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

Parkinson Disease Clinical Trial

— 2T-DBS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04571112
• Other study ID #: 17-5400-B
• Status: Completed
• Phase: N/A
• Start date: December 4, 2017
• Est. completion date: March 1, 2021

Study information

• Verified date: November 2022
• Source: University of Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: March 1, 2021
• Est. primary completion date: October 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

1. 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)

2. PD fulfilling standard criteria for bilateral GPi DBS surgery

3. Patient's ability to provide informed consent and comply with study protocol.

Exclusion Criteria:

1. Severe Parkinson's disease dementia, preventing completion of the neuropsychological assessment, compliance with the study protocol, or ability to provide informed consent.

2. Inability to be fluent in English.

3. Unstable dose of any cognitive enhancing medication.

4. Presence of other neurological disorders, severe active psychiatric conditions or previous brain surgery.

Other conditions contraindicating DBS, PET scanning or MRI scanning.

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Memory Disorders
• Parkinson Disease

Intervention

Device:
• NBM stimulation using the Vercise device (Boston Scientific, Marlborough, Massachusetts, US)
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.

Locations

Country	Name	City	State
Canada	Toronto Western Hospital	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
University of Toronto

Country where clinical trial is conducted

Canada, 

References & Publications (22)

Bentley P, Driver J, Dolan RJ. Cholinergic modulation of cognition: insights from human pharmacological functional neuroimaging. Prog Neurobiol. 2011 Sep 1;94(4):360-88. doi: 10.1016/j.pneurobio.2011.06.002. Epub 2011 Jun 17. Review. — View Citation

Bosboom JL, Stoffers D, Stam CJ, Berendse HW, Wolters ECh. Cholinergic modulation of MEG resting-state oscillatory activity in Parkinson's disease related dementia. Clin Neurophysiol. 2009 May;120(5):910-5. doi: 10.1016/j.clinph.2009.03.004. Epub 2009 Apr 21. — View Citation

Combs HL, Folley BS, Berry DT, Segerstrom SC, Han DY, Anderson-Mooney AJ, Walls BD, van Horne C. Cognition and Depression Following Deep Brain Stimulation of the Subthalamic Nucleus and Globus Pallidus Pars Internus in Parkinson's Disease: A Meta-Analysis. Neuropsychol Rev. 2015 Dec;25(4):439-54. doi: 10.1007/s11065-015-9302-0. Epub 2015 Oct 12. Review. — View Citation

Di Santo SG, Prinelli F, Adorni F, Caltagirone C, Musicco M. A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer's disease. J Alzheimers Dis. 2013;35(2):349-61. doi: 10.3233/JAD-122140. Review. — View Citation

Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Dickson D, Duyckaerts C, Cummings J, Gauthier S, Korczyn A, Lees A, Levy R, Litvan I, Mizuno Y, McKeith IG, Olanow CW, Poewe W, Sampaio C, Tolosa E, Emre M. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007 Dec;22(16):2314-24. Review. — View Citation

Fasano A, Appel-Cresswell S, Jog M, Zurowkski M, Duff-Canning S, Cohn M, Picillo M, Honey CR, Panisset M, Munhoz RP. Medical Management of Parkinson's Disease after Initiation of Deep Brain Stimulation. Can J Neurol Sci. 2016 Sep;43(5):626-34. doi: 10.1017/cjn.2016.274. Review. — View Citation

Freund HJ, Kuhn J, Lenartz D, Mai JK, Schnell T, Klosterkoetter J, Sturm V. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol. 2009 Jun;66(6):781-5. doi: 10.1001/archneurol.2009.102. Erratum in: Arch Neurol. 2011 Apr;68(4):421. — View Citation

Gratwicke J, Jahanshahi M, Foltynie T. Parkinson's disease dementia: a neural networks perspective. Brain. 2015 Jun;138(Pt 6):1454-76. doi: 10.1093/brain/awv104. Epub 2015 Apr 16. Review. — View Citation

Kuhn J, Hardenacke K, Lenartz D, Gruendler T, Ullsperger M, Bartsch C, Mai JK, Zilles K, Bauer A, Matusch A, Schulz RJ, Noreik M, Bührle CP, Maintz D, Woopen C, Häussermann P, Hellmich M, Klosterkötter J, Wiltfang J, Maarouf M, Freund HJ, Sturm V. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia. Mol Psychiatry. 2015 Mar;20(3):353-60. doi: 10.1038/mp.2014.32. Epub 2014 May 6. — View Citation

