Atherosclerosis Risk in Communities (ARIC) Cohort

This manual, entitled Magnetic Resonance Imaging Protocol, is one of a series of protocols and manuals of operation for the Atherosclerosis Risk in Communities (ARIC) Study. The complexity of the ARIC Study requires that a sizeable number of procedures be described, thus this rather extensive list of materials has been organized into the set of manuals listed below. Manual 1 provides the background, organization, and general objectives of the ARIC Study. Manuals 2 and 3 describe the operation of the Cohort and Surveillance Components of the study. Detailed Manuals of Operation for specific procedures, including those of reading centers and central laboratories, make up Manuals 4 through 11 and 13 through 15. Manual 12 on Quality Assurance contains a general description of the study's approach to quality assurance as well as the details for quality control for the different study procedures.

The Atherosclerosis Risk in Communities (ARIC) Study is an epidemiological examination of the major factors contributing to the occurrence and trend of cardiovascular disease in middle-aged (age 35-74) adults in the United States. The study has two main objectives: to investigate factors associated with both atherosclerosis and incidence of clinical cardiovascular disease, and to measure coronary heart disease (CHD) occurrence and trends and relate them to community levels of risk factors, medical care and atherosclerosis.

At inception, the ARIC cohort consisted of approximately 4,000 persons (roughly equal numbers of men and women) aged 45-64 in each of four US communities: Forsyth County, North Carolina (biracial); Jackson, Mississippi (all black); suburbs of Minneapolis, Minnesota, and Washington County, Maryland. Examinations are conducted every three years on cohort participants. It is estimated that about 14,500 persons will be seen at the third examination visit that begins in March, 1993 and extends for three years.

Selected participants at two of the ARIC community Field Centers (Forsyth County and Jackson) receive cerebral magnetic resonance imaging (MRI) examinations. The pilot study, consisting of 10 volunteers in each Field Center, was conducted during February, 1993. The main study consists of approximately 2,000 MRI studies to be completed over a two-year period beginning in March, 1993.

The role of the ARIC cerebral MRI Field Centers is to perform approximately 2,000 MRI exams in ARIC. The MRI Reading Center assisted in protocol development for cerebral MRI and will perform interpretations of these images in a standardized and reproducible manner.

The goal of the ARIC cerebral MRI component is to evaluate cerebral changes detected by MRI in a representative biracial population aged 56-70 and to evaluate the relationship of these images to clinical stroke, coronary heart disease, cardiovascular risk factors, retinal microvascular changes, extracranial carotid atherosclerosis and changes in cognitive function.

The MRI data are expected to supplement current ARIC clinical descriptors of cerebrovascular disease (CBVD) by increasing the sensitivity of detecting CBVD, by including subclinical disease, and by distinguishing small-vessel from large-vessel disease. These data will form the basis for testing a number of hypotheses about the relationship between current ARIC clinical descriptors of CBVD and the criteria of CBVD as identified by MRI. A representative sample of the ARIC clinical descriptors and MRI criteria of CBVD are listed below:

ARIC Clinical Descriptors of CBVD

• Stroke (CVA)
• Transient Ischemic Attack (TIA)
• Approximate Location
• Dementia

MRI Variables of CBVD

• Type of Stroke
  • Ischemic
    • Major vessel
    • Small vessel
  • Hemorrhagic
    • Number, Size
• Location
  • Frontal
  • Parietal
  • Occipital
  • Temporal
  • Cerebellum
  • Brain Stem
• Subcortical White Matter Disease (SWMD)
• Brain atrophy (reflected by):
  • Sulcal size
  • Ventricle size

The ability to perform correlations between current ARIC measures of CBVD and MRI measures of CBVD is key to testing several hypotheses for the relationship between CBVD risk factors and clinical/subclinical CBVD, including cognitive decline and dementia:

1. Risk factor profiles in small vessel disease (SVD) (such as lacunar CVA or possibly SWMD) and hemorrhagic CVA differ from those in large vessel disease (LVD) (such as myocardial infarction (MI), extracranial carotid atherosclerosis, or large vessel atherothrombotic stroke).
2. The prevalence of SVD relative to LVD is greater in blacks and women than in whites and men, respectively.
3. Early hypertensive changes noted in retinal arterioles are associated with or predict CBVD, especially SVD, independently of blood pressure and other risk factors.
4. Small incidental cerebral lesions (sometimes referred to as subcortical white matter "disease") seen on MRI in healthy people with increasing frequency in advancing age are predicted by blood pressure and are associated with early hypertensive changes in retinal arterioles and decline in cognitive function.
5. MRI evidence of CBVD predicts future CBVD events and cognitive decline.

The following are the Field Center MR Instruments used in the ARIC MR study.

