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