Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial)

A Two Year Follow-up Including Results of Delayed Activation

Jeannie-Marie S Leoutsakos, Haijuan Yan, William S Anderson, Wael F. Asaad, Gordon Baltuch, Anna Burke, M. Mallar Chakravarty, Kristen E. Drake, Kelly D. Foote, Lisa Fosdick, Peter Giacobbe, Zoltan Mari, Mary Pat McAndrews, Cynthia Munro, Esther Oh, Michael S. Okun, Jo Cara Pendergrass, Francisco A. Ponce, Paul B Rosenberg, Marwan N. Sabbagh & 7 others Stephen Salloway, David F. Tang-Wai, Steven D. Targum, David Wolk, Andres M. Lozano, Gwenn Smith, Constantine G Lyketsos

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)597-606
Number of pages10
JournalJournal of Alzheimer's Disease
Volume64
Issue number2
DOIs
StatePublished - Jan 1 2018

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Deep Brain Stimulation
Alzheimer Disease
Safety
Therapeutics
Electrodes
Age Groups
Placebos

Keywords

  • Alzheimer's disease
  • deep brain stimulation
  • delayed start
  • dementia
  • fornix
  • treatment

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

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

In: Journal of Alzheimer's Disease, Vol. 64, No. 2, 01.01.2018, p. 597-606.

Research output: Contribution to journalArticle

Leoutsakos, J-MS, Yan, H, Anderson, WS, Asaad, WF, Baltuch, G, Burke, A, Chakravarty, MM, Drake, KE, Foote, KD, Fosdick, L, Giacobbe, P, Mari, Z, McAndrews, MP, Munro, C, Oh, E, Okun, MS, Pendergrass, JC, Ponce, FA, Rosenberg, PB, Sabbagh, MN, Salloway, S, Tang-Wai, DF, Targum, SD, Wolk, D, Lozano, AM, Smith, G & Lyketsos, CG 2018, 'Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation', Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 597-606. https://doi.org/10.3233/JAD-180121
Leoutsakos, Jeannie-Marie S ; Yan, Haijuan ; Anderson, William S ; Asaad, Wael F. ; Baltuch, Gordon ; Burke, Anna ; Chakravarty, M. Mallar ; Drake, Kristen E. ; Foote, Kelly D. ; Fosdick, Lisa ; Giacobbe, Peter ; Mari, Zoltan ; McAndrews, Mary Pat ; Munro, Cynthia ; Oh, Esther ; Okun, Michael S. ; Pendergrass, Jo Cara ; Ponce, Francisco A. ; Rosenberg, Paul B ; Sabbagh, Marwan N. ; Salloway, Stephen ; Tang-Wai, David F. ; Targum, Steven D. ; Wolk, David ; Lozano, Andres M. ; Smith, Gwenn ; Lyketsos, Constantine G. / Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial) : A Two Year Follow-up Including Results of Delayed Activation. In: Journal of Alzheimer's Disease. 2018 ; Vol. 64, No. 2. pp. 597-606.
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T2 - A Two Year Follow-up Including Results of Delayed Activation

AU - Leoutsakos, Jeannie-Marie S

AU - Yan, Haijuan

AU - Anderson, William S

AU - Asaad, Wael F.

AU - Baltuch, Gordon

AU - Burke, Anna

AU - Chakravarty, M. Mallar

AU - Drake, Kristen E.

AU - Foote, Kelly D.

AU - Fosdick, Lisa

AU - Giacobbe, Peter

AU - Mari, Zoltan

AU - McAndrews, Mary Pat

AU - Munro, Cynthia

AU - Oh, Esther

AU - Okun, Michael S.

AU - Pendergrass, Jo Cara

AU - Ponce, Francisco A.

AU - Rosenberg, Paul B

AU - Sabbagh, Marwan N.

AU - Salloway, Stephen

AU - Tang-Wai, David F.

AU - Targum, Steven D.

AU - Wolk, David

AU - Lozano, Andres M.

AU - Smith, Gwenn

AU - Lyketsos, Constantine G

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N2 - 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.

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