1. Bowman Gray - GE Signa 1.5 T or Picker 1.5 T
2. Jackson - GE Signa 1.5 T

Any changes in imaging equipment at the Field Centers requires prior approval from both the MRI Reading Center and the ARIC Steering Committee.

Members of the ARIC cohort at Forsyth County and Jackson who are 56 years of age or older at the time of their Visit 3 examination are eligible for the cerebral magnetic resonance imaging (MRI) examination. Field center personnel explain the study procedure and its purpose (Appendix 1.1) to age-eligible individuals, and screen them for reasons for exclusion from an MRI examination using the standard MRI Screening Form (MSC: Appendix 1.2). The following are reasons for exclusion identified on the MRI Screening Form: having had surgery on an aneurysm in the brain; having metal fragments in the eyes, brain, or spinal cord; having a valvular prosthesis, a cardiac pacemaker, cochlear implant, spinal cord stimulator, or other internal electrical device; and pregnancy. If the latter cannot be ruled out, the staff person schedules a call at a later date.

If the participant passes all exclusion criteria the staff person administers the Informed Consent Form (Appendix 1.3), with a full explanation of the procedure, its potential risks, and benefits. Scheduling the MRI examination takes place at this time, either by telephone or during the participant's regular cohort re-examination visit. Before the MRI examination is performed, a staff person of the MRI Center explains the procedure again, as described below, and another form is signed by the participant to indicate that he/she has been fully informed and has agreed to the examination.

The MRI technologist explains the study procedure to the ARIC participant and answers any questions. The participant is instructed to remove any metallic objects, including jewelry, dentures, hearing aids, hairpins, etc. and to secure all items in the patient's locker. The technologist explains to the participant that the exam will take approximately 30 minutes. The participant is told that there are microphones in the MRI machine to communicate with the technologist and that the exam may be stopped at any time. The participant is also told that movement, and/or speaking during the exam will compromise the quality of the images, and is asked to refrain from such activity during the scan. Prior to escorting the participant into the scan room, the technologist verifies that all equipment necessary for the exam is ready. The technologist accompanies the participant into the scanning room and offers assistance in getting on to the scanning table and the participant is told that the table will move into the scanner. After the participant is comfortably positioned on the table, the technologist explains that positioning aids will be placed along the sides of the head to help him/her to hold still, and a helmet-like apparatus placed about their head. Knee pillows and ear plugs are also offered. The longitudinal localizing light is used to align the mid-sagittal plane. The participant is asked to close his/her eyes, and the transverse light is aligned along the lids of the eyes. The technologist reminds the participant to refrain from movement during the exam, adjusts the head coil, advances the participant into the magnet and enters the necessary information into the system.

For purposes of archiving and retrieval, it is required that the ARIC identification number be placed in the ID field, and that the name field be filled with the letters ARC and the ID number, with no space between them. The examples shown below need to be followed exactly:

1.7.3. Localization of AC/PC Line

1.7.3.1. Anterior Commissure

The Anterior Commissure is a two to three mm vertically ovoid white matter structure located along the anterior wall of the third ventricle at approximately one third of the distance from the bottom of the rostrum of the corpus callosum to the top of the optic chiasm. It has the same signal intensity as the corpus callosum.

1.7.3.2. Posterior Commissure

The Posterior Commissure is the small focus of tissue located immediately posterior and superior to the junction of the cerebral aqueduct and the third ventricle.

1.7.3.3. AC/PC Line

The Anterior Commissure/Posterior Commissure line passes through the superior edge of the Anterior Commissure and the inferior edge of the Posterior Commissure.

Figure 1.

Figure 2.

After each MRI study is completed, the MRI technologist fills the MRI Procedure Form (Appendix 1.4). This form is also filled for every examination that is scheduled but not attempted, or attempted but not completed according to the ARIC protocol. The Procedure Form also serves to record the scanning pulse sequence, the orientation of the oblique axial scan, and whether any emergent alert conditions were noted. If the latter is the case, the condition is recorded on the form, as is the name of the person who was notified, and the alert notification date.

The ARIC Field Center staff retrieves the data tapes (or disks) from the MRI Center once per week, and follows standard procedures for shipping them to the MRI Reading Center. The MRI Procedure Form (completed by the MRI technologist) is reviewed by the ARIC staff to verify that the form is complete and the identifying information correct. The Field Center staff completes the MRI Weekly Log Sheet (Appendix 1.5). The participants' initials, ID number label, and dates of scan are transferred on this log sheet, which is sent with the magnetic tapes (disks) to the MRI Reading Center. Each magnetic tape is labelled with the ID number and initials of the participant contained on that tape. The MRI Completion Form (Appendix 1.6) corresponding to each participant study included in the shipment is also added to the mailer.

