Tau Protein and SV2a Imaging in Patients With Tau Protein-related Diseases

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Brief Title

Tau Protein and SV2a Imaging in Patients With Tau Protein-related Diseases

Official Title

Cross-sectional Validation and Longitudinal Study of Tau Protein and SV2a Imaging in Patients With Tau Protein-related Diseases and Normal Controls

Brief Summary

      Tau protein has been identified as one of the key pathological features of Tau
      proteinopathies, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP),
      frontotemporal dementia (FTD). Tau protein-targeted PET imaging can detect the amount and
      distribution of Tau protein deposition in human body, and has great research and application
      value in the diagnosis and evaluation of Tau protein disease. This study will be the first to
      introduce a complete quantitative, repeatable detection and analysis method in China. For the
      SV2a tracer [18F]MNI-1126, cross-sectional evaluation of its imaging in patients with Tau
      protein-related diseases and normal controls will be carried out. Later, longitudinal
      clinical symptoms and two tracers will be evaluated in patients with Tau protein-related
      diseases and normal controls.([18F]APN1607 and [18F]MNI1126) Imaging follow-up to explore
      longitudinal changes in brain Tau protein deposition and synaptic density in Tau
      protein-related diseases, thus providing support for future clinical drug trials using
      imaging biomarkers.
    

Detailed Description

      Tau protein has been identified as one of the key pathological features of Tau protein
      diseases such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP),
      frontotemporal dementia (FTD). Tau protein targeting PET imaging can detect the amount and
      distribution of Tau protein deposition in human body. It has significant research and
      application value in diagnosis and evaluation for Tau protein diseases. Previous studies have
      shown that Tau radiotracer can detect Tau pathology in early stage of AD, and Tau signal
      increases as the disease progresses. In addition, Tau binding may be associated with
      increased cognitive impairment in AD subjects. [18F] APN-1607 is a newly developed PET
      imaging agent targeting to Tau protein, which has high affinity with Tau protein in brain
      tissue of AD patients, high selectivity for Aβ protein, MAO-A and MAO-B, and no non-specific
      uptake in normal brain tissue. Toxicological studies show that intravenous injection of [18F]
      APN-1607 with dosage less than 20μg is safe. Its clinical research has been initiated in the
      United States, Japan and Taiwan.

      Synaptic vesicle glycoprotein 2 (SV2) is a membrane protein in presynaptic envelope. SV2 is
      an important component of normal synaptic function and plays an important role in
      neurotransmitter release. Three isomers of SV2 are known, of which SV2A is the only subtype
      distributed throughout the brain. Studies have shown that synaptic loss in hippocampus and
      cerebral cortex is closely related to cognitive impairment in Alzheimer's disease. Therefore,
      PET imaging and quantification of SV2A signal may be an excellent representative of synaptic
      density in vivo, which can be used to measure the brain level of SV2A in Alzheimer's disease,
      Parkinson's disease or other neurological and psychiatric diseases, and potentially as a
      biomarker of synaptic density in neurodegenerative diseases. Researchers have reported the
      development and evaluation of 18F labeled tracers for SV2A protein imaging. The best
      candidate [18F] MNI-1126 has shown excellent in vivo binding properties in preliminary
      studies in non-human primates. These preliminary in vivo pre-clinical evaluations suggest
      that [18F] MNI-1126 exhibits excellent quality as a F-18 labeled PET tracer for multicenter
      SV2A imaging trials.

      The greatest advantage of PET imaging technology is that it can visualize the structure or
      function of tissues and organs which could not be observed in vivo without trauma. Visual
      observation of the distribution of radioactivity concentration in PET images can
      qualitatively distinguish the positive and negative cases. Standard uptake value ratio (SUVR)
      can be used to semi-quantitatively analyze the abnormal uptake of a region of interest in
      patients for clinical and daily work. However, in the development of new molecular targeting
      markers, in order to make better use of the information in images to obtain the parameters
      and contents of molecular markers such as distribution, miss targeting or not, condition for
      blood-brain barrier passage ,and stability, a complete set of quantitative and repetitive
      detection and analysis methods should be applied. It includes detection of radioactivity in
      arterial blood, detection of metabolites of molecular markers, dynamic modeling of PET,
      repeated measurement and analysis, and so on.

