Cerebrovascular manifestations of vascular Amyloid deposition in HCHWA-D | An assessment of the cerebrovascular reactivity in Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) patients using Magnetic Resonance Imaging and transcranial Doppler.

In cerebral amyloid angiopathy (CAA) the toxic protein amyloid accumulates in
the wall of the small blood vessels in the brain and repeatedly causes
intracerebral hemorrhages, which leads to focal neurological deficits, dementia
and eventually death. Sporadic cerebral amyloid angiopathy (sCAA) is a common
cerebrovascular disease in elderly. Sensitive biomarkers to detect CAA in vivo
are not yet available, but are important not only to diagnose CAA as an
important cause of dementia, but also to decide on specific treatments, detect
CAA formation as a consequence of treatment and for clinical trial design.

We want to fill this gap by developing new methods to demonstrate the effect of
the accumulation of this protein in the blood vessels of the brains by looking
for biomarkers with MR imaging.

Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is an
autosomal dominant condition in which excessive CAA, most severe in the
occipital lobe, causes lobar hemorrhages and hemorrhagic infarcts already at a
young age, followed by cognitive decline.
First indications and most severe manifestations of CAA in HCHWA-D are found in
the occipital lobe. Provocation of neuronal activation by a visual task can be
exploited to detect microvascular impairment. However, the use of visual
activation to detect microvascular impairment can not give any information on
the spreading of the disease to other brain areas.

Therefore, a CO2-challenge (normal breathing alternated with inhalation of 5%
CO2) will be applied to target more specifically the functioning of the
(micro)vascular bed in the whole brain. The analysis will not only focus on the
relationship of the visual task with the global stimuli, but also the added
value of providing whole brain coverage for these measurements of hemodynamic
functioning.

To study the effect on the large blood vessels, measurements with transcranial
Doppler echosound (TCD) will be performed under hyperventilation, normal
breathing and inhalation of 5% CO2. The capacity to counteract the alterations
in cerebral blood flow in response to fast changes in blood pressure14, the
cerebrovascular autoregulation will be assessed with a stand-up test using TCD.

With these combined studies we can evaluate global and local cerebral perfusion
changes at arterial and microvascular level respectively high temporal
resolution TCD and more detailed MRI perfusion measurements in HCHWA-D. The
possible insight into the cerebral manifestations of HCHWA-D is of great
significance. This neuroimaging biomarker could provide an effective diagnostic
tools that will allow detection of CAA during life, establish the contribution
of CAA to cognitive decline and dementia and to facilitate potential future
personalized therapy.

The primary objective for this study is to evaluate the cerebrovascular
reactivity of HCHWA-D patients:
1. To compare the (autoregulatory) function of small brain vessels in HCHWA-D
patients with matched controls using the cerebrovascular reactivity to CO2 and
visual stimulation measurement with MRI.
2. To assess the dynamic cerebrovascular autoregulation (dCA) and cerebral
vasomotor reactivity (CVMR), which are major controllers of cerebral blood flow
(CBF), using transcranial doppler (TCD) in the same groups.

This is an observational cross-sectional study comparing the cerebral
autoregulation in symptomatic HCHWA-D patients with healthy age and sex matched
controls. The controls will follow the same study protocol as the patients.

The first part of this study consists of a single MRI scan session with a 3
Tesla clinical MRI scanner consisting of different MR image types and
cerebrovascular reactivity measurements with CO2 and visual stimulation.

In the second part of the study transcranial Doppler ultrasound (TCD) will be
used to continuously measure the capacity to counteract the alterations in CBF
in response to fast changes in blood pressure with a stand-up test
(cerebrovascular autoregulation) and the vasodilatory response of the cerebral
vessels to changes in arterial carbon dioxide concentration (cerebral vasomotor
reactivity).

Blood will be sampled to get insight in the cardiovascular risk factors and
cognitive tests will be performed.

All measurements are acquired in a single visit with a total duration of the
session of approximately 6 hours, of which the MRI will take maximally 60
minutes and the TCD-measurement maximally 40 minutes. The participants will all
be included at the LUMC. The duration of the study will be approximately 1 year
and inclusion will start in Januari 2016.

MRI-scans will be made of the heads of the participants during challenges
visual stimulation and low concentration CO2-inhalation. Before participation
to the study the subject will be elaborately informed about the study and
carefully screened for MRI-contraindications. The MRI-scans will be acquired by
certified personnel of who at least one is an expert on CO2-reactivity scans.
In case a patient has migraine or epilepsy, the MRI part with the visual
stimulus will be omitted from the protocol, because the bright flashing light
could evoke an attack.
TCD-scans will be measured during challenges like standing up and low
concentration CO2-inhalation. Earlier MRI- and TCD-studies with these low
concentrations of CO2 in healthy subjects and patient populations did not show
any adverse reactions. The risk of related to participation in this study will
be minimal for the subjects.
Finally, the duration of the MRI-measurements will be restricted to a maximum
of 60 minutes and TCD-measurements to a maximum of 40 minutes to limit the
burden for the participants. There is no direct benefit for the participants,
since currently there is no treatment.