Deep Brain Stimulation in Alzheimer's Disease: Biomarkers and Dose Optimization
Deep Brain Stimulation in Alzheimer's Disease: Biomarkers and Dose Optimization
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.
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 Objectives:

 1. Influence of DBS on AD Pathology

 Early results suggest that DBS may influence cognitive and memory functions in patients
 with early Alzheimer's Disease (AD). It is not clear, however, whether DBS can directly
 influence pathology in AD, such as CSF protein biomarkers and amyloid plaque load in the
 brain. The objective of this study is to analyze CSF and brain plaque load prior to and
 after surgery to determine whether DBS influences central nervous systems pathology
 associated with AD.

 2. Dose Optimization

 Currently, selecting the optimal stimulation dose for patients with non-motor conditions
 (i.e. Alzheimer's Disease, depression, obsessive-compulsive disorder) is performed largely
 arbitrarily, and borrows heavily from settings used in motor conditions (i.e. Parkinson's
 Disease, Tremor). The objective of this study is to establish a clinically meaningful dose
 optimization test that will use the patients' performance on an experimental memory task to
 determine the optimal stimulation settings.

 Study Hypotheses:

 Our study has the following exploratory hypotheses:

 i. DBS may lead to changes in CSF biomarkers of AD pathology, including tau, phosphorylated
 tau, and beta amyloid, consistent with plaque clearance ii. DBS may lead to reductions in
 plaque burden, demonstrated by amyloid PET imaging iii. The optimal dose of brain
 stimulation, which maximizes benefits and minimizes adverse events, can be selected using an
 acute memory task performed in the post-operative period.

 Design and Methodology:

 This is an open-label, prospective trial designed to measure the influence of DBS on AD brain
 pathology and to optimize stimulation parameter selection post-operatively. Twelve (12)
 patients will be enrolled and operated, and followed in an open-label fashion. All subjects
 will be followed to a common closing date, which will be at the time the last subject
 enrolled is followed for 12 months.

 Patient selection and enrollment:

 1. Pre-treatment procedures

 The schedule for individual subjects is outlined below in table format and is displayed
 in Figure 1 as a flowchart. This study is divided into four phases: screening, baseline,
 surgery, and on-stimulation. All patients will be recruited through the memory clinic at
 Toronto Western Hospital and local advertisements. Patients meeting inclusion/exclusion
 criteria will be approached for participation. There will be two distinct periods of
 informed consent in this study: the first, to allow study investigators to screen
 patients for study inclusion, and the second, to formally enroll patients into the
 study. Figure 1 outlines the process that will take place for identified patients and
 the estimated number of individual subjects at each stage.

 Once patients are identified by the study neurologist, screening consent will be
 obtained. This consent will signal entrance into the first phase of the study, and
 indicates that the patient meets inclusion/exclusion criteria. During the screening
 visit, patients will undergo a medical history and general physical examination,
 medication screening, electrocardiogram, relevant pre-operative blood work,
 neuropsychological testing and psychiatric screening: the Alzheimer's Disease Assessment
 Scale-Cognitive Subscale(ADAS-Cog) Clinical Dementia Rating (CDR) scale,
 Neuropsychiatric Inventory (NPI), Columbia Suicide Severity Rating Scale (C-SSRS),
 Cornell Scale for Depression in Dementia (CSDD), Young Mania Rating Scale (YMRS), which
 will be used to classify participants by inclusion/exclusion criteria. Once the
 screening is complete, patients will be discussed by the study team to determine whether
 they should continue in the trial, and progress to the baseline stage.

 The baseline stage will require an additional informed consent, as this stage signals
 entry into the formal trial. Baseline investigations will commence within 2 months of
 signing baseline consent, and can take place up to within 1 day of surgery
 ("implantation"). Baseline investigations will include all tests and examinations done
 during Screening (excepting the ECG), with the addition of: the Alzheimer's Disease
 Cooperative Study Activities of Daily Living Inventory 23-item Scale (ADCS-ADL23), the
 Hopkins Verbal Learning Test (HVLT), neuroimaging (MRI and Amyloid PET) as well as a
 lumbar puncture (LP) for AD protein markers. Participants will also complete acute
 experimental memory tasks that will be used in the 'dosing' phase, to familiarize them
 with the procedure. For these memory tasks, patients will view stimuli (e.g., objects,
 faces, scenes, words), and then be asked to remember them. In addition, an experimental
 visual associative recognition task, which is a simplified version of the one that was
 critical in identifying memory-specific effects in the sentinel case (Hamani et al
 2008), will be introduced at this stage.

 Once all baseline investigations are complete, patients will be scheduled for surgery
 and implantation.

 2. Treatment procedures - DBS surgery

 DBS surgery will be performed as is done routinely and has been performed on the
 previous 18 patients with AD at our centre. Patients will arrive on the morning of
 surgery at the Toronto Western Hospital medical imaging department. They will have a
 small part of their head shaved and then have a stereotactic frame attached directly to
 their skull, after infiltration with local anaesthesia. The frame allows precise
 co-ordinates to be acquired so that deep brain structures can be targeted with implanted
 electrodes. The patient will then undergo an MRI scan (for surgical planning) with the
 frame in place, followed by transport directly to the operating room. The anaesthesia
 team will insert an intravenous line followed by induction and initiation of general
 anaesthesia (GA). The entire case, including electrode implantation and implantation of
 the pulse generator, will be done under general anaesthesia with the patient fully
 asleep. In the operating room the patient's head, via the frame, will be attached to the
 operating room table, and their scalp infiltrated with additional local anaesthetic. A
 skin incision will be made and two 2.5 mm diameter burr holes drilled through the skull.
 A DBS electrode will be delivered at the fornix target as identified on the MRI scan
 obtained earlier in the morning. The patient will be monitored throughout the entire
 case. Once implanted, the second stage of the operation with begin (about 30 min)
 whereby the electrodes are connected to a battery placed under the right collarbone.
 With the patient asleep, the electrodes are tunneled to the battery, and connected. Both
 the head and chest incisions are then closed and the patient transferred to the recovery
 room. Following surgery, the patient will be transferred to the neurosurgical ward for
 recovery. On the first post-op day, they will undergo an MRI of their brain to confirm
 the electrode location. Should the electrodes be in a suboptimal location (e.g. nearby
 but not within the target), patients will be offered several options: re-operation for
 lead repositioning, leave the system in place and turn device on, leave the system in
 place and keep device off, or removal of the system completely.

