Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia: A Randomized Clinical Trial

Abstract

Importance: Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a treatment option for Parkinson disease dementia.

Objective: To evaluate the safety and potential symptomatic effects of NBM DBS in patients with Parkinson disease dementia.

Design, setting, and participants: A randomized, double-blind, crossover clinical trial evaluated the results of 6 patients with Parkinson disease dementia who were treated with NBM DBS at a neurosurgical referral center in the United Kingdom from October 26, 2012, to July 31, 2015. Eligible patients met the diagnostic criteria for Parkinson disease dementia, had motor fluctuations, were appropriate surgical candidates aside from the coexistence of dementia, were age 35 to 80 years, were able to give informed consent, had a Mini-Mental State Examination score of 21 to 26, had minimal atrophy seen on results of brain magnetic resonance imaging, and lived at home with a caregiver-informant.

Interventions: After surgery, patients were assigned to receive either active stimulation (bilateral, low-frequency [20 Hz] NBM DBS) or sham stimulation for 6 weeks, followed by the opposite condition for 6 weeks.

Main outcomes and measures: The primary outcome was the difference in scores on each item of an abbreviated cognitive battery (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale-III digit span, verbal fluency, Posner covert attention test, and simple and choice reaction times) between the 2 conditions. Secondary outcomes were exploratory and included differences in scores on standardized measurements of cognitive, psychiatric, and motor symptoms and resting state functional magnetic resonance imaging.

Results: Surgery and stimulation were well tolerated by all 6 patients (all men; mean [SD] age, 65.2 [10.7] years), with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional magnetic resonance imaging. An improvement in scores on the Neuropsychiatric Inventory was observed with NBM DBS (8.5 points [range, 4-26 points]) compared with sham stimulation (12 points [range, 8-38 points]; median difference, 5 points; 95% CI, 2.5-8.5 points; P = .03) and the preoperative baseline (13 points [range, 5-25 points]; median difference, 2 points; 95% CI, -8 to 5.5 points; P = .69).

Conclusions and relevance: Low-frequency NBM DBS was safely conducted in patients with Parkinson disease dementia; however, no improvements were observed in the primary cognitive outcomes. Further studies may be warranted to explore its potential to improve troublesome neuropsychiatric symptoms.

Trial registration: clinicaltrials.gov Identifier: NCT01701544.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Gratwicke reported receiving honoraria from Medtronic, UCB Pharmaceuticals, Britannia Pharmaceuticals, and Bial. Dr Zrinzo reported receiving honoraria from Medtronic and Boston Scientific. Dr Hyam reported receiving honoraria from Medtronic and St Jude Medical. Dr Day reported receiving personal fees from Takeda Development Centre Europe Ltd. Dr Limousin reported receiving honoraria from Medtronic, St Jude Medical, and Boston Scientific. Dr Hariz reported receiving honoraria from Medtronic and Boston Scientific. Dr Jahanshahi reported receiving honoraria and travelling expenses from Medtronic. Dr Foltynie reported receiving honoraria from Medtronic, St Jude Medical, Profile Pharma, Bial, Abbvie Pharmaceuticals, UCB Pharmaceuticals, and Oxford Biomedica. No other disclosures were reported.

Figures

Figure 1.. Trial Profile

DBS indicates deep brain stimulation; GPi, globus pallidus internus; and NBM, nucleus basalis of Meynert.

Figure 2.. Study Design

The downward-pointing arrows indicate study time points, and the upward-pointing arrows indicate assessments at those time points as per protocol. All 6 patients who underwent surgery completed the double-blind phase of the protocol. GPi indicates globus pallidus internus; NBM, nucleus basalis of Meynert.

Figure 3.. Determining Deep Brain Stimulation Lead Contact Location From Stereotactic Proton Density Magnetic Resonance (MR) Images

A, Axial image (top panel) and reconstruction along lead trajectory (bottom panel). Postimplantation stereotactic MR images were imported into FrameLink software (Medtronic), reconstructed along the axis of the lead, and a template placed on the lead artifact to determine the stereotactic coordinates of each contact. B, Axial (top panel) and coronal (bottom panel). Coordinates for each contact were then transposed onto preoperative stereotactic images, allowing accurate assessment of lead location (white dot). C, Axial (top panel) and coronal (bottom panel). The heavily myelinated optic tract and anterior commissure (lateral extension), hypointense on proton density MR images, are light blue. The intervening hyperintense nucleus basalis of Meynert (NBM) is yellow. In the coronal image, the NBM is seen to lie superior to the amygdala and inferior to the internal (green) and external (red) segments of the globus pallidus. The active contact (black dot) is seen to lie within the NBM.