Kumar R, Lang AE, Rodriguez-Oroz MC, Lozano AM, Limousin P, Pollak P, Benabid AL, Guridi J, Ramos E, van der Linden C, Vandewalle A, Caemaert J, Lannoo E, van den Abbeele D, Vingerhoets G, Wolters M, Obeso JA. Deep brain stimulation of the globus pallidus pars interna in advanced Parkinson's disease. Neurology. 2000;55(12 Suppl 6):S34-9. — View Citation

Liu AK, Chang RC, Pearce RK, Gentleman SM. Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer's and Parkinson's disease. Acta Neuropathol. 2015 Apr;129(4):527-40. doi: 10.1007/s00401-015-1392-5. Epub 2015 Jan 30. Review. — View Citation

McGaughy J, Kaiser T, Sarter M. Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density. Behav Neurosci. 1996 Apr;110(2):247-65. — View Citation

Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, Sano M, Bieliauskas L, Geldmacher D, Clark C, Thal LJ. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S13-21. — View Citation

Pagano G, Rengo G, Pasqualetti G, Femminella GD, Monzani F, Ferrara N, Tagliati M. Cholinesterase inhibitors for Parkinson's disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2015 Jul;86(7):767-73. doi: 10.1136/jnnp-2014-308764. Epub 2014 Sep 15. Review. — View Citation

Park M, Hood MM, Shah RC, Fogg LF, Wyatt JK. Sleepiness, parkinsonian features and sustained attention in mild Alzheimer's disease. Age Ageing. 2012 Nov;41(6):765-70. doi: 10.1093/ageing/afs084. Epub 2012 Jun 27. — View Citation

Picillo M, Lozano AM, Kou N, Puppi Munhoz R, Fasano A. Programming Deep Brain Stimulation for Parkinson's Disease: The Toronto Western Hospital Algorithms. Brain Stimul. 2016 May-Jun;9(3):425-437. doi: 10.1016/j.brs.2016.02.004. Epub 2016 Feb 12. Review. — View Citation

Ponce FA, Asaad WF, Foote KD, Anderson WS, Rees Cosgrove G, Baltuch GH, Beasley K, Reymers DE, Oh ES, Targum SD, Smith GS, Lyketsos CG, Lozano AM; ADvance Research Group. Bilateral deep brain stimulation of the fornix for Alzheimer's disease: surgical safety in the ADvance trial. J Neurosurg. 2016 Jul;125(1):75-84. doi: 10.3171/2015.6.JNS15716. Epub 2015 Dec 18. — View Citation

Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease. Cochrane Database Syst Rev. 2012 Mar 14;(3):CD006504. doi: 10.1002/14651858.CD006504.pub2. Review. — View Citation

Rouaud T, Dondaine T, Drapier S, Haegelen C, Lallement F, Péron J, Raoul S, Sauleau P, Vérin M. Pallidal stimulation in advanced Parkinson's patients with contraindications for subthalamic stimulation. Mov Disord. 2010 Sep 15;25(12):1839-46. doi: 10.1002/mds.23171. — View Citation

Sarter M, Givens B, Bruno JP. The cognitive neuroscience of sustained attention: where top-down meets bottom-up. Brain Res Brain Res Rev. 2001 Apr;35(2):146-60. Review. — View Citation

Smith GS, Laxton AW, Tang-Wai DF, McAndrews MP, Diaconescu AO, Workman CI, Lozano AM. Increased cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease. Arch Neurol. 2012 Sep;69(9):1141-8. doi: 10.1001/archneurol.2012.590. — View Citation

Witt K, Daniels C, Krack P, Volkmann J, Pinsker MO, Kloss M, Tronnier V, Schnitzler A, Wojtecki L, Bötzel K, Danek A, Hilker R, Sturm V, Kupsch A, Karner E, Deuschl G. Negative impact of borderline global cognitive scores on quality of life after subthalamic nucleus stimulation in Parkinson's disease. J Neurol Sci. 2011 Nov 15;310(1-2):261-6. doi: 10.1016/j.jns.2011.06.028. Epub 2011 Jul 5. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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