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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)777-787
Number of pages11
JournalJournal of Alzheimer's Disease
Volume54
Issue number2
DOIs
StatePublished - Sep 6 2016

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Brain Fornix
Deep Brain Stimulation
Alzheimer Disease
Glucose
Brain
Cognition
Electric Stimulation
Dementia
Safety

Keywords

  • Alzheimer's disease
  • deep brain stimulation
  • dementia
  • fornix

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. / Lozano, Andres M.; Fosdick, Lisa; Chakravarty, M. Mallar; Leoutsakos, Jeannie-Marie S; Munro, Cynthia; Oh, Esther; Drake, Kristen E.; Lyman, Christopher H.; Rosenberg, Paul B; Anderson, William S; Tang-Wai, David F.; Pendergrass, Jo Cara; Salloway, Stephen; Asaad, Wael F.; Ponce, Francisco A.; Burke, Anna; Sabbagh, Marwan; Wolk, David A.; Baltuch, Gordon; Okun, Michael S.; Foote, Kelly D.; McAndrews, Mary Pat; Giacobbe, Peter; Targum, Steven D.; Lyketsos, Constantine G; Smith, Gwenn.

In: Journal of Alzheimer's Disease, Vol. 54, No. 2, 06.09.2016, p. 777-787.

Research output: Contribution to journalArticle

Lozano, AM, Fosdick, L, Chakravarty, MM, Leoutsakos, J-MS, Munro, C, Oh, E, Drake, KE, Lyman, CH, Rosenberg, PB, Anderson, WS, Tang-Wai, DF, Pendergrass, JC, Salloway, S, Asaad, WF, Ponce, FA, Burke, A, Sabbagh, M, Wolk, DA, Baltuch, G, Okun, MS, Foote, KD, McAndrews, MP, Giacobbe, P, Targum, SD, Lyketsos, CG & Smith, G 2016, 'A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease', Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 777-787. https://doi.org/10.3233/JAD-160017
Lozano, Andres M. ; Fosdick, Lisa ; Chakravarty, M. Mallar ; Leoutsakos, Jeannie-Marie S ; Munro, Cynthia ; Oh, Esther ; Drake, Kristen E. ; Lyman, Christopher H. ; Rosenberg, Paul B ; Anderson, William S ; Tang-Wai, David F. ; Pendergrass, Jo Cara ; Salloway, Stephen ; Asaad, Wael F. ; Ponce, Francisco A. ; Burke, Anna ; Sabbagh, Marwan ; Wolk, David A. ; Baltuch, Gordon ; Okun, Michael S. ; Foote, Kelly D. ; McAndrews, Mary Pat ; Giacobbe, Peter ; Targum, Steven D. ; Lyketsos, Constantine G ; Smith, Gwenn. / A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. In: Journal of Alzheimer's Disease. 2016 ; Vol. 54, No. 2. pp. 777-787.
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AU - Munro, Cynthia

AU - Oh, Esther

AU - Drake, Kristen E.

AU - Lyman, Christopher H.

AU - Rosenberg, Paul B

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AU - Foote, Kelly D.

AU - McAndrews, Mary Pat

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N2 - 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.

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