A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease

Abstract

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown.

Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD).

Methods: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation.

Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism.

Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

Keywords: Keywords: Alzheimer’s disease; deep brain stimulation; dementia; fornix.

Fig.1

Change in ADAS-Cog 13 and CDR by treatment groups (all subjects) and effect of patient age on clinical outcome. A decreased score (down on the y axis) indicates improvement while an increased score (up on the y axis) indicates worsening. a) Change in ADAS-Cog13 over 12 months by treatment group in all subjects (n = 42). b) Change in CDR-SB over 12 months by treatment group in all subjects (n = 42). c) Change in ADAS-Cog13 over 12 months by treatment group in patients <65 (n = 12). d) Change in CDR-SB over 12 months by treatment group in patients <65 (n = 12). e) Change in ADAS-Cog13 over 12 months by treatment group in patients≥65 (n = 30). f) Change in CDR-SB over 12 months by treatment group in patients≥65 (n = 30). Values shown on graphs are mean ± standard error.

Fig.2

PET Cerebral glucose metabolism images by treatment groups. Summed Axial Images of standardized update values (SUV). BL, baseline, 6 months or 12 months after continuous bilateral deep brain stimulation (DBS) of the fornix. Representative axial sections show that patients in the “Off” group had stable or declining cortical glucose metabolism over time. In patients assigned to “On,” there were increases in brain metabolism at 6 months, particularly in the temporal and parietal regions, that were sustained at 12 months. The color scale indicates SUVs, with red showing highest, yellow and green intermediate and blue lowest. The patients remained on the same medications from baseline to 12 months while receiving DBS.