Deep Brain Stimulation for Alzheimer’s Not for Everyone

10/17/2018

Patients with late-onset Alzheimer’s may show some long-term benefit, but none for early-onset

In a report of the phase II ADvance clinical trial, Johns Hopkins researchers report that people diagnosed under age 65—those with early-onset Alzheimer’s disease—didn’t benefit from deep brain stimulation. Their findings appeared in the July issue of the Journal of Alzheimer’s Disease.

“Our results suggest that as we look at deep brain stimulation as a treatment for Alzheimer’s disease, we should probably focus on those over 65, which is the bulk of people with Alzheimer’s,” says Jeannie-Marie Leoutsakos, Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “Over the years there’s been little in the pipeline that is promising for Alzheimer’s, so there are now plans in the works for a larger trial only including people over 65.”

Deep brain stimulation has proved an effective therapy for easing the motor symptoms of people with Parkinson’s disease. The researchers are hopeful that the therapy could be used for other types of neurodegenerative diseases such as Alzheimer’s disease.

At the beginning of the small trial, 42 people with mild Alzheimer’s had deep brain stimulation devices implanted in the brain in a spot between the hippocampus, which is responsible for learning and memory, and the hypothalamus, which regulates body temperature, hunger and thirst. Participants included people with early-onset and late-onset Alzheimer’s because researchers didn’t think initially that one group would be more likely than the other to be responsive. Twelve participants were under 65 with early-onset Alzheimer’s and 20 participants were over 65. Half the devices were turned on at the beginning of the first year; the other half of the devices were turned on after a year. Each device delivered continuous stimulation at 130 hertz between 3 and 3.5 volts—a similar stimulation successfully used on people with Parkinson’s disease.

To track clinical dementia rating and progression of disease, the researchers used two questionnaires that looked at word memory, cognitive tasks, judgment and personal care. The researchers say halting or reversing declining cognition is a tall order and unlikely, but even slowing or delaying decline would have significant public health impacts in terms of care costs and patient and family quality of life. They also used PET scans to track changes in the participants’ brain structure.

The researchers didn’t see any benefit such as slowing of cognitive decline for those participants under age 65. They still declined on the tests at the same rate as those people who hadn’t had their devices turned on and forgot words in the test as often. There is a possibility of benefit among participants over 65 in that they didn’t seem to be declining as fast as those without the device turned on, but they won’t know unless they complete a larger study.

As to why there wasn’t a clear benefit in those with early-onset Alzheimer’s, the researchers suggest that it’s possible that the participants may have been too far into the disease progression to make a difference. It’s possible that the early-onset condition is a different disease progression, and the PET scans in their study did show that younger patients had more deficits in metabolism than the older patients.

Eight participants reported serious adverse events such as falls, fainting, seizures, infection and mental agitation after having the brain implant. According to the researchers, the safety profile is similar to or better than those of medications that are being developed to treat Alzheimer’s disease.

Constantine Lyketsos, M.D., the Elizabeth Plank Althouse Professor of Psychiatry and Behavioral Sciences at The Johns Hopkins University, led the trial along with Andres Lozano, professor and chair of neurosurgery at the University of Toronto. 

Additional authors include Haijuan Yan, William Anderson, Cynthia Munro, Esther Oh, Paul Rosenberg and Gwenn Smith of Johns Hopkins; Wael Asaad and Stephen Salloway of Brown University; Gordon Baltuch and David Wolk of University of Pennsylvania; Anna Burke of University of Arizona; M. Mallar Chakravarty at McGill University; Kristen Drake, Lisa Fosdick and Steven Targum at Functional Neuromodulation Ltd; Kelly Foote and Michael Okun of the University of Florida; Peter Giacobbe, Mary McAndrews and David Tang-Wai of University of Toronto; Jo Cara Pendergrass of Clintara LLC; and Francisco Ponce and Marwan Sabbagh of St. Joseph’s Hospital and Medical Center.

This research is supported by the National Institute on Aging (R01AG042165), Federal Economic Development Agency for Southern Ontario and Functional Neuromodulation Ltd., the sponsor of the ADvance study.

COI: Anderson has consulted for Globus Medical and served on the advisory board of Longeviti, LLC; Foote has grants from Medtronic; Fosdick has stock with her company employer; Giacobbe has consulted for Janssen; Lozano has consulted for Medtronic and Boston Scientific, holds intellectual property in using neuromodulation for Alzheimer’s and has grants from Medtronic and GE Healthcare; Lyketsos has consulted for Astra-Zeneca, Glaxo-Smith Kline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, Abbvie, Janssen, Orion, Otsuka, Astellas and Merck; Mari has consulted for Ipsen; Rosenberg has consulted for Leerink GLG Consulting and has a grant from Lilly Pharmaceuticals; Sabbagh has consulted for Biogen, Grifols, vTv Therapeutics, Bracket, Allergen and Sanofi and has equity in Versanum Inc., Brain Health Inc., Optimal Cognitive Health Company, uMethod Health and receives royalties from Harper Collins; Salloway has consulted for Biogen, Genentech, Axovant, Lilly, Pfizer and Roche; Targum has consulted for Functional Neuromodulation Inc., Methylation Sciences Inc., Navitor, Resilience Therapeutics, Bracket LLC., served as an advisor to Karuna and holds stock in Prana Biotechnology Ltd., Methylation Sciences Inc., Functional Neuromodulation Inc., Resilience Therapeutics, Bracket LLC; and Wolk has consulted for GE Healthcare and has grants from Merck, Eli Lilly and Biogen.


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