Background: Neuroimaging markers of cerebral small vessel disease (SVD) are common in older individuals, but the pathophysiological mechanisms causing these lesions remain poorly understood. Although hypertension is a major risk factor for SVD, the direct causal effects of increased blood pressure are unknown. The Hyperintense study is designed to examine cerebrovascular and structural abnormalities, possibly preceding SVD, in young adults with hypertension. These patients undergo a diagnostic work-up that requires patients to temporarily discontinue their antihypertensive agents, often leading to an increase in blood pressure followed by a decrease once effective medication is restarted. This allows examination of the effects of blood pressure increase and decrease on the cerebral small vessels. Methods: Hyperintense is a prospective observational cohort study in 50 hypertensive adults (18–55 years) who will temporarily discontinue antihypertensive medication for diagnostic purposes. MRI and clinical data is collected at four timepoints: before medication withdrawal (baseline), once antihypertensives are largely or completely withdrawn ( T = 1), when patients have restarted medication ( T = 2) and reached target blood pressure and 1 year later ( T = 3). The 3T MRI protocol includes conventional structural sequences and advanced techniques to assess various aspects of microvascular integrity, including blood-brain barrier function using Dynamic Contrast Enhanced MRI, white matter integrity, and microperfusion. Clinical assessments include motor and cognitive examinations and blood sampling. Discussion: The Hyperintense study will improve the understanding of the pathophysiological mechanisms following hypertension that may cause SVD. This knowledge can ultimately help to identify new targets for treatment of SVD, aimed at prevention or limiting disease progression.

BackgroundSmall hyperintense lesions are found on diffusion-weighted imaging (DWI) in patients with sporadic small vessel disease (SVD). Their exact role in SVD progression remains unclear due to their asymptomatic and transient nature. The main objective is to investigate the role of DWI+lesions in the radiological progression of SVD and their relationship with clinical outcomes.MethodsParticipants with SVD were included from the Radboud University Nijmegen Diffusion tensor MRI Cohort. DWI+lesions were assessed on four time points over 14 years. Outcome measures included neuroimaging markers of SVD, cognitive performance and clinical outcomes, including stroke, all-cause dementia and all-cause mortality. Linear mixed-effect models and Cox regression models were used to examine the outcome measures in participants with a DWI+lesion (DWI+) and those without a DWI+lesion (DWI−).ResultsDWI+lesions were present in 45 out of 503 (8.9%) participants (mean age: 66.7 years (SD=8.3)). Participants with DWI+lesions and at least one follow-up (n=33) had higher white matter hyperintensity progression rates (β=0.36, 95% CI=0.05 to 0.68, p=0.023), more incident lacunes (incidence rate ratio=2.88, 95% CI=1.80 to 4.67, p<0.001) and greater cognitive decline (β=−0.03, 95% CI=−0.05 to −0.01, p=0.006) during a median follow-up of 13.2 (IQR: 8.8–13.8) years compared with DWI− participants. No differences were found in risk of all-cause mortality, stroke or dementia.ConclusionPresence of a DWI+lesion in patients with SVD is associated with greater radiological progression of SVD and cognitive decline compared with patients without DWI+lesions.

Objective:Cerebral Small vessel disease (SVD) is a disorder of the cerebral microvessels and is the commonest vascular cause of stroke and dementia. Hypertension is the most established risk factor for SVD, but the pathophysiological mechanisms following hypertension that cause SVD remain poorly understood. We aim to examine the effects of changes in blood pressure on cerebral microvasculature in young- and middle-aged adults with hypertension to detect the earliest microvascular changes associated with SVD.Design and method:The Hyperintense study is an ongoing observational cohort study aiming to include 50 hypertensive adults (18–55 years). These patients temporarily discontinue antihypertensive medication for diagnostic purposes, often leading to a temporary increase in blood pressure. Data are collected before medication withdrawal (T = 0), once antihypertensives are withdrawn (T = 1), when patients have restarted medication and reached target blood pressure (T = 2) and 1 year later (T = 3). At each time-point, high-resolution 3T MRI scans are performed with conventional structural sequences and advanced techniques to assess various aspects of microvascular integrity, including integrity of the blood-brain barrier, microperfusion and microstructural integrity. Clinical data includes motor and cognitive examinations and blood sampling.Results:Between July-December 2021, 7 patients (86% male, mean age 47.4 ± 4.4 years) were enrolled. Baseline characteristics and SVD burden are shown in Table. In 3/4 participants who completed T = 1, systolic blood pressure increased after medication withdrawal (median increase systolic blood pressure: 13.7 [3.3 – 15.3] mmHg), demonstrating proof of principle of our approach.Conclusions:First data show increased blood pressure after medication withdrawal in most participants and demonstrate feasibility of our design. Analysis of the effect of blood pressure increase and decrease on MRI outcomes will improve understanding of the pathological mechanisms following hypertension that may lead to MRI markers of SVD. This knowledge can help identify new targets for treatment of SVD, aimed at preventing or limiting disease progression.