Simultaneous DBS of the GPi and the NBM in Patients With Parkinson's Disease and Mild Cognitive Impairment

Simultaneous Deep Brain Stimulation of the Globus Pallidus Internus and the Nucleus Basalis of Meynert in Patients With Parkinson's Disease and Mild Cognitive Impairment

Phase 1 study evaluating the safety of combined bilateral globus pallidus internus (GPi) and nucleus basalis of Meynert (NBM) stimulation in treating levodopa responsive motor symptoms of Parkinsonism and cognitive dysfunction, respectively, in patients with moderate to advanced Parkinson's disease having mild cognitive impairment.

This study aims to provide a proof of safety of combined bilateral Globus Pallidus internus (GPi) and Nucleus Basalis of Meynert (NBM) stimulation in patients with moderate to advanced Parkinson's disease having mild cognitive impairment.

GPi stimulation with high-frequency ameliorates the cardinal motor symptoms and motor complications in Parkinson's disease patients, and this present study also wants to determine if additional NBM stimulation, with low-frequency stimulation, improves or slows progression of cognitive decline in patients with moderate to advanced Parkinson's disease having mild cognitive impairment, and to evaluate the effect of NBM stimulation on gait and balance impairment.

Study Design: Prospective single center Phase 1 study with double-blind randomized delayed activation of basal nucleus of Meynert neurostimulation (staggered onset design).

Planned Number of Subjects: 10 patients.

Planned Number of Sites / Countries: Single center in Brazil.

Study schedule:

• Presurgical baseline evaluation (motor on and off medication state; cognitive testing in best motor on state).
• DBS Implant Procedure.
• Postsurgical baseline evaluation (motor off state; cognitive testing in best motor on state) at 3±1 weeks after surgery and activation of globus pallidus internus neurostimulation using individualized stimulation parameters after a standard monopolar review.
• Regular adjustments of the GPi stimulation parameters aiming at the best motor improvement.
• Visit 1 (16 weeks after activation of GPi neurostimulation): motor off medication + GPi stimulation state, cognitive testing in on medication + GPi stimulation state. Randomization and blinded activation of NBM neurostimulation according to a 1:1 scheme.
• Visit 2 (16 weeks after randomization): motor off and on medication + stimulation state (GPi stimulation ± NBM stimulation); cognitive testing in motor on medication + stimulation state (GPi stimulation ± NBM stimulation). Activation of NBM neurostimulation in all patients.
• Visit 3 (16 weeks after activation of NBM stimulation in all patients): motor off and on medication + GPi and NBM stimulation state; cognitive testing in motor on medication + GPi and NBM stimulation state.
• Annual follow-up visit for up to 5 years after activation of NBM stimulation.

Inclusion Criteria:

• Age at the time of enrollment: 50 - 75 years.
• Diagnosis of idiopathic PD according to Movement Disorders Society (MDS) criteria (Albanese et al., 2017).
• Mild cognitive impairment (MCI) related to Parkinson's disease according to MDS criteria. (Livtan et al. 2012).
• Duration of bilateral idiopathic PD: ≥ 5 years of motor symptoms.
• Modified Hoehn and Yahr stage ≥ 2 on off medication state.
• UPDRS subset III (motor) ≥ 30 points on off medication state.
• Levodopa must improve PD symptoms by ≥ 30% in a levodopa challenge test, as measured by UPDRS subset III score.
• Presence of motor complications related to Parkinson's disease.
• Be willing and able to comply with all visits and study related procedures
• Able to understand the study requirements and the treatment procedures and to provide written informed consent before any study-specific tests or procedures are performed.

Exclusion Criteria:

• Alcohol or drug abuse.
• Any significant psychiatric problems, including acute confusional state (delirium), ongoing psychosis, or clinically significant depression.
• Contraindications for deep brain stimulation (DBS) surgery.
• Heart failure, heart disease or any condition that contraindicates surgical procedures.
• Pacemaker or other active implanted stimulators.
• Clearly established Parkinson's disease dementia according to Movement Disorders Criteria.
• Participation in another drug, device, or biologics trial concurrently.