Blood-Brain Barrier Disruption in People With White Matter Hyperintensities Who Have Had a Stroke

Objective: To follow a cohort of stroke patients with white matter hyperintensities (WMH),
using MRI, and thereby track the natural history of changes in blood-brain barrier (BBB)
disruption. By establishing a better understanding of the relationship between the presence
of BBB disruption and WMH progression, we hope to identify BBB permeability on MRI as a
biomarker for disease pathogenesis, disease activity, and disease progression.

Study Population: Stroke patients will be eligible for this study if their MRI shows evidence
of confluent WMH on FLAIR imaging (Fazekas score 2 or greater), obtain a MoCA score greater
than 13, and have no other diagnosis to explain the finding (e.g. multiple sclerosis). The
NIH stroke service currently evaluates 600 patients a year with MRI. Approximately 20% have
confluent WMH on their FLAIR MRI and would meet the inclusion criteria for this study. Thus,
the cohort for this study will be recruited from the population evaluated by the NIH stroke
service.

Design: Patients admitted to one of the two enrolling sites (Suburban Hospital and Medstar
Washington Hospital Center) who had a stroke evaluation by the NIH stroke team will be
eligible for enrollment. Enrolled subjects who meet the inclusion/exclusion criteria will be
followed serially with MRI. The first research evaluation will be within 3-4 months of the
qualifying event whenever possible, but could be up to 6 months. Research procedures will
consist of an MRI, interval history and cognitive/clinical scaling. Research procedures will
occur every 3 months for the first year, every 6 months for the second year, and then yearly
thereafter for a total of 6 years.

Outcome measures: Using a previously described and independently validated method, BBB
permeability will be assessed at each research time point as will WMH burden. The presence of
BBB will be compared with progression of WMH into normal appearing white matter (NAWM). The
primary outcome is the relationship between BBB disruption and WMH progression. It is
postulated that BBB disruption in the NAWM will be associated with progression of the WMH.
Secondary outcomes will examine the spatial relationship between BBB disruption and WMH
progression and changes in cognitive scaling. Additionally, other exploratory MRI biomarkers
for disease progression will be examined (e.g. susceptibility weighted imaging with 7T MRI to
examine regions of known BBB disruption).

- INCLUSION CRITERIA:

- Age greater than or equal to 18

- Have been admitted to one of the study sites for evaluation of stroke-like symptoms (
qualifying event ) such as difficulty moving or speaking, blurred vision, dizziness or
balance issues; and had an MRI scan. Symptoms must be attributable to a stroke or TIA
with no other definitive cause identified at the time of screening.

- Provides written informed consent prior to study participation OR is able to provided
assent and consent is provided by a qualifying LAR.

- Is willing to return to one of the two study sites to initiate serial study visits
between 3-4 months whenever possible, but could be up to 6 months from the qualifying
event and continue participation for at least one year.

Is willing to appoint a Durable Power of Attorney (DPA) for NIH research

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from this study:

- Medical contraindications for MRI (e.g., any non-organic implant or other device such
as a cardiac pacemaker or infusion pump or other metallic implants, objects, or body
piercings that are not MRI-compatible or cannot be removed)

- Psychological contraindications for MRI (e.g., claustrophobia), to be assessed at the
time the medical history is collected

- If unable to lie comfortably on their back for up to 1 hour.

- Contraindication to gadolinium (pregnant or nursing, previous allergic reaction, renal
insufficiency)

- Known diagnosis that is thought to be the cause of their WMH (e.g. multiple sclerosis)
other than chronic cerebrovascular disease, cerebral autosomal dominant arteriopathy
with subcortical infarcts (CADASIL), or migraine.

- Clinically significant medical or neurological disorders that might expose the patient
to undue risk of harm, confound study outcomes or prevent the participant from
completing the study; examples of such conditions include but are not limited to
respiratory compromise, cardiovascular instability or cerebral edema.

- History of an ongoing seizure disorder, structural brain abnormality or nonvascular
brain injury.

- Unlikely to be released from the hospital following the qualifying event or has severe
disability preventing ambulation or verbal communication.

- Known malignant disease or other chronic illness with poor 5-year prognosis other than
dementia.

- Attaining a MoCA score less than or equal to 13 during screening assessment.