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

Overview

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.

Interventions

• Procedure Deep Brain Stimulation of the Pedunculopontine Nucleus
  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.

Primary outcome measures

• Intervention Feasibility - Recruitment Rates [Time frame: Study Initiation to End of Study Enrolment Period (36 month period)]
• Intervention Feasibility - Adherence to Study Protocol [Time frame: Study Initiation to Final Participant Study Completion (3 years)]
• Intervention Feasibility - Attrition Rates [Time frame: Study Initiation to Final Participant Study Completion by (3 years)]
• Intervention Feasibility - Participant Evaluation of Intervention [Time frame: Participants will complete the exit interview at the final follow-up visit (month 12).]
• Intervention Safety - Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Assessed at final follow-up visit 12-months post-DBS surgery, or at the last time of observation.]

Secondary outcome measures (9)

• Gamma Oscillation (GO) Power and Synchrony [Time frame: 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 [Time frame: 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 [Time frame: 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) [Time frame: 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): [Time frame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.]
• Montreal Cognitive Assessment (MoCA) [Time frame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.]
• Neuropsychiatric Inventory (NPI) [Time frame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.]
• Sleep Disorders Inventory (SDI) [Time frame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.]
• Quality of Life in Alzheimer's Disease (QoL-AD) [Time frame: Baseline before DBS surgery and at 3-months, 6-months, 9-months, and 12-months post-DBS surgery.]

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 1 center

• Toronto Western Hospital — Toronto

Identifiers

NCT: NCT06936124 · 24-5380

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