Multimodal Biomarkers for Diagnosis and Prognosis in CAA (CAA)

Multimodal Biomarkers for Diagnosis and Prognosis in Cerebral Amyloid Angiopathy

By combination of plasma (Aβ40, Aβ42, total tau, and phosphorylated tau, etc.), genetic (ApoE ε2 or ε4 allele), MRI (cerebral perfusion, microbleeds, cortical superficial siderosis, enlarged perivascular space, etc.) and PET imaging (amyloid and tau) biomarkers, the study aims to

1. Enhance the diagnostic potentials of the radiological biomarkers by combining MRI and amyloid PET in CAA patients.
2. Investigate the biological pathogenesis in CAA patients using the less invasive plasma biomarkers and to correlate with structural and function imaging, including MRI, amyloid and tau imaging.
3. Study the characteristics of long-term progression of amyloid deposition in CAA patients using the radiological, biochemical and genetic biomarkers.
4. Study the prognosis predicting markers.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease; Intracranial Hemorrhages; Cerebral Amyloid Angiopathy
• Intervention / Treatment: Drug: 1. amyloid PET；2. T807 PET

Detailed Description

Intracranial hemorrhage (ICH) consists of about a quarter of stroke subtype. For elderly, cerebral amyloid angiopathy (CAA) is a common etiology of ICH. In National Taiwan University Hospital, we have established a CAA team including neurologists, radiologists and nuclear medicine physicians since 2014. We hope to go deep into the diagnosis and pathophysiology of CAA. To the best of our knowledge, there is no other CAA team in Taiwan.

In patients with CAA, abnormal beta amyloid protein diffusely deposits at cerebral vasculatures, which disrupts the normal vessel structure and increases the risk of bleeding. The standard diagnosis for CAA requires pathological evidences of amyloid deposition at cerebral arteries. Clinically, a diagnosis of CAA-related ICH is usually only made in an elderly developing cortical or subcortical lobar ICH without undergoing biopsy. Brain images using the SWI sequence of MRI study may show lobar microbleeds in patients with CAA. However, there is still no direct and precise non-invasive diagnostic tool for CAA until now.

Amyloid PET, using 11C-PiB to image amyloid burden, has been used for detecting the cerebral amyloid protein deposition in patients with Alzheimer's dementia (AD) for years. Recently, amyloid PET has also been applied in the diagnosis of CAA. CAA patients showed diffusely increased global PiB retention as compared to control subjects and the distribution of PiB retention is also different from that seen in patients with AD in general. Nevertheless, the applications of amyloid PET in CAA diagnosis are still not well established and many important issues still need to be extensively addressed. Furthermore, tau PET has emerged as a potential molecular imaging marker for SVD. Tau PET provides a noninvasive method for measuring brain tau load. The correlation of tau PET findings in patients with CAA has not been investigated before.

In addition, ApoE gene has been reported to be risk factor for sporadic CAA as well as AD. Biochemical biomarkers, such as the levels of Aβ40 and Aβ42, also help us understand the pathophysiology of CAA. Recently, immunomagnetic reduction (IMR) assay, using bio-functionalized magnetic nanoparticles, has been proved to be a sensitive and accurate tool for the detection of these biological molecules.

By combination of plasma (Aβ40, Aβ42, total tau, and phosphorylated tau, etc.), genetic (ApoE ε2 or ε4 allele), MRI (cerebral perfusion, microbleeds, cortical superficial siderosis, enlarged perivascular space, etc.) and PET imaging (amyloid and tau) biomarkers, the study aims to

1. Enhance the diagnostic potentials of the radiological biomarkers by combining MRI and amyloid PET in CAA patients.
2. Investigate the biological pathogenesis in CAA patients using the less invasive plasma biomarkers and to correlate with structural and function imaging, including MRI, amyloid and tau imaging.
3. Study the characteristics of long-term progression of amyloid deposition in CAA patients using the radiological, biochemical and genetic biomarkers.
4. Study the prognosis predicting markers.

• Study Type: Interventional
• Enrollment (Anticipated): 240
• Phase: Phase 3

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 100
    • Recruiting
    • National Taiwan Univeristy Hospital
    • Contact: Yen Ruoh Fang, MD, PhD; Phone Number: 65581 886-2-23123456; Email: rfyen@ntu.edu.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ICH：

  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.

• AD：

  1. Age：above 20 years old.
  2. Patients who fulfills the clinical criteria of possible or probable Alzheimer's disease (AD).51
  3. Patient agrees to participate in the study and receive neurophsychological examinations, genetic and biochemical markers test, MRI and PET imaging.

• Control：

  1. Age：above 20 years old.
  2. Patient agrees to participate in the study and receive neurophsychological examinations, genetic and biochemical markers test, MRI and PET imaging.

Exclusion Criteria:

• ICH：

  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.

• AD：

  1. 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.
  2. Patients with pregnancy or recently having a plan for pregnancy.
  3. Patients with breast feeding or recently having a plan for breast feeding.
  4. Patients with history of allergy to 11C-PiB and 18F-T807, or severe allergy history.
  5. Patient or family who does not agree to participate in the study.
  6. patient with high risk by doctor evaluate.

• Control：

  1. History of neurological or psychiatric disease, abnormal neurological examination.
  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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: amyloid PET、T807 PET; PET/CT	Drug: 1. amyloid PET；2. T807 PET; Dynamic PET acquisition for 60 minutes will be acquired after injection of 10 mCi 11C-PiB (39 frames: 8 x 15 seconds, 4 x 60 seconds, 27 x120 seconds).; Dynamic PET imaging 3D acquisition will be acquired 80 minutes after injection of 10 mCi 18F-T807 (4 x 300 seconds)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PET imaging	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.	in 3 days

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2018
• Primary Completion (Anticipated): July 31, 2022
• Study Completion (Anticipated): July 31, 2022

Study Registration Dates

• First Submitted: May 29, 2019
• First Submitted That Met QC Criteria: May 29, 2019
• First Posted (Actual): May 31, 2019

Study Record Updates

• Last Update Posted (Actual): March 12, 2021
• Last Update Submitted That Met QC Criteria: March 10, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: MRI; Stroke; intracerebral hemorrhage; amyloid PET; ApoE; cerebral amyloid angiopathy; Aβ; tau PET
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Neurodegenerative Diseases; Proteostasis Deficiencies; Metabolism, Inborn Errors; Dementia; Tauopathies; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Cerebral Small Vessel Diseases; Amyloidosis, Familial; Hemorrhage; Amyloidosis; Alzheimer Disease; Intracranial Hemorrhages; Cerebral Amyloid Angiopathy; Cerebral Amyloid Angiopathy, Familial
• Other Study ID Numbers: 201612094MINB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No