WASHINGTON, DC—Deep brain stimulation (DBS) of the fornix appears safe and well tolerated in patients with mild Alzheimer’s disease, according to data from a phase II trial. Although stimulation did not appear to provide clinical benefit in the study population overall, researchers found indications that DBS might have benefited a subgroup of patients in the trial. Andres M. Lozano, MD, PhD, Dan Family Chair in Neurosurgery at the University of Toronto and Toronto Western Research Institute, presented results from the ADvance trial at the 2015 Alzheimer’s Association International Conference.

Prior studies in animal models and a phase I trial with six patients have suggested that DBS directed at cognitive circuits may improve symptoms of Alzheimer’s disease and slow disease progression. To further evaluate the safety of DBS in patients with Alzheimer’s disease, researchers enrolled 42 patients with mild Alzheimer’s disease in a randomized, double-blind, placebo-controlled, delayed-start trial that was conducted at seven sites in the United States and Canada.

Patients Received Bilateral Implants

Patients were between ages 48 and 80, with an average age of approximately 68 and an average time since diagnosis of 2.5 years. Mean Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog-13) score at entry was 27.8. Two-thirds of participants had a Clinical Dementia Rating (CDR) score of 0.5, and one-third had a CDR score of 1. All patients were receiving stable doses of cholinesterase inhibitors.

Participants received bilateral implants to stimulate the fornix. All of the implantations were completed in April 2014. Researchers randomized equal groups of the 42 patients to continuous on or off stimulation for 12 months. Patients whose electrodes were not switched on served as the control group. After 12 months, researchers turned on stimulation for all of the patients and continued to follow the participants in an open-label phase of the study. Investigators based the stimulation settings (ie, 3 V to 3.5 V, 138 PPS) on the settings used to treat patients with Parkinson’s disease. Further studies are needed to determine which dose might provide the best clinical outcome in Alzheimer’s disease, Dr. Lozano said.

DBS Appears Safe

Acute serious adverse events (ie, events that occurred within 30 days of surgery) included an infection in one patient and persistent nausea in another patient—a rate of serious adverse events of 5%. In addition, one long-term adverse event involved psychiatric symptoms in a patient who was randomized to off stimulation. The 21 patients who received stimulation tolerated it well. The study’s data and safety monitoring committee concluded that the treatment had an acceptable safety profile, and no subjects were withdrawn from the trial. “The surgical procedure was quite safe, surprisingly so,” Dr. Lozano said. “We were expecting more adverse events in these patients.”

Secondary End Points

In addition to the primary end point of safety, the investigators measured several other factors, including cognitive changes over time using the ADAS-cog-13 and the CDR-Sum of Boxes (CDR-SB). They also measured cerebral glucose metabolism using FDG-PET and hippocampal volume. “I want to emphasize that [the study is] exploratory in nature and it’s not powered to detect statistically significant change,” said Dr. Lozano.

Investigators found no effect of stimulation on the ADAS-cog-13 or CDR-SB. Both the on and off groups declined by 8 points on the ADAS-cog-13 after a year and deteriorated by 2.6 points on the CDR-SB over a year.

On FDG-PET, participants in the control group had stable or decreased glucose utilization in six prespecified brain regions, while those who received stimulation had increased glucose utilization in all six areas, as the researchers expected. “There was a difference here, although this [finding] is not statistically significant because of the sample size,” said Dr. Lozano. Investigators are still assessing how DBS affected hippocampal volume.

Older Patients Responded Better

Further analysis showed that younger patients had worse outcomes on the cognitive measures than older patients did. This finding “might be related to the fact that they start out with more severe disease, and this could be seen in PET scans,” Dr. Lozano said. “When we separate out the young and old patients and just look at the older patients, now we start seeing more interesting separation.” When researchers included only patients who were over age 65 in their analysis, those who received on stimulation declined less on the ADAS-cog and CDR-SB, compared with controls, though the effect was not statistically significant.

Informing Future Trials

That neurosurgery and DBS appear safe and well tolerated in this population “is something that we did not know,” said Dr. Lozano. “This is the first large trial of DBS in patients with Alzheimer’s disease.” The surgery, psychiatry, and neurology teams at seven centers were able to manage the patients safely, and the clinical efficacy findings can inform the design of the next clinical trial, said Dr. Lozano.

—Jake Remaly

Can Deep Brain Stimulation Help Patients With Alzheimer’s Disease?

Can Deep Brain Stimulation Help  Patients With Alzheimer’s Disease?