Hyperintense: Midlife Hypertension and the Brain

Study Overview
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Brief Summary
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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. Therefore, the investigators aim to examine abnormalities in brain (micro) structure and vascular function in young patients with hypertension. Furthermore, the investigators aim to 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.

Official Title
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Midlife Hypertension and Structural and Functional Brain MRI: Catching the First Signs of Cerebral Small Vessel Disease

Conditions
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Hypertension, Small Vessel Cerebrovascular Disease

Intervention / Treatment
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* Drug: Antihypertensive medication withdrawal


Participation Criteria
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Eligibility Criteria
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Study 1: cross-sectional study Inclusion Criteria: Age 18-40 years Blood pressure above 140/90 mmHg, measured within three months prior to study participation Exclusion Criteria: Pre-existing cerebrovascular disease Pregnancy Contraindications for 3 T MRI Renal function eGFR below 30 ml/min (for Dynamic Contrast Enhanced [DCE]-MRI Major risk factors for acute ischemic stroke other than SVD according to the TOAST criteria, including, but not limited to, large-artery atherosclerosis, cardioembolism and vasculitis based on medical history and ultrasound of the carotids collected at baseline or any chronic disease that could lead to brain lesions mimicking SVD Major (neurological/psychiatric) disease (e.g. multiple sclerosis) Not able to give informed consent Study 2: longitudinal study Inclusion criteria: Age 18-55 years Undergoing diagnostic routine of temporary antihypertensive withdrawal for biochemical analysis as part of clinical work-up Exclusion criteria: Pre-existing cerebrovascular disease Pregnancy Contraindications for 3 T MRI Renal function eGFR below 30 ml/min (for Dynamic Contrast Enhanced [DCE]-MRI Major risk factors for acute ischemic stroke other than SVD according to the TOAST criteria,22 including, but not limited to, large-artery atherosclerosis, cardioembolism and vasculitis based on medical history and ultrasound of the carotids collected at baseline or any chronic disease that could lead to brain lesions mimicking SVD Major (neurological/psychiatric) disease (e.g. multiple sclerosis) Not able to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cross-sectional study<br>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. | |
| Longitudinal study<br>In a cohort study, we will examine the effects of an increase and decrease in blood pressure on the brain. For this analysis, we will include hypertensive patients that are referred to the Radboudumc Department of Internal Medicine for a diagnostic work up on the cause(s) of their hypertension. The diagnostic procedure entails withdrawal of antihypertensives for approximately four weeks, as per the routine diagnostic protocol to allow for diagnosis of the cause of hypertension, and subsequent restart of treatment until the target blood pressure is reached (normotension). Measurements are performed just before antihypertensive medication is withdrawn (baseline), approximately four weeks after withdrawal (T=1), once patients have reached their target blood pressure and blood pressure is stable, estimated to occur within 2-4 months (T=2) and approximately 1 year after T=2 (T=3). | Drug: Antihypertensive medication withdrawal<br>* To determine if high blood pressure is caused by an overproduction of aldosterone in the adrenal gland (i.e. primary hyperaldosteronism), the plasma aldosterone/renin ratio (ARR) can be determined. Because many common hypertensive drugs are known to interfere with this ratio, patients often have to discontinue drugs prior to screening or switch to drugs that are known not to affect ARR (i.e. doxazosin, verapamil, diltiazem, hydralazine). Drugs have to be stopped for at least four weeks (for mineralocorticoid receptor antagonists) or two weeks (for diuretics, Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs)). This often leads to a temporary increase in blood pressure. After diagnostics are completed, medication is adjusted accordingly and blood pressure levels drop again.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Standard neuroimaging markers of SVD, assessed using STRIVE criteria | This includes white matter hyperintensity volumes, lacunes, microbleeds, DWI+ positive lesions. | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| DCE-MRI outcomes | Leakage rate (Ki) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| DCE-MRI outcomes | Volume fraction (Vl) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| DTI outcomes | Fractional Anisotropy (FA) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| DTI outcomes | Mean Diffusivity (MD) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| DTI outcomes | Peak Skeleton ofMean diffusivity (PSMD) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| Intravoxel Incoherent Motion outcomes | Parenchimal Diffusivity (D) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| Intravoxel Incoherent Motion outcomes | Perfusion fraction (F) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| Intravoxel Incoherent Motion outcomes | Microvascular perfusion (fD*) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| Resting state fMRI | Functional connectivity | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognition | Cognitive functioning is assessed using a 60-min cognitive assessment covering six domains: processing speed, attention, executive functioning, verbal memory, working memory and psychomotor functioning. | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| Motor functioning | Motor functioning is assessed using a 6-m walking test (in seconds) and the Timed Up & Go test (in seconds) | Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later. | 
| Blood markers | This includes circulating markers of inflammation, including cytokines and chemokines, in mmol/l measured in blood. | Four weeks after antihypertensive drug withdrawal and after 1-4 months when blood pressure is stable. |