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Familial Cerebral Cavernous Malformation

Aim 1: To investigate the relationship between lesion burden and outcomes in familial CCM.

Aim 2: To investigate the role of the gut microbiome in familial CCM disease severity.

Aim 3: To establish blood markers predictive of disease severity and progression for medical treatment of CCM.

Helen Kim, PhD

Phillip Evans

Mikayla Carlson

Joseph Zabramski, MD

Michael T. Lawton, MD

Eliel Rios Leon

Nerissa U. Ko, MD

Agnieszka Stadnik, MS, CCRP

Issam Awad, MD

Adam Porter, MPH

Edward R Smith, MD

Edward R. Smith, MD

Dawn Aldridge, RN

Michel Torbey, MD

Marc Mabray, MD

Sarah Mierke

Sudhakar Vadivelu, DO

Cerebral cavernous malformations (CCMs) are clusters of abnormal blood vessels in the brain and spine. CCMs can bleed and cause strokes, seizures, and headaches. CCMs are often caused by an inherited gene mutation (alteration) in one of three CCM genes (CCM1, CCM2, or CCM3). There is a wide range of disease severity even among family members with this disease, though the natural history has not been clearly described for this particular population.

This study will continue to enroll and follow participants with familial CCM to identify factors that influence CCM disease severity and progression, focusing on barriers to clinical trial preparedness. Our long-term goal is to identify measurable outcomes and robust biomarkers that will help select high-risk patients and help monitor drug response in future clinical trials.

The specific goals of this study are to:

* Identify factors that influence lesion progression to symptomatic hemorrhage and other outcomes, including quality of life;
* Investigate the role of the gut microbiome and lesion burden in CCM disease, and
* Identify blood biomarkers predictive of CCM disease severity and progression for clinical trials.

This study is one of three projects participating in the Brain Vascular Malformation Consortium (BVMC) funded by the Office of Rare Diseases Research, which is part of the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Neurological Disorders and Stroke (NINDS).

The CCM project is a cross-sectional and longitudinal study of familial CCM patients. The study is currently in the third 5-year cycle. During the first 5 year cycle (BVMC1), the CCM project was focused on recruiting CCM1 cases with the common Hispanic mutation (CHM). In the second 5-year cycle (BVMC2), we expanded recruitment to include not only CCM1-CHM cases, but also other CCM familial patients and mutation carriers. In the third 5-year cycle (BVMC3), we will continue to recruit familial CCM cases and expand to additional recruitment sites.

We collect clinical, genetic, imaging, treatment, and outcome data in participants, and follow enrolled participants over time to understand the natural history of this disease.

For new study participants, you will be asked to:

* Give permission for study staff to access your medical records to collect clinical information and to obtain copies of MRI scans and reports.
* Fill out a questionnaire about your quality of life, family history, and medical/surgical history.
* Give a blood and/or saliva sample, and stool sample.
* Give permission to store and use your CCM resected tissue for research (if undergoing surgery).
* Participate in annual follow-ups to update medical, surgical, and neurological information.

Eligible cases include those with a known genetic mutation in one of the three CCM genes or those that meet 2 of 3 following clinical criteria:

1. Clinical diagnosis of CCM,
2. Multi-focal lesions on MRI, and/or
3. Family history of CCMs.

Exclusion Criteria:

1. Patients who cannot or are unwilling to sign informed consent and for whom no appropriate surrogate is available.
2. Prisoners and homeless individuals because of the inability to contact the subject and collect follow-up data using standard procedures.

We will collect stool specimens in newly recruited familial CCM cases. We collect and store saliva as well as whole blood for DNA, RNA, and plasma or serum samples. Brain cavernous malformation tissue will be collected and banked as available.

Modifiers of Disease Severity in Cerebral Cavernous Malformations

Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformations

Available data will be released to the Rare Diseases Clinical Research Network repository and will become available to the scientific community one year after publication of planned analyses, or after a period of 5 years from the date when the data were collected, whichever comes first

Standardized patient reported outcome measurement tools to assess pain, fatigue, physical function, emotional distress, and social participation.

The number of lesions (or cavernous angiomas) located in the brain will be counted by a neuroradiologist and by an automated algorithm developed as part of this project.

Symptomatic hemorrhage is defined as diagnostic evidence of new lesional bleeding or hemorrhagic growth, in association with directly attributable symptoms. Rate of symptomatic hemorrhage and the factors that influence hemorrhage rates will be assessed.

The number of lesions (or cavernous angiomas) counted on the baseline MRI will be compared to the number of lesions observed in follow up MRIs.

The modified Rankin score will be assessed at baseline and at approximately one year intervals while remaining in study

University of New Mexico

University of Chicago

National Institute of Neurological Disorders and Stroke (NINDS)

Boston Children's Hospital

Children's Hospital Medical Center, Cincinnati

Barrow Neurological Institute

Alliance to Cure Cavernous Malformation

University of California, San Francisco

Lipid Regulating Agents

All Drugs and Chemicals

Simvastatin

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Enzyme Inhibitors

20-40 mg tablet taken daily by mouth. Month 1: 20 mg; Months 2 and 3: 40 mg.

Leslie A Morrison, MD

Blaine Hart, MD

Cerebral cavernous malformations (CCMs) are clusters of abnormal blood vessels in the brain and spine. CCMs can bleed and cause strokes, seizures, and headaches. In some patients, CCMs affect the blood brain barrier (BBB). The BBB is the body's separation of blood and its contents in the brain from the brain tissue itself. Abnormal leakiness or permeability of this barrier can cause disease. We will measure the permeability (leakiness) of the BBB using a magnetic resonance imaging (MRI) technique called dynamic contrast-enhanced MRI (DCEMRI). The purpose of this study is to look at whether statin medications change the permeability (leakiness) of the blood brain barrier in CCM patients. Statin medications are used to lower cholesterol levels and prevent heart attack and stroke. In addition, this medication may decrease the risk of brain hemorrhage or bleeding in patients with CCM. This study will examine whether the permeability of the BBB changes following the administration of simvastatin for three months.

Permeability MRI in Cerebral Cavernous Malformations Type 1 in New Mexico: Effects of Statins

We will measure the change in blood brain barrier permeability with dynamic contrast enhanced MRI from baseline to three months. We will compare the change in permeability for a group of CCM patients placed on statin medication (treatment group) with a group of CCM patients not on statin medication (control group).

Use dynamic contrast-enhanced MRI to detect abnormalities in brain permeability in CCM patients and correlate with anatomic lesion information.

Vice Chancellor for Academic Affairs

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Modifiers of Disease Severity in Cerebral Cavernous Malformations	NCT01764529	Cavernous Angio... Cerebral Cavern... Cerebral Cavern...		-	University of California, San Francisco
Permeability MRI in Cerebral Cavernous Malformations Type 1 in New Mexico: Effects of Statins	NCT01764451	Cavernous Angio... Cerebral Cavern... Cerebral Cavern...	Simvastatin	18 Years -	University of New Mexico
Modifiers of Disease Severity in Cerebral Cavernous Malformations	NCT01764529	Cavernous Angio... Cerebral Cavern... Cerebral Cavern...		-	University of California, San Francisco
Modifiers of Disease Severity in Cerebral Cavernous Malformations	NCT01764529	Cavernous Angio... Cerebral Cavern... Cerebral Cavern...		-	University of California, San Francisco

Spots Global Cancer Trial Database for cerebral cavernous hemangioma