Deep brain stimulation (DBS) of the frontal lobe may slow decline in executive function in patients with mild or early-stage Alzheimer's disease (AD), a small study suggests.

Investigators found that in AD patients who received DBS, decline in performance was slowed in comparison with matched control persons, with only minimal and transient adverse effects.

"The take-home message is that DBS in Alzheimer's patients appears to be safe and that targeting the frontal site appears to provide symptomatic help with executive impairments," lead author Douglas W. Scharre, MD, director of the Division of Cognitive Neurology, the Ohio State University Wexner Medical Center, Columbus, told Medscape Medical News.

"With further study, if DBS at this site can be found to improve decision making, problem solving, planning, organization, and focused attention, that will greatly help patients and caregivers trying to care for them," he said.

The study was published online January 30 in the Journal of Alzheimer's Disease.

Logical Approach

DBS implants have shown benefit for patients with Parkinson's disease. Some reports have suggested "that improving neuronal metabolic rate and activating neurons by brain stimulation techniques including DBS can improve cognitive, behavioral, and functional impairments," the authors write.

In previous research on DBS in AD in which memory circuits of the fornix were targeted, patients showed improvements in memory. In research in which the nucleus basalis of Meynert was targeted, cognitive scores were stable or improved for some patients.

Although memory impairments are an important target for treatment, it is the deficits in executive abilities, decision making, and problem solving that lead to functional impairment and that increase the need for supervision, the authors note.

Targeting the regions of the brain associated with executive function has the potential to yield improvement in these areas, they add.

The researchers used DBS to "specifically modulate frontal networks involved in cognition and behavior." They regarded this as a "logical treatment approach for AD patients," because "AD neurodegeneration propagates over time along neural networks that link the entorhinal cortex to limbic structures (including ventral striatum and nucleus accumbens) and to frontal and posterior neocortex," they write.

For this reason, DBS that targets the ventral capsule/ventral striatum (VC/VS), which play an important role in executive and behavioral self-regulation, shows promise as a potential target of neuromodulation in AD.

"We need better treatments for AD patients, and there is some evidence that if you can keep your mind stimulated with physical and mental exercises, you may be able to slow down the course of the condition," said Dr Scharre.

"We decided to try DBS as a way to keep the brain stimulated and hopefully provide symptomatic improvement, and we chose our target to be in the frontal lobes to help patients with executive abilities," he added.

To investigate the impact of DBS on these regions, the researchers conducted a phase 1, nonrandomized, open-label study of DBS implantation at the VC/VS region.

Attention Enhanced

The researchers recruited three participants (aged 45 to 85 years), who met criteria for AD and probable dementia and who showed evidence of an AD pathophysiologic process. Such evidence was based on results of amyloid positron-emission tomography (PET) scanning and cerebrospinal fluid amyloid--42 and tau assessment.

The participants had Mini–Mental State Examination (MMSE) scores of 18 to 24, and all had received a stable dose of a cholinesterase inhibitor and memantine for at least 120 days prior to implantation. In addition, all participants were medically stable.

Each participant was matched to control persons from the Alzheimer's Neuroimaging Initiative study (n = 11, n = 78, and n = 7). These control persons had been assessed at least twice during the first 24 months of enrollment and were matched according to MMSE scores, age, and ApoE4 status.

The surgical procedure consisted of "standard stereotactic implantation of DBS electrodes bilaterally in the VC/VS."

In the patients who underwent DBS, the stimulator was turned on 4 to 6 weeks following implantation. The stimulation parameters were titrated to their final settings during the following 12 weeks. DBS then continued without change for the next 12 months, after which new adjustments were allowed.

Participants received a 2-deoxy-2-[18 F]fluoro-D-glucose (FDG) PET scan at baseline before surgery, 1 month after surgery before stimulation titration, immediately after stimulation titration, after 12 months, and then after 18 months of brain stimulation.

Participants also received an extensive neuropsychiatric assessment of cognition, auditory learning, word recall, depression, and activities of daily living. The primary outcome measure was Clinical Dementia Rating–Sum of Boxes (CDR-SB), a "widely used global measure summating six domains of cognitive and functional performance," the authors state.

The assessment protocol was conducted at baseline, before surgery, after surgery, before stimulation titration, and immediately after stimulation titration. It was then repeated approximately every 3 months.

The researchers applied score trajectory slopes and found that, compared to the matched comparison groups, all DBS recipients experienced less decline in performance; two patients showed "meaningfully" less decline over time, as determined on the basis of CDR-SB scores.

"We achieved our primary study objective for those participants," the authors report.

Participants showed either minimal changes or increased metabolism on FDG-PET in the frontal cortical regions after long-term DBS at the VC/VS target.

Notably, the treatment was well tolerated, with no serious or permanent adverse effects. Stimulation-induced side effects were transient and reversed with adjustments in setting.

Participants and caregivers "consistently reported feelings of improved energy, focus, alertness, and attention with DBS," the authors recount.

Dr Scharre regards the procedure as a "success," saying that he and his group "had hoped the procedure would be safe and that we would reduce the rate of decline in our Alzheimer's patients, which is what we found in our three subjects."

The "most surprising findings were the enhancement in focused attention and problems solving that was observed," he said.

"This, I believe, drove the improvement in activities of daily living," he added.

"Encouraging" Results

Commenting on the study for Medscape Medical News, Gwenn S. Smith, PhD, Richman Professor of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, who was not involved in the study, said that it "provides preliminary support for further investigation of DBS that targeted a circuit in the brain that has been investigated in treatment-resistant depression and other psychiatric conditions."

She added that the results are "encouraging and suggest further studies of DBS of this target to evaluate cognitive and behavioral outcomes."

Dr Scharre said that his group "hopes to secure funding to consider a larger, possibly multicenter trial to better determine if this treatment is helpful in a larger groups of patients."

The study was supported by the Ohio State University Center for Neuromodulation, by the Wright Center of Innovation in Biomedical Imaging, and by philanthropic donations. Dr Scharre has disclosed no relevant financial relationships. The other authors' disclosures are available online. Dr Smith has received grant support from Functional Neuromodulation, Inc, and the National Institutes of Health to study DBS in patients with Alzheimer' s disease.

J Alzheimers Dis. Published online January 30, 2018. Abstract