A multicenter phase 2 study showed that some patients with mild Alzheimer's disease (AD) who received deep brain stimulation of the fornix (DBS-f) experienced an increase in cerebral glucose metabolism, and some patients experienced a slowing of cognitive decline.
These positive effects were seen only in patients aged 65 years and older, not in younger patients.
Nevertheless, the findings are encouraging, said lead researcher Andres Lozano, MD, PhD, professor and chairman, Department of Neurosurgery, University of Toronto, Canada.
"These findings indicate that we are headed in the right direction with our research on DBS as a treatment of Alzheimer's disease. In AD, certain areas of the brain shut down and no longer metabolize glucose to the normal level, and we hope that by stimulating the circuits in the brain that are involved, that we can restore function within the fornix and that that in turn will lead to improvement in the signs and symptoms of Alzheimer's," Dr Lozano told Medscape Medical News.
The study was published online July 18 in the Journal of Alzheimer's Disease.
Age a Predictor of Response?
Dr Lozano and his group conducted an earlier phase 1 study involving six patients with Alzheimer's disease. In that study, in some patients who received constant DBS to the fornix, which is a major fiber bundle in the brain's memory circuit, there was an increase in hippocampal volume after 1 year.
The current phase 2 study included 42 patients aged 45 to 85 years. Twelve patients were younger than 65 years; 30 were 65 years of age or older.
The patients had mild dementia with global Clinical Dementia Rating (CDR) scale scores of 0.5 or 1 and Alzheimer's Disease Assessment Scale–11 (ADAS-Cog 11) scores of 12 to 24 at baseline.
All patients were taking stable doses of donepezil (Aricept, Eisai Inc), galantamine (Razadyne, Janssen Pharmaceuticals, Inc), or rivastigmine (Exelon, Novartis Pharmaceutical Corporation) for at least 2 months prior to the start of the study.
The patients were implanted with DBS electrodes directed at the fornix. They were then were randomly assigned to receive either active or sham stimulation and were monitored for 12 months. Once follow-up was complete, the electrodes were turned on for all patients.
In addition to evaluating the safety of DBS-f, the investigators measured changes in cognitive function using the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating–Sum of Boxes (CDR-SB) scales at 6 and 12 months.
Secondary clinical outcomes at 6 and 12 months included the California Verbal Learning Test, Second Edition (CVLT-II), the Alzheimer's Disease Cooperative Study Activities of Daily Living scale (ACDS-ADL), and the Neuropsychiatric Inventory (NPI).
Changes in cerebral glucose metabolism were assessed with [18F]-2-deoxy-2-fluoro-D-glucose positron emission tomography (FDG-PET).
Overall, at 12 months, there was no significant difference between the patients who were receiving stimulation and those who were not. For both groups, changes in scores on the ADAS-Cog 13 and the CDR-SB were similar; both showed comparable declines.
he same result was seen for the secondary clinical measures.
However, in a post hoc subgroup analysis, older patients appeared to derive some benefit from DBS, with those in the active, or "on," stimulation group showing less decline in both ADAS-Cog 13 and CDR-SB scores.
The difference in worsening of ADAS-Cog-13 scores in patients aged 65 years and older who received stimulation vs those who received no stimulation was 4.5 + 2.0 points at 9 months and 4.1 + 2.6 at 12 months.
A similar benefit was observed in the CDR-SB scores in older patients.
A similar trend for benefit for older patients was seen with regard to FDG-PET for glucose metabolism. Patients younger than 65 years showed a decrease in metabolism while both "on" and "off" stimulation, whereas patients aged 65 years and older showed increased metabolism while "on" stimulation that was 14% to 20% greater than that observed in the group as a whole at 6 and 12 months.
"This was an exploratory study, so we didn't have a fixed number of patients and a set hypothesis we were testing. It was to see whether there might be some patients who might respond," said Dr Lozano.
He explained how increasing glucose metabolism could be of benefit to patients with AD.
"These areas of the brain are underperforming. It's as if the lights are dim in some areas of the brain. They are shut down. We are trying to turn them back on. We think that the symptoms come because these circuits are underperforming, so we would like to boost the activity of these circuits using electricity to see if that, in turn, restores the cognitive function of patients," Dr Lozano said.
Interesting, Intriguing
Commenting on the findings for Medscape Medical News, Gregory A. Jicha, MD, PhD, professor of neurology, Alzheimer’s Disease Center, University of Kentucky, in Lexington, described the study as "interesting."
"I was exposed to it very early on in the development process, when [the investigators] were treating a woman for an overeating disorder, and as they were aiming for the part of the brain that controls appetite, they missed by a little bit and got close to the fornix, and what happened was her memory became close to photographic with the stimulator there.
"That really intrigued them and got them to think that the DBS stimulating that fornix is going to turn on the memory circuits that are turning down in Alzheimer's disease, in much the same way we use DBS to turn back on motor circuits that are shutting down in Parkinson's disease."
Dr Jicha noted that he found the FDG-PET data that show increased metabolic activity "intriguing."
"We know that the health of nerve cells is critically dependent on their activity, and the fact that they were able to show in the older subjects effects that persisted to 1 year is intriguing. That raises interest in determining how stimulating one area of the brain can have very distant effects on other areas of the brain, something that's not really been looked at in Parkinson's disease per se," he said.
The study raises important questions, Dr Jicha added.
"For one, why do the elderly appear to benefit while younger Alzheimer's disease patients do not appear to benefit from DBS? The researchers say they feel that the elderly may have a less aggressive form of disease. That still needs to be determined, especially since their study population was really a mild disease population.
"Also, there was a very small number of subjects. So is that finding a fluke? Is the negative effect seen in the younger folks a real effect or is the post hoc positive effect in the older individuals really what the effect will turn out to be when larger populations are studied?
"I think that they've raised some interesting points, but clearly we haven't definitively proven that deep brain stimulation either is beneficial or is not beneficial on the basis of the results of this study. We're left with that lingering question. This appears to be a safe way to approach the disease, but we always watch for post hoc analyses because the study was not designed for that."
The study was supported by the National Institute on Aging, the Federal Economic Development Agency for Southern Ontario, and Functional Neuromodulation Ltd. The authors' financial relationships with industry are listed in the original article. Dr Jicha has disclosed no relevant financial relationships.
http://www.medscape.com/viewarticle/866489?src=wnl_edit_tpal#vp_1
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