Alzheimer’s patient Robert Linton sits in a chair at the Toronto Western Hospital wearing what resembles building scaffolding on his head. The structure helps surgeons home in on the areas of the brain where they will implant electrodes. The electrodes will deliver stimulation to a specific area of the fornix, within the hypothalamus, a region of the brain important in memory function. A programmable pulse generator, implanted under the skin on the his chest, will control the stimulation. The process, called deep brain stimulation (DBS), has been used to treat people with Parkinson’s and other movement disorders for many years, and is also being studied for the treatment of depression. Linton is one of just six patients who took part in a recent study designed to test the safety of deep brain stimulation in people in the early stages of Alzheimer’s disease. (A Dana Foundation grant helped support this research.)
The idea to try deep brain stimulation to treat Alzheimer’s came about by chance. Andres Lozano, senior scientist at the division of brain imaging and behaviour systems at the Toronto Western Research Institute, and his colleagues were testing DBS in an obese patient as a way to control appetite. As soon as they turned the electrodes on, the patient experienced a vivid memory.
“He flashed back to a memory of when he was 20 years old,” says Lozano. “He could describe the scene in detail, and as we turned [the stimulation] off or down, the scene would disappear.” Memory testing before and after the operation showed a striking increase in his verbal memory after one month of stimulation. “This told us that the circuits in the brain that control memory are reachable,” says Lozano.
In the recent Phase 1 study (to test the safety of the technique), Robert Linton and his fellow patients all received deep brain stimulation for at least one year. Researchers assessed their cognitive function before treatment and at regular intervals after, using a number of standard cognitive tests. Clinical outcomes are difficult to measure in people with Alzheimer’s because the rate of each person's decline is so different. To assess the effects of the treatment in their patients, the researchers compared the observed changes in cognitive function on these tests to the average expected change, as determined by prior research. Three of the six subjects deteriorated less than expected, leading the researchers to conclude that there was a possible clinical benefit. The Phase I requirements were met: All six patients tolerated the surgery well and had no serious adverse effects.
In addition, researchers measured the levels of glucose metabolism in the brain. Glucose is the brain's main fuel supply; in people with Alzheimer's, its use appears to be severely reduced in some areas. “We wanted to know if we could reactivate these areas,” says Lozano. In all six patients, glucose metabolism in affected areas increased after one month of stimulation, and the increase persisted after one year. The research was published in the Aug 4 issue of Annals of Neurology.
“It’s a very intriguing study,” says Laurie Ryan, program director of Alzheimer’s disease clinical trials at the National Institute on Aging, who was not involved in the research. “I don’t think we can predict how it will turn out with a larger number of subjects, but they did have some very interesting data, particularly the PET data [on glucose metabolism]."
Although Lozano is careful to stress that deep brain stimulation is a potential therapy, aiming to improve symptoms of Alzheimer’s without necessarily tackling the underlying cause, he does feel that it opens up a new way of looking at the disease. “We should think of Alzheimer’s as a brain circuit disorder,” he says. This is in keeping with some of the research being done on the effects of normal aging on brain circuits, says Ryan. “I think this is another piece of the puzzle that is pointing us in that direction.” Lozano and his colleagues now plan to undertake a larger, Phase II, clinical trial.
Robert Linton, a little over a year after his operation, is optimistic about his recovery. “I feel rejuvenated,” he said, speaking at a press conference at the Toronto Western Research Unit. “I would say that it’s a new lease on life, to be able to…” he hesitated. "I guess just, remember things more on a day-to-day basis. When you hear the word Alzheimer’s, you figure your life is over, and I think I got a whole new future.”