Why Deep Brain Stimulation Could Offer Hope to People Suffering from Alzheimer’s Disease

Why Deep Brain Stimulation Could Offer Hope to People Suffering from Alzheimer’s Disease

A study on a handful of people with suspected mild Alzheimer’s disease (AD) suggests that a device that sends continuous electrical impulses to specific “memory” regions of the brain appears to increase neuronal activity. Results of the study using deep brain stimulation, a therapy already used in some patients with Parkinson’s disease and depression, may offer hope for at least some with AD, an intractable disease with no cure.

“While our study was designed mainly to establish safety, involved only six people and needs to be replicated on a larger scale, we don’t have another treatment for AD at present that shows such promising effects on brain function,” said the study’s first author, Gwenn Smith, Ph.D., a professor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. The research, published in the Archives of Neurology, was conducted while Smith was on the faculty at the University of Toronto, and will be continuing at Toronto, Hopkins and other U.S. sites in the future. The study was led by Andres M. Lozano, chairman of the Department of Neurosurgery at the University of Toronto.

One month and one year after implanting a device that allows for continuous electrical impulses to the brain, Smith and her colleagues performed PET scans that detect changes in brain cells’ metabolism of glucose, and found that patients with mild forms of AD showed sustained increases in glucose metabolism, an indicator of neuronal activity. The increases, the researchers say, were larger than those found in patients who have taken the drugs currently marketed to fight AD progression. Other imaging studies have shown that a decrease in glucose metabolism over the course of a year is typical in AD. Alzheimer’s disease cannot be precisely diagnosed by brain biopsies until after death.

The team observed roughly 15 percent to 20 percent increases in glucose metabolism after one year of continuous stimulation. The increases were observed, to a greater extent, in patients with better outcomes in cognition, memory and quality of life. In addition, the stimulation increased connectivity in brain circuits associated with memory.

Deep brain stimulation (DBS) requires surgical implantation of a brain pacemaker, which sends electrical impulses to specific parts of the brain. For the study, surgeons implanted a tiny electrode able to deliver a low-grade electrical pulse close to the fornix, a key nerve tract in brain memory circuits. The researchers — most with the University of Toronto — reported few side effects in the six subjects they tested. Just as importantly, says Smith, was seeing that DBS appeared to reverse the downturn in brain metabolism that typically comes with AD.

AD is a progressive and lethal dementia that mostly strikes the elderly. It affects memory, thinking and behavior. Estimates vary, but experts suggest that as many as 5.1 million Americans may have AD and that, as baby boomers age, prevalence will skyrocket. Smith says decades of research have yet to lead to clear understanding of its causes or to successful treatments that stop progression.

The trial of DBS came about, Smith reports, when Lozano used DBS of the fornix to treat an obese man. The procedure, designed to target the regions of the brain involved in appetite suppression, unexpectedly had significant increases in his memory. Inspired, the scientists persisted through rigorous ethical and scientific approvals before their AD phase I safety study could begin.

Smith, who also is director of the Division of Geriatric Psychiatry and Neuropsychiatry at Johns Hopkins Bayview Medical Center, is an authority on mapping the brain’s glucose metabolism in aging and psychiatric disease. It was Smith’s earlier analysis of AD patients’ PET scans that revealed their distinct pattern of lowered brain metabolism. She determined that specific parts of the temporal and parietal cerebral cortex — memory network areas of the brain where AD’s earliest pathology surfaces— became increasingly sluggish with time.

The new study was supported by grants from the Neurosurgical Research and Education Foundation, the Dana Foundation and the Krembil Neuroscience Discovery Fund.

Clifford I. Workman, B.S., of Johns Hopkins also contributed to this research.

There has been a lot of interest lately in the use of deep brain stimulation (DBS), and it is not hard to see why the surgical treatment has been getting so much attention. It has shown promise in treating conditions ranging from obesity to Parkinson’s disease, obsessive compulsive disorder, and treatment-resistant depression. In addition, DBS has been associated with neurogenesis in studies on mice.

