%0 Journal Article %J J Alzheimers Dis %D 2018 %T Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation. %A Leoutsakos, Jeannie-Marie S %A Yan, Haijuan %A Anderson, William S %A Asaad, Wael F %A Baltuch, Gordon %A Burke, Anna %A Chakravarty, M Mallar %A Drake, Kristen E %A Foote, Kelly D %A Fosdick, Lisa %A Giacobbe, Peter %A Mari, Zoltan %A McAndrews, Mary Pat %A Munro, Cynthia A %A Oh, Esther S %A Okun, Michael S %A Pendergrass, Jo Cara %A Ponce, Francisco A %A Rosenberg, Paul B %A Sabbagh, Marwan N %A Salloway, Stephen %A Tang-Wai, David F %A Targum, Steven D %A Wolk, David %A Lozano, Andres M %A Smith, Gwenn S %A Lyketsos, Constantine G %X

BACKGROUND: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years.

OBJECTIVE: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years.

METHODS: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial.

RESULTS: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants.

CONCLUSION: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

%B J Alzheimers Dis %V 64 %P 597-606 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914028?dopt=Abstract %R 10.3233/JAD-180121 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. %A Lozano, Andres M %A Fosdick, Lisa %A Chakravarty, M Mallar %A Leoutsakos, Jeannie-Marie %A Munro, Cynthia %A Oh, Esther %A Drake, Kristen E %A Lyman, Christopher H %A Rosenberg, Paul B %A Anderson, William S %A Tang-Wai, David F %A Pendergrass, Jo Cara %A Salloway, Stephen %A Asaad, Wael F %A Ponce, Francisco A %A Burke, Anna %A Sabbagh, Marwan %A Wolk, David A %A Baltuch, Gordon %A Okun, Michael S %A Foote, Kelly D %A McAndrews, Mary Pat %A Giacobbe, Peter %A Targum, Steven D %A Lyketsos, Constantine G %A Smith, Gwenn S %X

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 

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.

%B J Alzheimers Dis %V 54 %P 777-87 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567810?dopt=Abstract %R 10.3233/JAD-160017