By Karen Blum
John's Hopkins
Date: 03/21/2017

When neuropsychologist Gwenn Smith was on staff at the University of Toronto, she worked on deep brain stimulation of Alzheimer’s patients with neurosurgeon Andres Lozano.

DBS, in which a medical device is implanted into the brain to stimulate a particular circuit, is used to control tremors in Parkinson’s disease and is under investigation for managing depression
and chronic pain, but its application in Alzheimer’s was novel.

For their pilot, in which DBS was tested in six patients to target the fornix, a bundle of nerve fibers involved in brain memory circuits, Smith analyzed PET scans to study cerebral glucose metabolism to assess safety of the DBS procedure. “Usually, over a 1-year course of Alzheimer’s disease, a decrease in metabolism is observed that correlates with memory getting worse,” Smith explains. Instead, their study observed a sustained increase in glucose metabolism of the brain over one year.

After Smith moved to Johns Hopkins in 2008, she suggested Lozano as the inaugural speaker for the Michael M. Ossoff Visiting Lectureship in Memory Disorders and Alzheimer’s Disease, and introduced Lozano to psychiatrist Constantine Lyketsos. The trio collaborated on a multi-center phase II study of DBS in 42 Alzheimer’s disease patients, further demonstrating safety and a potential benefit for patients over age 65. The study group included an interdisciplinary team of psychiatrists, neurologists, neurosurgeons and neuropsychologists. The work, published last fall in the Journal of Alzheimer’s Disease, was also presented at the Alzheimer’s Association International and Clinical Trials on Alzheimer’s Disease conferences in 2015.

Their study enrolled patients ages 45-85 with mild Alzheimer’s disease. All had caregivers who could reliably report their activities and functioning, and all were taking a stable dose of a cholinesterase inhibitor medication. After the participants were implanted with electrodes, half were randomly assigned to receive continuous stimulation for one year, while the other half received no stimulation. Investigators measured cognitive function and cerebral glucose metabolism.

"Although there were no differences in cognitive outcomes for participants as a whole, in analyses limiting the sample to those 65 and older," says Smith, “there was a trend for cognitive benefit, or even stability, in the older Alzheimer’s patients who were treated with DBS. They showed greater increases in cerebral glucose metabolism, compared with the older patients not treated with DBS. This was not seen in the younger patients.”

Additional analyses of the data are ongoing, some suggesting that stimulation may cause an increase in the volume of the hippocampus, where early Alzheimer’s pathology surfaces.

It’s not clear why younger patients didn’t fare as well. “We hypothesize that an effect in younger patients would be more difficult to detect because both glucose metabolism and cognition decline more rapidly than in older patients,” says Smith. still, “the sense is the treatment is still worth pursuing, but we need to learn more about how to optimize DBS for individual patients, as is well established in Parkinson’s.”

In Parkinson’s disease, clinicians implanting electrodes can determine which contact is more effective by testing the contacts and seeing immediately that if they stimulate in a particular place, tremors stop. In Alzheimer’s disease, explains Smith, it’s not that simple: “We need to develop methods to detect short-term improvement in memory, which is challenging. We also need to learn more about the mechanisms of action of DBS so that we can develop biomarkers to predict treatment response.”

The team is working to define parameters for its next study. Their study enrolled patients ages 45-85 with mild Alzheimer’s disease. All had caregivers who could reliably report their activities and functioning, and all were taking a stable dose of a cholinesterase inhibitor medication. After the participants were implanted with electrodes, half were randomly assigned to receive continuous stimulation for one year, while the other half received no stimulation. Investigators measured cognitive function and cerebral glucose metabolism.

"Although there were no differences in cognitive outcomes for participants as a whole, in analyses limiting the sample to those 65 and older," says Smith, “there was a trend for cognitive benefit, or even stability, in the older Alzheimer’s patients who were treated with DBS. They showed greater increases in cerebral glucose metabolism, compared with the older patients not treated with DBS. This was not seen in the younger patients.”

Additional analyses of the data are ongoing, some suggesting that stimulation may cause an increase in the volume of the hippocampus, where early Alzheimer’s pathology surfaces.

It’s not clear why younger patients didn’t fare as well. “We hypothesize that an effect in younger patients would be more difficult to detect because both glucose metabolism and cognition decline more rapidly than in older patients,” says Smith. Still, “the sense is the treatment is still worth pursuing, but we need to learn more about how to optimize DBS for individual patients, as is well established in Parkinson’s.”

In Parkinson’s disease, clinicians implanting electrodes can determine which contact is more effective by testing the contacts and seeing immediately that if they stimulate in a particular place, tremors stop. "In Alzheimer’s disease," explains Smith, "it’s not that simple: We need to develop methods to detect short-term improvement in memory, which is challenging. We also need to learn more about the mechanisms of action of DBS so that we can develop biomarkers to predict treatment response.”

The team is working to define parameters for its next study.

-hopkinsmedicine.org