Deep Brain Stimulation of the Fornix in Alzheimer's Disease: Investigations Into Clinical and Imaging Biomarkers and Dose Optimization
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 11
- Locations
- 1
- Primary Endpoint
- Change in MRI scan
Study Overview
Brief Summary
Title:
Deep Brain Stimulation of the Fornix in Alzheimer's Disease: Investigating clinical and imaging biomarkers and dose optimization
Objective:
To evaluate the influence of deep brain stimulation in Alzheimer's Disease (AD)on markers of AD pathology in cerebrospinal fluid (CSF) and on neuroimaging with positron emission tomography (PET) and to optimize electrical stimulation parameters.
Population size:
Twelve (12) patients will be recruited and enrolled in this study.
Study design:
This is a prospective, open-label trial designed to study the effect of brain stimulation on CSF and brain amyloid pathology in AD. In addition, patients will undergo neuropsychological testing at various stimulation settings to help determine optimal stimulation parameters.
Study duration:
Patients will complete screening and baseline assessments before undergoing DBS implantation surgery, after which they will be followed-up for 12 months.
Detailed Description
Background/Rationale:
Despite years of recognition and attempts at treatment, Alzheimer's Disease (AD) remains a pervasive and challenging condition, with an inexorable progression to severe disability and death once a diagnosis is made. The latest attempts at pharmacologic have yielded, at best, very modest results. There exists, therefore, no treatment for AD that significantly slows down its progression, and alters the metabolic milieu of AD brains.
We have conducted and published the world's first phase I safety and feasibility trial of deep brain stimulation (DBS) for early Alzheimer's Disease and the first Phase II randomized, placebo-controlled study of DBS in the same population. These trials have had the following three objectives: 1) establishing the safety of DBS in AD, 2) studying the possible slowing of cognitive decline in AD, and 3) studying the relationship between focal brain stimulation and metabolic changes in regions known to be affected by AD neurodegeneration.
With this background, we now want to continue and expand our DBS for AD trials. The rationale of the currently proposed study is to optimize patient selection and stimulation parameter dose for DBS for AD. We will measure the effects of DBS on brain amyloid load, on cerebrospinal fluid (CSF) Alzheimer protein metabolites and will screen various stimulation parameter settings for their acute effects on memory function. The latter will be used in an attempt to define the optimal stimulation dose.
The significance of this study is two-fold: 1) A possible demonstration that DBS may directly influence brain pathology in AD as measured by amyloid imaging and CSF protein changes, hence providing a mechanism of action for its clinical effects, and 2) the first study to empirically determine, using a memory task, the optimal stimulation parameters for DBS patients to improve memory function.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 45 Years to 85 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Informed consent signed by the subject AND a reliable caregiver
- •45-85 years of age (inclusive)
- •Probable Alzheimer's disease according to the National Institute of Aging Alzheimer's disease Association criteria.
- •Clinical Dementia Rating (CDR) global rating of 0.5 or 1 at screening.
- •ADAS-cog-11 score of 12-30 inclusive at screening AND baseline (with a score ≥ 4 on ADAS-cog item 1) or a Mini Mental State Examination (MMSE) of 16-
- •If female, post-menopausal, surgically sterile or willing to use birth control methods for the duration of the study.
- •The patient has an available caregiver or other appropriate knowledgeable informant who can reliably report on daily activities and function and signs the informed consent for participation as such.
- •Patient is living at home and likely to remain at home for the study duration.
- •General Medical Health Rating (GMHR) ≥ 3 (good or excellent general health).
- •Patient must be a good surgical candidate for placement of a deep brain stimulator as judged by the DBS surgical team.
- •Fluency (oral and written) in the language in which standardized tests will be administered.
- •The patient is taking a stable dose of cholinesterase inhibitor (AChEI) medication (donepezil, galantamine, or rivastigmine) for at least 60 days prior to signing the informed consent form and there is no intention to modify the dose over the course of the study (NOTE: These medications may NOT be initiated, discontinued or modified after study initiation for the length of study participation).
Exclusion Criteria
- •Neuropsychiatric Inventory (NPI) total score ≥ 10 or score ≥ 4 in any NPI domain (clinically significant neuropsychiatric symptoms). Apathy score ≥ 4 acceptable.
- •Subjects at risk for suicide in the opinion of the investigator or the subject answers "yes" to "Suicidal Ideation" Item 4 or 5 on the C-SSRS (at time of evaluation) at the screening or baseline visit.
- •Cornell Scale for Depression and Dementia (CSDD) score > 10 at the screening visit
- •Young Mania Rating Scale (YMRS) ≥ 11 at the screening visit
- •Current major psychiatric disorder such as schizophrenia, bipolar disorder or major depressive disorder based on psychiatric consult at screening visit
- •The subject has attempted suicide in the 2 years prior to signing the consent to participate in the study.
- •In the judgment of the investigator, the subject is at significant risk for suicidal behavior during the course of his/her participation in the study
- •History of head trauma in the 2 years prior to signing the consent to participate in the study
- •History of brain tumor, subdural hematoma, or other clinically significant (in the judgment of the investigator) space-occupying lesion on CT or MRI
- •Active psychiatric disorder
- •Mental retardation
- •Current alcohol or substance abuse as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)
- •Contraindications for PET scanning (e.g., insulin dependent diabetes)
- •Contraindications for MRI scanning, including implanted metallic devices (e.g. non-MRI-safe cardiac pacemaker or neurostimulator; some artificial joints metal pins; surgical clips; or other implanted metal parts), or claustrophobia or discomfort in confined spaces.
- •Radiation exposure in the 1 year prior to signing the informed consent form that, in combination with the radiation exposure from this study, would exceed 5 rem.
- •Abnormal lab results that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study.
- •Abnormal cardiovascular or neurovascular disorder that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study.
- •Unstable dose of any medication prescribed for the treatment of memory loss or Alzheimer's disease.
- •Currently prescribed any non-AD medications that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study.
- •Is unable or unwilling to comply with protocol follow-up requirements.
- •Has a life expectancy of < 1 year.
- •Is actively enrolled in another concurrent clinical trial.
Arms & Interventions
Treatment
All patients will be implanted with a deep brain stimulation system and will receive personalized fornix stimulation; parameters will be selected based on the dose finding cognitive tests.
Intervention: Deep Brain Stimulation (Device)
Outcomes
Primary Outcomes
Change in MRI scan
Time Frame: Baseline, Post-Operative Months 6, 12
Volumes of specified brain areas
Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)
Time Frame: Screening, Baseline, Post-Operative Months 1, 3, 6, 9, 12
Cognitive abilities
Change in Clinical Dementia Rating (CDR) Scale
Time Frame: Screening, Baseline, Post-Operative Months 3, 6, 9, 12
Dementia staging, Minimum score of 0 (better) and Maximum score of 3 (worse)
Change in PET scan
Time Frame: Baseline, Post-Operative Months 6, 12
Levels of amyloid beta in brain
Change in Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease
Time Frame: Baseline, Post-Operative Months 6, 12
Levels of amyloid beta, tau proteins in CSF
Secondary Outcomes
- Visual Association Memory Test(Baseline, Post-Operative Months 3, 6, 9, 12)
- Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory 23-item Scale (ADCS-ADL23)(Baseline, Post-Operative Months 3, 6, 9, 12)
- Hopkins Verbal Learning Test (HVLT)(Baseline, Post-Operative Months 3, 6, 9, 12)
Investigators
Andres M. Lozano
Neurosurgeon
University Health Network, Toronto