Donald Whiting, MD, chair of Allegheny Health Network’s Neurosciences Institute, provided insight on ADvance II, a multinational trial exploring the use of deep brain stimulation in patients with mild Alzheimer disease.
One of the most innovative medical advances of the 21st century—deep brain stimulation (DBS)—has allowed clinician to target specific areas of the brain and treat conditions such as dystonia, epilepsy, essential tremor, Parkinson disease, and obsessive-compulsive disorder. This neurosurgical procedure involves implanted electrodes that generate impulses that control abnormal brain activity. With the growth of DBS, those within the medical community have speculated where it may expand to next.
Announced in 2022, the ADvance II study (NCT03622905) evaluates the efficacy and safety of DBS in patients with Alzheimer disease (AD), a disease that affects an estimated 6.2 million Americans.1 The double-blind study will last 4 years for participants, who will be randomized 2:1 to either neurostimulator activated or left off. DBS for AD will involve the use of an implanted device similar to a pacemaker, with 2 attached wires that deliver mild electrical pulses directly to the fornix, which has been previously linked with memory and learning.
Allegheny Health Network (AHN) will be one of the trial sites for ADvance II, with efforts led by Donald Whiting, MD, AHN’s chief medical officer and chair of its Neurosciences Institute. Whiting sat down to provide context on the innovative study, how it is conducted, and why it differs from traditional DBS research. He also provided context on previous findings that led up to the trial, the outcome measures being observed, and why targeting the fornix has substantial potential.
NeurologyLive®: How is the ADvance II study constructed?
Donald Whiting, MD: The first thing to know is that this ADvance study is a second iteration. The ADvance I study was initially done to look at safety of deep brain stimulation in the fornix for memory issues in the elderly. In that study, DBS was shown to be very safe, much like regular DBS is very safe. There were some differences detectable within the hippocampus and then the median temporal lobe, with stimulation of the fornix suggesting there was the increased activity that we thought would be there.
In addition to improving Alzheimer symptoms, it also seemed to improve executive function, judgment, and problem solving, as well as memory itself. The initial ADvance study showed that it was safe and that was at 9 centers—we [AHN] were not one of them. That led to the ADvance II study, which is going on now. We’re one of 14 centers in that study in the US and there are several being added. There are 8 in Germany and 1 in Canada, I believe.
This is the result of a serendipitous finding by Andres Lozano, MD, PhD, FRCPC, FRSC, FCAHS, in Toronto, who was researching deep brain stimulation for another reason, obesity, and was a little bit off from the target and ended up in the fornix.2 What they found was that stimulation of that forniceal region, the patient had very intense memories of distant past type activities. Memories of being on a playground as a child, seeing vivid colors of the things around them, the detailed facial features of people. It was almost like, taking a rheostat on a lightbulb and turning up the power of the memory function and making it brighter. That’s sort of what it was like, which then led to the ADvance study.
ADvance II is specifically a study designed for people with mild Alzheimer disease. Not severe, but only mild. Not only are we looking at safety, but the group is looking at efficacy to make sure its beneficial. It’s looking at patients with the stimulatory off and on and comparing a control and active groups. Also, it will look at a couple of different frequencies because with deep brain stimulation, the electrode combination, pulse width, frequency, amplitude, all matter in the effect that you’re creating with stimulation. This study is mainly for that group of mild Alzheimer, and it’s looking for efficacy.
Are there major differences in how DBS is administered for these patients relative to other movement disorders? Or how we've previously used DBS in the past?
Deep brain stimulation has multiple uses. Essentially, where we put it depends on the symptoms that we’re trying to treat. In the brain, there’s circuits and there’s relay centers. And sometimes the circuitry is asynchronous or out of synchrony. When they get to the relay center, the impulses aren’t appropriately processed. For example, for essential tremor, we typically like to put the electrode in the ventral intermediate nucleus of the thalamus, which is the relay center for tremor where the fibers come in. By adjusting those parameters I mentioned, we can realign the circuitry. It gets more synchronous.
Parkinson disease, similarly, for the subthalamic nucleus. In this case, it’s very similar. For Alzheimer disease, the relay pathway is the fornix for memory. That’s where we’re stimulating. The location is different, but the procedure is the same. The reasoning behind it and science is the same. The other thing we find when we operate different areas for stimulation is that sometimes the typical amplitude or pulse wide or frequency, are different for that location and for that disease than others. You can’t say “well, I set the settings on the same stimulant as they were for patients with Parkinson, but I didn’t get much benefit.” That part of the science we’re figuring out. What’s the right electrical settings to get maximum benefit. We’re doing a similar thing for obesity and stimulation of hypothalamus. What we found was a markedly different set of settings to be effective in that area than in movement disorders.
How do you decide what are quality outcome measures, considering this is a relatively unexplored area of research?
It’s a hot topic for research. There’s a lot of pharmaceutical companies and researchers looking at different things. A lot of the research is focused around plaques, plaque resolution, predictive biomarkers, [vitamin] B12, a bunch of different things. That’s all good, and that research is all good. The plaque researchers are trying to reverse the problem to get improvement, which is potentially toward a cure, whereas this is more toward improving the symptoms of a chronic disease. With this, there are 4 main standard memory tests that are well-accepted gauges of Alzheimer disease and functionality. All those tests are used with all the patients before, during, and after. When you look at all the different things you’re examining in a study, it’s good to keep constants and few variables, because you then know what you’re changing. I’m just one of the investigators. I’m not the principal investigator, there’s many people doing it. But in this study, we’re looking at standard tests that everybody accepts to show improvement. All we’re trying to do is improve the symptoms rather than cure.
Transcript edited for clarity.