Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease
Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease
The objective of this study is to determine the mechanisms of stroke in patients with
 Intracranial Atherosclerotic Disease (IAD) by specifically evaluating limitations of
 antegrade flow through the stenotic artery, distal tissue perfusion to the affected
 territory, and artery-to-artery embolism. The hypothesis is that non-invasive imaging
 biomarkers that stratify stroke risk and distinguish mechanisms of IAD. This prospective
 multicenter study will enroll 175 patients with recently symptomatic high-grade IAD. Patients
 will be studied within 21 days of the index event (allowing appropriate time to arrange for
 diverse imaging modalities), with the following advanced neuroimaging techniques to elucidate
 mechanisms of recurrent ischemia:

 -  Quantitative magnetic resonance imaging (QMRA) to assess volumetric flow rate through
 the stenotic artery.

 -  Magnetic resonance perfusion weighted imaging (PWI-MRI) to determine distal tissue
 perfusion.

 -  Vasomotor reactivity by Transcranial Doppler using the breath-holding technique
 (BHI-TCD) to assess compensatory flow characteristics to the territory distal to the
 affected artery;

 -  Transcranial Doppler with embolic signal monitoring to evaluate artery-to-artery
 embolism that reflects plaque instability.

 Patients will receive standardized medical management and its effectiveness on blood
 pressure, lipid, and glycemic control will be monitored.

 The primary outcome is recurrent stroke in the territory of the stenotic artery during a
 1-year follow-up period; secondary outcomes are: a) new asymptomatic ischemic lesions on MRI
 in the distribution of the stenotic artery at 6-8 weeks, and b) transient ischemic attack
 (TIA) in the distribution of the stenotic artery during a 1-year follow-up period.

 Patients will be recruited at various sites that will be trained and certified on the imaging
 techniques employed. Raw imaging data will be interpreted centrally.
Inclusion Criteria:

 1. Stroke defined as symptoms lasting >24 hours and associated with imaging evidence of
 acute ischemia in the distribution of the stenotic vessel on CT or MRI.

 2. Eligible TIA defined as transient neurological symptoms lasting <24 hours, need to be:

 1. accompanied by DWI abnormalities in the distribution of the stenotic artery; or

 2. multiple (≥2), stereotyped events associated with unequivocal ischemic symptoms
 (weakness, aphasia), and attributed to the symptomatic artery.

 3. IAD should involve the intracranial carotid, middle cerebral, intracranial vertebral
 or basilar arteries.

 4. Stenosis 50-99% quantified by digital subtraction angiography (DSA), CT
 angiography-CTA or MR angiography-MRA tests. DSA is not required but will be used if
 obtained as part of clinical care.

 The criteria for 50-99% are:

 1. CTA or DSA: measured 50-99% stenosis by WASID criteria (percent stenosis =
 (1-[diameter stenosis/diameter normal]) x 100%.

 2. MRA: measured 50-99% stenosis or presence of a flow gap.

 5. Age >30; those 30-49 years of age must also have the presence of established
 atherosclerotic disease in another vascular bed (coronary, extracranial carotid,
 peripheral) or the presence of 2 or more risk factors (hypertension, diabetes
 mellitus, hyperlipidemia, tobacco abuse within the last 2 years).

 6. Enrollment within 21 days of symptom onset and completion of study imaging tests
 within 21 days of index event (stroke or TIA).

 7. Provide informed consent for participation in the study.

 Exclusion Criteria:

 1. Other cause for stroke: atrial fibrillation, acute anterior wall ST-elevation
 myocardial infarction <30days, mitral stenosis, mechanical valve, intracardiac
 thrombus or vegetation, dilated cardiomyopathy or ejection fraction <30%, proximal
 extracranial carotid or vertebral stenosis >50%.

 2. Contraindications to MRI, including MR-incompatible metallic implants, implanted
 electronic devices, other potentially mobile ferromagnetic material, pregnancy (women
 in fertile age should have a negative pregnancy test), lactation, morbid obesity, and
 severe claustrophobia.

 3. Renal impairment defined as either a creatinine level >1.5 mg/dL or a glomerular
 filtration rate (GFR) <30 mL/min/1.73 m2.

 4. Known allergy to gadolinium.

 5. Unable to obtain informed consent by patient or legally authorized representative.

 6. Severe behavioral or social problems that may interfere with the conduct of the study.

 7. In the investigator's opinion, patient unlikely return for follow up visit and to
 complete the study.

 8. Participation in a drug or device clinical trial within the last 30 days.