Tapes containing studies performed on Picker scanners are labelled as Picker tapes to let the MRI Reading Center know which scanner was used for each study.

On an assigned day each week, the ARIC staff prepares the tapes for mailing. This includes ascertaining that all tapes are labelled completely, packing them securely, checking the contents of the shipping container against that week's log sheet, copying the log sheet and MRI Completion Forms, stapling the Completion Forms for that week to the original log sheet, and mailing the package to the MRI Reading Center on schedule. A copy of each log sheet is kept at the Field Center. Once the magnetic tapes are sent to the MRI Reading Center they are retained there permanently.

Each tape can contain approximately 3 MRI scans. If on the assigned shipping day a-tape has only 1 or 2 scans on it, it is included with that week's shipment. Magnetic tapes/disks are mailed via Federal Express or equivalent carrier (48 hour delivery).

Magnetic Tapes are mailed to:
Linda Wilkins, R.T.
Johns Hopkins Hospital
Dept. of Neuroradiology
Nelson B-100
600 N. Wolfe Street
Baltimore, Md. 21205
(410) 955-8216

The procedure for handling optical disks differs slightly from the above procedure for magnetic tapes.

Field Centers using optical disks allocate approximately 3-4 disks (or as many as needed to hold approximately 1,000 MR studies) to the ARIC study. These optical disks become the property of the ARIC MRI study and should only contain the ARIC MRI protocol studies on them. At the end of the study or when an optical disk becomes full (whichever occurs first), the optical disk is sent to the ARIC MRI Reading Center for permanent storage.

At the beginning of the study the ARIC Field Center and the MRI Reading Center establish a rotation exchange process for these optical disks. Optical disks are identified with a permanent label, which specifies t h e disk number and side (a or b). For example:

ARIC MRI STUDY
DISK #1 SIDE A

Each ARIC MRI Center can place approximately 20-25 MR participants studies (approximately two weeks of participant MR exams) on such a disk. The MRI Optical Disk Log (Appendix 1.7) is completed with all pertinent information provided. This disk log is copied prior to mailing by the study coordinator. Additions to the log are made each time more participant studies are added t o disk #1.

At the completion of the 20-25 studies this disk and the original log which accompanies it are sent to the MRI Reading Center via Federal Express or equivalent carrier (48 hour delivery) to:

Linda Wilkins, R.T.
Johns Hopkins Hospital
Division of Neuroradiology
Nelson B-100
600 N. Wolfe Street
Baltimore, MD 21205
(410) 955-8216

When disk #1 has been sent to the MRI Reading Center, the Field Center starts the next batch of participant studies on disk #2, and a new disk log for disk #2. This log is then sent following the same procedure as used for disk #1.

Upon receipt of t h e disks the MRI Reading Center data manager archives these studies, logs the studies received by shipment date and returns the disk to the Field Center so that more ARIC MRI studies can be added to this disk. Studies are never to be deleted from these optical disks. The MRI Reading Center retains a separate log for each disk in the rotation. The rotation exchange of optical disks may require 3-4 disks at any one time, to eliminate any delay due to mailing or scheduling.

This system results in 2 separate logs - one at the MRI Reading Center and one at the ARIC Field Center. Each disk has a separate log associated with it, at each location.

During the initial six months of the MRI study, each Field Center conducts a survey to monitor the acceptability of the MRI examination. The Study Coordinator and the Field Center PI monitor the survey results to ascertain any concerns on the part of the study participants. At the conclusion of 24 interviews at each Field Center, the copies of the completed forms are sent to the Chair of the Cohort Committee for summarization and distribution.

Prior to an ARIC participant leaving the Field Center MRI Unit, the MRI technologist reviews the scan. This includes a check to see that the protocol is complete and the scans are technically satisfactory. If a series needs to be repeated, it is done at this time, to avoid bringing the participant back.

A formal evaluation of the physical performance parameters of each machine will be conducted at regular intervals by the Field Center using standard manufacturer-recommended evaluation methods. Each Field Center has at its disposal MR calibration phantoms. These phantom images provide evaluation of field homogeneity, noise characteristics, spatial, and contrast resolution.

At the start of the study and once a year thereafter, the ARIC Field Centers send a phantom quality control scan to the MRI Reading Center. If this phantom scan is sent on magnetic tape, a separate tape is used, labeled as a phantom. If sent on optical disc, it is included with the regular ARIC participant studies but identified on the disc as a phantom. The phantom scan is mailed to:

Linda Wilkins, R.T.
Johns Hopkins Hospital
Division of Neuroradiology
Nelson B-100
600 N. Wolfe Street
Baltimore, MD 2120'5
(410) 955-8216

At the end of the pilot study, the MRI Reading Center makes a site visit to each of the two Field Centers. The purpose of the site visit is to meet all ARIC personnel and to observe the scanning of an ARIC participant or volunteer. Questions related to the MRI study are addressed at that time.

