Midlife hypertension and structural and functional brain MRI: catching the first signs of cerebral small vessel disease

Cerebral small vessel disease (SVD) describes a set of pathologies affecting
the smallest blood vessels in the brain. SVD contributes to up to a fifth of
ischemic and hemorrhagic strokes en is the main vascular cause of dementia. On
MRI, SVD is marked by different types of lesions, including white matter
abnormalities, and small infarcts and hemorrhages. Recent studies indicate that
SVD develops slowly over the years, starting presumably decades before the
typical MRI lesions become apparent. High blood pressure plays an important
role in the development of SVD MRI lesions. However, it remains unclear exactly
how hypertension leads to vascular pathology. To gain more insight into how
hypertension leads to SVD it is important to study mechanisms in individuals
(largely) free of SVD, that is before midlife.

Study 1: Cross-sectional

To examine if there are cerebral abnormalities present following hypertension
before MRI markers of SVD have manifested, we will do high-resolution 3T MRI in
100 young (18-40 years) hypertensive adults. In addition to MRI, during each
visit patients will undergo standardised tests and questionnaires to probe
cognitive and motor functioning, and lifestyle and medical information. We will
compare this group to normotensive, healthy age-matched participants of the
Healthy Brain Study to examine if there are abnormalities following high blood
pressure.

Study 2: Longitudinal

The prevalence of hypertension in the Netherlands in adults aged 30-49 years is
approximately 10-20%. Part of the patients with hypertension are referred to an
internist to identify the cause(s) of the hypertension. As part of the routine
diagnostic work up, antihypertensive agents are temporarily withdrawn. As a
consequence blood pressure will increase, followed by a decrease in blood
pressure once antihypertensive agents are restarted. This period of medication
withdrawal and subsequent restart offers a unique opportunity to study within
subjects the acute effects of blood pressure increase and subsequent decrease
on several MRI measures of SVD. In HYPERINTENSE 100 patients with hypertension
will undergo MRI three times during the described diagnostic process, that is
at baseline before antihypertensives are withdrawn, once antihypertensives are
largely or completely withdrawn (T=1) and once patients have reached their
target blood pressure (T=2). 1 year after T=2, patients will undergo a final
MRI scan (T=3). In addition to MRI, during each visit patients will undergo
standardised tests and questionnaires to probe cognitive and motor functioning,
and lifestyle and medical information.

Primary objectives:
1. Examine abnormalities in brain (micro)structure and vascular function in
patients with hypertension aged 18-40
2. Determine the effects of blood pressure increase and subsequent blood
pressure reduction during a period of withdrawal and restart of blood pressure
lowering drugs on brain (micro)structure and vascular function measured with
high-resolution MRI in patients with hypertension aged 18-55

Secondary objectives are:
- Investigate the effect of withdrawal and restart of antihypertensives on
cognitive an motor functioning
- Explore the association between circulating markers of inflammation,
including cytokines and chemokines, determined after withdrawal of
antihypertensive medication, and blood pressure and brain MRI parameters
- Determine in the same patients changes in MRI parameters of brain
(micro)structure and microvascular function at follow-up after 1 year
- Assess the association between cardiovascular risk factor profile and MRI
parameters of brain (micro)structure and vascular function
- Determine the association between early-life hypertension and future incident
clinical events

HYPERINTENSE is a prospective observational cohort study

Patients will undergo a standardized MRI protocol, vena puncture to sample
blood, and standardised tests and questionnaires to probe cognitive and motor
and lifestyle and medical history.
MRI is considered to be safe and without risks, as long all safety measures are
adequately followed. To study the integrity of the blood-brain barrier during
part of the 3 T MRI scan, patients will receive a gadolinium-based contrast
agent. Side effects of injection of this contrast agent occur very incidentally
and include mild effects such as nausea, headache and injection site reactions
(sense of warm feeling). In case of adverse effects, patients will be treated
reasonably and professionally.