Biomarkers of CASH

Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH)

The project aims to develop prognostic and diagnostic blood tests for symptomatic brain hemorrhage in patients diagnosed with cavernous angiomas, a critical clinical challenge in a disease affecting more than a million Americans. We further examine whether blood biomarkers can replace or enhance the accuracy of advanced imaging in association with lesional bleeding. The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease, with a clinically relevant context of use.

Study Overview

• Status: Recruiting
• Conditions: Cerebral Cavernous Malformation; Cavernous Angioma; Hemorrhagic Microangiopathy
• Intervention / Treatment: Other: observational

Detailed Description

Cerebral cavernous angioma (CA) is a capillary microangiopathy affecting more than a million Americans, predisposing them to a premature risk of brain hemorrhage. Fewer than 200,000 cases who have suffered a recent symptomatic hemorrhage (SH) are most likely to re-bleed again with serious clinical sequelae, and are the primary focus of therapeutic development. Genetic mechanisms of CA have been extensively studied, and consequent signaling aberrations in the neurovascular unit. These include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammation and immune mediated processes, anticoagulant vascular domain, and gut microbiome-driven mechanisms. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and hemorrhage leak on magnetic resonance imaging (MRI) have been correlated with CA hemorrhage in pilot studies. It would be desirable to optimize these biomarkers to accurately diagnose CASH, to prognosticate the risk of future SH, and to monitor cases after a bleed and in response to therapy. This would influence clinical management, and select higher risk cases for clinical trials. Additional candidate biomarkers are emerging from ongoing mechanistic and differential transcriptome studies, which would be expected to further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Weighed combinations of levels of plasma proteins and characteristic micro-ribonucleic acids (miRNA) may further strengthen biomarker associations. Plasma biomarkers may reflect (and potentially replace) more cumbersome and expensive imaging biomarkers for monitoring CA hemorrhage. We here assemble CA researchers and propose to deploy advanced statistical and computational biology approaches for the integration of novel candidate biomarkers. In Specific Aim 1 we assess these biomarkers in a large CA cohort to discover the best plasma biomarkers and validate them in sex, age and relevant clinical subgroups. In Specific Aim 2 we compare changes in MRI measures of vascular permeability and hemorrhage with plasma biomarkers over time. In Specific Aim 3 we query the biomarkers in non-CA subjects, to identify potential confounders in the clinical context. This project integrates analytic and computational biology expertise to develop blood tests for better CASH diagnosis and prognosis. The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use. This approach is applicable to other neurological diseases with similar pathobiologic features.

• Study Type: Observational
• Enrollment (Estimated): 1040

Contacts and Locations

• Study Contact: Name: Agnieszka Stadnik, MS; Phone Number: 7737028896; Email: astadnik@surgery.bsd.uchicago.edu

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Recruiting
      • Barrow Neurological Institute at St. Joseph's Hospital and Medical Center
      • Contact: Jennifer Cibrian, MPH; Phone Number: 602-406-3678; Email: neurosurgeryresearch@dignityhealth.org
      • Contact: Amanda Land, BSN; Phone Number: 602-406-2575; Email: neurosurgeryresearch@dignityhealth.org
      • Principal Investigator: Michael T Lawton, MD
  • California
    • San Francisco, California, United States, 94117
      • Recruiting
      • University of California, San Francisco
      • Contact: Helen Kim, PhD; Phone Number: 628-209-8906; Email: helen.kim2@ucsf.edu
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • The University of Chicago Medical Center
      • Principal Investigator: Issam A Awad, MD
      • Contact: Justine Hsu, BSN; Phone Number: 773-834-1485; Email: justinelee89@bsd.uchicago.edu
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
      • Contact: Kelly Flemming, MD; Phone Number: 507-266-4143; Email: flemming.kelly@mayo.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

We propose to recruit human subjects at three sites, with the project approved and coordinated by the University of Chicago Medicine (UCM) central institutional review board (IRB) and endorsed by respective IRBs at the other two enrolling sites. The study involves no more than minimal risks, discussed herein. The enrolling sites include UCM where the project will be led and where the data coordinating center (DCC) is located and all plasma biomarker assays and statistical analyses are planned, the University of California at San Francisco (UCSF), and Mayo Clinic, Rochester, MN (Mayo). UCSF and Mayo are participants in imaging biomarker validations in longitudinal follow-up of cavernous angioma with symptomatic hemorrhage (CASH) subjects in the TR Project. We project enrolling 1,040 cases during 4 years to address hypotheses in 3 Specific Aims (40 cases enrolled in Specific Aim 2 are also included among the 800 subjects addressing hypotheses of Specific Aim 1).