The MRI Reading Center maintains an ongoing review of each Field Center to monitor the number of studies acceptable for interpretation; the number of studies rejected for protocol non-compliance; and the number of studies found to be technically suboptimal. If a Field Center is found to have more than 10% of studies unacceptable for interpretation, the MRI Reading Center requests a report from the Field Center documenting the reasons for the deficiencies and the proposed corrective actions. Two weeks after receipt of the Field Center report the MRI Reading Center verifies that corrective measures have been taken. Copies of these reports are provided by the MRI Reading Center to the ARIC Quality Control Committee.

Study participants with certain MR scan abnormalities may require further medical attention. ARIC does not assume responsibility for diagnosis and management of its participants, but has assumed an obligation to refer such cases to their local source of medical care. The referral system is based on the urgency of the XR abnormality. An "alert" is defined as an immediate or urgent referral.

Result categories:

1. No participant referral indicated
   1. no clinically significant findings
2. Participant referral optional.
   1. old infarcts, white matter ischemic changes, atrophy, other chronic abnormalities
3. Urgent referral (alert)
   1. tumor without significant mass effect, AVM, aneurysm, obstructive hydrocephalus
   2. Cavernous angioma, venous angioma
   3. Arterial occlusion (or slow flow)
4. Immediate referral (alert)
   1. acute subdural or epidural hematoma, subarachnoid hemorrhage, acute intraparenchymal hematoma, acute infarct, subacute infarct, obstructive hydrocephalus (some cases), cerebral venous thrombosis, abscess and suspected tumor with significant mass

Conditions not listed here which require referral in the opinion of an MR technician are triaged and reported accordingly, per the judgement of the Field Center or Reading Center neuroradiologist. Doubtful cases are triaged to the more severe category.

The MR technologist at the local MR Center reviews each study for the presence of any condition identified by the ARIC protocol as an emergent alert. If such a condition is found, the neuroradiologist (referred to below as the MR Center physician) is notified, and this occurrence recorded on the MRI Procedure Form. After review of the potential alert by the MRI Center neuroradiologist, a brief report is prepared and the Field Center physician is notified. Each field center has identified a physician (and back-up) for this purpose. Key information describing this process is recorded on the MRI Procedure Form, such as a specification of the alert condition, the name of the Field Center person notified, and the date of this notification. A summary overview of this process is shown below.

At the MRI Reading Center each participant's alert status is recorded in the MR results data file at the time of image interpretation. The alert status codes are shown below:

• 1 = No referral
• 2 = Routine referral (ARIC coordinating center option).
• 3 = Urgent referral required.
• 4 = Immediate referral required.

A value of 2 (routine referral) is entered automatically by the MRI Reading Center software. Readers then change this field to either 1, 3, or 4, as appropriate.

1. The MR Reading Center sends the participants' MR results data file to the Coordinating Center by electronic mail or by shipping a diskette.
2. The portion of the MR results data file containing participant alert status and results to be reported to the participant is sent to the respective Field Center by electronic mail or disk.

When a condition identified by the ARIC protocol as an emergent alert is noted at the Reading Center, the alert status is recorded on the participant's result file, as described above. If the alert has previously been identified at the local MRI Center, as indicated on the MRI Procedure Form which accompanies each data shipment from the Field Center, no action is taken by the MRI Reading Center. If the MRI Procedure Form does not identify an alert, or refers to an alert condition different from that detected at the MRI Reading Center, the actions summarized below take place.

When Field Center physicians communicate an emergent alert to the study participant and his/her physician, contact is made first by phone, followed by a letter. A copy of the report from the neurologist/neuroradiologist is enclosed with this letter. In the absence of alert conditions, the Field Center prepares a (routine) report to communicate the study results to the participant by mail. Overall, three types of reports serve this purpose: a) normal results; b) minor abnormal findings, no referral indicated; and c) referral for abnormal results.

Emergent reports originate from the process described above. Study results identified as notifiable on a routine basis, include (old) hematomas and their size, and (old) infarcts and their size. The data contained in these reports are extracted from the participant result file at the MRI Reading Center, and sent to the Field Center for inclusion in the report to the participant and their physician.

The type of report distributed by the ARIC field centers is summarized below, as letters addressed to the study participant and the equivalent letters to his/her physician. A letter is also provided for the -- unusual -- occurrence of participants who do not identify a provider of medical care.

Prototypes of these letters can be found in Appendix 2.0.