      Measuring radioactive activity of arterial blood is a method to obtain the input parameters
      of molecular targeted markers in the brain by detecting the radioactivity of per unit volume
      in arterial blood at multiple time points. High Performance Liquid Chromatography (HPLC) can
      be used to detect the metabolites of molecular markers with radioactivity, which can be used
      to calibrate the total radioactivity of arterial blood samples and obtain the concentration
      of free molecular targeted markers in arterial plasma. On the basis of acquiring the input
      parameters of brain molecular targeting markers, the dynamic behavior of a given PET tracer
      can be described by establishing a dynamic model of radiotracer and estimating the relevant
      parameters. The required data can be obtained under the minimum possible traumatic
      conditions, and then the parameters related to physiological, biochemical or metabolic
      processes can be quantitatively estimated. Then through repeated measurements of brain
      molecular targeting markers, that is, multiple scans of the same molecular marker and the
      same patient at different time points, the results of the two scans can be qualitatively and
      quantitatively analyzed and compared, and the pharmacokinetics of the markers in the brain,
      the properties of binding targets and the stability between batches can be further obtained.
      However, because of the intolerance of patients and other factors in the study of arterial
      blood radioactivity detection and repeated measurement for radioactive markers, although it
      is a mature PET-related research technology around the world, it has not been effectively
      carried out in China.

      In this study, we will introduce a complete quantitative and repetitive analysis method for
      the first time in China to evaluate the cross-sectional imaging of Tau protein tracer
      [18F]APN-1607 and SV2a tracer [18F] MNI-1126 in patients with Tau protein-related diseases
      and normal controls. Subsequently, the longitudinal changes of Tau protein deposition and
      synaptic density in the brain of patients with Tau protein-related diseases will be explored
      through the evaluation of longitudinal clinical symptoms and follow-up of two kinds of tracer
      ([18F]APN1607 and [18F]MNI1126) imaging in patients with Tau protein-related diseases and
      normal controls, so as to provide support for the design of clinical trials using imaging
      biomarkers in the future.
    


Study Type

Observational


Primary Outcome

The difference of Tau protein deposition and SV2a protein between patients with Tau protein-related diseases and healthy controls


Condition

Alzheimer Disease


Study Arms / Comparison Groups

 Cross-sectional validation study
Description:  Each tracer's study will enroll 5 normal controls and 5 cases for each relevant disease, which means [18F]APN-1607 imaging with arterial line will be performed in 5 normal controls, 15 patients with Alzheimer's disease patients, progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD), and [18F] MNI-1126 imaging with Aline test will be performed in 5 normal controls, 15 patients with Alzheimer's disease, progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD); a total of 40 patients will be enrolled in this study group. Patients may choose to participate in the cross-sectional validation study for both tracers, or only for one of them.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

155

Start Date

November 18, 2020

Completion Date

December 31, 2022

Primary Completion Date

December 31, 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Males and females aged 40 to 80 years.

          -  Females have no fertility due to surgery or at least one year after menopause.
             Otherwise, pregnancy tests should be conducted during screening and every scan visit
             and should be negative. Males with fertility must use two methods of contraception
             during the study period and one of them should be barrier contraception. No sperm
             donation is allowed during the study period and within 90 days after the completion of
             this study.

          -  The subject and the subject's legally authorized representative or caregiver should be
             willing and able to cooperate during the whole research process. According to the
             judgement of the researcher, there can be a research companion who has regular and
             sufficient contact with the subjects (spend more than 10 hours a week together). The
             companion can provide accurate information about the cognitive and functional aspects
             of the subject, and agrees to accompany the subjects and provide relevant information
             during the visits. Research companions must be confirmed by researchers that they have
             sufficient cognitive ability to accurately report subjects' behavior, cognition and
             function, and can accompany throughout the whole research process with subjects.

          -  Researchers believe that the subject can complete all the relevant contents of this
             study.

        Exclusion Criteria:

          -  Current or prior history of any alcohol or drug abuse within the past 3 years (self
             report).

          -  Laboratory tests or ECG with clinically significant abnormalities and/or clinically
             significant unstable medical illness.

          -  Radiation exposure received from clinical care prior participation in the last year,
             combined with that from the present study, exceeds an effective dose of 50 mSV.

          -  Pregnant, lactating or breastfeeding or intention to become pregnant.

          -  Evidence of clinically significant gastrointestinal, cardiovascular, hepatic, renal,
             hematological, neoplastic, endocrine, alternative neurological, immunodeficiency
             (including a positive HIV result), pulmonary, or other disorder or disease. Stable,
             treated chronic medical conditions like hypertension, hypercholesterolemia, diabetes
             mellitus, non-metastatic dermatologic or prostatic cancer, etc. are acceptable as long
             as they do not, in the investigator's opinion, contribute to cognitive dysfunction or
             limit participation in study procedures.

          -  In the opinion of the investigator, unsuitable to complete lumbar puncture. For
             example: history of vertebral deformities, major lumbar back surgery, clinically
             significant back pain, clinically significant abnormal x-ray, and/or injury or taking
             blood thinners or lab results that would preclude the subject/patient participation or
             CSF collection during study.

          -  MRI exclusion criteria include: findings that may impact cognition such as significant
             evidence of cerebrovascular disease (more than two lacunar infarcts, any territorial
             infarct >1cm3, or deep white matter abnormality corresponding to an overall Fazekas
             scale of 3, with at least one confluent hyperintense lesion on the FLAIR sequence that
             is ≥20 mm in any dimension), infectious disease, space-occupying lesion, normal
             pressure hydrocephalus, CNS trauma, or any other structural abnormality that may
             impact cognition.

          -  Veins are not suitable for repeated puncture.

          -  Implants such as implanted cardiac pacemakers or defibrillators, insulin pumps,
             cochlear implants, metallic ocular foreign body, implanted neural stimulators, CNS
             aneurysm clips and other medical implants that have not been certified for MRI, or
             history of claustrophobia in MRI.

          -  Daily treatment with anticholinergic antidepressants, typical antipsychotics, or
             barbiturates, daily treatment with benzodiazepines, opiates, or opioids; treatment
             with soporifics, stimulants, atypical antipsychotics, centrally acting anticholinergic
             antihistamines, or centrally acting anticholinergic antispasmodics is prohibited,
             unless administered intermittently and on a short-term basis and not used within 5
             half-lives prior to screening or any neurocognitive assessment.

          -  Treatment with soporifics, stimulants, atypical antipsychotics, centrally acting
             anticholinergic antihistamines, or centrally acting anticholinergic antispasmodics is
             prohibited unless (a) administered daily that initiation or discontinuation of therapy
             or dose change does not occur within 5 half-lives prior to screening or at any point
             during the study, or (b) administered intermittently and on a short-term basis and not
             used within 5 half-lives prior to screening or any neurocognitive assessment.

          -  Treatment with any therapeutic molecule or treatment that targets Aβ or Tau within 12
             months prior to screening.

          -  Have participated in a clinical trial within 30 days prior to screening or within 5
             half-lives since last administration of investigational drug (whichever is greater).

          -  Researchers consider that other diseases or causes might prevent subjects from
             completing the entire study.

          -  Others that do not meet the specific inclusion/exclusion criteria of each part of this
             study.
      

Gender

All

Ages

40 Years - 80 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Biao Chen, M.D., Ph.D, 13466660933, [email protected]

Location Countries

China

Location Countries

China

Administrative Informations


NCT ID

NCT05260151

Organization ID

2019SQGH5295


Responsible Party

Principal Investigator

Study Sponsor

Xuanwu Hospital, Beijing

Collaborators

 XINGIMAGING LLC

Study Sponsor

Biao Chen, M.D., Ph.D, Principal Investigator, Xuanwu Hospital, Beijing


Verification Date

February 2022