A recent study published in the Archives of Neurology reports that DBS appears to increase neuronal activity and connectivity in a handful of patients with suspected mild Alzheimer’s disease. The study, titled “Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in Alzheimer Disease,” states:

Increased connectivity after 1 year of DBS is observed, which is in contrast to the decreased connectivity observed over the course of [Alzheimer's disease (AD) ]. The persistent cortical metabolic increases after 1 year of DBS were associated with better clinical outcomes in this patient sample and are greater in magnitude and more extensive in the effects on cortical circuitry compared with the effects reported for pharmacotherapy over 1 year in AD.

SMITH gwenn2 Why Deep Brain Stimulation Could Offer Hope to People Suffering from Alzheimer’s Disease Medgadget recently had the opportunity to speak with the study’s first author, Gwenn Smith, PhD, a professor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. Working with DBS pioneer Andres Lozano, MD, PhD, Smith and a team of researchers tracked the patients to monitor their cognitive function or memory. “We don’t want to oversell the findings because it was a small sample of individuals but the imaging results were encouraging,” she said. “I think there is some enthusiasm for continuing the study in a larger scale.”

“We also did serial PET scans to look at glucose metabolism in the brain as a measure of brain function to see if there were any changes in metabolism over the course of the one year,” Smith explains. “We picked the metabolism measurements because they are very sensitive to detecting pathology in Alzheimer’s disease and also for detecting changes induced by medication in a variety of illnesses including depression and so forth.”

The researchers chose to monitor glucose, which is the major substrate of fuel to the brain, because it provides an indirect measure of neuronal activity. “Neurons that are working hard use more glucose,” Smith says. “In the opposite case, if there is a region of the brain where there some sort of damage to the brain or pathology leading to either neuronal death or neuronal dysfunction, you see that reflected as lower metabolism.”

In the study, the researchers reported overall increases in glucose metabolism over the course of one year in patients treated with DBS. “If you just studied a group of Alzheimer’s patients and followed them for one year, there would be a reduction in glucose metabolism because of progressive neuronal dysfunction,” Smith says.

“The sort of obvious question that arose was whether the increases in glucose metabolism were related to the clinical outcome—how patients did in terms of overall cognition,” Smith says. To answer that question, the researchers correlated the changes in metabolism to the changes in clinical outcome. “As you would expect, the patients who did a bit better or even stayed the same clinically, had greater increases in metabolism over the course of one year.”

In the study, the researchers also used functional connectivity analysis to monitor changes in the networks of the brain and to analyze the relationship between different brain regions. “If you did a functional connectivity analysis in Alzheimer’s disease, you would see a decrease [in connectivity],” Smith explains. “You would find that the regions aren’t really working together as they are in normal function.” The study reported an increase in connectivity in patients treated with DBS and that the networks were interacting in a pattern more consistent with what is seen in the normal brain.

The Inspiration for the Study

The idea for the study initially came about when Andres Lozano, MD, PhD was investigating the use of DBS of the fornix to treat an obese individual. Surprisingly, the patient demonstrated significant improvement in his memory. That patient did not have a memory problem. “What happened was when they were doing the implantation in this area of the brain that they were doing serial memory testing just to make sure that they weren’t producing an adverse effect on memory,” Smith says. “What was really remarkable is that they showed this improvement in memory—almost a doubling of performance in a verbal learning test.”

“This individual actually showed this striking improvement in memory and also in the operating room when they turned on the electrodes, he began to vividly recall memories of his, which were later confirmed by family members,” Smith says. “Dr. Lozano saw this striking improvement in memory and they had the idea to try this intervention in Alzheimers’ disease.”

Source : http://www.hopkinsmedicine.org/news/media/releases/deep_brain_stimulation_may_hold_promise_for_mild_alzheimers_disease

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