Examining Cognitive Function and Brain Abnormalities in Adults With Sickle Cell Disease

Neuropsychological Dysfunction and Neuroimaging Abnormalities in Neurologically Intact Adults With Sickle Cell Disease

Sickle cell disease (SCD), also known as sickle cell anemia, is an inherited blood disease that can cause intense pain episodes and may lead to organ failure. Preliminary studies have shown that adults with SCD may have brain abnormalities that contribute to problems with cognitive functioning, including attention and memory difficulties. This study will use brain magnetic resonance imaging (MRI) and neuropsychological testing to examine the differences in cognitive functioning in adults with SCD and adults without SCD.

212 subjects participated in this cross-sectional study consisting of screening questionnaires, a neuropsychological testing battery, and MRI testing. Enrollment into this study ended in May 2008.

Study Overview

• Status: Completed
• Conditions: Anemia, Sickle Cell
• Intervention / Treatment: Behavioral: NP Battery; Procedure: MRI

Detailed Description

SCD is an inherited blood disorder. Symptoms include anemia, infections, organ damage, and intense episodes of pain, which are called "sickle cell crises." In the past, SCD was considered a fatal disease, and many people with SCD died at a young age. Due to advances in medical care, people with SCD are now living longer lives; however, they often experience a deterioration in quality of life due to progressive organ failure. Past research has suggested that children with SCD commonly have frontal lobe dysfunction syndrome, which is a brain disorder that can affect cognitive functioning in areas such as attention, concentration, information processing, and decision making. Often times, however, neurocognitive and brain disorders are not diagnosed or treated in people with SCD. In preliminary brain imaging studies, at least half of adult participants with SCD had cognitive dysfunction that could be seen in images of the brain, while participants without SCD rarely had visible changes in the brain. Brain dysfunction may be one of the most important and least-studied problems affecting adults with SCD. The purpose of this study is to evaluate the extent of cognitive functioning problems in adults with SCD. The study will also determine if there is a connection between cognitive functioning problems and abnormalities seen on MRI brain images of adults with SCD.

This study is an observational case/control study that will enroll adults with SCD and a control group of healthy adults who do not have SCD. At a study visit on Day 1, participants will undergo blood collection and will complete psychosocial questionnaires. Female participants will provide a urine sample for pregnancy testing. Study researchers will conduct a medical record review, a physical exam, and a neurological exam. They will also interview participants to collect medical history information. On Day 2, participants will undergo either a brain MRI or neuropsychological testing; on Day 3, the other procedure will be completed. On Day 4, study researchers will explain the study procedure results to participants. Participants will be asked if they are willing to take part in a second phase of the study in the future. Enrollment into this study ended in May 2008.

A pilot interventional study follows this study, and is reported separately in ClinicalTrials.gov under NCT 00850018.

• Study Type: Observational
• Enrollment (Actual): 212

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Oakland, California, United States, 94609
      • Children'S Hospital & Research Center At Oakland
  • Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Cancer Institute
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • Children's Medical Center at Dallas
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

212 participants, 160 will have sickle cell anemia, 52 will be matched controls based on gender, age, and education level

Description

Inclusion Criteria:

Individuals who meet all of the following criteria are eligible for enrollment as cases into the study:

1. Adult between the ages of 21 and 55
2. African descent
3. Proficient/fluent in English
4. Hemoglobin electrophoresis confirming hemoglobin SS or SB0 (%A <= 15)
5. Hemoglobin <= 10 g/dL
6. Capable of giving informed consent for the protocol

Individuals who meet all of the following criteria are eligible for enrollment as community controls into the study:

1. Adult between the ages of 21 and 55
2. African descent
3. Proficient/fluent in English
4. Capable of giving informed consent for the protocol

Exclusion Criteria:

Individuals who meet any of the following criteria are disqualified from enrollment in the case group of the study:

1. Overt stroke
2. Previous evidence of an abnormal MRI or CT other than small peri-ventricular or watershed lesions
3. History of head injury that resulted in neurological symptoms or medical visit
4. Abnormal neurologic exam with focal findings
5. Mini-Mental Status Examination (MMSE) score of < 20
6. Profile of Mood States (POMS) score on the Depression-Dejection Subscale suggestive of a clinical depression (score > 40)
7. Alcohol consumption exceeding 14 drinks/week if female, 21 drinks/week if male
8. Drug abuse, defined as using non-prescribed medication
9. History of claustrophobia and/or presence of metallic implants such as pacemakers, surgical aneurysm clips, or known metal fragments embedded in the body
10. Pregnancy
11. Baseline blood pressure > 140/90 on two repeated measurements. A second measurement is needed only if the first is > 140/90
12. History of uncontrolled hypertension

13. Any chronic disorder that may result in neurocognitive or brain dysfunction that is not secondary to SCD including:

    1. Inflammatory arterial disorders (lupus, polyarteritis)
    2. History of cancer requiring chemotherapy and/or radiation
    3. Untreated hyperlipidemia
    4. Diabetes
    5. Ongoing active infection such as HIV, tuberculosis, sarcoidosis
    6. History of chronic transfusion
    7. Chronic renal failure/Dialysis
    8. Chronic lung disease characterized by need for oxygen
    9. Morbid obesity (weight >115 kg)
    10. Heart disease: history of congestive heart failure, history of severe coronary artery disease characterized by angioplasty or surgery, or history of angina
    11. Active hepatitis or liver failure
    12. Acquired or congenital immune deficiency
    13. History of psychoses (delusions, hallucinations) and/or schizophrenia
    14. Neurodegenerative disorders
    15. Genetic disorder associated with neurocognitive dysfunction such as Down Syndrome
    16. Other chronic illness or disorder other than SCD that will adversely affect the subject's performance in the study
14. Currently on Procrit or related drug that stimulates red blood cell production

