Hyperintense: Midlife Hypertension and the Brain

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Hypertension; Small Vessel Cerebrovascular Disease
• Intervention / Treatment: Drug: Antihypertensive medication withdrawal

• Study Type: Observational
• Enrollment (Estimated): 130

Contacts and Locations

• Study Contact: Name: Esther Janssen; Phone Number: +31651758279; Email: esther.janssen@radboudumc.nl

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525GA Nijmegen
    • Recruiting
    • Radboudumc
    • Contact: Esther Janssen; Phone Number: +31651758279; Email: esther.janssen@radboudumc.nl
    • Sub-Investigator: Esther Janssen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

• 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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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; 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.

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Frank-Erik de Leeuw, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2021
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: December 6, 2023
• First Submitted That Met QC Criteria: December 14, 2023
• First Posted (Estimated): December 19, 2023

Study Record Updates

• Last Update Posted (Estimated): December 19, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypertension; Cerebrovascular Disorders; Cerebral Small Vessel Diseases; Antihypertensive Agents
• Other Study ID Numbers: NL75003.091.20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No