Vascular reactivity as a surrogate marker in CADASIL

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
Leukoencephalopathy) is a hereditary dementia and stroke syndrome, caused by
mutations in the NOTCH3 gene. CADASIL patients typically suffer from mid-adult
onset stroke and cognitive decline, leading to severe disability and dementia
in generations of family members. There is no therapy for CADASIL. We have
developed a potential therapeutic intervention for CADASIL patients, which is
currently in the pre- clinical stage of development. An important bottle-neck
in advancing therapeutic development is the lack of feasible read-outs. These
read-outs are needed to enable assessment of therapeutic efficacy of any novel
therapies in patients, especially in the early or pre-symptomatic stages of the
disease. Therefore, for both CADASIL patients and their pre-symptomatic family
members, development of surrogate markers is important in view of furthering
the development of CADASIL therapeutics. A potential surrogate marker is
cerebrovascular reactivity (CVR). CVR has previously been shown to be altered
in CADASIL patients, already in the early symptomatic stages of the disease.
Moreover, CVR has been shown to correlate with disease severity, and to be
predictive of disease progression. Therefore, CVR might be a candidate marker
for potential future clinical trials in CADASIL, especially in pre-and early
symptomatic patients. In this study, we determine which technique is most
optimal for measuring vascular reactivity. Furthermore, we will assess the
correlation between vascular reactivity and other candidate surrogate markers,
and CADASIL disease progression.

Primary Objectives:
- To determine which technique is most optimal for measuring vascular
reactivity in CADASIL patients

Secondary Objectives:
- To study CADASIL disease progression over a 17- year time frame
- To determine the correlation between candidate surrogate markers (vascular
reactivity, skin NOTCH3 score and serum NOTCH3 levels) and CADASIL disease
progression

This study is a cross-sectional study of 16 CADASIL patients and 16 controls.
We will ask individuals who participated in our baseline 2000 study (41
patients, 22 controls), to participate in the present study. This also provides
the opportunity for a 17-year follow-up of the baseline 2000 cohort.

This is a group-related, non- therapeutic study in CADASIL patients. We will
first include CADASIL patients and controls who also participated in the
baseline 2000 study. In this way, we can do a sub-study with a unique 17-year
follow-up analysis. All investigations will be performed during a one-day visit
to the LUMC. Prior to the research day at the LUMC, patients will be asked to
fill in a questionnaire. During the research day, maximum 60 ml of blood will
be drawn, a skin biopsy will be taken, an MRI scan will be made (60 minutes),
and participants will undergo neuropsychological testing (60 minutes).
Acetazolamide will be administered intravenously during the MRI examination, to
assess cerebrovascular reactivity. The risks of acetazolamide are minimized by
excluding individuals which have a higher risk for an adverse reaction, and by
consulting the LUMC pharmacy if participants are taking medications which are
known to interact with acetazolamide. Overall the risks associated with this
study are minimal. There is no direct benefit for the participants in this
research. However, the knowledge obtained through this research is important
for furthering the development of potential future therapeutic strategies for
CADASIL, and to get a better understanding of CADASIL disease course.