In patients with mild Alzheimer's disease (AD), deep brain stimulation (DBS) modulates specific brain circuits important in memory and is safe, according to results of the first phase 1 study of DBS for AD, published online July 30 in the Annals of Neurology.
In addition, cognitive tests, including the AD Assessment Scale cognitive subscale (ADAS-Cog) and the Mini-Mental State Examination (MMSE) suggested possible improvements and/or slowing in the rate of cognitive decline in some patients, the study team reports.
"We have been able to see that 3 of the 6 patients have deteriorated less than one would have expected so DBS is also potentially useful in the treatment of Alzheimer's," Andres M. Lozano, MD, PhD, FRCSC, of the University of Toronto, Toronto Western Research Institute, in Ontario noted in a telephone interview with Medscape Medical News.
Ronald C. Petersen, MD, PhD, who was not involved in the study, told Medscape Medical News: "The fact that they were able to affect a memory-relevant system in the brain is interesting and that's a good thing, but to say that this could be a treatment for Alzheimer's disease I think is probably premature; that's a whole other kettle of fish."
Dr. Petersen is director of the Alzheimer's Disease Research Center at the Mayo Clinic, Rochester, Minnesota, and a member of the American Academy of Neurology.
From Parkinson's to Depression to AD
In this phase 1 study, Dr. Lozano said he and his colleagues leveraged their experience using DBS in Parkinson's disease and depression. "We thought just as you can stimulate circuits that control movement or mood, it might also be possible to drive under performing circuits that control cognitive function and memory in patients with Alzheimer's," he explained.
The study involved 6 patients (2 female, 4 male) who met National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association diagnostic criteria for probable (mild) AD. The subjects had a mean MMSE score at baseline of 22.3. Their mean age was 60.7 years. Two were receiving ongoing treatment with donepezil, 1 with donepezil plus memantine, 2 with reminyl, and 1 with rivastigmine.
All patients received DBS stimulation to the fornix/hypothalamus region at 3.0 to 3.5 V with the frequency set at 130 Hz and the pulse width at 90 microseconds. Treatment lasted for 12 months. The fornix, the study authors explain, constitutes the major inflow and output pathway from the hippocampus and medial temporal lobe. Its importance in memory function is supported by studies in animals and humans showing that lesions in this area produce memory deficits.
With the targets identified, electrodes were implanted bilaterally with fluoroscopic guidance while the patient was awake. They were discharged 1 to 3 days later with stimulators turned off and returned 2 weeks later to have the stimulators turned on.
"Strong Biological Effects"
Using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), the researchers say they observed "early and striking" reversal of impaired glucose metabolism (relative to baseline) in temporal and parietal cortical areas in all patients 1 month and 1 year after DBS treatment.
"By placing electrodes in the brain circuits that regulate memory," Dr. Lozano added, "we were able to show that we can drive the activity of these circuits; we can reestablish glucose utilization in the temporal and parietal lobes. In Alzheimer's disease, glucose usage is impaired and we were able to restore that, and that restoration lasts at least 1 year, which is as far as we have looked," he noted.
There was also evidence that DBS activated the brain's default mode network. Reduced default network activity has been seen in AD patients, the study team points out, perhaps as a consequence of amyloid deposition or through other mechanisms responsible for some of the cognitive deficits in AD.
"With the caveat that this pilot trial is open label and uncontrolled," note the researchers, there was also a suggestion that fornix/hypothalamic stimulation could have benefits on recall and recollection. The improvement or reduced decline in the memory-related measures of the ADAS-Cog scores, when they occurred, correlated with increased glucose metabolism.
No Serious Adverse Events
The surgery was well tolerated, the study authors note; stimulation-related adverse effects were autonomic and cardiovascular in nature and occurring only at high stimulation settings. In dose-finding tests, 5 of 6 patients experienced sensations of warmth, flushing, or sweating at the upper levels of stimulation (7 to 10 V), and 3 experienced increased heart rate and blood pressure.
Chronic stimulation settings were chosen at levels of approximately 50% of the voltage threshold for adverse effects. None of the study subjects experienced sleep problems, weight changes, hypothalamic dysfunction, or metabolic or endocrine abnormalities after 1 year.
Dr. Lozano and his colleagues conclude that the findings in this phase 1 study demonstrating safety and biological effects of DBS in AD are "sufficiently compelling to warrant a more thorough appraisal of the possible therapeutic benefits of this strategy in AD." A phase 2 multicenter trial is now in the planning stages.
Dr. Petersen also thinks further study is worthwhile, "especially earlier in the disease process, the mild cognitive impairment stage, where a memory impairment is the only feature," he told Medscape Medical News. "Could electrical stimulation of the relevant regions of the brain elicit a neurochemical response — for example, brain-derived growth factors — and could that could help with neurogenesis. I think it's worthwhile pursuing further."
The study was supported by the Neurosurgical Research and Education Foundation, the Dana Foundation, and the Krembil Neuroscience Discovery Fund. Dr. Lozano holds intellectual property in the field of DBS. The study authors have disclosed no relevant financial relationships. Dr. Petersen has disclosed no relevant financial relationships.
Ann Neurol. Published online July 30, 2010.
