Deep Brain Stimulation of the Pedunculopontine Nucleus for Alzheimer's Disease

NCT06936124 | Recruiting

• 1 other identifier: 24-5380
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Alzheimer's disease (AD) is a brain disorder that gradually impacts cognitive functions such as memory, thinking, and daily functioning. Gamma oscillations are a type of brain activity thought to play a role in memory and cognition (thinking abilities). In AD, these oscillations are impaired - meaning they are smaller and slower than the brain waves observed in healthy individuals. Research suggests that enhancing these brain waves may help slow the progression of AD. This research is investigating a technique called deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) as an experimental intervention. An electrode will be implanted in the PPN and deliver mild stimulation over the course of a 12-month period. As a novel intervention, the priority of the study is to determine if DBS-PPN is a safe and feasible intervention for mild-AD. Additionally, the study investigators are evaluating whether DBS-PPN can increase natural gamma oscillations in ways that improve memory and cognition. The insights from this study will guide the design of an accessible larger trial to more definitively assess how effective DBS-PPN could be as a treatment for AD. Participants will:

• Undergo a 12-month experimental intervention involving DBS of the PPN. The procedure for implanting the DBS device takes approximately 2-3 hours under general anesthesia, followed by an overnight stay in the hospital for safety monitoring.
• Be required to attend regular appointments every 3 months from DBS implantation for the duration of the study. The follow-up visits will include safety and feasibility monitoring, brain scans (EEG and MEG), and cognitive assessments/questionnaires.
• Participants' caregiver will also complete questionnaires about their cognition, functioning, and overall health at the follow-up visits.

Conditions

Alzheimer Disease

Keywords

Alzheimer Disease; Deep Brain Stimulation; Pedunculopontine Nucleus; DBS-PPN; DBS

Outcome Measures

Primary Outcomes (8)

• Intervention Feasibility - Recruitment Rates

  Determined by assessing recruitment trends. The effectiveness of recruitment strategies will be assessed by monitoring the rate at which eligible participants are enrolled.

  Study Initiation to End of Study Enrolment Period (36 month period)

• Intervention Feasibility - Adherence to Study Protocol

  To ensure procedural consistency across participants, adherence to the study protocol will be systematically monitored. Any protocol deviations will be documented and evaluated for their potential impact on study outcomes, ensuring the reliability and reproducibility of findings

  Study Initiation to Final Participant Study Completion (3 years)

• Intervention Feasibility - Attrition Rates

  Participant retention will be assessed through an analysis of attrition rates, with particular attention to identifying the causes of dropout.

  Study Initiation to Final Participant Study Completion by (3 years)

• Intervention Feasibility - Participant Evaluation of Intervention

  Exit interviews will be conducted with participants and their caregivers to gather quantitative and qualitative information on their subjective experience and evaluation of the study intervention. Quantitative feedback on six items assessing satisfaction (e.g., understanding of study protocol, follow-up schedule manageability, likelihood of participating in future studies with same procedure) are measured on a a 5-point Likert scale (1 - "Very Dissatisfied" to 5 - "Very Satisfied"). Total score on quantitative items ranges from 6 - 30, with a higher score representing a more positive participant and caregiver evaluation of the study intervention.

  Participants will complete the exit interview at the final follow-up visit (month 12).

• Intervention Safety - Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Possible adverse events (AEs), serious adverse events (SAEs), or unanticipated problems related to the DBS device, related surgery and/or stimulation will be closely monitored and managed as per standard of care and definitions and classifications set forth in the following subsections. An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational devices or procedures. An SAE is an event that: Led to death; Led to serious deterioration in the health of the subject Led to foetal distress, foetal death or a congenital abnormality or birth defect Could have led to death or a serious deterioration were it to recur.

  Assessed at DBS implantation (Month 0) and at regular follow-up visits 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.

• Intervention Safety - AE Severity

  All AEs will be assessed by the study team using The Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 published by the U.S. Department of Health and Human Services (November 27, 2019) grading system. For AEs not included in the CTCAE defined grading system, the following guidelines will be used to describe severity: Grade 1, Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2, Moderate; minimal, local or non-invasive intervention indicated; limiting age- appropriate instrumental activities of daily life (ADL)\*; Grade 3, Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL\*\*; Grade 4, Life-threatening consequence; urgent intervention indicated; or Grade 5, Death related to AE.

  Assessed at DBS implantation (Month 0) and at regular follow-up visits 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.

