Blood Brain Barrier Opening in Alzheimer' Disease
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      In Alzheimer's disease (AD) an imbalance between the production and clearance of the
      ß-amyloid peptide is hypothesized as the driving event of the disease. The decreased
      clearance of Aß could be partly linked to a progressive dysfunction of the brain vasculature
      and of the blood brain barrier (BBB). Among many possible explanations for these failures of
      the multiple clinical trials evaluating innovative drugs in AD, one is the lack of target
      engagement, as none of these drugs is able to readily cross BBB. This barrier acts as a wall
      that actively and passively prevents the crossing of molecules between the blood and the
      brain parenchyma compartments. Only 0.3% of intravenously injected anti-Aß immunoglobulins
      reach the brain despite a half-life of 15-20 days. Low intensity Focal ultrasound associated
      to microbubble injection can open the BBB in a non invasive way. These openings are
      reversible in 2 hours to 2 days depending on the intensity of the ultrasound. Ultrasound
      opening of the BBB was initially used in a transgenic mouse model of AD to increase the brain
      delivery of an anti-Aß antibody. In this article, the Aß load was reduced in ultrasound
      treated brain region. Surprisingly it was then demonstrated that the simple opening of the
      BBB without any adjunct anti-Aß treatment was able to drive the same Aß clearance effects.
      This is probably linked to endogenous antibodies that are able to penetrate the brain
      parenchyma and target Aß plaques. Four opening sessions elicited positive promnesic effects
      in these mice. Our group conceived and developed a mean to easily, reproductively and
      innocuously open the BBB. A unique extra-dural ultrasound emitter (sonoCloud®) is surgically
      implanted in the skull under local anesthesia. It emits low intensity contact ultrasound
      (LICU) that are not deterred by bone and thus are able to open the BBB.Preclinical studies
      show the SonoCloud® device is safe and efficient as it allowed reproducible and repeatable
      opening of the BBB in rabbits, dogs and non human primates. Drugs up to 2000 Kilo Daltons
      (kDa) are able to cross the BBB to reach the brain parenchyma in which the concentration of
      Carboplatin was increased by 700% in the BBB opened region. No adverse event was evidenced
      both clinically, by EEG, Evoked potential, MRI, 18 Fluorodeoxyglucose (FDG) PET and histology
      in the primates after 7 bi-monthly sessions of LICU BBB opening. SonoCloud® and its external
      generator have been certified by the academic start-up CarThéra (APHP, UPMC). Our
      multidisciplinary skills (neurology, neurosurgery, neuroimaging, basic science departments in
      the same University hospital setting) and our previous experience of BBB opening in Man give
      us the unique opportunity to translate this procedure from neuro-oncology to AD which could
      1) Have a positive effect on brain lesion load and symptoms by itself and 2) allow anti-AD
      (or more broadly, central nervous system) drugs to engage their targe
    

Detailed description: 
      Background:

      Alzheimer's disease is the most prevalent neurodegenerative disease totalizing 33 million
      patients worldwide. If nothing is done to decrease the incidence of 1.8 Million patient/year,
      the prevalence will double in the next 20 years.

      Physiopathologically, the amyloid cascade remains the predominant hypothesis. It states that
      an imbalance between the production and clearance of the ß-amyloid peptide is the driving
      event of the disease, leading to Tau hyperphosphorylation and accumulation in neurons as
      neurofibrillary tangles, neurodegeneration (synaptic and neuronal loss) and cognitive
      impairment. The decreased clearance of Aß could be partly linked to a progressive dysfunction
      of the brain vasculature and of the BBB.

      New sets of diagnosis criteria for AD have been proposed to address the low specificity (70%)
      of the previous ones, that could be one of the causes of failure of previous clinical trials.
      Among these new criteria, cerebrospinal fluid (CSF) biomarkers and positon emission
      tomography (PET) with new ligands of amyloid plaques and more recently tau deposition are
      indicators of the underlying histopathology of the disease, and can also be used to evaluate
      early intervention efficacy as they are pathologic in the preclinical phase of AD, its
      prodromal phase.

      the investigators aim to test an innovative BBB opening procedure that could drastically
      decrease AD patients' brain lesion load and alleviate their symptomatology.