Individuals who meet any of the following criteria are disqualified from enrollment as community controls in to the study:

1. Hb electrophoresis other than AA
2. Abnormal Hb (females: < 12 g/dL; males: < 13.5 g/dL)
3. Overt stroke
4. Previous abnormal MRI or CT
5. History of head injury that resulted in neurological symptoms or medical visit
6. Abnormal neurologic exam with focal findings
7. Mini-Mental Status Examination (MMSE) score of < 20
8. Profile of Mood States (POMS) score on the Depression-Dejection Subscale suggestive of a clinical depression (score > 40)
9. Alcohol consumption exceeding 14 drinks/week if female, 21 drinks/week if male
10. Drug abuse, defined as using non-prescribed medication
11. History of claustrophobia and/or presence of metallic implants such as pacemakers, surgical aneurysm clips, or known metal fragments embedded in the body
12. Pregnancy
13. Baseline blood pressure > 140/90 on two repeated measurements. A second measurement is needed only if the first is > 140/90
14. History of uncontrolled hypertension

15. Any chronic disorder that may result in neurocognitive or brain dysfunction including:

    1. Inflammatory arterial disorders (lupus, polyarteritis)
    2. History of cancer requiring chemotherapy and/or radiation
    3. Untreated hyperlipidemia
    4. Diabetes
    5. Ongoing active infection such as HIV, tuberculosis, sarcoidosis
    6. History of chronic transfusion
    7. Chronic renal failure/Dialysis
    8. Chronic lung disease characterized by need for oxygen
    9. Morbid obesity (weight > 115 kg)
    10. Heart disease: history of congestive heart failure, history of severe coronary artery disease characterized by angioplasty or surgery, or history of angina
    11. Active hepatitis or liver failure
    12. Acquired or congenital immune deficiency
    13. History of psychoses (delusions, hallucinations) and/or schizophrenia
    14. Neurodegenerative disorders
    15. Genetic disorder associated with neurocognitive dysfunction such as Down Syndrome
    16. Other chronic illness or disorder that will adversely affect the subject's performance in the study
16. Currently on Procrit or related drug that stimulates red blood cell production

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cases (CLOSED); These are patients diagnosed with sickle cell disease (confirmed by hemoglobin electrophoresis).	Behavioral: NP Battery; Neuropsych Battery with 7 different tests that evaluate the patients neurological functioning.; Other Names: The Weschler Adult Intelligence Scale - Third Edition; The Woodcock Johnson Revised - Test of Achievement; The Delis-Kaplan Function System; The Wisconsin Card Sorting test; The Test of Everday Attention; The California Verbal Learning Test; The Weschler Memory Scales - Third Edition; Procedure: MRI; The MRI is a standard procedure involving 30 minutes under the machine in order to obtain various images of the patients brain.
Controls (CLOSED); These are persons that do not have sickle cell disease (confirmed by hemoglobin electrophoresis); matched to cases by age, gender, and education level	Behavioral: NP Battery; Neuropsych Battery with 7 different tests that evaluate the patients neurological functioning.; Other Names: The Weschler Adult Intelligence Scale - Third Edition; The Woodcock Johnson Revised - Test of Achievement; The Delis-Kaplan Function System; The Wisconsin Card Sorting test; The Test of Everday Attention; The California Verbal Learning Test; The Weschler Memory Scales - Third Edition; Procedure: MRI; The MRI is a standard procedure involving 30 minutes under the machine in order to obtain various images of the patients brain.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wechsler Adult Intelligence Scale (WAIS)-III Performance IQ	Extent of neurocognitive dysfunction in neurologically asymptomatic adult patients with sickle cell disease as measured by WAIS-III performance IQ. This quotient is based on an average of 100, with a standard deviation of 15. The Wechsler intelligence scales are not considered adequate measures of extremely high and low intelligence (IQ scores above 160 and below 40, respectively). The performance IQ is derived from scores on seven subtests: picture completion, picture arrangement, block design, object assembly, digit symbol, matrix reasoning, and symbol search.	Within 2 months of signing informed consent.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Brain Lacunae as Measured by Clinical MRI	Particpants with imaging abnormalities as measured by MRI (Magnetic Resonance Imaging) specifically brain lacunae. Lacunar infarcts are 3-15 mm in diameter located at the basal ganglia, capsular and thalamic regions. Lesions located at the level of the anterior commisure are considered perivascular spaces unless >5 mm in diameter.	Within 2 months of informed consent
Volume of Total Cortical Gray Matter as Measured by Volumetric MRI.	The cortical gray matter is the gray matter of the cerebral cortex only and does not include subcortical gray matter such as hippocampus or basal ganglia.	Within 2 months of informed consent

Collaborators and Investigators

• Sponsor: UCSF Benioff Children's Hospital Oakland
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Elliott Vichinsky, MD, Northern California CSCC (Children's Hospital Oakland)

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: September 10, 2007
• First Submitted That Met QC Criteria: September 10, 2007
• First Posted (Estimate): September 12, 2007

Study Record Updates

• Last Update Posted (Actual): March 21, 2017
• Last Update Submitted That Met QC Criteria: February 14, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; Sickle Cell Anemia; Hemoglobin SS; Hemoglobin SB0
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: 480 (Swiss HIV Cohort Study); U54HL070587-04 (U.S. NIH Grant/Contract); U54HL070587 (U.S. NIH Grant/Contract)