• Intervention Safety - AE Relationship to Study Intervention

  Team will determine AE's causality based on categories below: Definitely Related - There is clear evidence to suggest a causal relationship, and other possible contributing factors can be ruled out. Probably Related - There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. Possibly Related - There is some evidence to suggest a causal relationship (e.g., the event occurred within a reasonable time. However, other factors may have contributed to the event (e.g., the participant's clinical condition, other concomitant events). Unlikely to be related - A clinical event whose temporal relationship to implantation/use of the study device makes a causal relationship improbable and in which other drugs, devices or underlying disease provides plausible explanations. Not Related - The AE is completely independent of implantation/use of the study device, and/or evidence exists that the event is definitely related to another etiology.

  Assessed at DBS implantation (Month 0) and at regular follow-up visits 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.

• Intervention Safety - AE Outcome

  The outcome of the AE will be defined according to the following: Recovered/ Resolved: The event has fully resolved at the end of the study\*; Recovering/ Resolving: The event is improving but has not fully resolved at the end of the study\*; Recovered/ Resolved with sequelae: The event has resolved, but retained pathological conditions resulting from the prior disease or injury; Not recovered/ not resolved: The event is ongoing at the end of the study\*; Fatal: This event is determined to be the cause of death; and Unknown: Outcome information could not be obtained.

  Assessed at final follow-up visit 12-months post-DBS surgery, or at the last time of observation.

Secondary Outcomes (9)

• Gamma Oscillation (GO) Power and Synchrony

  Baseline before DBS surgery and at 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.

• Theta-Gamma Coupling During N-Back Memory Task

  Baseline before DBS surgery and at 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.

• Working Memory Performance on N-Back Memory Task

  Baseline before DBS surgery and at 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.

• Clinical Dementia Rating (CDR) - Sum of Boxes (CDR-SB)

  Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.

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

  Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.

Study Arms (1)

Deep Brain Stimulation of the Pedunculopontine Nucleus

EXPERIMENTAL

The experimental intervention employs deep brain stimulation (DBS), a neuromodulation therapy involving the precise application of electrical impulses to targeted brain regions (the PPN) to modulate neural activity. The study intervention will span 12 months, with key milestones including DBS-PPN implantation, DBS activation and initial programming, and follow-up assessments at 3-month intervals. These follow-up visits will assess safety, feasibility, electrographic measures, and cognitive outcomes. All patient participants will receive the experimental intervention. This is the only arm in this study.

Procedure: Deep Brain Stimulation of the Pedunculopontine Nucleus

Interventions

Deep Brain Stimulation of the Pedunculopontine Nucleus PROCEDURE

The DBS implantation procedure targeting the PPN involves a neurosurgical operation performed under general anesthesia. During the procedure, thin electrodes are implanted in the PPN with the aid of advanced pre-operative imaging (MRI and CT scan) to confirm precise targeting. This device generates and transmits electrical impulses to the PPN, which can be adjusted to optimize therapeutic outcomes.

Also known as: DBS, DBS-PPN

Deep Brain Stimulation of the Pedunculopontine Nucleus

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults over 60 years old.
• Diagnosis of Alzheimer's Disease: Satisfied the diagnostic criteria of the National Institute of Aging - Alzheimer's Association criteria for probable AD.
• Clinical dementia rating scale global score of ≤ 1.
• Not taking an acetylcholinesterase inhibitor and/or memantine, or taking a stable dose for at least six months.
• Fluent in English.
• Caregiver available to participate in the study.

You may not qualify if:

• Pre-existing structural brain abnormalities (e.g., significant white matter disease, tumor, infarction, or intracranial hematoma).
• Other neurologic or psychiatric diagnoses, or medical comorbidities that would preclude patients from undergoing surgery.
• Non-fluent in English (it will be very difficult to conduct standard cognitive tests in English on non-fluent English speakers. In addition, language barrier is significant hurdle in providing standard care with communication and cognition being a main outcome measure).

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Alzheimer Society of Canada: collaborator
• Brain Canada: collaborator

Study Sites (1)

Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

RECRUITING

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Taufik A. Valiante, MD PhD FRCS

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Delaney Sharp

CONTACT

416-918-4059; delaney.sharp2@uhn.ca

Steven Carcone

CONTACT

steven.carcone@uhn.ca

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: Principal Investigator, Director of Surgical Epilepsy Program, Senior Scientist

Study Record Dates

• First Submitted: March 31, 2025
• First Posted: April 20, 2025
• Study Start: May 1, 2025
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028
• Last Updated: May 1, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)