      Scientific/medical questions:

      1) What is the tolerance of LICU and the SonoCloud® device in a population of patients with
      mild AD? 2) What are the physiopathological impact of LICU BBB opening in these patients as
      asserted by amyloid and 18FDG PET-MRI?

      Objectives:

      For the first phase I clinical trial in the world using LICU in AD to repeatedly open the
      BBB.

      Primary objective: To evaluate the tolerance of the BBB opening session in 5 AD patients
      (Adverse event recording, cognitive and MRI evaluations).

      Co-primary objective: To assess the impact of BBB opening on the hallmark lesions of AD (Aß &
      Tau) through PET-MRI imaging (decrease of the standardized uptake value ratio (SUVR) after
      vs. before treatment in the left supramarginal gyrus and left (treated) vs. right (untreated)
      supramarginal gyrus).

      Secondary objective: increase cognitive performance in AD patients through the repeated
      opening of the BBB in the left supramarginal gyrus

      Methods :

      Ten patients suffering from mild AD will be included in the study.

      Protocol :

      Seven BBB opening session will be performed at a bi-monthly rate focusing on the left
      supramarginal gyrus, a cortical structure known to be affected by both amyloid and tau
      lesions early on during the evolution of the disease. All adverse events induced by surgery
      itself or by the LICU will be recorded. Amyloid ß and Tau lesion load will be evaluated
      benefiting from the PET-MRI that allows to clearly evaluate fine changes in SUVR taking into
      account loco-regional cortical specificity (cortical thickness). PET image analysis.

      Mean Standard Uptake Values Ratios (SUVR) will be calculated with cerebellar gray matter
      activity as reference in volumes of interest. Voxel-wise uptake will then be divided by this
      reference value to get SUVR maps. PET images will be corrected for motion and partial volume
      effect thanks to simultaneous MRI acquisition. To analyze the longitudinal PET data, each
      follow-up T1-weighted MRI will be co-registered to the baseline MRI, and a within-subject
      template image will be calculated by averaging the coregistered T1-weighted images. This mean
      image will be used to calculate optimal transformation parameters to Montreal Neurological
      Institute (MNI) space. Next, baseline and follow-up PET images will be co-registered to the
      baseline MRI, spatially normalized to MNI using this optimal transformation, and scaled with
      cerebellar gray uptake. Individual percent annual changes maps will be then calculated. These
      maps will represent the voxel-wise calculation of percent metabolic change after BBB opening.

      The investigators think that the clinical trial will be well tolerated by the patients as the
      rate of local adverse events is expected to be 1% since the SonoCloud device implantation is
      extra dural (without dura opening). The implantation is performed under local anaesthesia in
      an outclinic fashion.

      Drawbacks and possible solution to overcome the problems :

      Among expected drawback the investigators will have to be very vigilant for Amyloid related
      imaging anomalies (ARIAs) due to the sudden entry of endogenous antibodies in the brain
      parenchyma of patients with Aß and Tau prevalent lesions. If these ARIAs were to happen, an
      amendment of the protocol could be devised to add steroids, or reduce ultrasound intensity,
      or extend time during each opening session, or reduce number of BBB opening session, or in
      last use immunosuppressive drugs prior to the opening of the BBB.

      This is the first study worldwide with the means to safely, repeatedly and reproductively
      open the BBB in AD, or more broadly, in any neurodegenerative disease. It is noteworthy to
      consider that it is only a phase I study aiming to demonstrate the feasibility of the
      technique in a mild form of AD. If this is the case and even in the absence of a positive
      effect on the lesions and symptoms it will then be possible to propose new projects aiming to
      associate these safe BBB opening to anti-AD drugs. In fact, this study could pave the way for
      further treatment venues of various neurodegenerative disease that share a brain accumulation
      of proteins that cannot be readily targeted in case of BBB integrity.
    

Intervention name(s): SONOCLOUD®
Intervention type(s): Device
Intervention description(s): BBB opening by ultrasound
Other intervention name(s): BBB opening
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Amyloid Amyloid Plaque; Tau Protein; Sonication