 Recovery following surgery should take 1-2 days, and patients will be discharged home on
 post-op day 2, with the stimulator in the off position. Patients will return to the
 neurosurgical clinic two weeks after discharge to check the wound, remove staples, and
 for routine post-op follow-up.

 3. Other Procedures

 Beta-Amyloid Positron Emission Tomography (PET) scans. Beta-Amyloid PET scans will be used to
 estimate amyloid burden in the brains of the patients and to probe whether DBS has an impact
 on this process. Flutemetamol (GE Healthcare) is an FDA-approved amyloid PET radiotracer that
 has been approved by Health Canada for research use. PET scans will be performed on a Siemens
 HRRT scanner. During radiotracer uptake, patients will be maintained in a quiet, dimly lit
 room, with eyes open and ears unoccluded. Ninety minutes after a 5mCi ± 10% radiotracer
 injection, patients will be positioned in the scanner, and a 20-minute emission scan will be
 obtained, followed by a transmission scan.

 Lumbar Puncture (LP) for protein analysis. The procedure is done with patients lying on their
 side. The skin is washed with sterilizing solution; 3 ml of local anesthetic is injected in
 the skin and subcutaneous tissue at the lumbar 4/5 level. 6 ml of CSF is removed and
 distributed in aliquots. The samples are immediately frozen and stored at -80C. CSF levels of
 Tau, phosphoTau and beta amyloid are determined by standard protein analysis. The analysis
 will be performed as per the Alzheimer's Disease Neuroimaging Initiative (ADNI) guidelines.

 Stimulation dose finding studies. At the patient visits, the DBS will be programmed to test
 the effects of various stimulus settings on memory performance. Testing sessions will last up
 to 2.5 hours or less if, the patient becomes tired. Settings will be adjusted to ensure that
 the patients do not feel or experience adverse effects. Heart rate will be monitored during
 programming. Patients will be asked to perform a memory task at each of the tested settings
 to determine optimal setting during subsequent visits. This setting will remain stable until
 the next visit, at which time settings will again be evaluated and may be changed. For the
 memory tasks, patients will view stimuli (e.g., objects, faces, scenes, words), and will then
 be asked to remember the stimuli. Each test will last approximately 5-10 minutes.
Inclusion Criteria:

 1. Informed consent signed by the subject AND a reliable caregiver

 2. 45-85 years of age (inclusive)

 3. Probable Alzheimer's disease according to the National Institute of Aging Alzheimer's
 disease Association criteria.

 4. Clinical Dementia Rating (CDR) global rating of 0.5 or 1 at screening.

 5. 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 16-28.

 6. If female, post-menopausal, surgically sterile or willing to use birth control methods
 for the duration of the study.

 7. 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.

 8. Patient is living at home and likely to remain at home for the study duration.

 9. General Medical Health Rating (GMHR) ≥ 3 (good or excellent general health).

 10. Patient must be a good surgical candidate for placement of a deep brain stimulator as
 judged by the DBS surgical team.

 11. Fluency (oral and written) in the language in which standardized tests will be
 administered.

 12. 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:

 1. Neuropsychiatric Inventory (NPI) total score ≥ 10 or score ≥ 4 in any NPI domain
 (clinically significant neuropsychiatric symptoms). Apathy score ≥ 4 acceptable.

 2. 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.

 3. Cornell Scale for Depression and Dementia (CSDD) score > 10 at the screening visit

 4. Young Mania Rating Scale (YMRS) ≥ 11 at the screening visit

 5. Current major psychiatric disorder such as schizophrenia, bipolar disorder or major
 depressive disorder based on psychiatric consult at screening visit

 6. The subject has attempted suicide in the 2 years prior to signing the consent to
 participate in the study.

 7. 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

 8. History of head trauma in the 2 years prior to signing the consent to participate in
 the study

 9. History of brain tumor, subdural hematoma, or other clinically significant (in the
 judgment of the investigator) space-occupying lesion on CT or MRI

 10. Active psychiatric disorder

 11. Mental retardation

 12. Current alcohol or substance abuse as defined by Diagnostic and Statistical Manual of
 Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)

 13. Contraindications for PET scanning (e.g., insulin dependent diabetes)

 14. 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.

 15. 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.

 16. Abnormal lab results that, in the opinion of the investigator and/or enrollment review
 committee, would preclude participation in the study.

 17. Abnormal cardiovascular or neurovascular disorder that, in the opinion of the
 investigator and/or enrollment review committee, would preclude participation in the
 study.

 18. Unstable dose of any medication prescribed for the treatment of memory loss or
 Alzheimer's disease.

 19. Currently prescribed any non-AD medications that, in the opinion of the investigator
 and/or enrollment review committee, would preclude participation in the study.

 20. Is unable or unwilling to comply with protocol follow-up requirements.

 21. Has a life expectancy of < 1 year.

 22. Is actively enrolled in another concurrent clinical trial.