Deep Brain Stimulation in Alzheimer's Disease: Biomarkers and Dose Optimization
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Study type: Interventional

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 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.
    

Intervention name(s): Deep Brain Stimulation
Intervention type(s): Device
Intervention description(s): Personalized Deep Brain Stimulation of Fornix
Intervention model: Single Group Assignment
Intervention model description: Group of 12 patients will be implanted with a deep brain stimulation system and followed up for a 12-month post-operative period.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Deep Brain Stimulation; Biomarkers; Memory; Beta Amyloid; Limbic System; Fornix; Tau