years, also cleared up an outstanding mystery from the original work: why patients under 60 seemed to benefit most from transplant. The reason is, they didn't.
Age differences, which showed up in the original study that followed subjects only one year after the operation, disappeared after the two-year mark. Dr. Eidelberg thinks it just takes aging brains longer to form the necessary connections with the graft.
"The [nerve] signaling has to move across multiple synaptic contacts till it hits the motor region," he says. "When you're older, the grafts don't readily form these synaptic connections. It's not that they don't do it, it just takes longer."
The earlier study also found a sex difference, with men, but not women, showing significant improvements after transplant, but these also went away. Although no one knows why they were present in the original study, Dr. Eidelberg suspects it was just an artifact from the small sample size.
FUTURE OF RESEARCH
Right now, Dr. Eidelberg says a European study has just begun further investigating fetal nerve tissue transplants for Parkinson's. The team is using a different approach: instead of planting grafts on the brain, "like hair plugs," Dr. Eidelberg says, they're actually spraying cells over the target region. This technique, as it prevents clumping, will likely drastically reduce any chances of the GID side effects.
But even so, is the treatment something he would recommend to patients now?
"At this stage, I would say no: this is a highly, highly experimental procedure," he says, noting that gains from deep brain stimulation, using implantable pacemaker-like devices to shock the brain, but which weren't available when his project started, generally show better results.
But Dr. Eidelberg isn't completely ruling the nerve-tissue transplant therapy out.
"The studies are promising, although the results are not optimal," he says. "But it's not a taboo subject to continue. These people did OK."