Biomarker changes associated with fornix deep brain stimulation in Alzheimer's disease

Jürgen Germann, Division of Neurosurgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Robert S. Amaral, Cerebral Imaging Centre, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
Jennifer Tomaszczyk, Division of Neurosurgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Kazuaki Yamamoto, Division of Neurosurgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Gavin J. Elias, Division of Neurosurgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Flavia Venetucci Gouveia, Neuroscience and Mental Health, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Anna Vasilevskaya, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Foad Taghdiri, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Gabriel A. Devenyi, Cerebral Imaging Centre, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
Tejas Sankar, Division of Neurosurgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
Jeannie-Marie Leoutsakos, Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Cynthia A. Munro, Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Paul B. Rosenberg, Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Constantine G. Lyketsos, Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Esther S. Oh, Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
William S. Anderson, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Zoltan Mari, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Lisa Fosdick, Functional Neuromodulation Ltd., Minneapolis, Minnesota, USA.
Kristen E. Drake, Functional Neuromodulation Ltd., Minneapolis, Minnesota, USA.
Steven D. Targum, Functional Neuromodulation Ltd., Minneapolis, Minnesota, USA.
Jo Cara Pendergrass, Avanti Clinical Research, Plymouth, Massachusetts, USA.
Anna Burke, Barrow Neurological Institute, Phoenix, Arizona, USA.
Stephen Salloway, Department of Neurology, Butler Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Wael F. Asaad, Department of Neurosurgery, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Francisco A. Ponce, Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Marwan Sabbagh, Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
David A. Wolk, Penn Memory Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Gordon Baltuch, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Michael S. Okun, Departments of Neurology and Neurosurgery, University of Florida, Fixel Institute for Neurological Diseases, Gainesville, Florida, USA.
Kelly D. Foote, Departments of Neurology and Neurosurgery, University of Florida, Fixel Institute for Neurological Diseases, Gainesville, Florida, USA.
Peter Giacobbe, Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Document Type

Article

Abstract

INTRODUCTION: Deep brain stimulation of the fornix (fx-DBS) is being investigated for treatment of Alzheimer's disease (AD). The therapy aims at alleviating memory and cognitive circuit dysfunction. In preclinical models of AD, electrical stimulation of the memory circuit has demonstrated a possible disease-modifying potential. Here we examined changes resulting from fx-DBS in hippocampal atrophy and amyloid accumulation in AD patients with fx-DBS. METHODS: Repeated magnetic resonance imaging and positron emission tomography (PET) images acquired over the course of 12 months were used to assess changes in hippocampal volume in 36 ADvance trial patients compared to 40 matched untreated AD patients from the Alzheimer's Disease Neuroimaging Initiative, and in 10 separate patients with repeated flutemetamol PET and cerebrospinal fluid (CSF) markers. RESULTS: We observed a reduction of hippocampal atrophy and amyloid beta (Aβ) PET binding, and an increase in the CSF Aβ/total-tau ratio in DBS patients. DISCUSSION: These findings highlight the potential of fornix deep brain stimulation to modify AD biomarkers and possibly progression in some patients. HIGHLIGHTS: Fornix deep brain stimulation (fx-DBS) is being investigated to treat Alzheimer's disease (AD). Results show that fx-DBS modifies imaging and cerebrospinal fluid (CSF) markers. It reduces hippocampal atrophy and increases the amyloid beta/total-tau CSF ratio. These findings highlight the potential of fx-DBS to modify AD.

Medical Subject Headings

Humans; Alzheimer Disease (therapy, diagnostic imaging, pathology, cerebrospinal fluid); Deep Brain Stimulation (methods); Fornix, Brain (diagnostic imaging); Male; Female; Positron-Emission Tomography; Amyloid beta-Peptides (metabolism, cerebrospinal fluid); Aged; Hippocampus (pathology, diagnostic imaging); Biomarkers (cerebrospinal fluid); Magnetic Resonance Imaging; tau Proteins (cerebrospinal fluid); Atrophy; Middle Aged

Publication Date

6-1-2025

Publication Title

Alzheimer's & dementia : the journal of the Alzheimer's Association

E-ISSN

1552-5279

Volume

21

Issue

6

First Page

e70394

PubMed ID

40566800

Digital Object Identifier (DOI)

10.1002/alz.70394

Link to Full Text

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