GPi+NBM DBS in Parkinson's Disease With Mild Cognitive Impairment

Study Overview
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Brief Summary
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This study examines the safety and feasibility of DBS in treating the movement and cognitive dysfunction in Parkinson's disease (PD). Globus pallidus interna (GPi) stimulation is an established treatment for the motor symptoms in PD, but it does not treat the cognitive symptoms that can also be seen in this condition. It is theorized that we can improve cognitive dysfunction by stimulating a part of the brain called the nucleus basalis of Meynert (NBM), which releases a chemical (acetylcholine) and plays a role in memory and attention. By using a novel DBS system (Vercise device) with 2 electrodes that are designed to stimulate the GPi and NBM, we can potentially target the motor and cognitive symptoms of PD with a single intervention.

Detailed Description
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Neuronal loss within the cholinergic nucleus basalis of Meynert (NBM) correlates with cognitive decline in dementing disorders such as Alzheimer's disease and Parkinson's disease (PD). Deep Brain Stimulation targeting the Globus Pallidus interna (GPi) is an established treatment for the motor symptoms in Parkinson's Disease, and stimulating the NBM is believed to stimulate cognitive function. Targeting these two regions was previously impossible because they require different frequency stimulations, but recent developments in DBS technology allow for the dual stimulation of these nuclei at different frequencies. This phase-II double-blind cross-over pilot trial will investigate the motor and cognitive effects as well as the presence of adverse effects of combined NBM and GPi DBS. The main goal of this pilot trial is to demonstrate the feasibility and safety of the multi-targeting approach in 6 patients with PDD and disabling motor symptoms.

Official Title
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Multi-targets, Single-lead GPi+NBM DBS in Parkinson's Disease With Mild Cognitive Impairment

Conditions
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Parkinson Disease, Memory Disorders

Intervention / Treatment
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* Device: NBM stimulation using the Vercise device (Boston Scientific, Marlborough, Massachusetts, US)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PD-MCI that affects multiple cognitive domains (including memory, visuo-spatial deficits etc.). diagnosis based on a comprehensive neuropsychological assessment (gold-standard) allowing the application of Level II MDS diagnostic criteria (Dubois et al. 2007) PD fulfilling standard criteria for bilateral GPi DBS surgery Patient's ability to provide informed consent and comply with study protocol. Exclusion Criteria: Severe Parkinson's disease dementia, preventing completion of the neuropsychological assessment, compliance with the study protocol, or ability to provide informed consent. Inability to be fluent in English. Unstable dose of any cognitive enhancing medication. Presence of other neurological disorders, severe active psychiatric conditions or previous brain surgery. Other conditions contraindicating DBS, PET scanning or MRI scanning.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: To target both the NBM and GPi in a single trajectory, using the Vercise system (Boston Scientific, Marlborough, Massachusetts, US) which is now approved for human use in Canada. This system includes a novel 8-contact electrode and an IPG system with 16 independent power sources allowing the so-called 'Multiple Independent Current Control' (MICC) that permits concurrent high- and low-frequency stimulation, as well as a variety of amplitudes and pulse widths independently controlled at each stimulated region.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NBM ON<br>The post-surgical double-blind cross-over phase with randomization will follow once programming settings are determined. Under constant GPi DBS, patients will receive NBM DBS active or sham for 8 weeks followed by an 8-week cross-over. The NBM ON arm will have constant NBM stimulation for 8 weeks. | Device: NBM stimulation using the Vercise device (Boston Scientific, Marlborough, Massachusetts, US)<br>* This will either be turned on or off depending on the arm which the patient is randomized to. After 8-weeks, the subject will switch arms for another 8-weeks.<br>|
| Sham Comparator: NBM OFF<br>The post-surgical double-blind cross-over phase with randomization will follow once programming settings are determined. Under constant GPi DBS, patients will receive NBM DBS active or sham for 8 weeks followed by an 8-week cross-over. The NBM OFF arm will have NBM stimulation turned off for 8 weeks. | Device: NBM stimulation using the Vercise device (Boston Scientific, Marlborough, Massachusetts, US)<br>* This will either be turned on or off depending on the arm which the patient is randomized to. After 8-weeks, the subject will switch arms for another 8-weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cognition after GPi/NBM DBS | This will be measured by the ADAS-Cog 13, verbal fluency test and sustained attention task. | at baseline and 6, 14, 22, 30 and 52 weeks post surgery | 
| Change in motor function (UPDRS)GPi/NBM DBS | Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a comprehensive 65 item assessment of both motor and non-motor symptoms associated with Parkinson's Disease. Each symptom is rated on a 5-point scale (from 0 to 4), and the maximum total score is 199, indicating severe impairment from parkinson's disease. | at baseline and 6, 14, 22, 30 and 52 weeks post surgery | 
| To assess the occurrence of adverse events from GPi/NBM DBS and occurrence of adverse events. | We define an adverse event (AE) as any untoward medical occurrence that occurs in the course of this study whether or not considered related to the study device, study procedures or study requirements that is identified or worsens during the study. | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the impact on health-related quality-of-life and various non-motor symptoms of PD | This is measured by the Parkinson's Disease Questionnaire, with a score range from 0 (never have difficulty) to 100 (always have difficulty), and with lower scores reflecting a better quality of life | 1 year | 
| To use neuroimaging biomarkers (MEG and FDG-PET) to examine localized effects of NBM stimulation | Region of interest analysis will be used to determine the localized effects of NBM in the surrounding structures and cortex for both MEG and PET imaging. | with NBM turned on and off, 22 and 30 weeks after surgery respectively |