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Deep Brain Stimulation: New Promise in Alzheimer Disease and Depression?: Page 2 of 4

Deep Brain Stimulation: New Promise in Alzheimer Disease and Depression?: Page 2 of 4

Alzheimer disease

“There have been several failed medication trials for Alzheimer disease recently,” Giacobbe noted. “Our current therapeutics are really only palliative, they don’t address the core issue of plaques and tangles, so there is a great need for some new treatments.”

DBS’s potential for treating Alzheimer disease was discovered “quite unexpectedly” by Lozano’s team while they were using fornix/hypothalamus DBS to treat a patient with morbid obesity. The patient experienced memory improvement.4

These findings led Laxton, Lozano, and colleagues at the University of Toronto to develop a phase 1 trial of fornix/hypothalamus DBS in 6 patients with early Alzheimer disease who continued to receive medication treatment.5 The study involved bilateral DBS implantation, detailed neuropsychological and neurological testing, and brain imaging to detect alterations in brain activity induced by stimulation. The patients received continuous stimulation for 12 months.

Increased glucose metabolism was observed in the temporal and parietal cortical areas at 1 month in all patients and was sustained in most of the affected areas at 1-year follow-up. Some patients showed possible improvements or slowing of anticipated cognitive decline at 6 and 12 months based on the cognitive subscale of the Alzheimer Disease Assessment Scale and the Mini-Mental State Examination (MMSE). For example, the rate of decline on the MMSE in the 11 months preceding surgery was 2.8 compared with 0.8 in the 11 months after surgery.6

In September’s Archives of Neurology, Lozano’s research team analyzed results for 5 of the 6 patients in the phase 1 trial.7 The 5 had been studied with the same PET scanner. The scans measured regional cerebral glucose metabolism preoperatively, after 1 month, and after 1 year of continuous DBS.

The researchers’ functional connectivity analysis demonstrated increased cerebral metabolism in cortical-subcortical and cortical-hippocampal networks.

“The persistent cortical metabolic increases after 1 year of DBS were associated with better clinical outcomes in this patient sample and were greater in magnitude and more extensive in the effects on cortical circuitry compared with the effects reported for pharmacotherapy over 1 year in Alzheimer disease,” the team concluded.

Currently, a double-blind, randomized, controlled study is under way at 6 sites in North America to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable Alzheimer disease.

“We are comparing active stim­ulation to sham stimulation,” Giacobbe said. The study, he explained, will help answer the questions of whether it is the active stimulation that is helping patients get better or other factors, such as coming to appointments and related nonspecific effects.

Called ADvance, the proof-of-concept study initially involves 20 people aged 55 to 80 years. It will compare the effects of DBS turned on with those observed with the system turned off. The patients will undergo regular physiological, psychological, and cognitive assessments for a year, at which time those patients in the “off” group will be eligible to have the system activated. The study sponsor is Functional Neuromodulation Ltd, of which Lozano is a company co-founder and chair of its scientific advisory board; Medtronic is providing DBS devices.

“All sites are actively recruiting patients,” said Dan O’Connell, company co-founder and chief executive officer. The 6 sites are Toronto Western Hospital; Johns Hopkins Bayview Medical Center in Baltimore; the Banner Alzheimer’s Institute in Phoenix; the University of Florida Center for Movement Disorders and Neurorestoration at Gainesville; the University of Pennsylvania; and Brown University in Providence, RI.

The 20 patients should be enrolled and implanted with the device by the second quarter of next year, O’Connell said, noting, “If all goes well and DBS is found to be reasonably safe and effective, the study may be expanded to 40 patients.”

Asked about informed consent concerns, Giacobbe said the sites are recruiting patients with early Alzheimer disease only, because of the complexities of consent and because intervening early in the disease’s course will facilitate maximization of patients’ functioning.


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