Clinical trial NCT05882344: Cholinergic Deep Brain Stimulation for Alzheimer's Disease
Official title: Cholinergic Deep Brain Stimulation for Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Alzheimer Disease, Early Onset
Dementia
Alzheimer Disease
Keywords: Stimulation
Nucleus Basalis
Alzheimer
Memory
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: Boston Scientific Corporation
First posted: 2023-05-31
Enrollment: 2
Sex: ALL
Minimum age (years): 60
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a feasibility study to investigate the potential of Deep Brain Stimulation to improve cognitive abilities and counteract the effects of Alzheimer's disease. Deep Brain Stimulation electrodes targeting the Nucleus Basalis of Meynert (NB) will be implanted bilaterally in patients. NB is the sole source of acetylcholine to the neocortex. Such stimulation may not only treat the cognitive symptoms but may have disease-modifying effects. Intermittent stimulation will be delivered at 60 pulses per second for 20 seconds of each minute for one hour per day. The study design will test the safety and feasibility of stimulation, potential benefits in cognitive function assessed with a battery of neurocognitive tests, cholinergic neurotransmission evaluated with Positron Emission Tomography, and ability to reverse Alzheimer's biomarkers, including beta amyloid and tau in the cerebrospinal fluid.
Primary purpose: TREATMENT

Brief summary: This project will investigate the potential of Deep Brain Stimulation to improve cognitive abilities and counteract the effects of Alzheimer's disease. Deep Brain Stimulation electrodes targeting the Nucleus Basalis of Meynert (NB) will be implanted bilaterally in a cohort of patients. NB is the sole source of acetylcholine to the neocortex. Such stimulation may not only treat the cognitive symptoms but may have disease-modifying effects. Drawing from animal experiments in non-human primates that showed success of this approach, intermittent stimulation will be delivered at 60 pulses per second for 20 seconds of each minute for one hour per day. The study team will recruit patients, shortly after first being diagnosed with Alzheimer's disease. The study design will test the safety and efficacy of stimulation, potential benefits in cognitive function assessed with a battery of neurocognitive tests, cholinergic neurotransmission evaluated with Positron Emission Tomography, and ability to reverse Alzheimer's biomarkers, including beta amyloid and tau in the cerebrospinal fluid. Successful completion of this project will lead to a potential new intervention for the cognitive impairments of Alzheimer's disease.


Eligibility criteria: Inclusion Criteria:

* Probable, early-stage AD, as defined by NIA-AA 2018 criteria, including amnestic Mild Cognitive Impairment (MCI)

  * Clinical Dementia Rating (CDR) global score of 0.5-1.0 with a memory box score of at least 0.5
  * MMSE ³ 23
  * Stable cognitive enhancer medication equivalent to 10 mg/day donepezil or less for at least 60 days
  * Stable other medications (e.g., psychotropics)
  * Valid informed consent if female, subjects who are post-menopausal or surgically sterile or willing to use birth control methods for the duration of the study
  * an available caregiver willing to participate
  * subject is living at home and likely to remain at home for the study duration.

Exclusion Criteria:

* Active or unstable psychiatric illness
* Inability to tolerate general anesthesia.
* Another concurrent CNS condition or clinical co-morbidity interfering with the study (ie, stroke, Parkinson's disease, Lewy-Body dementia or other form of dementia, other evidence of significant structural brain pathology).
* Current major psychiatric disorder such as schizophrenia, bipolar disorder or major depressive disorder based on psychiatric consult at screening visit
* Verbal IQ\<85
* Contraindication regarding anesthesia, stereotactic operation, MRI (e.g. claustrophobia, or implants), or PET (e.g. insulin dependent diabetes) procedures
* Inability to undergo PET or MRI imaging
* Active alcohol or substance abuse as defined by DSM5
* Is unable or unwilling to comply with protocol follow-up requirements
* Is actively enrolled in another concurrent clinical trial.
* Terminal illness associated with expected survival of \<12 months

Primary outcomes:
measure: Clinical Dementia Rating score change
timeFrame: 12 - 24 Months
Secondary outcomes:
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
Study officials:
affiliation: Augusta University
name: Dave Blake, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Dario Englot, MS, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Koh EJ, Golubovsky JL, Rammo R, Momin A, Walter B, Fernandez HH, Machado A, Nagel SJ. Estimating the Risk of Deep Brain Stimulation in the Modern Era: 2008 to 2020. Oper Neurosurg (Hagerstown). 2021 Oct 13;21(5):277-290. doi: 10.1093/ons/opab261.
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, Buhrle CP, Maintz D, Woopen C, Haussermann P, Hellmich M, Klosterkotter 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.
citation: McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.
citation: Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412-4. doi: 10.1212/wnl.43.11.2412-a. No abstract available.
citation: Todd S, Barr S, Passmore AP. Cause of death in Alzheimer's disease: a cohort study. QJM. 2013 Aug;106(8):747-53. doi: 10.1093/qjmed/hct103. Epub 2013 May 7.
citation: van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. doi: 10.1056/NEJMoa2212948. Epub 2022 Nov 29.
citation: Williams MM, Storandt M, Roe CM, Morris JC. Progression of Alzheimer's disease as measured by Clinical Dementia Rating Sum of Boxes scores. Alzheimers Dement. 2013 Feb;9(1 Suppl):S39-44. doi: 10.1016/j.jalz.2012.01.005. Epub 2012 Aug 1.