Bret S. Stetka, MD


May 04, 2016

Editor's Note:
Deep brain stimulation (DBS) has been used to treat movement disorders for many years. But a growing cast of researchers are also exploring its therapeutic potential in Alzheimer disease (AD); these include Douglas W. Scharre, MD, professor of clinical neurology and psychiatry and director of the Center for Cognitive and Memory Disorders at the Ohio State University Wexner Medical Center. While on site at the 2016 American Academy of Neurology Annual Meeting, Medscape spoke with Dr Scharre about the potential of this research.[1]

Medscape: What were the objectives of your study?

Dr Scharre: We were looking for improved treatments for patients with AD. Because we don't have many treatments that work well, we decided to look at DBS.

We always tell our patients, use it or lose it: Go out and do something, and utilize your brain and your body. Because all of this appears to help the brain, we thought that maybe directly stimulating the brain might help patients with AD, and maybe delay the disease or improve quality of life.

DBS has been used for years in Parkinson disease and tremors and has been proven mostly safe, including in older individuals. A few DBS studies have been conducted in dementia; these have mostly focused on the temporal memory circuits, including such areas as the fornix, and they haven't been overly successful.

These memory targets are in areas of active degeneration, so I reasoned that maybe we should try the next node: the frontal lobes, where the neurons are more intact. Frontal areas are important in decision-making, problem-solving, alertness, and focus. Memory lists and calendars help memory, but they don't do much for assisting executive functioning. Cells in the frontal lobes will eventually degenerate, but they don't degrade as early or as fast as those involved in memory in most cases.

Medscape: Is your group the first to assess the potential of frontal lobe DBS in AD?

Dr Scharre: Yes. Only three patients worldwide have been stimulated in this area of the brain for AD.

We looked at the ventral striatum region, and it turned out that the ventral capsule was the key: It was the white-matter DBS that seemed to provide the best responses in patients. DBS electrodes have four contacts, and it was the white-matter contacts as opposed to the gray-matter contacts that resulted in the best response in terms of focus and alertness in patients with AD.

Medscape: Can you summarize your findings?

Dr Scharre: We looked at the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), a typical outcome measure in many AD trials. It measures cognition, memory, and function. Using CDR-SB, two of the three patients performed statistically significantly better than a matched group from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study who did not undergo DBS; we didn't have any sham control. This was an open-label pilot trial.

Each patient was individualized in terms of their DBS programming to achieve what we felt gave their best results. All three patients did better than their matched ADNI group, and two of the three did significantly better. One patient was young and homozygous for APOE and so may not have been the ideal candidate for this study.

The US Food and Drug Administration has allowed 10 patients for this trial, so the plan is to study another seven patients. So in the future, we'll focus on more typical cases of AD.

Medscape: Do you envision DBS as being applied to multiple areas of the brain in patients with AD?

Dr Scharre: It's possible. However, you'll have more wires in the brain, which could be problematic. I think you would have to weigh the effects of multiple surgeries and multiple electrodes. Each electrode has four contacts, so if you have more than two electrodes on both sides in different brain areas, it could be a bit much.

It's possible that certain patients (perhaps with different cognitive or behavioral problems) might do better with stimulation in particular areas. The reason we targeted the frontal lobes was because it is an important area governing behavior.

After a few years, one of our three study patients requested that her stimulation be lowered, so I dropped it by 30%. Within a day, her husband called, saying, "Please, we want it back up." Without the full voltage applied, she became very apathetic.

Medscape: So maybe this approach would be best for a patient with significant affective or attention symptoms, as opposed to a patient with primarily memory loss?

Dr Scharre: Maybe yes. Our frontal lobe stimulation didn't help the patient's memory functioning. However, I think stimulating the frontal circuits really helped the patients and their caregivers, particularly with regard to improving the patient's focus, attention, and problem-solving skills.

We think that DBS of a frontal target is worthwhile to pursue further.


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