Deep Brain Stimulation in Alzheimer's Disease: Biomarkers and Dose Optimization

NCT04856072 | Completed FDA Device

• 1 other identifier: 14-8162
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

Title: Deep Brain Stimulation of the Fornix in Alzheimer's Disease: Investigating clinical and imaging biomarkers and dose optimization Objective: To evaluate the influence of deep brain stimulation in Alzheimer's Disease (AD)on markers of AD pathology in cerebrospinal fluid (CSF) and on neuroimaging with positron emission tomography (PET) and to optimize electrical stimulation parameters. Population size: Twelve (12) patients will be recruited and enrolled in this study. Study design: This is a prospective, open-label trial designed to study the effect of brain stimulation on CSF and brain amyloid pathology in AD. In addition, patients will undergo neuropsychological testing at various stimulation settings to help determine optimal stimulation parameters. Study duration: Patients will complete screening and baseline assessments before undergoing DBS implantation surgery, after which they will be followed-up for 12 months.

Conditions

Alzheimer Disease

Keywords

Deep Brain Stimulation; Biomarkers; Memory; Beta Amyloid; Limbic System; Fornix; Tau

Outcome Measures

Primary Outcomes (5)

• Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)

  Cognitive abilities

  Screening, Baseline, Post-Operative Months 1, 3, 6, 9, 12

• Change in Clinical Dementia Rating (CDR) Scale

  Dementia staging, Minimum score of 0 (better) and Maximum score of 3 (worse)

  Screening, Baseline, Post-Operative Months 3, 6, 9, 12

• Change in PET scan

  Levels of amyloid beta in brain

  Baseline, Post-Operative Months 6, 12

• Change in Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease

  Levels of amyloid beta, tau proteins in CSF

  Baseline, Post-Operative Months 6, 12

• Change in MRI scan

  Volumes of specified brain areas

  Baseline, Post-Operative Months 6, 12

Secondary Outcomes (3)

• Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory 23-item Scale (ADCS-ADL23)

  Baseline, Post-Operative Months 3, 6, 9, 12

• Hopkins Verbal Learning Test (HVLT)

  Baseline, Post-Operative Months 3, 6, 9, 12

• Visual Association Memory Test

  Baseline, Post-Operative Months 3, 6, 9, 12

Other Outcomes (4)

• Neuropsychiatric Inventory (NPI)

  Screening, Baseline, Post-Operative Months 3, 6, 9, 12

• Cornell Scale for Depression in Dementia (CSDD)

  Screening, Baseline, Post-Operative Months 3, 6, 9, 12

• Columbia Suicide Severity Rating Scale (C-SSRS)

  Screening, Baseline, Post-Operative Months 3, 6, 9, 12

Study Arms (1)

Treatment

EXPERIMENTAL

All patients will be implanted with a deep brain stimulation system and will receive personalized fornix stimulation; parameters will be selected based on the dose finding cognitive tests.

Device: Deep Brain Stimulation

Interventions

Deep Brain Stimulation DEVICE

Personalized Deep Brain Stimulation of Fornix

Treatment

Eligibility Criteria

• Age: 45 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent signed by the subject AND a reliable caregiver
• years of age (inclusive)
• Probable Alzheimer's disease according to the National Institute of Aging Alzheimer's disease Association criteria.
• Clinical Dementia Rating (CDR) global rating of 0.5 or 1 at screening.
• ADAS-cog-11 score of 12-30 inclusive at screening AND baseline (with a score ≥ 4 on ADAS-cog item 1) or a Mini Mental State Examination (MMSE) of 16-28.
• If female, post-menopausal, surgically sterile or willing to use birth control methods for the duration of the study.
• The patient has an available caregiver or other appropriate knowledgeable informant who can reliably report on daily activities and function and signs the informed consent for participation as such.
• Patient is living at home and likely to remain at home for the study duration.
• General Medical Health Rating (GMHR) ≥ 3 (good or excellent general health).
• Patient must be a good surgical candidate for placement of a deep brain stimulator as judged by the DBS surgical team.
• Fluency (oral and written) in the language in which standardized tests will be administered.
• The patient is taking a stable dose of cholinesterase inhibitor (AChEI) medication (donepezil, galantamine, or rivastigmine) for at least 60 days prior to signing the informed consent form and there is no intention to modify the dose over the course of the study (NOTE: These medications may NOT be initiated, discontinued or modified after study initiation for the length of study participation).

You may not qualify if:

• Neuropsychiatric Inventory (NPI) total score ≥ 10 or score ≥ 4 in any NPI domain (clinically significant neuropsychiatric symptoms). Apathy score ≥ 4 acceptable.
• Subjects at risk for suicide in the opinion of the investigator or the subject answers "yes" to "Suicidal Ideation" Item 4 or 5 on the C-SSRS (at time of evaluation) at the screening or baseline visit.
• Cornell Scale for Depression and Dementia (CSDD) score \> 10 at the screening visit
• Young Mania Rating Scale (YMRS) ≥ 11 at the screening visit
• Current major psychiatric disorder such as schizophrenia, bipolar disorder or major depressive disorder based on psychiatric consult at screening visit
• The subject has attempted suicide in the 2 years prior to signing the consent to participate in the study.
• In the judgment of the investigator, the subject is at significant risk for suicidal behavior during the course of his/her participation in the study
• History of head trauma in the 2 years prior to signing the consent to participate in the study
• History of brain tumor, subdural hematoma, or other clinically significant (in the judgment of the investigator) space-occupying lesion on CT or MRI
• Active psychiatric disorder
• Mental retardation
• Current alcohol or substance abuse as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)
• Contraindications for PET scanning (e.g., insulin dependent diabetes)
• Contraindications for MRI scanning, including implanted metallic devices (e.g. non-MRI-safe cardiac pacemaker or neurostimulator; some artificial joints metal pins; surgical clips; or other implanted metal parts), or claustrophobia or discomfort in confined spaces.
• Radiation exposure in the 1 year prior to signing the informed consent form that, in combination with the radiation exposure from this study, would exceed 5 rem.

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Johns Hopkins University: collaborator

Study Sites (1)

Toronto Western Hospital, University Health Network

Toronto, Ontario, M5T 2S8, Canada

Location

Related Publications (3)

• Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, Lozano AM. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010 Oct;68(4):521-34. doi: 10.1002/ana.22089.

  PMID: 20687206 BACKGROUND

• Lozano AM, Fosdick L, Chakravarty MM, Leoutsakos JM, 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 GS. A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. J Alzheimers Dis. 2016 Sep 6;54(2):777-87. doi: 10.3233/JAD-160017.

  PMID: 27567810 BACKGROUND

• Hamani C, McAndrews MP, Cohn M, Oh M, Zumsteg D, Shapiro CM, Wennberg RA, Lozano AM. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol. 2008 Jan;63(1):119-23. doi: 10.1002/ana.21295.

  PMID: 18232017 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease; Plaque, Amyloid; Pick Disease of the Brain

Interventions

Deep Brain Stimulation

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Frontotemporal Dementia; Frontotemporal Lobar Degeneration

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics; Surgical Procedures, Operative

Study Officials

• Andres Lozano, MD, PhD

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Neurosurgeon

Model Details: Group of 12 patients will be implanted with a deep brain stimulation system and followed up for a 12-month post-operative period.

Study Record Dates

• First Submitted: April 16, 2021
• First Posted: April 22, 2021
• Study Start: December 19, 2014
• Primary Completion: December 5, 2023
• Study Completion: December 5, 2023
• Last Updated: December 5, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)