Description

Aim 1 and 2:

Inclusion Criteria:

1. Clinical diagnosis of CA
2. age 18 or older
3. solitary or multiple
4. familial or sporadic
5. with or without prior symptoms

Exclusion Criteria:

1. Prior excision of a solitary CA lesion
2. prior stereotactic radiosurgery or any brain irradiation
3. spinal cavernoma without brain lesion
4. other brain pathology unrelated to CA (demyelinating disease, brain tumor)
5. seizures or stroke unrelated to CA in the prior year
6. current pregnancy or within 6 months postpartum
7. reluctance to undergo venipuncture or donate blood specimen, or be called for clinical follow-up for up to one year
8. homeless or incarcerated persons, or other reason a subject will be unable/unlikely to be reached for follow-up

Aim 3:

Inclusion Criteria:

1. < 30 years of age
2. one or more seizures (with or without medical therapy) in the prior year

OR

1. > 50 years of age
2. having received an MRI of the brain with SWI (susceptibility weighted imaging) sequences for any indication in the year prior to enrollment
3. No HMA on brain MRI SWI sequences

OR

1. > 50 years of age
2. having received an MRI of the brain with SWI sequences for any indication in the year prior to enrollment
3. Two or more microbleeds on SWI brain MRI sequences, adjudicated by neuroradiologist

Exclusion Criteria:

1. concurrent brain disease or structural brain pathology
2. medical illness requiring hospitalization or surgery, seizure or stroke in the prior 12 months
3. active use of prescription medications in the prior 12 months
4. current pregnancy or within 6 months postpartum
5. reluctance to undergo venipuncture or donate blood specimen

OR

1. concurrent brain disease or structural brain pathology
2. medical illness requiring hospitalization or surgery, or stroke in the prior 12 months other than seizure disorder
3. active use of prescription medications in the prior 12 months except anticonvulsants
4. current pregnancy or within 6 months postpartum
5. reluctance to undergo venipuncture or donate blood specimen

OR

1. concurrent brain disease or structural brain pathology
2. medical illness requiring hospitalization or surgery within the prior year
3. any history of stroke or epileptic seizure within the prior year
4. current pregnancy or within 6 months postpartum
5. reluctance to undergo venipuncture or donate blood specimen

OR

1. concurrent brain disease or structural brain pathology
2. medical illness requiring hospitalization or surgery within the prior year
3. any history of stroke or epileptic seizure within the prior year
4. current pregnancy or within 6 months postpartum
5. reluctance to undergo venipuncture or donate blood specimen

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CA (non-CASH); Cavernous Angioma (CA) without symptomatic hemorrhage cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting	Other: observational; There is no intervention for any group in this observational study.
CA (CASH); Cavernous Angioma (CA) with Symptomatic Hemorrhage (SH) cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting	Other: observational; There is no intervention for any group in this observational study.
Young with seizure; Young (<30 years old) healthy control cohorts with seizures in the prior year	Other: observational; There is no intervention for any group in this observational study.
Young without seizure; Young (<30 years old) healthy control cohorts without seizures in the prior year	Other: observational; There is no intervention for any group in this observational study.
Older with HMA; Older (>50 years old) with hemorrhagic microangiopathy (HMA)	Other: observational; There is no intervention for any group in this observational study.
Older without HMA; Older (>50 years old) without hemorrhagic microangiopathy (HMA)	Other: observational; There is no intervention for any group in this observational study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating Diagnostic and Prognostic Biomarkers of CASH	To test whether individual and combined levels of candidate plasma proteins and miRNAs can be associated with diagnosis of CASH (cross sectional) and can predict/prognosticate future SH (longitudinal) in CAs	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of Imaging and Plasma Biomarkers of CASH	To assess whether changes in QSM (quantitative susceptibility mapping) and DCEQP (dynamic contrast enhanced quantitative permeability) used as monitoring biomarkers after a SH, are reflected by changes in plasma biomarkers and miRNAs	5 years
Confounders of CASH Biomarkers	To assess the plasma biomarkers in non-CA young and older subjects, with and without seizures and hemorrhagic microangiopathy on MRI, to clarify potential confounders in the context of clinical use, and to motivate novel hypotheses for broader applications	5 years

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: Mayo Clinic; National Institute of Neurological Disorders and Stroke (NINDS); University of California, San Francisco; Barrow Neurological Institute
• Investigators: Principal Investigator: Issam Awad, MD, University of Chicago

Publications and helpful links

General Publications

• Girard R, Li Y, Stadnik A, Shenkar R, Hobson N, Romanos S, Srinath A, Moore T, Lightle R, Shkoukani A, Akers A, Carroll T, Christoforidis GA, Koenig JI, Lee C, Piedad K, Greenberg SM, Kim H, Flemming KD, Ji Y, Awad IA. A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH). Neurosurgery. 2021 Feb 16;88(3):686-697. doi: 10.1093/neuros/nyaa478.

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2020
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: July 8, 2020
• First Submitted That Met QC Criteria: July 8, 2020
• First Posted (Actual): July 13, 2020

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: machine learning; plasma biomarker; imaging biomarker
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Cardiovascular Abnormalities; Neoplasms, Vascular Tissue; Nervous System Malformations; Vascular Malformations; Central Nervous System Vascular Malformations; Hemangioma; Hemangioma, Cavernous, Central Nervous System; Hemangioma, Cavernous
• Other Study ID Numbers: IRB20-0518

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Within the first year, we will publish the protocol paper. At the end of the 5 year study, we will publish the data dictionary along with study findings. The expression profile data will be made publicly available no later than the date of initial publication or six months after the receipt of the final sequencing data, whichever comes first.
• IPD Sharing Time Frame: The expression profile data will be made publicly available no later than the date of initial publication or six months after the receipt of the final sequencing data, whichever comes first.
• IPD Sharing Access Criteria: The expression profile data will be made publicly available.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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