MRI-visible Enlarged Perivascular Spaces and the Alteration of Lymphatic Drainage System in CAA (CAA)

• ClinicalTrials.gov Identifier: NCT04604587
• Recruitment Status: Recruiting
• First Posted: October 27, 2020
• Last Update Posted: October 27, 2020
• Sponsor: National Taiwan University Hospital
• Information provided by (Responsible Party): National Taiwan University Hospital

Study Description

Brief Summary:

In this three-year proposal, we will explore the MRI-visible EPVS in CAA and investigate its pathophysiology using animal models. Our specific aims include: (1) Establish the relationship of MRI-visible enlarged perivascular space and CAA, (2) Determine whether vascular amyloid clearance in CAA is associated with lymphatic drainage system, (3) Establish longitudinal data for MRI-visible enlarged perivascular space and cerebral amyloid angiopathy progression.

Condition or disease	Intervention/treatment	Phase
Cerebral Amyloid Angiopathy; Intracerebral Hemorrhage	Drug: 1. amyloid PET；2. T807 PET	Phase 3

Detailed Description:

Cerebral amyloid angiopathy (CAA) involves amyloid deposition in the vessel walls in the cerebral cortex and overlying leptomeninges, causing symptomatic intracerebral lobar intracerebral hemorrhage (ICH) in the elderly. CAA is considered as a form of cerebral small vessel disease, which refers to a group of vascular pathologies that affect the small vessels of the brain. In addition to lobar ICH, patients may present with other parenchymal injuries that can be detected on blood-sensitive MRI, such as multiple strictly lobar cerebral microbleeds, cortical superficial siderosis and leukoariosis. Recently, CAA has been suggested in association with MRI-visible enlarged perivascular space (EPVS) in centrum-semiovale (CSO), contrary to more severe MRI-visible EPVS in basal ganglia that is frequently found in chronic hypertension. The dilated perivascular space in CAA is suggestive of chronic poor perivascular drainage of the leptomeningeal arteries, predisposing individuals to impaired or altered meningeal lymphatic drainage and causing defect in amyloid clearance and subsequent CAA development. Nevertheless, it is unknown whether lymphatic drainage are the main routes for vascular amyloid clearance, and its relationship to the long-term outcome has not been clearly investigated in clinical patients yet.

In this three-year proposal, we will explore the MRI-visible EPVS in CAA and investigate its pathophysiology using animal models. Our specific aims include: (1) Establish the relationship of MRI-visible enlarged perivascular space and CAA, (2) Determine whether vascular amyloid clearance in CAA is associated with lymphatic drainage system, (3) Establish longitudinal data for MRI-visible enlarged perivascular space and cerebral amyloid angiopathy progression. In the first year, we will recruit spontaneous ICH patients for brain MRI, in vivo amyloid imaging and measuring their plasma Aβ40/42 levels. We aim to confirm EPVS in CSO as a specific marker for CAA, and to provide direct evidence that dilated perivascular space is worse with more advanced CAA; For the second year, we plan to use transgenic CAA mouse models to confirm that meningeal lymphatic drainage routes are crucial for clearance of vascular amyloid-β. We will manipulate the lymphatic drainage routes by either blockage or enhancement of the lymphatic vessels, to see if the vascular amyloid clearance is affected; For the third year, the main research focus will on be establishing the longitudinal data on amyloid and tau deposition in clinical ICH patients. We plan to repeat in vivo amyloid imaging in 2 years, for the purpose of validating our hypothesis in human that baseline worse lymphatic drainage function is associated with quicker cerebral vascular amyloid progression or prediction of future CAA development. We will also recruit patients for in vivo tau imaging to investigate long-term neuronal injury and neurodegeneration, namely tau-mediated neurofibrillary tangle, in relation to the impaired perivascular drainage in CAA.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: MRI-visible Enlarged Perivascular Spaces and the Alteration of Lymphatic Drainage System in Cerebral Amyloid Angiopathy
• Actual Study Start Date: October 8, 2020
• Estimated Primary Completion Date: July 31, 2023
• Estimated Study Completion Date: July 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: amyloid PET、T807 PET; PET/CT	Drug: 1. amyloid PET；2. T807 PET; Dynamic PET acquisition for 70 minutes will be acquired after injection of 10±5 mCi 11C-PiB; Dynamic PET imaging 3D acquisition will be acquired 80 minutes after injection of 10 mCi 18F-T807

Outcome Measures

Primary Outcome Measures :

1. PET imaging [ Time Frame: in 3 days ]
   PET data will reconstruct with ordered set expectation maximization, corrected for attenuation, and each frame will be evaluated to verify adequate count statistics and absence of head motion.

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age：above 20 years old.
2. Evidence of intraparenchymal hemorrhage on CT or MRI.
3. Patient agrees to participate in the study and receive neurophsychological examinations, genetic and biochemical markers test, MRI and PET imaging.

Exclusion Criteria:

1. patients with potential causes of hemorrhage including trauma, structural lesion, brain tumor, or coagulopathy due to systemic disease or medication.
2. Patients could not receive the PET and MRI studies, including but not limited to poor cooperative agitation impeding adequate study, allergy to contrast medium, hemodynamic instability, implantation of cardiac pacemaker, past history of receiving aneurysm clipping, panic mood to MRI study, impaired kidney function.
3. Patients with pregnancy or recently having a plan for pregnancy.
4. Patients with breast feeding or recently having a plan for breast feeding.
5. Patients with history of allergy to 11C-PiB and 18F-T807, or severe allergy history.
6. Patient or family who does not agree to participate in the study.
7. patient with high risk by doctor evaluate.

Contacts and Locations

Locations

Taiwan

National Taiwan Univeristy Hospital; Recruiting

Taipei, Taiwan, 100

Contact: Yen Ruoh Fang, MD, PhD 886-2-23123456 ext 65581 rfyen@ntu.edu.tw

Sponsors and Collaborators

National Taiwan University Hospital

More Information

• Responsible Party: National Taiwan University Hospital
• ClinicalTrials.gov Identifier: NCT04604587
• Other Study ID Numbers: 201912003MINC
• First Posted: October 27, 2020
• Last Update Posted: October 27, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Taiwan University Hospital:

Cerebral Amyloid Angiopathy; Intracerebral Hemorrhage; Magnetic resonance imaging; Position emitting topography

Additional relevant MeSH terms:

Cerebral Hemorrhage; Cerebral Amyloid Angiopathy; Cerebral Amyloid Angiopathy, Familial; Amyloidosis; Hemorrhage; Pathologic Processes; Proteostasis Deficiencies; Metabolic Diseases; Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Cerebral Small Vessel Diseases; Amyloidosis, Familial; Metabolism, Inborn Errors; Genetic Diseases, Inborn