Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation

Article type: Research Article

Authors: Leoutsakos, Jeannie-Marie S.^{a; *} | Yan, Haijuan^a | Anderson, William S.^b | Asaad, Wael F.^c | Baltuch, Gordon^d | Burke, Anna^e | Chakravarty, M. Mallar^f | Drake, Kristen E.^g | Foote, Kelly D.^h | Fosdick, Lisa^g | Giacobbe, Peterⁱ | Mari, Zoltan^j | McAndrews, Mary Patⁱ | Munro, Cynthia A.^a | Oh, Esther S.^a | Okun, Michael S.^h | Pendergrass, Jo Cara^k | Ponce, Francisco A.^l | Rosenberg, Paul B.^a | Sabbagh, Marwan N.^m | Salloway, Stephenⁿ | Tang-Wai, David F.^{i; o} | Targum, Steven D.^g | Wolk, David^p | Lozano, Andres M.ⁱ | Smith, Gwenn S.^a | Lyketsos, Constantine G.^a

Affiliations: [a] Department of Psychiatry and Behavioral Sciences, Memory and Alzheimer’s Treatment Center andAlzheimer’s Disease Research Center, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [b] Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [c] Department of Neurosurgery, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA | [d] Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA | [e] Banner Alzheimer’s Institute, Phoenix, AZ, USA | [m] Department of Neurology, University of Arizona College of Medicine, Phoenix, AZ, USA | [f] Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, QC, Canada; Departments of Psychiatry and Biomedical Engineering, McGill University, Montreal, QC, Canada | [g] Functional Neuromodulation Ltd, Minneapolis, MN, USA | [h] Departments of Neurology and Neurosurgery, University of Florida Center for Movement Disorders and Neurorestoration, Gainesville, FL, USA | [i] Departments of Medicine (Neurology), Surgery (Neurosurgery) Psychologyand Psychiatry, University of Toronto, Toronto, ON, Canada | [j] Department of Neurology, NevadaMovement Disorders Program, Cleveland Clinic Lou Ruvo Center for Brain Health, University of Nevada, Las Vegas, NV, USA | [k] Clintara LLC, Boston, MA, USA | [l] Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA | [m] Alzheimer’s Disease and Memory Disorders Division, Barrow Neurological Institute, St. Joseph’sHospital and Medical Center, Phoenix, AZ, USA | [n] Department of Neurology, Butler Hospital and theAlpert Medical School of Brown University, Providence, RI, USA | [o] University Health NetworkMemory Clinic, University of Toronto, Division of Neurology, Toronto, ON, Canada | [p] Department of Neurology, Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA

Correspondence: [*] Correspondence to: Jeannie-Marie S. Leoutsakos, 5300 Alpha Commons Drive, 4th Floor, Baltimore, MD 21224, USA. Tel.: +1 410 550 9884; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, deep brain stimulation, dementia, delayed start, fornix, treatment

DOI: 10.3233/JAD-180121

Journal: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 597-606, 2018