Hyperintense: Midlife Hypertension and the Brain

NCT06175663 | Unknown

• 1 other identifier: NL75003.091.20
• Study Type: observational
• Target: 130
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hypertension; Small Vessel Cerebrovascular Disease

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (3)

• Cognition

  Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later.

• Motor functioning

  Baseline, four weeks after antihypertensive drug withdrawal, after 1-4 months when blood pressure is stable, 1 year later.

• Blood markers

  Four weeks after antihypertensive drug withdrawal and after 1-4 months when blood pressure is stable.

Study Arms (2)

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).

Drug: Antihypertensive medication withdrawal

Interventions

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.

Longitudinal study

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• Age 18-40 years
• Blood pressure above 140/90 mmHg, measured within three months prior to study participation

You may not qualify if:

• 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
• Age 18-55 years
• Undergoing diagnostic routine of temporary antihypertensive withdrawal for biochemical analysis as part of clinical work-up
• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

RadboudUMC

Nijmegen, 6525GA Nijmegen, Netherlands

RECRUITING

Related Publications (1)

• 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.

  PMID: 41091964 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

EDTA blood, EDTA plasma, citrate plasma, serum

MeSH Terms

Conditions

Hypertension; Cerebral Small Vessel Diseases

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Frank-Erik de Leeuw

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Esther Janssen

CONTACT

+31651758279; esther.janssen@radboudumc.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2023
• First Posted: December 19, 2023
• Study Start: July 6, 2021
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: December 19, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)