Deep Brain Stimulation Tolerated in Early Alzheimer's Study

WASHINGTON -- Deep brain stimulation appears safe and well-tolerated in Alzheimer's patients, although changes in cognition were no different from those in a sham group, researchers reported here.

In a study of 42 patients -- all of whom had electrodes implanted into the brain -- those who had their device turned on had similar changes in scores on the ADAS-Cog and CDR-SB as those whose device remained off, Andres Lozano, MD, PhD, of the Toronto Western Research Institute, reported at the Alzheimer's Association International Conference here.

The phase II study, however, was only meant to show safety and tolerability, and will inform future trial designs, Lozano said.

Deep brain stimulation is approved for Parkinson's disease, dystonia, and essential tremor, and is being evaluated for several other conditions, including epilepsy, depression, chronic pain, and stroke.

Lozano and colleagues conducted the ADvance study to assess its impact in Alzheimer's disease. They'd done a previous open-label trial of DBS involving six patients that showed increases in FDG-PET measurements of brain glucose metabolism with treatment as well as "possible" improvements in the rate of cognitive decline. Other data from the study suggested an association between brain glucose metabolism and changes in cognitive and functional outcomes at 1 year.

For the current phase II study, the researchers enrolled 42 patients with very mild Alzheimer's, all of whom were implanted with a Medtronic DBS system (Medtronic is an investor in Functional Neuromodulation Ltd., the Boston-based company sponsoring the trial). Mean age at enrollment was 68 and just over half were male.

Researchers placed the electrodes in the fornix because it sits astride neural circuits important for cognition. Preliminary studies indicated that stimulation delivered there could improve symptoms and possibly even slow disease progression, Lozano explained.

Patients were randomized to have the stimulator turned on immediately or to keep it switched off for 12 months; the latter group then had it turned on.

Evaluation of both groups will last for 4 years. Lozano reported interim results from the first year of treatment, providing a sham-controlled look at its short-term performance.

Overall, they found that acute adverse events such as infection and post-operative nausea were infrequent and similar in both groups, with one infection in each arm of the study.

They reported no serious long-term serious adverse effects in those with the device turned on. One patient who had the device turned off had 3 psychiatric events, Lozano reported.

From these primary-outcome data, the team concluded that both the surgical procedure and the electrical stimulation were safe and tolerated.

When it came to clinical measures of efficacy, the researchers found no differences between groups in terms of changes on the ADAS-Cog13 or the CDR-SB.

However, they did see increased glucose metabolism among patients who had their device turned on.

Further analyses revealed a significant interaction between age and treatment effect, with younger patients doing worse on the therapy compared with older patients.

It's not clear why, but baseline PET scans showed more severe deficits in glucose utilization among patients under age 65. Specifically, there were greater temporal and parietal cortical decreases in glucose metabolism in these younger patients.

When they looked at the results by these two age groups, they saw a non-significant trend toward separation for both the ADAS-Cog13 and the CDR-SB scores, Lozano reported.

He concluded that these findings will inform the design of the next trial.