Symptoms and General Pathology

All Conditions

Diseases and Abnormalities at or Before Birth

Neoplasms

Nervous System Diseases

Heart and Blood Diseases

Blood and Lymph Conditions

Rare Diseases

Hemorrhage

Congenital Abnormalities

Hemangioma

Hemangioma, Cavernous, Central Nervous System

Hemangioma, Cavernous

Neoplasms, Vascular Tissue

Neoplasms by Histologic Type

Syndrome

Brain Diseases

Central Nervous System Diseases

Vascular Malformations

Central Nervous System Vascular Malformations

Nervous System Malformations

Cardiovascular Abnormalities

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Hemorrhagic Disorders

Hematologic Diseases

Familial Cerebral Cavernous Malformation

Cavernous Angioma (CA) without symptomatic hemorrhage cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting

Cavernous Angioma (CA) with Symptomatic Hemorrhage (SH) cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting

Young (\<30 years old) healthy control cohorts with seizures in the prior year

Young (\<30 years old) healthy control cohorts without seizures in the prior year

Older (\>50 years old) with hemorrhagic microangiopathy (HMA)

Older (\>50 years old) without hemorrhagic microangiopathy (HMA)

There is no intervention for any group in this observational study.

observational

Agnieszka Stadnik, MS

Jennifer Cibrian, MPH

Amanda Land, BSN

Michael T Lawton, MD

Helen Kim, PhD

Justine Hsu, BSN

Issam A Awad, MD

Kelly Flemming, MD

Issam Awad, MD

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.

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.

Biomarkers of CASH

Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH)

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.

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

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

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

Mayo Clinic

University of California, San Francisco

National Institute of Neurological Disorders and Stroke (NINDS)

Barrow Neurological Institute

University of Chicago

Behaviors and Mental Disorders

Inflammation

Suicidal Ideation

Necrosis

Suicide

Suicide, Attempted

Self-Injurious Behavior

Behavioral Symptoms

All Drugs and Chemicals

Picolinic acid

Kynurenic Acid

Adolescents admitted to the Cleveland Clinic inpatient child and adolescent psychiatry unit after suicide attempt. Clinical assessments and blood samples; follow-up for 12 mos.

Healthy adolescents with no history of suicide attempt. Clinical assessments and blood samples; no 12mo follow-up.

Kiddie-Sads Present and Lifetime Version Diagnostic Interview, Columbia-Suicide Severity Rating Scale, Suicidal Ideation Questionnaire, Children's Depression Rating Scale-Revised, Multidimensional Anxiety Scale for Children (2nd Ed), Adverse Childhood Experiences Questionnaire, Life Events Checklist-5, Pubertal Development Scale. All assessments administered at baseline, and a smaller subset of assessments administered at discharge and other time points throughout 12 months follow-up. Blood samples taken at baseline (admission to unit) and day of discharge.

Clinical assessments and blood samples; follow-up for 12 mos

Kiddie-Sads Present and Lifetime Version Diagnostic Interview, Columbia-Suicide Severity Rating Scale, Suicidal Ideation Questionnaire, Children's Depression Rating Scale-Revised, Multidimensional Anxiety Scale for Children (2nd Ed), Adverse Childhood Experiences Questionnaire, Life Events Checklist-5, Pubertal Development Scale. All assessments administered at baseline, and a smaller subset of assessments administered at discharge time point (5-7 days after baseline). Blood samples taken at baseline and discharge time points (5-7 days after baseline).

Clinical assessments and blood samples; no 12mo follow-up

Tatiana Falcone, M.D.

Suicide is one of the most devastating events in society at all levels. The primary goal of this study is to predict suicide in adolescents at risk. We will utilize blood biomarker measurement and clinical risk factor scales to develop a tool to identify adolescents at risk for suicide earlier, which will allow clinicians to prescribe timely treatment and prevent suicide.

Suicide, the second leading cause of death in adolescents (15-24 year olds), is the most tragic complication of a psychiatric condition in this age group. Every year, approximately 157,000 youth receive medical care for suicide related injuries at emergency departments throughout the U.S. Despite some progress, suicide prevention continues to be a daunting task. In adolescents, the risk of a second suicide attempt is approximately 30% after discharge from an inpatient psychiatric unit. Up to 80% of suicidal patients who subsequently died by suicide deny suicidal ideation in their last communication with a health care provider. Therefore, there is an urgent need for the development of biomarkers that can objectively identify which youth are most likely to engage in subsequent suicide attempts.

