Clinical trial NCT06936124: Deep Brain Stimulation of the Pedunculopontine Nucleus for Alzheimer's Disease
Official title: A Pilot Clinical Trial Investigating Deep Brain Stimulation of the Pedunculopontine Nucleus for the Treatment of Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Alzheimer Disease
Keywords: Alzheimer Disease
Deep Brain Stimulation
Pedunculopontine Nucleus
DBS-PPN
DBS
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Alzheimer Society of Canada
name: Brain Canada
First posted: 2025-04-20
Enrollment: 6
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that gradually impairs memory, cognitive abilities, and daily functioning, placing a significant burden not only on patients but also on caregivers and the healthcare system. Despite extensive research, current treatments provide only symptomatic relief without halting or reversing the disease's progression.

This study investigates a novel approach using deep brain stimulation (DBS) to target the pedunculopontine nucleus (PPN), a region involved in generating and regulating gamma oscillations across the brain. DBS is a neurosurgical procedure that utilizes stereotactic techniques to implant an electrode in a specific brain target, delivering electrical stimulation via a pulse generator. By stimulating the PPN, the study intervention aims to enhance gamma activity, potentially improving memory and cognition in AD patients. Preclinical studies have demonstrated that gamma enhancement has disease modifying effects in AD. Furthermore, DBS-PPN has shown cognitive improvements in Parkinson's dementia patients with a firmly established safety profile.

This pilot study is designed as a single-centre, single-cohort, open-label, non-randomized prospective clinical trial. The open-label nature means that both the researchers and the participants will be aware of the intervention being administered. The trial will recruit a small group of participants (N=6) with AD (amnestic subtype), to evaluate the safety, feasibility, and preliminary efficacy of DBS-PPN in treating AD. Each participant will serve as their own control, with outcome measures compared from before DBS implantation, and at regular follow-up visits over a 12-month period. The primary outcomes will focus on safety and feasibility metrics, serving to inform the design of a subsequent RCT. The secondary outcomes will assess electrophysiological (EEG and MEG) and cognitive measures, providing proof-of-concept for the potential disease-modifying effects of DBS-PPN.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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).

Primary outcomes:
measure: Intervention Feasibility - Recruitment Rates
timeFrame: Study Initiation to End of Study Enrolment Period (36 month period)
measure: Intervention Feasibility - Adherence to Study Protocol
timeFrame: Study Initiation to Final Participant Study Completion (3 years)
measure: Intervention Feasibility - Attrition Rates
timeFrame: Study Initiation to Final Participant Study Completion by (3 years)
measure: Intervention Feasibility - Participant Evaluation of Intervention
timeFrame: Participants will complete the exit interview at the final follow-up visit (month 12).
measure: Intervention Safety - Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 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.
measure: Intervention Safety - AE Severity
timeFrame: 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.
measure: Intervention Safety - AE Relationship to Study Intervention
timeFrame: 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.
measure: Intervention Safety - AE Outcome
timeFrame: Assessed at final follow-up visit 12-months post-DBS surgery, or at the last time of observation.
Secondary outcomes:
measure: Gamma Oscillation (GO) Power and Synchrony
timeFrame: Baseline before DBS surgery and at 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
measure: Theta-Gamma Coupling During N-Back Memory Task
timeFrame: Baseline before DBS surgery and at 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
measure: Working Memory Performance on N-Back Memory Task
timeFrame: Baseline before DBS surgery and at 1-month, 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
measure: Clinical Dementia Rating (CDR) - Sum of Boxes (CDR-SB)
timeFrame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
measure: Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog):
timeFrame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
measure: Neuropsychiatric Inventory (NPI)
timeFrame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
measure: Sleep Disorders Inventory (SDI)
timeFrame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
measure: Quality of Life in Alzheimer's Disease (QoL-AD)
timeFrame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
Study officials:
affiliation: University Health Network, Toronto
name: Taufik A. Valiante, MD PhD FRCS
role: PRINCIPAL_INVESTIGATOR
References: