Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation
Open accessAbstract
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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In a phase II study with 2 years of follow-up on mild AD patients, DBS targeting the fornix was safe and well tolerated but with no clinical benefits.
“Even if in several murine models, DBS has been shown to improve visual-spatial memory, in a phase II study with 2 years of follow-up on mild AD patients, DBS targeting the fornix was safe and well tolerated but with no clinical benefits [197].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [197]
The Discussion reports a favorable safety profile over two years and no differences between treatment arms on primary clinical outcomes. But “no clinical benefits” is too categorical: the study was not powered to assess efficacy, and post-hoc analyses suggested a possible benefit in participants over 65 (Discussion; page numbers not provided). (LLM, conf=0.86)
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- [15]Holroyd K, Fosdick L, Smith G, Leoutsakos J (2015) Deep brain stimulation targeting the fornix for mild Alzheimer dementia. Access Journal of …. PMC6518401 29914028
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“Even if in several murine models, DBS has been shown to improve visual-spatial memory, in a phase II study with 2 years of follow-up on mild AD patients, DBS targeting the fornix was safe and well tolerated but with no clinical benefits [197].”
Background
- Authors
- Leoutsakos, J.-M. S., Yan, H., Anderson, W. S., Asaad, W. F., Baltuch, G., Burke, A., Chakravarty, M. M., Drake, K. E., Foote, K. D., Fosdick, L., Giacobbe, P., Mari, Z., McAndrews, M. P., Munro, C. A., Oh, E. S., Okun, M. S., Pendergrass, J. C., Ponce, F. A., Rosenberg, P. B., Sabbagh, M. N., Salloway, S., Tang-Wai, D. F., Targum, S. D., Wolk, D., Lozano, A. M., Smith, G. S., & Lyketsos, C. G.
- Affiliations
- Johns Hopkins University (US)
- Brown University (US)
- University of Pennsylvania (US)
- Banner Alzheimer’s Institute (US)
- Douglas Mental Health University Institute (CA)
- Functional Neuromodulation Ltd, Minneapolis, MN, USA
- University of Florida (US)
- University of Toronto (CA)
- Cleveland Clinic (US)
- Clintara LLC, Boston, MA, USA
- Barrow Neurological Institute (US)
- Departments of Medicine (Neurology), Surgery (Neurosurgery) Psychologyand Psychiatry, University of Toronto, Toronto, ON, Canada
- Corresponding author
- Leoutsakos, Jeannie-Marie S.
- ORCID
- Leoutsakos, Jeannie-Marie S.
- Anderson, William S.
- Asaad, Wael F.
- Burke, Anna
- Chakravarty, M. Mallar
- Foote, Kelly D.
- Giacobbe, Peter
- Mari, Zoltan
- McAndrews, Mary Pat
- Munro, Cynthia A.
- Oh, Esther S.
- Okun, Michael S.
- Ponce, Francisco A.
- Rosenberg, Paul B.
- Sabbagh, Marwan N.
- Salloway, Stephen
- Targum, Steven D.
- Wolk, David
- Smith, Gwenn S.
- Lyketsos, Constantine G.
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2018-06-19
- Volume
- 64
- Issue
- 2
- Pages
- 597-606
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC6518401
- OpenAlex
- W2808280305
- Cited by
- 104
- References
- 34
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 11 · 2023: 17 · 2022: 14 · 2021: 22 · 2020: 13 · 2019: 7 · 2018: 1
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG042165, P50AG005146)
- National Institute of Nursing Research (R01NR014852)
- National Institute of Neurological Disorders and Stroke (R01NS096008)
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- deep brain stimulation, fornix
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Psychiatric Status Rating Scales, Fornix, Brain, Deep Brain Stimulation
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