Several lines of evidence (postmortem studies, genetic studies, biomarker studies) as well as preliminary studies conducted by our group have pointed to neuroinflammation as one of the neurobiological findings observed in suicidal behavior. In particular, the principal investigator and co- investigators have identified S100B - an astrocytic protein, which is a marker of blood brain barrier (BBB) impairment, as a novel biomarker associated with suicidality in adolescents. We are now also investigating three additional and important markers Kynurenic Acid (KYNA), Quinolinic Acid (QUIN), and Picolinic Acid (PIC) identified by Dr. Lena Brundin (Van Andel Institute) to be altered in patients after a suicide attempt. Other studies have reported several other peripheral inflammatory markers (PlMs) including interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) as associated with suicidality. Hence, PlMs either on their own or along with clinical markers may be particularly useful in predicting future suicide attempts. This study will investigate whether PIM levels, with or without clinical predictors, can be useful at the time of discharge from an inpatient psychiatric unit to predict suicidality in adolescent patients in the subsequent 12 months. The first aim of this study is to determine whether plasma levels of S100B, IL-1ß, IL-6, TNF-α, KYNA, QUIN, and PIC correlate with suicidal behavior (SB). Secondly, this study will investigate if any of the PlMs can predict suicidal attempts. Finally, we will test which combination of clinical risk factors and PlMs is able to most efficiently predict SB post-discharge from the inpatient unit.

Innovative aspects of this study include: 1) The first study to longitudinally investigate levels of PlMs at the time of admission and their change at the time of discharge in adolescent patients being admitted for SB. 2) The first study to investigate whether level of PIMS (alone or in combination with clinical risk factors) at the time of discharge can predict readmissions for SB in the next 12 months. 3) Beside the well-studied PIMs in adult samples, specifically investigate novel biomarkers of inflammation- S100B and 3 markers of the Kynurenine pathway (KYNA, QUIN and PIC).

Biomarkers as Predictors of Suicidal Risk in Adolescents

Peripheral Neuroinflammatory Predictors of Suicidal Risk at Time of Inpatient Discharge in Adolescents

Comparison of the levels of peripheral inflammatory markers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) between participants with and without suicide attempt

Comparison of the levels of peripheral inflammatory markers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) between baseline and discharge time points

Studying relation between inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) and suicide ideation intensity (scores on Columbia Suicide Severity Rating Scale)

Studying relation between inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) and suicide ideation intensity (Suicidal Ideation Questionnaire)

Studying relation between inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) and depression (scores on Children's Depression Rating Scale, Revised)

Studying relation between inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) and anxiety (scores on Multidimensional Anxiety Scale for Children, 2nd Ed)

Studying relation between inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) and trauma (scores on Adverse Childhood Experiences Questionnaire (ACE) and Life Events Checklist-5 (LEC-5))

Peripheral inflammatory markers: S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid

Studying inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) as suicide attempt risk factors (frequency of attempts)

Studying inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) as suicide ideation intensity risk factors (scores on Columbia Suicide Severity Rating Scale)

Studying inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) as suicide ideation intensity risk factors (scores on Suicidal Ideation Questionnaire)

Studying inflammatory biomarkers (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) as suicide attempt re-admission risk factors (frequency of re-admissions)

Studying the change in inflammatory biomarkers from baseline to discharge (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) as suicide attempt risk factors (frequency of attempts)

Studying the change in inflammatory biomarkers from baseline to discharge (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) as suicide ideation intensity risk factors (scores on Columbia Suicide Severity Rating Scale)

Studying the change in inflammatory biomarkers from baseline to discharge (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) as suicide ideation intensity risk factors (scores on Suicidal Ideation Questionnaire)

Studying the change in inflammatory biomarkers from baseline to discharge (S100B, IL-6, IL-1β, TNF-α, kynurenic acid, quinolinic acid, and picolinic acid) as suicide attempt re-admission risk factors (frequency of re-admissions)

Studying which clinical assessments can help predict suicide attempt (frequency of attempts)

Studying which clinical assessments can help predict suicide ideation intensity scores on Columbia Suicide Severity Rating Scale

Studying which clinical assessments can help predict suicide ideation intensity scores on Suicidal Ideation Questionnaire

Studying which clinical assessments can help predict suicide attempt re-admission (frequency of re-admissions)

Studying which combination of inflammatory biomarkers and clinical predictors best predicts future suicide attempts (frequency of attempts)

Studying which combination of inflammatory biomarkers and clinical predictors best predicts suicide ideation intensity scores on Columbia Suicide Severity Rating Scale

Studying which combination of inflammatory biomarkers and clinical predictors best predicts suicide ideation intensity scores on Suicidal Ideation Questionnaire

Studying which combination of inflammatory biomarkers and clinical predictors best predicts future suicide attempt re-admissions (frequency of re-admissions)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Biomarkers of CASH	NCT04467489	Cerebral Cavern... Cavernous Angio... Hemorrhagic Mic...	observational	18 Years -	University of Chicago
Biomarkers as Predictors of Suicidal Risk in Adolescents	NCT03014518	Suicide, Attemp... Suicidal Ideati... Suicidal Intent... Suicide	Clinical assess... Clinical assess...	12 Years - 18 Years	The Cleveland Clinic
Biomarkers of CASH	NCT04467489	Cerebral Cavern... Cavernous Angio... Hemorrhagic Mic...	observational	18 Years -	University of Chicago

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