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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cross-sectional study | 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 | 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 Measurements are performed just before antihypertensive medication is withdrawn (baseline), approximately four weeks after withdrawal (T=1), once patients have reached their target blood pressure and blood pressure is stable, estimated to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). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Antihypertensive medication withdrawal | Drug | 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. |
| 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) |
| 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. |
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Study 1: cross-sectional study
Inclusion Criteria:
Exclusion Criteria:
Study 2: longitudinal study
Inclusion criteria:
Exclusion criteria:
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Patients will be recruited through the outpatient clinic of the Department of Internal Medicine of the Radboudumc and Rijnstate hospital, where they are referred to for their high blood pressure.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Esther Janssen | Contact | +31651758279 | esther.janssen@radboudumc.nl |
| Name | Affiliation | Role |
|---|---|---|
| Frank-Erik de Leeuw | Radboud University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| RadboudUMC | Recruiting | Nijmegen | 6525GA Nijmegen | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41091964 | Derived | Janssen E, de Jong JJA, Verburgt E, Ter Telgte A, van den Berg DTNA, Marques JP, Maas MC, Meijer FJA, Tuladhar AM, Riksen NP, Deinum J, Backes WH, de Leeuw FE. Higher Blood-Brain Barrier Permeability in Middle-Aged Adults With Hypertension. Hypertension. 2025 Dec;82(12):2172-2182. doi: 10.1161/HYPERTENSIONAHA.125.25290. Epub 2025 Oct 15. |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| D059345 | Cerebral Small Vessel Diseases |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
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EDTA blood, EDTA plasma, citrate plasma, serum
|
| 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. |
| 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. |
| D002493 |
| Central Nervous System Diseases |
| D009422 | Nervous System Diseases |